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Full text of "Nephrology In 30 Days"

NEPHROLOGY 

FS I N 30 DAYS 







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n. 02. 03, 04.1 
06.07. 08.09. 10, 



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B. 27. 28. 29. 



M 



ROBERT F. REILLY, Jr. 
MARK A. PERAZELLA 




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\. 



Nephrology 



In 30 Days 



Notice 

Medicine is an ever-changing science. As new research and clinical experience 
broaden our knowledge, changes in treatment and drug therapy are required. 
The authors and the publisher of this work have checked with sources 
believed to be reliable in their efforts to provide information that is complete 
and generally in accord with the standards accepted at the time of publication. 
However, in view of the possibility of human error or changes in medical sci- 
ences, neither the editors nor the publisher nor any other party who has been 
involved in the preparation or publication of this work warrants that the infor- 
mation contained herein is in every respect accurate or complete, and they dis- 
claim all responsibility for any errors or omissions or for the results obtained 
from use of the information contained in this work. Readers are encouraged to 
confirm the information contained herein with other sources. For example and 
in particular, readers are advised to check the product information sheet 
included in the package of each drug they plan to administer to be certain that 
the information contained in this work is accurate and that changes have not 
been made in the recommended dose or in the contraindications for adminis- 
tration. This recommendation is of particular importance in connection with 
new or infrequently used drugs. 



Nephrology 



In 30 Days 



ROBERT F. REILLY, JR., M.D. 

Frederic L. Coe Professor of Nephrolithiasis Research in Mineral Metabolism 

Chief, Section of Nephrology 

Veterans Administration North Texas Health Care System 

Professor of Medicine 

Department of Medicine 

The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research 

The University of Texas Southwestern Medical Center at Dallas 

Dallas, Texas 



MARK A. PERAZELLA, M.D., F.A.C.P. 

Associate Professor of Medicine 

Director, Renal Fellowship Program 

Director, Acute Dialysis Services 

Section of Nephrology 

Department of Medicine 

Yale University School of Medicine 

New Haven, Connecticut 



McGraw-Hill 

Medical Publishing Division 

New York Chicago San Francisco Lisbon London Madrid Mexico City Milan 
New Delhi San Juan Seoul Singapore Sydney Toronto 



The McGraw-Hill Companies 



Nephrology in 30 Days 

Copyright © 2005 by The McGraw-Hill Companies, Inc. All rights reserved. 
Printed in the United States of America. Except as permitted under the United 
States Copyright Act of 1976, no part of this publication may be reproduced 
or distributed in any form or by any means, or stored in a database or 
retrieval system, without the prior written permission of the publisher. 



1234567890 DOC/DOC 9 8 7 6 5 



ISBN 0-07-143701-0 



This book was set in Garamond by International Typesetting 

and Composition. 

The editors were James Shanahan and Robert Pancotti. 

The production supervisor was Rick Ruzycka. 

Project management was provided by International Typesetting 

and Composition. 

The indexer "was Roger Wall. 

RR Donnelley was printer and binder. 

This book is printed on acid-free paper. 



Library of Congress Cataloging-in-Publication Data 

Reilly, Robert R, M.D. 

Nephrology in 30 days / Robert F. Reilly Jr., Mark A. Perazella. 

p. ; cm. 
Includes bibliographical references and index. 
ISBN 0-07-143701-0 (alk. paper) 

1. Nephrology. 2. Kidneys — Diseases. I. Title: Nephrology in thirty days. II. Perazella, 
Mark A. III. Title. 

[DNLM: 1. Kidney Diseases. 2. Metabolic Diseases. WJ 300 R3626n 2005] 
RC902.R363 2005 
6l6.6'l— dc22 

2004055997 



To my wife Sheli, 

my parents Robert Sr and Nancy, 

my son Rob, and 

my brothers Steven and Fred 

whose help and support are invaluable 

in both my life and career. 

Robert F. Reilly, Jr. 

To my parents Joe and Santina Perazella 

who sacrificed much to educate me, 

to my brothers Joe and Scott 

for their encouragement, 

to my wife Donna 

who wholeheartedly supported 

my efforts in this endeavor, and 

to my boys Mark and Andrew 

who gave up their time with me. 

Mark A. Perazella 



Contributors ix 

Preface xi 

Acknowledgments xiii 

1 INTRODUCTION 1 

2 DISORDERS OF SODIUM BALANCE 13 

3 DISORDERS OF WATER BALANCE (HYPO- AND HYPERNATREMIA) 30 

4 DIURETICS 51 

5 INTRAVENOUS FLUID REPLACEMENT 67 

6 POTASSIUM HOMEOSTASIS 78 

7 METABOLIC ACIDOSIS 96 

8 METABOLIC ALKALOSIS 119 

9 RESPIRATORY AND MIXED ACID-BASE DISTURBANCES 133 

10 DISORDERS OF SERUM CALCIUM 142 

11 DISORDERS OF SERUM PHOSPHORUS l6l 

12 DISORDERS OF SERUM MAGNESIUM 177 

13 NEPHROLITHIASIS 192 

14 URINALYSIS 208 

15 ACUTE RENAL FAILURE 227 

16 CHRONIC KIDNEY DISEASE 251 

17 GLOMERULAR DISEASES 275 

18 TUBULOINTERSTITIAL DISEASES 306 

19 OBSTRUCTION OF THE GENITOURINARY TRACT 321 

20 ESSENTIAL HYPERTENSION 330 

21 SECONDARY CAUSES OF HYPERTENSION 353 

22 URINARY TRACT INFECTION 375 

Index 389 



Contributors 



Richard Formica, M.D. 

Assistant Professor of Medicine and Surgery 

Director, Transplant Nephrology 

Co-Director, Outpatient Transplant Service 

Section of Nephrology 

Department of Medicine 

Yale University School of Medicine 

New Haven, Connecticut 

Dinkar Kaw, M.D. 

Assistant Professor of Medicine 
Division of Nephrology 
Department of Medicine 
Medical College of Ohio 
Toledo, Ohio 

Aldo J. Peixoto, M.D. 

Associate Professor of Medicine 

Section of Nephrology 

Department of Medicine 

Yale University School of Medicine 

Director, Hypertension Clinic 

Veterans Affairs Connecticut Healthcare System 

West Haven Campus 

West Haven, Connecticut 

Mark A. Perazella, M.D., F.A.C.P. 

Associate Professor of Medicine 
Director, Renal Fellowship Program 
Director, Acute Dialysis Services 
Section of Nephrology 
Department of Medicine 
Yale University School of Medicine 
New Haven, Connecticut 



Robert F. Reilly, Jr., M.D. 

Frederic L. Coe Professor of Nephrolithiasis 

Research in Mineral Metabolism 
Chief, Section of Nephrology 
Veterans Administration North Texas Health 

Care System 
Professor of Medicine 
Department of Medicine 
The Charles and Jane Pak Center for Mineral 

Metabolism and Clinical Research 
The University of Texas Southwestern Medical 

Center at Dallas 
Dallas, Texas 

Sergio F. F. Santos, M.D., Ph.D. 

Associate Professor of Medicine (Nephrology) 

Nephrology Division 

State University of Rio de Janeiro 

Rio de Janeiro, Brazil 

Joseph I. Shapiro, M.D. 

Mercy Health Partners Education Professor 
Chairman, Department of Medicine 
Professor of Medicine and Pharmacology 
Medical College of Ohio 
Toledo, Ohio 

Youngsook Yoon, M.D. 

Assistant Professor of Medicine 

Division of Pulmonary and Critical Care Medicine 

Department of Medicine 

Medical College of Ohio 

Toledo, Ohio 



Nephrology is a discipline that combines basic 
science and clinical disease. Recent times have 
seen a narrowing of the gap between basic and 
clinical science, bringing the "research bench to 
the patient's bedside." As a result, a better under- 
standing of clinical disease states has been 
achieved. Perhaps more than any other subspe- 
cialty of medicine, kidney disease has no spe- 
cialty boundaries. One such example includes the 
patient with diabetic nephropathy who manifests 
end-organ disease requiring expert care from the 
nephrologist, internist, cardiologist, endocrinologist, 
emergency medicine physician, vascular surgeon, 
intensivist, podiatrist, ophthalmologist, interven- 
tional radiologist, and renal transplantation sur- 
geon. It is imperative, therefore, that physicians 
early in their training as medical students, physi- 
cian assistants, house officers, and subspecialty 
fellows gain a solid understanding of basic aspects 
of nephrology. Kidney disease, disturbances of 
fluid and electrolyte balance, and disorders of 
acid-base and mineral metabolism homeostasis 
can be confusing to many trainees and non- 
nephrology physicians. This book was conceived 
to remove that confusion. Nephrology in 30 Days 
provides a comprehensive and concise text for 
physicians in training and practitioners. 

This textbook is an ideal tool for health care 
providers to attain rapidly a complete under- 
standing of the basics of nephrology, allowing an 
educated approach to diagnosis and manage- 
ment of kidney disease and its associated compli- 
cations. As the title suggests, those who read the 
book will gain this knowledge within 30 days. 
Such a time frame is ideal for medical students, 
physician assistants, and medical residents rotat- 
ing on the clinical nephrology service elective. 



The book will be a foundation on which they can 
build by intelligently using other sources of infor- 
mation such as primary literature from journals 
and more detailed reference textbooks. It will 
also serve as an efficient resource for non- 
nephrology practitioners in internal medicine and 
other fields of medicine and surgery. 

Nephrology in 30 Days is broken down into 
three major sections. The first section discusses 
electrolyte and acid-base disturbances. Experts in 
the field review disorders of sodium and potassi- 
um balance, use of intravenous fluids, pathogen- 
esis and treatment of diuretic resistance, and 
respiratory and metabolic acidosis/alkalosis. The 
second section deals primarily with disturbances 
of mineral metabolism. Concise discussions on 
calcium, phosphate, and magnesium homeostasis 
are presented. Clinical disease states associated 
with these divalent disorders are reviewed, as are 
the pathogenesis and treatment of nephrolithia- 
sis. The last section is dedicated to structural kid- 
ney disease. Acute renal failure and chronic 
kidney disease are explored separately. Aspects 
of urinalysis and examination of the urine sedi- 
ment are reviewed. Diseases of various structures 
within the kidney are also examined. Included 
are the glomerulopathies, both primary and those 
due to systemic processes, tubulointerstitial dis- 
eases, and abnormalities of the urinary tract 
including infection and obstruction. Finally, 
essential hypertension and secondary causes of 
hypertension are reviewed. Importantly, renal 
imaging and genetic causes of kidney disease are 
covered within each of the chapters where they 
figure prominently. 

Homer Smith in his book From Fish to 
Philosopher stated "What engineer, wishing to 



Xll 



Preface 



regulate the composition of the internal environ- 
ment of the body on which the function of every 
bone, gland, muscle, and nerve depends, would 
devise a scheme that operated by throwing the 
whole thing out sixteen times a day — and rely on 



grabbing from it, as it fell to earth, only those pre- 
cious elements 'which he wanted to keep?" 
Hopefully, after reading this book the reader will 
begin to comprehend the wonderful complexity 
and ingenuity of the engineer that is the kidney. 



Acknowledgments 



I wish to thank Drs. Peter Igarashi, Peter Aronson, 
David Ellison, Gary Desir, Asghar Rastegar, Norman 
Siegel, Herbert Chase, John Forrest, John Hayslett, 
Robert Schrier, Allen Alfrey, Laurence Chan, and 
Tomas Berl who served as mentors and teachers 
during my career. I would also like to thank Gregory 
Fitz, Clark Gregg, Charles Pak, Orson Moe, and 
Khashayar Sakhaee for their help in recruiting me to 
my current position. Dr. Perazella and I would also 
like to express our sincere appreciation and grati- 
tude to our contributors for their prompt and out- 
standing contributions, as well as Dr. Michael 
Kashgarian (Pathology Department, Yale University 
School of Medicine) for kindly providing many of 
the images of renal biopsy specimens and Drs. 
Arthur Rosenfield and Leslie Scoutt (Diagnostic 
Radiology Department, Yale University School of 
Medicine) for the ultrasound and CT images. 
Thanks to Jim Shanahan of McGraw-Hill for his out- 
standing efforts on behalf of the book. I would also 
like to thank the patients, medical students, house 
officers, and nephrology fellows who I have cared 
for, trained, and learned from over the years. 

Robert F. Reilly, Jr. 



I wish to thank Dr. Robert Reilly who had the 
vision to conceive this book and encouraged my 
role as a coeditor. I would like to extend my 
gratitude to the too numerous to name former 
and current mentors and colleagues who shaped 
my career in medicine and nephrology — they 
know who they are and I thank them all. Many 
thanks to Jim Shanahan of McGraw-Hill as pub- 
lication of this book would not have been possi- 
ble without his support. Finally, I would like to 
extend my most sincere thanks to the medical 
students, house officers, and in particular clini- 
cal nephrology fellows (Dinna Cruz, Tony Cayco, 
Aldo Peixoto, Raj Alappan, James Wood, Chris 
Cosgrove, Kory Tray, Marc Ciampi, Ursula 
Brewster, and Brian Rifkin) who I have had the 
distinct honor to train and who in the process, 
have also taught me a great deal. 



Mark A. Perazella 



Mark A. Perazella 



Introduction 




Recommended Time to Complete: 1 day 



QuXj^C Qi*t4&04<4> 



1. What are the essential functions of the kidney? 

2. The nephron is the basic unit of the kidney. What are its major 
components? 

1. How does the glomerular capillary loop prevent the filtration of 
macromolecules? 

ty. What factors are integral to the formation of glomerular ultrafiltrate? 

5. How is glomerular filtration rate (GFR) regulated in normal subjects 
on a day-to-day basis? 

6. What factors maintain renal perfusion and GFR during states of 
severe intravascular volume depletion? 

7- How is GFR best measured in the clinical setting? 

2. Are there accurate estimates of GFR that can substitute for a 24-hour 
urine collection? 




Introduction 



The kidney is designed to perform a number of 
essential functions. First, it contributes impor- 
tantly to the maintenance of the extracellular 



environment that is essential for normal cellular 
function. The kidney achieves an optimal extra- 
cellular environment through excretion of waste 
products such as urea, creatinine, uric acid, and 
other substances. Balanced excretion of water 
and electrolytes is another important role of the 
kidney. Second, the kidney regulates systemic 
and renal hemodynamics through the production 



Chapter 1 



Introduction 



of various hormones, as well as the regulation of 
salt and water balance. Hormones such as renin, 
angiotensin II (All), prostaglandins (PGs), endo- 
thelin, nitric oxide, adenosine, and bradykinin 
regulate vascular reactivity and renal blood flow. 
Third, the kidney produces other hormones that 
influence various end organ functions. Red blood 
cell production is stimulated by renal erythropoi- 
etin synthesis, which is controlled by a highly reg- 
ulated oxygen sensor in the proximal nephron. 
Hence the kidney can be viewed as a "critmeter." 
Bone metabolism is influenced by renal produc- 
tion of calcitriol, as well as proper balance of cal- 
cium and phosphorus. Finally, the kidney 
participates in gluconeogenesis during fasting to 
prevent hypoglycemia. It also contributes to the 
catabolism of various peptide hormones filtered 
by the glomerulus such as insulin. 

In order to perform these functions, the kidney 
is uniquely constructed to filter, reabsorb, and 
secrete a variety of substances in a very precise 
manner through integrated regulation of renal 
hemodynamics and tubular handling of water and 
solutes. Secretion of hormones such as erythro- 
poietin and calcitriol closely link kidney function 
with control of red cell mass and bone metabo- 
lism. Metabolism of peptide hormones and clear- 
ance of medications is another important kidney 
function to maintain health. Disturbances in these 
processes lead to several harmful and potentially 
life-threatening clinical syndromes. 




Gross examination of the kidney reveals an outer 
portion, the cortex, and inner portion, the medulla 
(Figure 1.1). Blood is supplied to the kidney via 
the renal artery (or arteries) and is drained via the 
renal vein. As will be discussed next, the glomeruli, 
which are the filtering units of the nephron, are 
found within the cortex. Tubules are located in 
both cortex and medulla. The medulla consists of 
an inner and outer stripe. Collecting tubules form 
a large part of the inner medulla and papilla. Urine 
is formed by glomerular filtration and modified by 
the tubules, leaves the collecting ducts and drains 
sequentially into the calyces, renal pelvis, ureter, 
and finally into the bladder. 

The nephron is the basic unit of the kidney. 
There are approximately 1.0-1.3 million nephrons 
in the normal adult kidney. The nephron consists 
of a glomerulus and a series of tubules (Figure 1.2). 
The glomerulus is composed of a tuft of capillaries 
with a unique vascular supply. Glomerular capil- 
laries are interposed between an afferent and 
efferent arteriole. They reside in the cortex and 
corticomedullary junction. Within the tubular 
lumen, glomerular filtrate is modified by tubu- 
lar cells. Tubules are lined by a continuous 
layer of epithelial cells, each of "which possesses 



Key Points 

Functions of the Kidney 



Figure 1. 1 



The kidney maintains the extracellular 
environment through excretion of waste 
products and proper electrolyte and water 
balance. 

Several hormones are produced in the 
kidney that act to control renal hemo- 
dynamics, stimulate red cell production, and 
maintain normal bone homeostasis. 



Cortex - 

Renal artery — 

Renal vein — 

Renal pelvis 

Ureter - 




Interlobular arteries 
Medulla 
Medullary ray 

Calyces 



Anatomy of the kidney. Shown are the cortex, medulla, 
calyces, renal pelvis, and ureter. 



Chapter 1 



Introduction 



Figure 1.2 



Juxtamedullary 
nephron 



Cortical 
nephron 



o 




Loop of 
henle 



Collecting 
duct 



The nephron. The nephron consists of a glomerulus and series 
of tubules. Nephrons can be subdivided into those in the 
cortex and those in the juxtamedullary region. The glomerulus 
is composed of a capillary tuft interposed between the afferent 
and efferent arteriole. Tubules are supplied by a peritubular 
capillary network that includes the vasa recta, which runs par- 
allel to the loop of Henle. 



characteristic morphology and function depending 
on its location in the nephron. 

An ultrafiltrate of plasma is formed by the 
glomerulus and passes into the tubules where it is 
modified by reabsorption (removal of a substance 
from the ultrafiltrate) and secretion (addition of a 
substance to the ultrafiltrate). Different tubular 
segments alter fluid contents by varying reabsorp- 
tion and secretion. Division of the nephron is 
based on morphology, as well as permeability 
and transport characteristics of the segments. For 
example, the proximal tubule and loop of Henle 



reabsorb the bulk of filtered water and solutes. In 
the distal nephron, and particularly in collecting 
tubules, fine adjustments in urinary composition 
are undertaken. Also, there is heterogeneity of cell 
types within the cortical collecting tubule. In this 
segment, the principal cell reabsorbs sodium and 
secretes potassium while the intercalated cell 
secretes hydrogen ion and reabsorbs potassium. 

The formation of urine occurs as glomerular fil- 
trate is sequentially modified in tubular segments. 
Plasma is ultrafiltered by the glomerulus and 
passes from Bowman's space into the proximal 
tubule. This nephron segment consists anatomi- 
cally of an initial convoluted segment, followed 
by a straight segment, the pars recta, that enters 
the outer medulla. The loop of Henle, which pos- 
sesses a hairpin configuration, follows the pars 
recta and includes a thin descending limb, and 
thin and thick ascending limb. The loop of Henle 
is not uniform in its length. Approximately 40% 
are short loops that don't enter the medulla or 
enter only the outer medulla. These loops do not 
have a thin ascending limb and are located pre- 
dominantly in the outer cortex. The remaining 
loops of Henle are long and extend into the 
medulla and may reach the inner medulla and 
papilla. Long loops are located in the jux- 
tamedullary region. Both short and long loops 
are found in the midcortex. 

The thick ascending limb of the loop of Henle 
has a cortical segment that returns to its own 
glomerulus. This tubule, which has specialized 
epithelial cells known as the macula densa, 
approximates the afferent arteriole, forming the 
juxtaglomerular (JG) apparatus. As will be dis- 
cussed later, the JG apparatus participates impor- 
tantly in regulation of GFR. 

Four cortical tubular segments follow the 
macula densa. They are the distal convoluted 
tubule, the connecting tubule, the initial collect- 
ing tubule, and the cortical collecting tubule. 
The connecting tubule drains into a single cortical 
collecting tubule, which then connects to the 
medullary collecting tubule. In cortex, initial 
collecting tubules drain into collecting ducts, 
whereas deeper connecting tubules join to form 



Chapter 1 



Introduction 



an arcade that drains into a cortical collecting 
tubule. From this segment, urine drains into the 
calyces, renal pelvis, ureters, and bladder. 



Key Points 



Morphology of the Kidney 



On gross examination, the kidney is com- 
posed of cortex, inner and outer medulla, 
calyces, pelvis, and ureter. 
The nephron is the basic unit of the kidney. 
It is composed of a glomerulus and a series 
of tubules. 

The tubules are divided into proximal 
tubule, loop of Henle, distal convoluteci 
tubule, connecting tubule, initial collecting 
tubule, and cortical anci medullary collecting 
tubule. 

Following modification of the glomerular 
ultrafiltrate by the tubules, urine is sequen- 
tially drained into the calyces, renal pelvis, 
ureter, and bladder. 




Renal Circulation 



Renal blood flow exceeds most other organs and, 
on average, the kidneys receive approximately 
20% of the cardiac output. This calculates to 
approximately 1 L/minute of blood and 600 ml of 
plasma. Of this, 20% of plasma is filtered into 
Bowman's space, giving a filtration rate of 
approximately 120 mL/minute. Renal arteries 
carry blood into the kidney where it passes 
through serial branches, which include the inter- 
lobar, arcuate, and interlobular arteries. Blood 
enters the glomerulus through the afferent arteri- 
ole. A plasma ultrafiltrate is formed within the 
capillary tuft and passes into Bowman's space. 
Blood remaining in the capillaries exits the 
glomerulus via the efferent arteriole. In the cortex, 
blood in postglomerular capillaries flows adjacent 



to the tubules, while branches from the efferent 
arterioles of juxtamedullary glomeruli enter the 
medulla and form the vasa recta capillaries. Blood 
exits the kidney through a venous system into the 
systemic circulation. 

The circulatory anatomy within the kidney 
determines the final urine composition. First, GFR 
importantly influences the amount of solute and 
water that is excreted. Second, peritubular capil- 
laries in cortex modify proximal tubular reabsorp- 
tion and secretion of solutes and water. They also 
return reabsorbed solutes and water to the sys- 
temic circulation. Third, creation of the countercur- 
rent gradient for water conservation is dependent 
on vasa recta capillary function. These capillaries 
also return reabsorbed salt and water to the sys- 
temic circulation. 



Key Points 

Renal Circulation 



1 . The kiciney receives 20% of the cardiac 
output or 1 L of blood per minute. 

2. Renal circulatory anatomy allows precise 
modulation of salt and water balance. 




As stated previously, the glomerulus is comprised 
of a capillary network with an afferent and efferent 
arteriolar circulation. This design sets the glomeru- 
lar circulation apart from other organ systems and 
allows modification of urine composition to meet 
the demands of various, often extreme diets. The 
glomerular capillary tuft sits within the parietal 
epithelial cell space, known as Bowman's capsule. 
The parietal epithelium is continuous with the vis- 
ceral epithelial cells (podocytes), which cover the 
glomerular capillary tuft. The glomerular capillary 
loop is comprised of endothelial cell, glomerular 
basement membrane (GBM), and podocyte, all of 



Chapter 1 



Introduction 



which are supported structurally by mesangial 
cells. The GBM consists of a fusion of endothelial 
and visceral epithelial cell basement membrane 
components, which include type IV collagen, 
laminin, nidogen, and heparan sulfate proteogly- 
cans. It functions to maintain normal glomerular 
architecture, anchor adjacent cells, and restrict 
passage of various macromolecules. The podocyte 
is attached to the GBM by discrete foot processes, 
which have pores containing slit diaphragms. The 
slit diaphragm is a thin membrane that acts as the 
final filtration barrier. 



Glomerular Filtration 

A key function of the glomerulus is to act as a fil- 
tration barrier that permits the passage of water 
and other solutes and restricts the movement of 
certain molecules. For example, filtration of water, 
sodium, urea, and creatinine are integral to proper 
toxin clearance, volume balance, and electrolyte 
homeostasis. In contrast, restriction of filtration 
of large proteins (albumin, immunoglobulin G) 
prevents the development of hypoalbuminemia, 
negative nitrogen balance, and infection. The 
glomerular capillary wall restricts solute move- 
ment by using both size and charge selectivity. 

Size selectivity is maintained by GBM and 
podocyte foot process slit diaphragms. The GBM 
contributes to size selectivity through the creation 
of functional pores present in the spaces between 
the cords of type IV collagen. Two populations of 
pores are present in glomerular capillary •wall: a 
more common small pore (radius 42 A) and a less 
numerous larger pore (70 A). Other capillary loop 
elements, however, provide additional size selec- 
tivity. This is known because isolated GBM stud- 
ies demonstrate more permeability in GBM than 
intact glomerulus, suggesting an important role of 
glomerular epithelial cells. Also, molecules that 
pass through the GBM are restricted from passage 
into Bowman's space by epithelial slit 
diaphragms. A number of podocyte proteins 
(nephrin, podocin, synaptopodin, podocalyxin, 
Gf-actin 3) interact to form the slit diaphragms and 
maintain podocyte integrity as a filtration barrier. 



Mutation in genes that synthesize these proteins, 
as well as effacement of foot processes by disease 
states, is associated with filtration barrier loss and 
the development of proteinuria. Glomerular 
endothelial cells, however, contribute very little to 
size selectivity, as their fenestrae are wide and do 
not restrict macromolecules until they reach a 
radius larger than 375 A. 

Macromolecule filtration is also prevented by 
charge selectivity. Electrostatic repulsion is cre- 
ated by anionic sites in the GBM and endothelial 
cell fenestrae. Heparan sulfate proteoglycans, 
which are synthesized by glomerular endothelial 
and epithelial cells, provide the bulk of negative 
charge. The charge barrier was first noted when 
the differential effect of similar-sized dextrans 
with various charges (neutral, cationic, anionic) 
on filtration was noted. Neutral and cationic dex- 
trans undergo greater filtration than anionic dex- 
trans, despite similar molecular weight (Figure 1.3). 
This finding supports a glomerular charge barrier. 
In humans, albumin is restricted from filtration 



Figure 1.3 



Normal rat 


1.0 




0.9 




g 0.8 
2 0.7 

CO 




% 0.6 


t \ ^Mdeae 


| 0.5 

o 

I 0.4 

CO 


S \. Neutral 1\ 
\ \dextran >L 
V Dextran ^ \- 


it 0.3 


" \ sulfate \^ ^\ 


0.2 


\ N_ \ 


0.1 


I I I I ? G 7f_ 7* ■* ^"""""S B_ * 


' ■ ■ ■ ■ ■ ■ =■= ^ ^ £2 2 S 2 


18 20 22 24 26 28 30 32 34 36 38 40 42 44 



Filtration curves for neutral, cationic (DEAE), and anionic dex- 
trans (dextran sulfate). The curves show that filtration of anionic 
dextrans is impeded by negative charge in the glomerular cap- 
illary wall supporting the conclusion that the glomerular capil- 
lary wall impedes protein movement via a charge and size 
barrier. (From Brenner, B.M., Bohrer, M.P., Baylis, C, and Deen, 
W.M. Kidney Int 12-229-237, 1977, with permission.) 



Chapter 1 



Introduction 



based on both size and charge selectivity. When 
glomerular injury occurs, impairment of both size 
and charge selectivity results. An increased 
number of larger pores, the development of rents 
and cavities in the GBM, and a defect in charge 
selectivity allow proteinuria in diseases such as 
membranous nephropathy, diabetic nephropa- 
thy, and focal glomerulosclerosis. Loss of charge 
selectivity plays a major role in the protein leak 
that occurs with minimal change disease, 
although loss of size selectivity may contribute. It 
is interesting to note that small solute and water 
clearance are impaired in this setting, likely due to 
loss of capillary surface area, while protein losses 
continue through large pores unimpeded because 
of loss of anionic charge repulsion. 



Other Glomerular Functions 

In addition to filtration, the glomerulus has other 
roles in the kidney. Endothelial cells secrete hor- 
mones (endothelin, prostacyclin, and nitric oxide) 
that influence vasomotor tone in the renal circula- 
tion. They also participate in inflammation by 
expressing adhesion molecules that enhance 
inflammatory cell accumulation. Glomerular 
epithelial cells remove macromolecules that pen- 
etrate the GBM and enter the subepithelial space. 
As noted previously, they synthesize key compo- 
nents of the GBM. 

An area of the glomerulus not discussed previ- 
ously but nonetheless an important member of the 
glomerular architecture is the mesangium. Two 
cell types comprise the mesangium. The mesan- 
gial cell has contractile properties that originate 
from its smooth muscle-like microfilaments. It can 
also synthesize PGs and react to AIL These prop- 
erties make the mesangial cell ideally suited to reg- 
ulate glomerular hemodynamics through changes 
in glomerular capillary surface area and in the 
vasomotor tone of the renal microcirculation. 
Mesangial cells are also involved in immune-medi- 
ated glomerular diseases. They produce various 
cytokines (interleukin [IL]-1, IL-6, chemokines) 
and proliferate following exposure to platelet 



derived growth factor (PDGF) and epithelial 
growth factor (EGF), leading to mesangial hyper- 
cellularity and matrix expansion, as well as 
glomerular injury. Circulating macrophages and 
monocytes that enter and exit the mesangium 
constitute the second cell type. They function 
primarily as phagocytes to remove macromole- 
cules that cannot pass through the GBM and 
remain in the capillary wall. They may also, however, 
contribute to inflammation in immune-mediated 
diseases. 



Key Points 



Glomerular Anatomy 



The glomerular capillary loop is comprised 
of an endothelial cell anci epithelial cell 
(podocyte) whose basement membranes 
fuse to form a common GBM. 
Both size and charge selectivity restrict pas- 
sage of macromolecules into Bowman's 
space. Loss of either of these from disease 
processes results in proteinuria. 
Size selectivity is determined by the GBM 
and, most importantly, the podocyte slit 
diaphragm. 

Charge selectivity is anionic and provided 
by heparan sulfate proteoglycans in GBM 
and endothelial cell fenestrae. 
Mesangial cells modulate glomerular hemo- 
dynamics and participate in phagocytic 
functions. 




Urine formation requires that an initial separation 
of ultrafiltrate from plasma occurs across the 
glomerular capillary wall into Bowman's space. 
The major determinant of ultrafiltrate formation is 



Chapter 1 



Introduction 



Starling's forces across the capillary wall. These 
forces are proportional to glomerular capillary 
permeability and the balance between hydraulic 
and oncotic pressure gradients. Thus, GFR can be 
described by the following formulas: 

GFR = (capillary porosity x surface area) 
x (A hydraulic pressure 
- A oncotic pressure) 

GFR = (capillary porosity x surface area) 



Table 1. 1 



Determinants of Glomerular Filtration (Primates) 



x CIPoc 



■ «J) 



GFR = (capillary porosity x surface area) 
xCPgc-Pb.-^) 

where P GC and P Bs are the hydraulic pressures in 
glomerular capillary and Bowman's space, respec- 
tively. Also, s is the reflection coefficient of proteins 
across the capillary wall (a measure of permeabil- 
ity) and n - 7t Bs are the oncotic pressure of plasma 
in glomerular capillaries and Bowman's space, 
respectively. Since n Bs is zero (the filtrate is essen- 
tially protein free) and the capillary wall is com- 
pletely permeable (making s = 1 ), the last equation 
GFR = (capillary porosity x surface area) x (P GC - 
P Bs - nj represents the formula for GFR. In gen- 
eral, hydraulic pressure in the capillaries and 
Bowman's space remains constant while oncotic 
pressure in plasma rises progressively with forma- 
tion of a protein-free ultrafiltrate. Thus, at some 
point along the capillary loop, the net filtration gra- 
dient falls to zero and filtration equilibrium occurs 
(Table 1.1). In contrast to other primates, humans 
only require a net gradient favoring filtration of 
approximately 4 mmHg to maintain glomerular fil- 
tration. It is also notable that plasma oncotic pres- 
sure entering the efferent arteriole and peritubular 
capillary is elevated, an effect that increases peri- 
tubular capillary oncotic pressure and enhances 
proximal tubular fluid and sodium reabsorption. 

As one can see from examining the GFR equa- 
tion, alterations in renal plasma flow rate (RPF) or 
any of the factors noted in the formula above can 
change the GFR. RPF is an important determinant 
of GFR in the presence of filtration equilibrium, as 
it influences glomerular capillary oncotic pres- 
sure. Thus, GFR rises or falls in proportion to 





Glomerular Pressures 






(mmHg) 


Afferent 


Efferent 




Arteriole 


Arteriole 


Hydraulic pressure 








Capillary 


46 




45 


Interstitium 


10 




10 


Mean gradient 


36 




35 


Oncotic pressure 








Capillary 


23 




35 


Interstitium 










Mean gradient 


23 




35 


Mean gradient 








favoring filtration 


+13 









(mean = 


+6 


mmHg) 



changes in RPF. Due to the unique design of the 
glomerulus, capillary hydrostatic pressure is influ- 
enced by variables such as the aortic (renal artery) 
pressure, as well as afferent and efferent arteriolar 
resistances. Resistance in these vessels is con- 
trolled by a combination of myogenic control, 
tubuloglomerular feedback (TGF) from the 
macula densa, and vasodilatory/vasoconstrictor 
hormones (All, norepinephrine, PGs, endothelin, 
atrial natriuretic peptide [ANP], nitric oxide). 
Changes in resistance of these arterioles have 
opposite effects on P GC and thus allows rapid reg- 
ulation of P GC and GFR. For example, an increase 
in afferent arteriolar resistance decreases P GC and 
GFR, while an increase in efferent resistance 
increases both. In addition, arteriolar tone affects 
RPF. An increase in the resistance of either 
glomerular arteriole will elevate total renal resis- 
tance and diminish RPF. Thus, the afferent arteriole 
regulates RPF and GFR in parallel, while the effer- 
ent arteriole regulates them inversely. This will 
determine the direction of change in the filtra- 
tion fraction (FF), which is the fraction of RPF that 
is filtered across the glomerulus (FF = GFR/RPF). 
Changes in efferent tone change the filtration 



Chapter 1 



Introduction 



fraction, whereas changes in afferent tone do not. 
GFR can then increase, not change or decrease 
based on the magnitude of efferent constriction. 

To be complete, factors considered less impor- 
tant in the regulation of GFR than the systemic arte- 
rial pressure, arteriolar tone, and RPF are noted 
below. In health, changes in capillary permeability 
are typically minimal and have no effect on GFR. 
Severe glomerular injury, however, can reduce per- 
meability and impair GFR. Reductions in the capil- 
lary surface area by disease (glomerulonephritis) 
or vasoactive hormones (All, antidiuretic hormone, 
PGs) can develop. These effects lead to a net 
decline in GFR. Alterations in hydrostatic pressure 
in Bowman's space, as occurs with complete uri- 
nary tract or tubular obstruction, initially reduces 
GFR through an elevation in hydrostatic pressure. 
Finally, increasing plasma oncotic pressure may 
counter hydrostatic pressure and reduce GFR. 
Clinical examples are therapy with hypertonic 
mannitol and severe intravascular volume deple- 
tion with marked hemoconcentration. 



Key Points 

Glomerular Filtration Rate 



1 . Formation of glomerular ultrafiltrate is 
dependent on glomerular capillary perme- 
ability and the balance between hydrostatic 
and oncotic pressure gradients. 

2. Arterial pressure, RPF, and afferent and effer- 
ent arteriolar tone importantly influence GFR. 

3. Changes in resistance of afferent and effer- 
ent arterioles have opposite effects on P GC . 
This allows rapid regulation of GFR. 




Regulation of RPF and GFR 



Regulation of GFR (and RPF) occurs primarily 
through changes in arteriolar resistance. In the 



normal host, autoregulation and TGF interact to 
maintain RPF and GFR at a constant level. In disease 
states such as true or effective volume depletion, 
however, these two intrarenal processes contribute 
minimally and are superceded by actions of systemic 
neurohormonal factors. A more detailed description 
of the regulation of renal hemodynamics follows. 

Autoregulation 

Autoregulation of the renal circulation serves the 
purpose of maintaining a relatively constant RPF 
and GFR. Since GFR is determined primarily by 
P GC , variations in arterial perfusion pressure 
would be expected to promote large changes in 
GFR. The phenomenon of autoregulation, how- 
ever, prevents large swings in RPF and GFR 
expected from changes in arterial perfusion pres- 
sure. Changes in afferent arteriolar tone likely 
play a major role in autoregulation, since RPF and 
GFR vary in parallel (versus changes in efferent 
tone where RPF and GFR vary inversely). An 
increase in afferent arteriolar tone prevents the 
transmission of high arterial pressures to the 
glomerulus, while low arterial pressure is associ- 
ated 'with reduced afferent arteriolar tone. These 
changes in afferent tone maintain the P GC and GFR 
constant despite swings in perfusion pressure. In 
general, autoregulation maintains GFR constant 
until either the mean arterial pressure exceeds 
70 mmHg or falls below 40-50 mmHg. 

Myogenic stretch receptors in the afferent arter- 
iolar walls are thought to play an important part in 
renal autoregulation. Increased wall stretch with 
high arterial pressure promotes vasoconstriction, 
perhaps mediated by enhanced cell calcium entry. 
The absence of voltage-gated calcium channels in 
efferent arterioles supports the less important or 
nonexistent role of this arteriole in autoregulation. 

Tubuloglomerular Feedback 

Changes in GFR are also mediated by alterations in 
tubular flow rate sensed by the macula densa. 
Specialized cells in the macula densa, located at the 
end of the thick ascending limb of Henle, sense 



Chapter 1 



Introduction 



changes in tubular fluid chloride entry into the cell. 
Increases in renal perfusion pressure are associ- 
ated with an increase in GFR, which is associated 
with enhanced sodium chloride delivery to the 
macula densa. To counterbalance this increase in 
GFR, macula densa cells send signals to the affer- 
ent arteriole that promote vasoconstriction. This 
reduces P GC and returns GFR toward normal and 
reduces sodium chloride delivery to the macula 
densa. In contrast, reduced sodium chloride deliv- 
ery to the macula densa, as occurs with prerenal 
azotemia, has the opposite effect — afferent arterio- 
lar vasodilatation occurs and GFR increases. This 
phenomenon is called tubuloglomerular feedback. 
The mediator(s) of TGF are not well under- 
stood. It is likely that multiple factors act to medi- 
ate the signal to the afferent arteriole. Factors that 
play a role include All (more as a permissive role), 
adenosine, thromboxane, and nitric oxide. 
Adenosine and thromboxane increase "when 
excessive chloride entry is sensed by the macula 
densa, thereby constricting the afferent arteriole. 
These substances are reduced when chloride 
delivery is low, allowing afferent arteriolar vasodi- 
latation. Nitric oxide is also thought to modulate 
the TGF response to sodium chloride delivery, 
allowing TGF to be reset by variations in salt 
intake. For example, low sodium chloride deliv- 
ery increases nitric oxide, whereas increased 
sodium chloride delivery reduces nitric oxide. 

Neurohumoral Factors 

Daily maintenance of renal hemodynamics in 
normal hosts is subserved primarily by autoregula- 
tion and TGF. These factors also participate in regu- 
lation of GFR in disease states such as renal artery 
stenosis (low renal perfusion) and hypertension 
(increased renal perfusion). In more severe states, 
however, the sympathetic nervous system (SNS), 
renin-angiotensin-aldosterone system (RAAS), as 
well as other vasoconstrictor (endothelin), and 
vasodilator (prostaglandins, nitric oxide) sub- 
stances are produced. For example, severe intravas- 
cular volume depletion, whether true (vomiting) or 
effective (congestive heart failure), stimulates the 



production of catecholamines and the RAAS to 
maintain circulatory integrity. The net renal effect of 
an outpouring of these mediators varies based on 
the severity of the initiating disease process, the 
degree of stimulation of neurohumoral substances, 
and other coexisting processes. Stimulation of both 
the SNS and RAAS reduces renal perfusion pressure 
but may have no net effect on GFR. As an example, 
the patient with congestive heart failure who has 
this type of neurohumoral response maintains rela- 
tively normal GFR because the afferent arteriolar 
constriction induced by the SNS is balanced by the 
preferential constriction of the efferent arteriole by 
All. Also, renal vasoconstriction is balanced by the 
production of vasodilatory substances such as PGs 
(PGE 2 , PGI 2 ) and nitric oxide. Administration of an 
inhibitor of PG synthesis (nonsteroidal anti-inflam- 
matory drugs) tips the balance in favor of vasocon- 
striction and reduced GFR. Severe states of volume 
depletion (i.e., hypovolemic and cardiogenic 
shock) will overcome all attempts by the body at 
preservation of renal perfusion, resulting in severe 
renal ischemia and renal failure. 



Key Points 

Regulation of RPF and GFR 



Autoregulation and TGF regulate minute-to- 
minute changes in GFR by modulating affer- 
ent arteriolar tone. 

Neurohumoral substances, such as the SNS, 
RAAS, nitric oxide, PGs, and endothelin 
influence GFR in disease states that disturb 
intravascular volume status. 




Clinical Assessment of GFR 



Measurement of GFR is essential to the manage- 
ment of patients with kidney disease. Functioning 
renal mass is best assessed by measuring total 



10 



Chapter 1 



Introduction 



kidney GFR, a reflection of the sum of filtration 
rates of functioning nephron units. Serial GFR 
measurement allows identification of kidney dis- 
ease, progression (or improvement) of kidney 
dysfunction, appropriate drug dosing, and initia- 
tion of dialysis when renal failure supervenes. To 
measure GFR precisely, the substance employed 
as a marker should be freely filtered by the 
glomerulus and not reabsorbed, secreted, or 
metabolized by the kidney. The following for- 
mula is used to measure GFR: 



GFR = 



urine concentration Ax volume 
plasma concentration A 



where A is the substance that meets the criteria as 
an ideal marker. The compound that is the best 
marker of GFR is inulin. Because of its character- 
istics, inulin clearance accurately reflects GFR. 
Inulin is not employed as a clinical marker of GFR, 
however, because it requires intravenous infu- 
sion, most clinical laboratories are unable to assay 
inulin, and it is expensive. Thus, other less opti- 
mal markers are employed to measure GFR. They 
are briefly reviewed. 



that uses a serum sample for creatinine concentra- 
tion and a 24-hour urine specimen for creatinine 
concentration and urine volume: 



CrCb 



UCr x volume 
Scr 



where Cr is creatinine, CI is clearance, U is urine, 
and S is serum. In addition to the inaccuracy of 
the creatinine clearance method to measure GFR, 
there are problems with patient collection (under- 
collection) of the urine sample. 



lothalamate 

The inaccuracy of creatinine clearance stimulated 
a search for other more accurate markers for GFR. 
Radiolabeled iothalamate provides an accurate 
estimate of GFR. It correlates tightly with inulin 
clearance and is used in clinical studies to replace 
inulin as the marker of choice to assess GFR. As 
with inulin, however, iothalamate is not widely 
available in all centers for clinical practice. It is also 
expensive and somewhat cumbersome to employ. 



Creatinine 

Endogenously produced creatinine is the marker 
most commonly employed to measure GFR. 
Creatinine is produced from the metabolism of 
skeletal muscle creatine. It is released into plasma 
at a stable rate in normal subjects and freely fil- 
tered at the glomerulus. Unfortunately, creatinine 
also enters urine via secretion by the organic 
cation transporter in proximal tubule, overestimat- 
ing GFR by 10-20%. As kidney function declines, 
the rate of tubular creatinine secretion increases. 
In this circumstance creatinine clearance may 
overestimate true GFR. Administration of cimeti- 
dine, which competitively blocks tubular cell crea- 
tinine secretion, enhances the accuracy of this test 
while combining creatinine and urea clearance 
gives a close estimate of GFR. Nonetheless, creati- 
nine clearance is widely employed in clinical 
practice. It is calculated by the following formula 



GFR Estimates 

Although serum creatinine concentration is used 
to assess kidney function, it is a poor marker of 
GFR. It is more useful when plotted as 1/serum 
creatinine, when used to follow changes in GFR 
over time. Serum creatinine concentration is 
inaccurate for various reasons (reviewed in 
Chapter 16) and alone is suboptimal to measure 
GFR. This is illustrated graphically in Figure 1.4. 
In both men and women serum creatinine con- 
centration rises little as the GFR falls from 120 to 
60 mL/minute. Large changes in GFR result in 
minimal changes in serum creatinine concentra- 
tion largely due to the fact that creatinine secre- 
tion by renal tubules increases. Once GFR has 
declined to 40-60 mL/minute creatinine secre- 
tion cannot increase further and fairly small 
changes in GFR result in large changes in serum 
creatinine concentration. Because of this problem, 



Chapter 1 



Introduction 



11 



Figure 1.4 



_l 




_i 








5 101 


Men 




10 


Women 




E 




E 




I 




c 




c 




i 




.2 8' 


, 


o 


8 


I 
















CO 




CO 




, i m . 




























c 




c 








o D 


\** 


CD 
O 


6- 


\ 'V.-.'. * 




c 




cr 








o 


\°- - 


o 




'■\ii : '^' 




o 


\ T^ 


o 




?&? * 




CD A. 


\ ^k 8 


CD 


4 


* Y^O* 




'c 


\ "l\So . 


cz 




Ag^K^ 






'^i^jipfc^ 






: ^SSftLoS!,, 




CO 




CO 




"^^if 




CD 2 


^T^^Safi&Fo 


CD 


2 


">^K^2^&. «■> - 




b 




b 




. • •■<* : ffiiJfc»!» ;M °V = 




E 


■.^N>T$5SSs?«*hTAiiw^, 


E 




'n; i 9^f" ' ii mtf _ 




=: 




Zi 








a 0J 




CD 















CO 


20 40 60 80 100 120 
GFR, mL/min per 1.73 m 2 


co 




20 40 60 80 100 
GFR, mL/min per 1.73 m 2 


120 



The relationship between serum creatinine concentration and GFR in men (A) and women (B). The relationship 
between serum creatinine concentration and GFR is not a linear one. Serum creatinine concentration is insensitive 
to changes in GFR within the range of GFRs between 60 and 120 mL/minute due to increasing tubular secretion. 
(From Levey, A.S., Bosch, J. P., Lewis, J.B., Greene, T, Rogers, N., Roth, D. Ann Intern Med 130:461-470, 1999, with 
permission.) 



formulas were created using serum creatinine 
concentration, as well as other clinical and labo- 
ratory data to more accurately estimate GFR. 
These include the Cockcroft-Gault formula (esti- 
mates creatinine clearance) and both the full and 
abbreviated forms of the Modification of Diet in 
Renal Disease (MDRD) formula. These formulas 
are discussed in Chapter 16. 



Key Points 



Clinical Assessment of GFR 



The gold standard measurement of GFR is 
inulin clearance because of its characteris- 
tics as a substance that is freely filtered at 
the glomerulus and not secreted, reab- 
sorbed, or metabolized in tubules. 
Endogenous creatinine is employed to esti- 
mate GFR, but is inaccurate and overestimates 
GFR due to its secretion by proximal tubular 
cells via the organic cation transporter. 



Iothalamate is an accurate marker but it has 
limited use in clinical practice. 
Estimates of GFR using equations such as 
the Cockcroft-Gault and MDRD formulas are 
available. 



Additional Reading 

Abrahamson, D.R. Structure and development of the 
glomerular capillary wall and basement membrane. 
Am J Physiol 253:F783-F796, 1987. 

Brewster, U.C., Perazella, M.A. The renin-angiotensin- 
aldosterone system and the kidney: effects on 
kidney disease. Am J Med 116:263-272, 2004. 

Dworkin, L.D., Ichikawa I., Brenner, B.M. Hormonal 
modulation of glomerular function. Am J Physiol 
244:F95-F111, 1983. 

Guasch, A., Deen, W.M., Myers, B.D. Charge selectivity 
of the glomerular filtration barrier in healthy and 
nephrotic humans. J Clin Invest 92:2274-2289, 1993. 

Levey, A.S., Bosch, J. P., Lewis, J.B., Greene, T, Rogers, 
N., Roth, D. A more accurate method to estimate 
glomerular filtration rate from serum creatinine: a 



12 



Chapter 1 



Introduction 



new prediction equation. Modification of Diet in 
Renal Disease Study Group. Ann Intern Med 
130:461-470, 1999. 
Perrone, R.D., Steinman, T.I., Beck, G.J., Skibinski, C.I., 
Royal, H.D., Lawlor, M., Hunsicker, L.G. Utility of 
radioisotopic filtration markers in chronic renal 
insufficiency: simultaneous comparison of 125 I- 



iothalamate, 169 Yb-DTPA, "TC-DTPA, and inulin. 

Am J Kidney Dis 16:224-237, 1990. 
Schnermann, J., Briggs, J. P. The macula clensa is worth 

its salt. / Clin Invest 104:1007-1009, 1999. 
Tischer, C.C., Madsen, KM. Anatomy of the kidney. In: 

Brenner, B.M., Rector, F.C. (eels.), The Kidney, 4th 

ed. WB Saunders, Philadelphia, PA, 1991, p. 3. 



Robert F. Reilly, Jr. 



Disorders of Sodium 
Balance 




Recommended Time to Complete: 2 days 



QulAit+c Q^t4t^04^t 



1. How does the kidney regulate extracellular fluid (ECF) volume 
differently from sodium concentration? 

2. What effector systems regulate renal sodium excretion? 
I. What is effective arterial blood volume (EABV)? 

t+. Can you describe the forces involved in edema formation? 

S. How does edema form in congestive heart failure (CHF) , cirrhosis, 

and nephrotic syndrome? 
i. What are the most common renal and extrarenal causes of total body 

sodium depletion? 




Introduction 



One of the more difficult concepts to grasp in 
nephrology is that disorders of ECF volume are 
the result of disturbances in sodium balance and 
that disorders of sodium concentration (hypo- and 



hypernatremia) are the result of disturbances in 
water balance. The control of ECF volume is 
dependent on the regulation of sodium balance. 
Sodium concentration alone is not reflective of 
ECF volume status. This is illustrated graphically 
by the cases in Figure 2.1. Patient A has diarrhea 
(Na concentration of diarrheal fluid is approxi- 
mately 80 meq/L) but does not have free access to 
water and the ECF volume as a result is depleted 



13 



14 



Chapter 2 



Disorders of Sodium Balance 



Figure 2. 1 



45.6 g Na 








40 g Na 




No po 












1 40 meq/L 












1 56 meq/L 








Diarrhea 
Na-Rfl mm/I 






14L 






11 L 

















(a) 







Drink 
water 






45.6 g Na 






40 g Na 










140 meq/L 












130 meq/L 








GI3L 
Na-RO men/I 






14L 






13.2 L 

















(b) 



Sodium concentration does not reflect ECF volume 
status. Both of the patients shown have decreased 
ECF volume but in case A the serum sodium con- 
centration is increased while in case B the serum 
sodium concentration is decreased. Abbreviations: 
po, by mouth; GI, gastrointestinal. 



3 L from its starting point of 14 L. The serum sodium 
concentration rises to 156 meq/L. Patient B has an 
equivalent amount of diarrhea but is awake, alert, 
and has free access to water. Patient B drinks 
enough free water to increase the ECF volume from 
11 to 13.2 L. Sodium losses in the diarrheal fluid 
coupled with free •water replacement result in a 
serum sodium concentration of 130 meq/L. The 
serum sodium concentration is high in case A and 
low in case B, yet in both patients ECF volume is 
decreased. These cases illustrate that serum 
sodium concentration, in and of itself, does not 
provide information about the state of ECF volume. 
In both patients sensor mechanisms detect ECF 
volume depletion and effector mechanisms are 
activated to increase renal sodium reabsorption. 

ECF volume reflects the balance between 
sodium intake and sodium excretion and is regu- 
lated by a complex system acting via the kidney. 
The average intake of sodium in developed coun- 
tries is between 150 and 250 meq/day and must be 
balanced by an equivalent daily sodium excretion. 



States where ECF volume is increased are 
related to a net gain of sodium and often present 
with edema in the presence or absence of hyper- 
tension. States where ECF volume is decreased 
reflect a total body sodium deficit and are often 
due to sodium and water losses from the gastroin- 
testinal or genitourinary tracts and commonly 
present with decreased blood pressure. 

A normal person maintains sodium balance 
without edema, hypertension, or hypotension 
across a broad range of sodium intake (10-1000 
meq/day). A variety of sensors detect alterations in 
sodium balance and effectors respond by adjust- 
ing renal sodium excretion (Table 2.1). Sodium 
sensors respond to the adequacy of intravascular 
filling and the effector limb modifies sodium 
excretion accordingly. When patients are edema- 
tous, however, there is sodium retention even in 
the setting of an expanded ECF volume. 

This phenomenon led to the postulation of an 
important but confusing concept known as the 
effective arterial blood volume (EABV) that is 
defined based on the activity of the sodium 
homeostasis effector mechanisms in the kidney. 

Table 2.1 

Sensors and Effectors of Sodium Balance 



Sodium Sensors 


Effectors 


Low pressure recep- 


Glomerular filtration 


tors (atria and 


rate 


veins) 




High pressure recep- 


Peritubular physical 


tors (aortic arch 


factors (ionic, 


and carotid sinus) 


osmotic, and 




hydraulic gradients) 


Hepatic volume 


Sympathetic nervous 


receptor 


system 


Cerebrospinal fluid 


Renin-angiotensin- 


sodium receptor 


aldosterone system 


Renal afferent arteri- 


Atrial natriuretic 


ole receptors 


factor 




Other natriuretic 




hormones 



Chapter 2 



Disorders of Sodium Balance 



15 



Effective arterial blood volume is a concept rather 
than an objectively measured volume. Since the 
stimulation of sodium sensors cannot be directly 
measured, their activity is inferred based on the 
response of the effector limb. It is an estimate of 
the net level of stimulation of all sodium sensors. 
Volume sensors in the arterial and venous circu- 
lation including the renal vessels monitor the 
sense of fullness of the vascular tree. Ultimately, 
it is the relationship between the cardiac output 
and peripheral vascular resistance that is sensed. 
Effective arterial blood volume can also be 
defined based on how far the mean arterial pres- 
sure (equal to the diastolic blood pressure plus 
one-third of the pulse pressure) is displaced from 
its set point. In many edematous disorders the set 
point is normal, as in congestive heart failure and 
cirrhosis of the liver, and the mean arterial pres- 
sure tends to be low. In nephrotic syndrome the 
set point is increased by kidney disease and the 
mean arterial pressure is high. Despite the fact 
that mean arterial pressure is high, it still remains 
below the set point. In both situations the kidney 
retains salt and water in an attempt to return 
blood pressure to its set point. In clinical prac- 
tice, however, net renal sodium handling deter- 
mines the state of the EABV. When the kidney 
retains sodium, it is inferred that the EABV is 
decreased and when the kidney excretes sodium, 
it is inferred that the EABV is increased. 



Key Points 

ECF and Sodium Concentration 



1 . Disorders of ECF volume result from distur- 
bances in sodium balance and disorders of 
serum sodium concentration (hypo- and 
hypernatremia) result from alterations in 
water balance. 

2. Extracellular fluid volume control is depen- 
dent on the regulation of sodium balance. 
Regulation of ECF volume reflects the bal- 
ance between sodium intake and sodium 
excretion. 



3. Serum sodium concentration is not reflective 
of ECF volume status. 

4. Extracellular fluid volume expansion is 
related to a net gain of sodium and often 
presents as edema. 

5. A variety of sensors detect alterations in 
sodium balance and effectors respond by 
modifying renal sodium excretion. Sodium 
sensors respond to the adequacy of intravas- 
cular filling and the effector limb adjusts 
renal sodium excretion accordingly. 

6. Effective arterial blood volume is a concept 
and not a volume that is objectively mea- 
sured. It is an estimate of the net level of 
activation of all sodium sensors. It is inferred 
that the EABV is decreased when the kidney 
retains sodium and that the EABV is 
increased when the kidney excretes sodium. 




Effector Systems 



Regulation of Sodium Transport 
in the Kidney 

When ECF volume is decreased, renal sodium 
excretion is minimized by decreasing the amount 
of sodium filtered and increasing tubular sodium 
reabsorption. Extracellular fluid volume depletion 
stimulates the release of angiotensin II (All), 
aldosterone, and arginine vasopressin (AVP), as 
well as activates the sympathetic nervous system 
resulting in salt and water retention. Thirst and 
the craving for salt are also stimulated. 
Angiotensin II and aldosterone act synergistically 
to stimulate salt appetite and All is a strong stimu- 
lator of thirst. Extrarenal losses of salt are mini- 
mized by decreased sweating and fecal losses. 
Decreased ECF volume decreases intravascular 
volume and results in decreased renal perfusion. 
The resultant decline in glomerular filtration 



16 



Chapter 2 



Disorders of Sodium Balance 



rate (GFR) decreases the filtered load (amount 
presented to the proximal tubule) of sodium. 
Tubular sodium reabsorption is increased by acti- 
vation of the renin-angiotensin-aldosterone 
system (RAAS), changes in peritubular physical 
forces, and suppression of natriuretic peptides. 

The filtered load of sodium chloride is 1.7 kg/day. 
This is 1 1 times the amount of sodium chloride in 
the ECF. Less than 1% of the filtered load is 
excreted in the final urine under the control of a 
complex system of effector mechanisms that reg- 
ulate sodium reabsorption along the nephron. 
The cellular and molecular mechanisms of action 
of these effector systems in each nephron seg- 
ment are discussed below. 



Proximal Tubule 

The proximal tubule reabsorbs 60-70% of the fil- 
tered sodium chloride load. Physical factors, the 
sympathetic nervous system, and the RAAS regulate 
sodium reabsorption in this segment. The principal 
pathway for sodium entry into the proximal tubular 
cell is the Na + -H + exchanger (isoform NHE3). 

Physical factors regulate sodium reabsorption 
through changes in filtration fraction (FF) that 
create hydrostatic and oncotic gradients for water 
movement. The filtration fraction is the ratio of 
GFR to renal plasma flow (RPF) shown in the 
equation below: 



FF: 



GFR 
RPF 



Efferent arteriolar constriction by All increases 
the FF via two mechanisms. It reduces renal blood 
flow (decreases RPF) and increases glomerular cap- 
illary pressure, which is the main determinant of 
GFR (raises GFR). The resultant increase in FF 
increases oncotic pressure and decreases hydrostatic 
pressure in the peritubular capillary. These changes 
promote the movement of salt and water from the 
tubular lumen to the interstitial space and finally into 
the peritubular capillary. In addition, All reduces 
medullary blood flow, which has similar effects on 
driving forces in medullary nephron segments. 



The RAAS also has direct effects on tubular 
transport mediated via NHE3 and the Na + -K + - 
ATPase. Angiotensin II and aldosterone both 
upregulate NHE3. The All effect may be mediated 
via protein kinase C, whereas aldosterone was 
recently shown to increase the insertion of pre- 
formed transporter proteins into the apical mem- 
brane. The Na + -K + -ATPase, which is present in the 
basolateral membrane of all nephron segments and 
is the major pathway by which sodium exits tubu- 
lar cells, is also stimulated by AIL The sympathetic 
nervous system and insulin also stimulate the 
movement of NHE3 into the apical membrane and 
increase proximal tubular sodium reabsorption. 

Systemic blood pressure itself also plays a key 
role in proximal tubular sodium reabsorption. As 
blood pressure rises the renal excretion of NaCl 
increases in an attempt to reduce ECF fluid volume 
and normalize blood pressure. This phenomenon is 
known as pressure natriuresis. Pressure natriuresis is 
not mediated by an increase in filtered sodium load. 
An acute rise in blood pressure does not change the 
amount of sodium filtered by the glomerulus due to 
autoregulation of the renal microvasculature. As 
blood pressure increases, the afferent arteriole con- 
stricts in order to maintain glomerular capillary 
hydrostatic pressure constant. Afferent arteriolar 
constriction results from both a direct myogenic 
reflex and tubuloglomerular feedback (discussed 
below). Acute rises in blood pressure are sensed in 
the vasculature and a signal is transmitted to the 
proximal tubule to reduce sodium chloride reab- 
sorption. This is mediated by removal of NHE3 from 
the luminal membrane of proximal tubule via a two- 
step internalization process regulated in part by All 
shown in Figure 2.2. NHE3 first moves from the 
microvillar membrane to the intermicrovillar cleft 
(first step) and then from the intermicrovillar cleft to 
subapical endosomes (second step). A fall in All 
concentration plays a role in the first step. Na + -K + - 
ATPase activity is also decreased via a similar 
process of internalization. 

Increased delivery of NaCl to the thick ascend- 
ing limb of Henle is sensed by macula densa 
cells. The macula densa is a specialized region 
near the junction of the cortical thick ascending 



Chapter 2 ♦ Disorders of Sodium Balance 



17 



Figure 2.2 




Luminal 
membrane 



Proteosome 



Basolateral 
membrane 



Sodium transporters in proximal tubule and pressure natriure- 
sis. NHE3 (filled circles) is internalized in two steps in 
response to elevated blood pressure. In step 1, NHE3 moves 
from microvilli to the intermicrovillar cleft, a process that is 
regulated by angiotensin II. In step 2, NHE3 moves from the 
intermicrovillar cleft to proteosomes and is degraded. The Na + - 
K + -ATPase is regulated in a similar fashion. 



limb and distal convoluted tubule (DCT). The 
macula densa is in close proximity to the granular 
renin-producing cells in the afferent arteriole and 
together this region is referred to as the juxta- 
glomerular (JG) apparatus. The JG apparatus 
mediates a process known as tubuloglomerular 
feedback. When increased sodium chloride deliv- 
ery is sensed by the macula densa a signal is trans- 
mitted to the afferent arteriole to constrict and the 
single-nephron GFR decreases. Renin release by 
the JG apparatus is suppressed and All levels fall. 
Conversely, when decreased sodium chloride is 
sensed by the macula densa, renin release is stim- 
ulated and the RAAS activated. Tubuloglomerular 
feedback serves two purposes. First, it maintains 
sodium chloride delivery to distal nephron seg- 
ments (distal convoluted tubule and collecting 
duct) relatively constant over a wide range of con- 
ditions in the short term. It is in distal nephron 
where the final fine-tune regulation of sodium 
and water balance occurs. Additionally, in the 



long term the JG apparatus is responsible for 
controlling renin secretion at a rate that is optimal 
in order to maintain sodium balance. 



Thick Ascending Limb ofHenle 

The thick ascending limb of Henle reabsorbs 
20-30% of the filtered sodium chloride load. Sodium 
and chloride enter the thick ascending limb cell via 
the Na + -K + -2Cr cotransporter, which is inhibited by 
loop diuretics. Since sodium and chloride concen- 
tration in urine are much higher than potassium, in 
order for the transporter to operate maximally there 
must be a mechanism present for potassium to 
recycle back into the tubular lumen. A ROMK potas- 
sium channel in the luminal membrane mediates 
potassium recycling. Sodium exits on the Na + -K + - 
ATPase and chloride exist via a chloride channel. 

The rate of NaCl absorption in this segment is 
load dependent. The higher the delivered load of 
NaCl the higher the absorption. Sodium reabsorp- 
tion is increased by /3-adrenergic agonists, argi- 
nine vasopressin in some species, parathyroid 
hormone, calcitonin, and glucagon. Prostaglandin 
E 2 inhibits sodium reabsorption. 



Distal Convoluted Tubule 

The DCT reabsorbs 5-10% of the filtered sodium 
load. Sodium and chloride enter the DCT cell via 
the thiazide-sensitive Na + -Cl" cotransporter (NCC) 
and sodium exits through the Na + -K + -ATPase. 
Aldosterone upregulates NCC expression. In 
order for mineralocorticoids to play a role in the 
regulation of sodium transport in any nephron 
segment that segment must also express the 
mineralocorticoid receptor and the type 2 11 
/3-hydroxysteroid dehydrogenase (HSD). The 
mineralocorticoid receptor is expressed in DCT, 
while type 2 11 /i-HSD is expressed in the later 
half (DCT2) of the DCT. DCT2 also contains 
the epithelial sodium channel (ENaC). Type 2 11 
/?-HSD degrades Cortisol to the inactive cortisone 
in mineralocorticoid target tissues. This is 



18 



Chapter 2 



Disorders of Sodium Balance 



required in order to maintain mineralocorticoid 
specificity, given the facts that the mineralocorti- 
coid receptor can also bind glucocorticoids and 
that glucocorticoids circulate at much higher con- 
centrations than mineralocorticoids. 

Genetic studies of a rare monogenic disorder 
provided insight into NCC regulation. Pseudohy- 
poaldosteronism type II (PHA II) is an autosomal 
dominant disease characterized by hypertension, 
hyperkalemia, and extreme sensitivity to thiazide 
diuretics. Mutations in two members of the WNK 
(with no lysine[K]) kinase family, WNK1 and 
WNK4, cause the disease. WNK4 is expressed in 
DCT and reduces expression of NCC in the cell 
membrane. It does this via a kinase-dependent 
mechanism that does not involve changes in the 
synthesis of NCC. Mutations in WNK4 lead to NCC 
overactivity. WNK4 also inhibits the ROMK potas- 
sium channel. ROMK inhibition is not dependent 
on WNK4 kinase activity but occurs through 
clathrin-dependent endocytosis of the channel. 
Interestingly, WNK4 mutations of PHA II increase 
NCC activity but decrease ROMK activity. This not 
only explains the hypertension and hyperkalemia 
of PHA II but also shows that WNK4 can differen- 
tially regulate NCC and ROMK. 

WNK4 may be the master switch that regulates 
the balance between NaCl reabsorption and potas- 
sium excretion in distal nephron. Aldosterone is 



stimulated by decreased ECF volume and hyper- 
kalemia. Yet when aldosterone concentrations are 
elevated, how does the distal nephron know 
whether to reabsorb sodium (stimulate NCC and 
inhibit ROMK) or excrete potassium (stimulate 
ROMK and inhibit NCC)? The answer to this ques- 
tion, which remains unknown, may lie in the reg- 
ulation of WNK4 kinase activity. 

WNK1 is expressed in a variety of chloride 
transporting epithelia including kidney, colon, 
sweat ducts, pancreas, and bile ducts. WNK1 does 
not appear to bind NCC but rather interacts with 
WNK4 and inhibits its ability to downregulate 
NCC. In PHA II, mutations in WNK1 increase its 
expression and further augment its ability to 
inhibit WNK4 resulting in increased NCC activity. 
In the model of DCT sodium transport shown in 
Figure 2.3 delivery of NCC to the luminal membrane 
is inhibited by WNK4, while WNK1 inhibits the 
activity of WNK4. Mutations in either WNK1 or 
WNK4 result in increased NCC expression in the 
cell membrane and the PHA II phenotype. 



Cortical Collecting Duct 

The collecting duct reabsorbs 1-3% of the filtered 
sodium load. The RAAS is the major regulator of 
NaCl reabsorption in this segment. Sodium enters 



Figure 2.3 



Lumen 






Blood 


Na + 


WMk-4 


N 


- OM-.+ 


; o^\o 


„ V. J nis+ 


CI 


WNK1 




Na + -K + -ATPase 











Model of DCT sodium transport and PHA II. The PHA II phenotype is caused 
by mutations in both WNK4 and WNK1. WNK4 impairs the delivery of the 
Na + -Cl" cotransporter (NCC) to the luminal membrane and mutations that 
decrease its activity increase NCC expression in the cell membrane. Wild- 
type WNK1 interacts with WNK4 and decreases its activity. 



Chapter 2 



Disorders of Sodium Balance 



19 



Figure 2.4 



Lumen 



Blood 




Aldosterone 



Aldosterone 



*- 3Na + 




Principal cell 



Model of CCD sodium transport and Liddle's syndrome. In Liddle's syndrome mutations in 
P and yENaC subunits increase ENaC activity. Mutations occur in a PY motif involved in pro- 
tein-protein interaction. The PY motif interacts with Nedd4 that ubiquitinates ENaC and 
leads to its internalization and proteosome-mediated degradation. Nedd4 is inactivated via 
phosphorylation by SGK1, which is upregulated by aldosterone. After phosphorylation 
Nedd4 no longer interacts with ENaC resulting in increased ENaC expression in the cell 
membrane. 



the cortical collecting duct (CCD) cell via ENaC 
and exits through the basolateral Na + -K + -ATPase 
(shown in Figure 2.4). The epithelial sodium 
channel is composed of three subunits (a,P,y). 
Aldosterone and possibly All increase ENaC 
abundance in CCD. Aldosterone also upregulates 
the Na + -K + -ATPase and the mitochondrial enzyme 
citrate synthetase. 

As in the DCT, studies of monogenic disorders 
causing hypertension led to important insights 
into ENaC regulation. Liddle's syndrome is an 
autosomal dominant disorder characterized by 
the onset of hypertension at an early age, 
hypokalemia, and metabolic alkalosis. Linkage 
studies revealed that Liddle's syndrome resulted 
from mutations in [5 and y ENaC subunits that 
increased ENaC activity. The mutations clustered 
in a PY motif, which is involved in protein-protein 
interaction, at the C-terminus of the protein. The 
PY motif of ENaC interacts with Nedd4. Nedd4 
ubiquitinates ENaC that leads to its internalization 
and proteosome-mediated degradation. Nedd4 is 
inactivated via phosphorylation by the serum and 
glucocorticoid-stimulated kinase (SGK1), which 
is upregulated by aldosterone. Once Nedd4 is 



phosphorylated it no longer interacts with ENaC. 
In summary, these studies revealed that aldo- 
sterone upregulates SGK1, SGK1 phosphorylates, 
and inactivates Nedd4, Nedd4 does not ubiquiti- 
nate ENaC and ENaC remains active in the cell 
membrane. Aldosterone increases the synthesis of 
SGK1 mRNA within 30 minutes, after several 
hours it also increases synthesis of the a subunit 
of ENaC and Na + -K + -ATPase mRNA. 



Medullary Collecting Duct 

In the inner medullary collecting duct (IMCD) 
there are two transport pathways whereby 
sodium enters the cell (Figure 2.5). The first is 
ENaC also expressed in CCD and the second is a 
cyclic GMP-gated cation channel that transports 
sodium, potassium, and ammonium. Sodium exits 
the cell via the Na + -K + -ATPase. 

The cyclic GMP-gated cation channel is inhib- 
ited by natriuretic peptides, the major effector 
pathway regulating sodium transport in IMCD. 
Although natriuretic peptides also increase GFR 
(via dilation of the afferent arteriole and constriction 



20 



Chapter 2 



Disorders of Sodium Balance 



Figure 2.5 



Lumen 



Blood 



ANP-*> 

NPR-A 




3Na + 

2K + 

Na + -K + -ATPase 



- \y — ?k + 



Sodium transport in the inner medullary collecting duct. Sodium enters the cell via 
either ENaC or a cyclic GMP-gated cation channel that transports sodium, potassium, 
and ammonium and exits through the Na + -K + -ATPase. Natriuretic peptides such as 
ANP bind to their receptors (NPR AC) and catalyze the conversion of GTP to cyclic 
GMP (cGMP). Cyclic GMP inhibits the cation channel directly and indirectly through 
the protein kinase G (PKG). Natriuretic peptides also inhibit the Na + -K + -ATPase either 
through protein kinase G (ANP) or prostaglandin E 2 . 



of the efferent arteriole), their major natriuretic 
effect is in IMCD. Natriuretic peptides are a family 
of proteins that include atrial natriuretic peptide 
(ANP), long-acting atrial natriuretic peptide, vessel 
dilator, kaliuretic peptide, brain-type natriuretic 
peptide (BNP), C-type natriuretic peptide (CNP), 
and urodilatin. They act on target cells by binding 
to three types of receptors, natriuretic peptide 
receptors (NPR) A, B, and C. Natriuretic peptide 
receptors A and B are isoforms of particulate 
guanylate cyclase that catalyze the conversion of 
GTP to cyclic GMP after ligand binding. NPR B 
may be a specific receptor for CNP. Atrial natri- 
uretic peptide acts through NPR A. The primary 
sites of production of these peptides are: ANP — 
cardiac atrium, BNP — cardiac ventricles, CNP — 
endothelial cells, and urodilatin — distal tubule of 
the kidney. Atrial natriuretic peptide also inhibits 
the basolateral Na + -K + -ATPase. All of the other 
effector systems discussed above are antinatri- 
uretic; these peptides constitute the major effector 
system that results in natriuresis. They are important 
in protecting against ECF volume expansion, 
especially in congestive heart failure. 



Key Points 

Effector Systems 



As ECF volume decreases, renal sodium 
excretion is minimized by reducing the fil- 
tered sodium load and increasing tubular 
sodium reabsorption. This is mediated via 
release of A-II, aldosterone, and arginine 
vasopressin, as well as activation of the sym- 
pathetic nervous system. 
In proximal tubule physical factors, the sym- 
pathetic nervous system and the RAAS regu- 
late sodium reabsorption. Physical factors 
operate through changes in FF, thereby 
altering hydrostatic and oncotic pressure 
gradients for sodium and water movement. 
The RAAS also has direct effects on tubular 
sociium transport mediated via NHE3 and 
Na + -K + -ATPase. 

Systemic blood pressure itself also plays a 
key role in proximal tubular sodium reab- 
sorption through pressure natriuresis that in- 
volves internalization of NHE3. The resultant 



Chapter 2 



Disorders of Sodium Balance 



21 



increase in NaCl delivery to the macula 
densa activates tubuloglomerular feedback 
reducing single-nephron GFR. 

4. The thick ascending limb of Henle reab- 
sorbs 20-30% of the filtered sodium chloride 
load and reabsorption is load dependent. 

5. The DCT reabsorbs 5-10% of the filtered 
sodium load. Activity of NCC is regulated via 
WNK1 and WNK4. WNK4 reduces NCC 
expression in the cell membrane. 

6. WNK4 may function as a master switch that 
integrates aldosterone action in distal 
nephron. 

7. The CCD reabsorbs 1-3% of the filtered 
sodium load under regulation by the RAAS. 
Aldosterone acts on both sodium entry 
(ENaC) and exit (Na + -K + -ATPase) pathways. 

8. Aldosterone increases ENaC activity 
through the phosphorylation of SGK1. 
SGK1 phosphorylates and blocks the 
activity of Nedd4, a protein that ubiquiti- 
nates ENaC causing its removal from the 
cell membrane. 

9. Natriuretic peptides constitute the major 
effector system resulting in natriuresis. They 
act primarily by inhibiting the IMCD cyclic 
GMP-gated nonspecific cation channel and 
the Na + -K + -ATPase. 




Disorders Associated with 

Increased Total Body Sodium 

(ECF Volume Expansion) 



Hypervolemic states (increased ECF volume) are 
associated with increased total body sodium and 
commonly present "with edema with or without 
hypertension. Edema is the accumulation of 
excess interstitial fluid. Interstitial fluid is that part 
of the ECF not contained within blood vessels. 



Edema fluid resembles plasma in terms of its 
electrolyte content and has a variable protein con- 
centration. Edema may be localized due to local 
vascular or lymphatic injury or can be generalized 
as in congestive heart failure, cirrhosis, and 
nephrotic syndrome. On physical examination, 
edema is detected by applying pressure with the 
thumb or index finger on the skin of the lower 
extremities or presacral region. If edema is pres- 
ent an indentation or "pitting" results. 

Edema is generated by an alteration in physical 
forces originally described by Starling that deter- 
mine the movement of fluid across the capillary 
endothelium. Alterations in these forces explain 
the development of both localized and general- 
ized edema. Major causes of edema are classified 
according to the mechanisms responsible and are 
illustrated in Table 2.2. The interaction between 
hydrostatic and oncotic pressure governs the 
movement of water across the capillary wall. An 
increase in hydrostatic pressure or a decrease in 
oncotic pressure within the capillary favors the 
movement of fluid out of the blood vessel and 
into the interstitium resulting in edema formation. 
Increases in capillary permeability also favor 
edema formation. The final common pathway 
maintaining generalized edema is the retention of 
excess salt and water by the kidney. 

The pathophysiology of ECF volume expan- 
sion based on the presence or absence of hyper- 
tension and edema is shown in Table 2.3. 



Hypertension Present, Edema Present 

With kidney disease and a decreased GFR hyper- 
tension and edema are often present. The 
decrease in renal function results in sodium reten- 
tion and ECF volume expansion. If the expansion 
is severe enough, hypertension and edema result. 
In acute glomerulonephritis the renal lesion 
results in a primary retention of NaCl. The stimulus 
for NaCl retention and the molecular mechanisms 
whereby it occurs remain unknown. Studies in 
children with acute poststreptococcal glomeru- 
lonephritis showed that renin activity is low 



22 



Chapter 2 



Disorders of Sodium Balance 



Table 2.2 



Pathophysiology of Edema Formation 



Increased Formation 




Decreased Removal 


Ill-Defened Mechanisms 


Increased capillary 




Decreased plasma colloid 


Idiopathic cyclic edema 


hydrostatic pressure 




osmotic pressure 




Venous obstruction 




Nephrotic syndrome 


Pregnancy 


Congestive heart failure 




Malabsorption 


Hypothyroidism 


Cirrhosis of the liver 




Cirrhosis of the liver 




Primary salt excess 








(nephrotic syndrome) 








Increased capillary permeability 


Impaired lymphatic outflow 




Trauma — burns 








Allergic reactions 









Abbreviations: ARF, acute renal failure: CKD, chronic renal failure. 



supporting the conclusion that ECF volume is 
expanded. In addition, studies of patients "with 
acute nephritis also showed increased concentra- 
tion of atrial natriuretic peptides, as would be 
expected if ECF volume were expanded. Expansion 
of ECF volume induces hypertension and edema 
that in turn suppresses renin production and stimu- 
lates release of atrial natriuretic peptides. 



Hypertension Present, Edema Absent (Excess 
Aldosterone or Aldosterone-Like Activity) 

These disorders are due to sodium retention by the 
kidney stimulated by excess mineralocorticoids 
(primary aldosteronism due to an aldosterone- 
producing tumor, renal artery stenosis, and renin- 
producing tumors of the JG apparatus), glucocor- 
ticoids binding to the mineralocorticoid receptor 
(Cushing's syndrome, licorice, and apparent min- 
eralocorticoid excess), or genetic diseases that 
result in increased sodium reabsorption in the 
distal nephron (Liddle's syndrome and pseudohy- 
poaldosteronism type II). Liddle's syndrome is 
due to overactivity of the sodium channel in CCD. 
Pseudohypoaldosteronism type II is due to 



overactivity of the thiazide-sensitive Na-Cl cotrans- 
porter in DCT caused by mutations in WNK 
kinases. 

In all of these conditions the kidney is able to 
maintain ECF volume homeostasis but at the cost 
of hypertension. The relationship between defects 
in renal salt excretion and the subsequent devel- 
opment of hypertension is best explained by the 
computer models of Guyton and his collabora- 
tors. In order for long-term increases in blood 
pressure to occur there must be a reduction in the 
kidney's ability to excrete salt and water. In 
normal individuals, raising arterial pressure 
results in increased sodium excretion and a return 
of blood pressure to normal. This effect is medi- 
ated via pressure natriuresis (discussed earlier). 
A steady state is reestablished where sodium 
intake equals sodium excretion at a normal blood 
pressure. Increases in salt intake may transiently 
raise blood pressure but if the pressure natriuresis 
mechanism is intact blood pressure must always 
return to normal as shown in Figure 2.6. Pressure 
natriuresis is the key component of a feedback 
system that stabilizes blood pressure and ECF 
volume. Activation of neurohumoral systems, 
especially the RAAS, shifts the curve to the right 
blunting the pressure natriuresis response. 



Chapter 2 



Disorders of Sodium Balance 



23 



Table 23 

Pathophysiology of ECF Volume (Total Body Sodium) Expansion 



Hypertension-present, edema-present 

Kidney disease 
Hypertension-present, edema-absent 

Mineralocorticoid excess 

Primary hyperaldosteronism 

Renal artery stenosis 

Renin-producing tumors 
Glucocorticoids binding to the mineral- 
ocorticoid receptor 

Cushing's disease 

Licorice 

AME 
Increased distal sodium reabsorption 
Liddle's syndrome 
Pseudohypoaldosteronism type II 
Hypertension-absent, edema-present 
Decreased cardiac output 

Congestive heart failure 

Constrictive pericarditis 

Pulmonary hypertension 
Decreased oncotic pressure 

Nephrotic syndrome 
Peripheral vasodilation 

Cirrhosis 

High-output heart failure 

Pregnancy 
Increased capillary permeability 

Burns 

Sepsis 

Pancreatitis 



Abbreviation: AME, apparent mineralocortieoid excess. 



Suppression of the RAAS increases the ability of 
the kidney to excrete sodium with minimal to no 
change in blood pressure. Long-term increases in 
blood pressure can only occur if the curve is 
shifted to the right. This rightward shift results in 
sustained hypertension that is a "trade-off" that 
allows the kidney to excrete normal amounts of 
sodium but at the expense of hypertension. 



Rightward shifts of the curve are caused by dis- 
eases that increase preglomerular resistance, 
increase tubular reabsorption of sodium, or reduce 
the number of functional nephrons. 

With nephron loss remaining nephrons must 
excrete greater amounts of sodium to maintain 
balance. Compensatory changes that must occur 
in order to achieve this include increased single- 
nephron GFR and decreased tubular sodium 
reabsorption. Decreased sodium reabsorption 
leads to increased NaCl delivery to the macula 
densa and suppression of renin release. In this 
situation since renin is already maximally sup- 
pressed, the kidney's ability to excrete a salt load 
(such as with a high-salt diet) is impaired and 
will require a higher blood pressure. This 
explains the higher prevalence of "salt-sensitive" 
hypertension in patients with kidney disease. 
Renal arteriolar vasodilation and a sustained 
increase in single-nephron GFR damage surviv- 
ing nephrons and lead to glomerulosclerosis. 
When this process becomes severe the pressure 
natriuresis curve shifts to the right and hyperten- 
sion develops. Damage to surviving nephrons is 
key in shifting the pressure natriuresis curve to 
the right. Studies in dogs with surgically induced 
nephron loss (five-sixths nephrectomy) show 
that sustained increases in sodium intake shift 
the curve to the right and induce "salt-sensitive" 
hypertension that resolves when sodium is 
restricted. 



Hypertension Absent, Edema Present 
(Decreased EABV) 

Congestive heart failure, nephrotic syndrome, and 
cirrhosis of the liver are characterized by edema; 
however, hypertension is absent. In these disor- 
ders a primary abnormality results in decreased 
EABV that stimulates effector mechanisms result- 
ing in renal sodium retention. The primary abnor- 
mality varies depending on the disease. 

In CHF the primary abnormality is a decreased 
cardiac output. There is a secondary increase 
in peripheral vascular resistance to maintain 



24 



Chapter 2 



Disorders of Sodium Balance 



Figure 2.6 




60 70 80 90 100 110 120 130 140 150 
Mean arterial pressure 



Pressure volume regulation in hypertension. Increases in sodium intake 
may transiently raise blood pressure (shown by the arrow at number 1) but 
if the pressure natriuresis mechanism is intact blood pressure must always 
return to normal (illustrated by the curved line at number 2). Activation of 
the RAAS shifts the curve to the right blunting the pressure natriuresis 
response. Suppression of the RAAS shifts the curve to the left of normal and 
increases the kidney's ability to excrete sodium with minimal change in 
blood pressure even at high sodium intakes. Hypertension can only occur 
if the pressure natriuresis (pressure volume) curve is shifted to the right. 
Sustained hypertension is the "trade-off that allows the kidney to excrete 
ingested sodium but at the cost of hypertension. 



blood pressure. Plasma volume is expanded. 
Since most of this increase is on the venous side 
of the circulation, however, arterial underfilling is 
sensed by baroreceptors. Effector systems are 
activated resulting in stimulation of the sympa- 
thetic nervous system and the RAAS, as well as the 
nonosmotic release of AVP. Plasma concentrations 
of renin, aldosterone, AVP, and norepinephrine 
are increased. The net effect is the renal retention 
of salt and water in order to compensate for arte- 
rial underfilling. The intensity of the neurohu- 
moral response is proportional to the severity of 
the heart failure. Sodium concentration correlates 
inversely with AVP concentration and the severity 
of the hyponatremia is a predictor of cardiovascu- 
lar mortality. Despite the fact that atrial natriuretic 



peptide concentrations are elevated in patients 
with CHF, there is resistance to their action. This is 
likely related to an increase in sodium reabsorp- 
tion in nephron segments upstream of the inner 
medullary collecting duct. Natriuresis is restored 
by renal denervation, probably due to decreased 
proximal tubular sodium reabsorption and 
increased distal sodium delivery. 

In cirrhosis of the liver the primary abnormality 
is decreased peripheral vascular resistance that 
leads to a secondary increase in cardiac output. 
Plasma volume in cirrhotic patients is increased 
and the increase occurs before the development 
of ascites. Splanchnic vasodilation is present early 
in the course of cirrhosis and results in arterial 
underfilling and activation of neurohumoral 



Chapter 2 



Disorders of Sodium Balance 



25 



mechanisms that lead to salt and water retention. 
There is a direct correlation between the degree 
of decrease in peripheral vascular resistance and 
the increase in plasma volume. As in CHF the 
severity of hyponatremia is a predictor of clinical 
outcome. Splanchnic vasodilation may be medi- 
ated by nitric oxide. Shear forces in splanchnic 
arteriovenous shunts stimulate nitric oxide pro- 
duction. Studies in cirrhotic rats showed that 
endothelial nitric oxide was increased in the aorta 
and mesenteric arteries. When nitric oxide syn- 
thase inhibitors were administered to these ani- 
mals there was a reversal of the increase in nitric 
oxide, the hyperdynamic circulation, and neuro- 
humoral activation. Water excretion increased 
and the serum sodium concentration rose. 

Two hypotheses were proposed to explain the 
edema of nephrotic syndrome, the underfill 
hypothesis, and the overflow hypothesis. The 
underfill hypothesis, which is most commonly 
taught, states that edema forms in nephrotic syn- 
drome as a result of decreased EABV. The 
decreased EABV is secondary to decreased capil- 
lary oncotic pressure that results from proteinuria. 
The reduced oncotic pressure leads to increased 
fluid movement into the interstitium (edema) and 
reduces the ECF volume. Effector mechanisms are 
activated increasing renal salt and water reab- 
sorption that maintain the edema. 

The overflow hypothesis argues that edema in 
nephrotic syndrome is due to a primary increase 
in renal sodium reabsorption as occurs with 
glomerulonephritis. This would result in ECF 
volume expansion and suppression of the RAAS. 
Although measurement of ECF volume would be 
expected to resolve this issue, ECF volume deter- 
minations are often not reproducible and contro- 
versy exists as to whether the measurement 
should be normalized per kilogram of dry or wet 
weight. 

Studies of counterregulatory hormone activity 
show conflicting results. Approximately one-half 
of nephrotic patients have elevated plasma 
renin activity (underfill subgroup). Plasma and 
urinary catecholamine concentrations are often 
increased compatible with the underfill hypothesis. 



Plasma vasopressin concentrations correlate with 
blood volume and are reduced by albumin infu- 
sion (underfill subgroup). Other authors point out 
that natriuresis precedes the increase in plasma 
albumin concentration in patients with minimal 
change disease that respond to corticosteroid 
therapy, blood pressure is often increased and 
falls with clinical remission in children with 
nephrotic syndrome, renin and angiotensin activity 
are suppressed in many patients, and in animal 
models of unilateral nephrosis, sodium is retained 
in the affected kidney arguing that there is a pri- 
mary defect in sodium reabsorption supporting 
the overfill hypothesis. 

One analysis of 217 nephrotic patients showed 
that plasma volume was reduced in 33%, normal 
in 42%, and increased in 25%. Based on this study 
it is likely that subgroups of patients exist, some 
with decreased ECF volume (underfill hypothe- 
sis) and others with increased ECF volume (over- 
fill hypothesis). The underfilled nephrotic patient 
will have decreased EABV, activation of the RAAS, 
and lack hypertension. The overfilled nephrotic 
patient will demonstrate hypertension, suppres- 
sion of the RAAS, and may be more likely to have 
a lower GFR. Attempts to better subdivide these 
groups may have important implications regard- 
ing therapy. The overfilled patient is likely to 
respond well to diuretics, whereas diuretics may 
further reduce renal perfusion in the underfilled 
patient. 

Disorders that increase capillary permeability, 
such as burns and sepsis, may also cause edema 
in the absence of hypertension, although other 
mechanisms may also play a role. Burns can result 
in localized or generalized edema. Localized 
edema is the result of thermal injury and the 
release of vasoactive substances that cause capil- 
lary vasodilation and increased permeability. This 
effect may persist for 24-48 hours. Diffuse edema 
occurs when full thickness burns involve more 
than 30% of body surface area. This is due to 
reduced capillary oncotic pressure resulting from 
loss of plasma proteins into the wounds. 
Extensive third-degree burns can result in the 
loss of as much as 350-400 g of protein per day. 



26 



Chapter 2 



Disorders of Sodium Balance 



In addition, there are increased insensible losses 
from damaged skin that may be as high as 300 ml/ 
hour/m 2 of burned skin. All of these factors con- 
tribute to decreased EABV that leads to increased 
renal salt and water reabsorption further increas- 
ing the edema. 

Septic patients with severe inflammatory 
response syndrome (SIRS) due to increased release 
of inflammatory mediators may develop edema. 
There is an increase in capillary permeability, as 
well as precapillary vasodilation. The resultant 
increase in capillary hydrostatic pressure associ- 
ated with increased capillary permeability, which 
increases interstitial oncotic pressure, results in 
edema formation. In addition, large amounts of 
intravenous fluids are often administered to main- 
tain systemic blood pressure, which may worsen 
the edema. Positive pressure ventilation and pos- 
itive end expiratory pressure (PEEP) ventilation 
may also worsen edema by decreasing venous 
return and reducing cardiac output. This results in 
activation of the sympathetic nervous system and 
the RAAS leading to increased renal salt and water 
reabsorption. Lymphatic drainage through the 
thoracic duct is also impeded by increased 
intrathoracic pressure. 



Approach to the Edematous Patient 

A careful history, physical examination, and 
selected laboratory tests will reveal the cause of 
edema. The clinician encountering the edematous 
patient should first ask whether edema is general- 
ized or localized. Localized edema is often due to 
vascular or lymphatic injury. One next searches 
for evidence of heart, liver, or kidney disease in 
the patient's history. The location of the edema 
may help narrow the differential diagnosis. Left- 
sided CHF results in pulmonary edema. In right- 
sided CHF and cirrhosis of the liver edema may 
accumulate in the lower extremities or abdomen 
(ascites). 

On physical examination the presence of an 
S3 gallop suggests CHF. One also looks for stig- 
mata of chronic liver disease, such as palmar ery- 
thema, spider angiomas, hepatomegaly, and 



caput medusae. Laboratory studies that should be 
obtained include serum blood urea nitrogen 
(BLJN) and creatinine concentrations, liver func- 
tion tests, serum albumin concentration, urinaly- 
sis for protein excretion, chest radiograph, and 
electrocardiogram . 



Treatment of the Edematous Patient 

Treatment is first directed at halting the progres- 
sion of the underlying disease. Therapies that aid 
in reversing the underlying pathophysiology, 
such as angiotensin converting enzyme inhibitors 
in CHF should be used when possible. A low-salt 
diet is critical to the success of any regimen. If 
these measures are unsuccessful a diuretic may be 
required. The clinical use of diuretics is discussed 
in detail in chapter 4. 



Key Points 

Disorders Associated with Increased Total Body Sodium 



1 . Hypervolemic states (increased ECF 
volume) are associated with increased total 
body sodium and commonly present with 
edema with or without hypertension. 

2. Edema is the accumulation of excess inter- 
stitial fluid and is detected by noting an 
indentation or "pitting" of the skin after 
applying pressure with the thumb or index 
finger on the skin of the lower extremities or 
presacral region. 

3. Edema is generated by an alteration in 
Starling's forces that govern the movement 
of fluid across the capillary endothelium. An 
increase in hydrostatic pressure or a 
decrease in oncotic pressure favors move- 
ment of fluid out of the capillary resulting in 
eciema formation. 

4. The pathophysiology of ECF volume expan- 
sion is divicied into three general categories 
based on the presence or absence of edema 
and hypertension. 



Chapter 2 



Disorders of Sodium Balance 



27 



Kidney disease is the major cause of ECF 
volume expansion with both hypertension 
and edema. 

Extracellular fluid volume expansion asso- 
ciated with hypertension and the absence 
of edema occurs with excess concentra- 
tions of mineralocorticoids, when glucocor- 
ticoids bind to the mineralocorticoid 
receptor, and with genetic diseases that 
increase sodium reabsorption in distal 
nephron. 

Disorders characterized by a decreased 
EABV such as CHF, nephrotic syndrome, 
and cirrhosis of the liver are major causes of 
ECF volume expansion associated with 
edema in the absence of hypertension. 



Table 2.4 



Manifestations of ECF Volume (Total Body Sodium) Depletion 


Symptoms 


Signs 


Increased thirst 


Orthostatic fall in 




blood pressure 


Weakness and 


Orthostatic rise 


apathy 


in pulse 


Headache 


Decreased pulse volume 


Muscle cramps 


Decreased jugular 




venous pressure 


Anorexia 


Dry skin and decreased 




sweat 


Nausea 


Dry mucous membranes 


Vomiting 


Decreased skin turgor 




Disorders Associated with 

Decreased Total Body Sodium 

(ECF Volume Depletion) 



Sodium is the most abundant extracellular ion. As 
a result it determines the osmolality and volume 
of the ECF. Sodium depletion means ECF volume 
depletion. Sodium depletion does not imply 
hyponatremia and conversely hyponatremia does 
not imply sodium depletion. The serum sodium 
concentration is primarily determined by changes 
in water metabolism (Chapter 3). Manifestations 
of sodium and ECF volume depletion are illus- 
trated in Table 2.4. 

When sodium excretion exceeds input, negative 
sodium balance and decreased ECF volume results. 
Given the fact that the normal kidney can rapidly 
lower sodium excretion to near zero, decreased 
sodium intake alone never causes decreased ECF 
volume. Sodium depletion results from ongoing 
sodium losses from the kidney, skin, or the gastroin- 
testinal tract. If the kidney is the source of sodium 
loss then urine sodium concentration exceeds 
20 meq/L. If losses are from skin or gastrointestinal 



tract and the kidney is responding normally, the 
urine sodium concentration is less than 20 meq/L. 

Renal sodium losses are due either to intrinsic 
kidney disease or external influences on renal 
function. Kidney diseases associated with sodium 
wasting include nonoliguric acute renal failure, 
the diuretic phase of acute renal failure, and "salt- 
wasting nephropathy." Salt-wasting nephropathy 
occurs after relief of urinary tract obstruction, with 
interstitial nephritis, medullary cystic disease, or 
polycystic kidney disease. External factors caus- 
ing natriuresis include solute diuresis from 
sodium bicarbonate, glucose, urea, and mannitol; 
diuretic administration; and mineralocorticoid 
deficiency as a result of hypoaldosteronism or 
decreased renin secretion. 

Gastrointestinal losses are external or internal. 
External losses occur with diarrhea, vomiting, gas- 
trointestinal suction, or external fistulas. Internal 
losses or so-called "third spacing" result from peri- 
tonitis, pancreatitis, and small bowel obstruction. 
Skin losses also are external or internal. External 
losses result from excessive sweating, cystic fibro- 
sis, and adrenal insufficiency. Burns cause exces- 
sive internal and external losses. 

In order to protect blood pressure and tissue 
perfusion during ECF volume depletion a variety 
of compensatory mechanisms are activated. 
These mechanisms maintain blood pressure, 



28 



Chapter 2 



Disorders of Sodium Balance 



minimize renal sodium excretion, and in the 
process maintain ECF volume. 

Approach to the Patient with Decreased 
ECF Volume 

As in the patient with an increased ECF volume, a 
careful history, physical examination, and selected 
laboratory tests often reveal the cause and extent 
of ECF volume depletion. Clinical signs and symp- 
toms of total body sodium deficit are shown in 
Table 2.4. The history focuses on identification of 
potential sources of sodium loss. The patient is 
questioned regarding polydipsia and diuretic use 
(kidney), diarrhea and vomiting (gastrointestinal 
tract), and sweating (skin). Physical examination 
can reveal the extent of ECF volume depletion 
(postural changes in blood pressure and pulse, 
degree of hypotension), as well its cause (intestinal 
obstruction or gastrointestinal fistula). Laboratory 
tests also aid in determining whether the sodium 
loss is renal or extrarenal. The presence of a 
decreased urine sodium concentration, concen- 
trated urine, and a BUN to creatinine ratio greater 
than 20:1 suggests that sodium losses are 
extrarenal and the kidney is responding appropri- 
ately. The one exception to this caveat is the 
patient in whom diuretics were recently discontin- 
ued. Even though sodium losses occurred via the 
kidney, once the diuretic effect has dissipated, the 
kidneys reabsorb salt and water appropriately in 
order to restore ECF volume. Conversely, an ele- 
vated urine sodium concentration suggests that the 
kidney is the source of the sodium loss. 



is required. The use of intravenous fluids is 
reviewed in more detail in Chapter 5 and only 
general guidelines are discussed here. 

The amount and rate of repletion depend on 
the clinical situation. Cerebral perfusion and urine 
output are used as markers of tissue perfusion. 
Response of blood pressure and pulse to postural 
changes are adequate noninvasive indicators of 
ECF volume status. Response to a rapid infusion 
of normal saline or direct measures of cardiovas- 
cular pressures are also used. 

Fresh frozen plasma and packed red cells are the 
most effective initial intravascular volume expander 
because they remain within the intravascular space 
(5% of total body weight). Increased cost and poten- 
tial infectious complications limit their use. Isotonic 
sodium chloride (normal saline) is an effective 
volume expander. Its space of distribution is con- 
fined to the ECF (20% of total body weight). Because 
of its widespread availability, low cost, and lack of 
infectious complications normal saline is often used 
when rapid increases in ECF volume are required. 
Five percent dextrose in water (D 5 W) is a poor 
intravascular volume expander. Once the glucose is 
metabolized, which happens quickly, the remaining 
water is distributed in total body water (60% of total 
body weight). It should never be used to expand the 
intravascular space since only approximately 8% of 
the administered volume remains intravascular. 

Depending on the source of sodium loss other 
electrolyte deficiencies may also need to be cor- 
rected. Potassium is lost with gastrointestinal 
causes such as diarrhea or vomiting. Magnesium 
may be deficient with thiazide diuretic use and 
diarrheal illnesses. 



Treatment of the Patient with Decreased 
ECF Volume 

In mild depletion states treatment of the underlying 
disorder and replacement of normal dietary salt 
and water intake are sufficient to correct deficits. 
When blood pressure and tissue perfusion are 
compromised or the oral route of replacement 
cannot be used, intravenous fluid administration 



Key Points 

Disorders Associated with Decreased Total Body Sodium 



1. Total body sodium determines ECF volume. 
Sodium depletion is synonymous with ECF 
volume depletion. 

2. Sodium depletion results from kidney, skin, 
or gastrointestinal tract losses. 



Chapter 2 



Disorders of Sodium Balance 



29 



3. If the kidney is the source of sodium loss, 
urine sodium concentration exceeds 

20 meq/L. 

4. Urine sodium concentration is less than 

20 meq/L if losses are from skin or gastroin- 
testinal tract and the kidneys are responding 
appropriately. 

5. Renal sodium loss is caused by intrinsic 
kidney disease or external influences on the 
kidney. 

6. Treatment of the underlying disorder and 
replacement of normal dietary salt and 
water intake are sufficient to correct deficits 
with mild sodium depletion. Intravenous 
fluid administration is required when blood 
pressure and tissue perfusion are compro- 
mised or oral replacement cannot be used. 



Additional Reading 

Beltowski, J., Wojcicka, G. Regulation of renal tubular 
sodium transport by cardiac natriuretic peptides: 
two decades of research. Med Sci Monit 8:RA39- 
RA52, 2002. 

De Santo, N.G., Pollastro, R.M., Saviano, C, Pascale, C, 
Di Stasio, V., Chiricone, D., Cirillo, E., Molino, D., 
Stellato, D., Frangiosa, A., Favazzi, P., Capodicasa, L., 
Bellini, L., Anastasio, P., Perna, A., Sepe, J., Cirillo, M. 
Nephrotic edema. Semin Nephrol 21:262-268, 2001. 

Greger, R. Physiology of renal sodium transport. Am J 
Med Sci 319:51-62, 2000. 

Guyton, A.C. Blood pressure control — special role of the 
kidneys and body fluids. Science 252:1813-1816, 1991. 

Guyton, A.C, Coleman, T.G. Quantitative analysis of 
the pathophysiology of hypertension. / Am Soc 
Nephrol 10:2248-2258, 1999- 

Hall, J. E., Guyton, A.C, Brands, M.W. Pressure-volume 
regulation in hypertension. Kidney Int 49(S55):S35- 
S41, 1996. 

Kahle, K.T., Wilson, F.H., Leng, Q., Lalioti, M.D., 
O'Connell, A.D., Dong, K., Rapson, A.K., 
MacGregor, G.G., Giebisch, G., Hebert, S.C, Lifton, 
R.P. WNK4 regulates the balance between renal 



NaCl reabsorption and K + secretion. Nat Genet 
35:372-376, 2003. 

Kahle, K.T., Gimenez, I., Hassan, H., Wilson, F.H., 
Wong, R.D., Forbush, B., Aronson, P.S., Lifton, R.P. 
WNK4 regulates apical and basolateral CI" flux in 
extrarenal epithelia. Proc Natl Acad Sci USA 101: 
2064-2069, 2004. 

Krug, A.W., Papavassiliou, F., Hopfer, U., Ullrich, K.J., 
Gekle, M. Aldosterone stimulates surface expression 
of NHE3 in renal proximal brush borders. Pflugers 
Arch 446:492-496, 2003. 

Kurtzman, N.A. Nephritic edema. Semin Nephrol 
21:257-261, 2001. 

McDonough, A. A., Biemesderfer, D. Does membrane 
trafficking play a role in regulating the sodium/ 
hydrogen exchanger isoform 3 in the proximal 
tubule? Curr Opin Nephrol Hypertens 12:533-541, 
2003. 

McDonough, A. A., Leong, P.K., Yang, L.E. Mechanisms 
of pressure natriuresis: how blood pressure regu- 
lates renal sodium transport. Ann NY Acad Sci 
986:669-677, 2003. 

O'Shaughnessy, K.M., Karet, F.E. Salt handling and 
hypertension. J Clin Invest 113:1075-1081, 2004. 

Schafer, JA. Abnormal regulation of ENaG syndromes of 
salt retention and salt wasting by the collecting duct. 
Am J Physiol Renal Physiol 283:F221-F235, 2002. 

Schnermann, J., Traynor, T., Yang, T., Arend, L., Huang, 
Y.G., Smart, A., Briggs, J. P. Tubuloglomerular feed- 
back: new concepts and developments. Kidney Int 
54(S67):S40-S45, 1998. 

Schnermann, J. The expanding role of aldosterone in 
the regulation of body Na content. Pflugers Arch 
446:410-411, 2003. 

Schrier, R.W., Fassett, R.G. A critique of the overfill 
hypothesis of sodium and water retention in the 
nephrotic syndrome. Kidney Int 53:1111-1117, 1998. 

Schrier, R.W. , Ecder, T. Gibbs memorial lecture. 
Unifying hypothesis of body fluid volume regula- 
tion: implications for cardiac failure and cirrhosis. 
Mt Sinai J Med 68:350-361, 2001. 

Skott, O. Body sodium and volume homeostasis. Am J 
Physiol Regul Integr Cornp Physiol 285:R14-R18, 
2003. 

Yang, C.L., Angell, J., Mitchell, R., Ellison, D.H. WNK 
kinases regulate thiazide-sensitive Na-Cl cotrans- 
port. J Clin Invest 111:1039-1045, 2003. 



Robert F. Reilly, Jr. 



Disorders of Water 



Balance (Hypo- and 
Hypernatremia) 




Recommended Time to Complete: 2 days 

1. What is the difference between tonicity and osmolality? 

2. How does the kidney excrete free water and defend against hypona- 
tremia? 

1. How does one formulate a clinical approach to the patient with 
hyponatremia? 

k. What is the definition of SIADH? 

S. Can you outline a treatment approach for the correction of hypona- 
tremia that minimizes potential complications? 

L How does the body defend against the development of hyperna- 
tremia? 

7- What is the differential diagnosis of the hypernatremic patient? 

$. How does one treat the patient with hypernatremia? 



30 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



31 




Introduction 



One of the more difficult concepts to grasp in 
nephrology is that changes in serum sodium con- 
centration result from derangements in water bal- 
ance, while disorders of extracellular fluid (ECF) 
volume regulation are related to total body 
sodium balance. This is best explained by the fact 
that serum sodium is a concentration term and 
reflects only the relative amounts of sodium and 
water present in the sample. Low serum sodium 
concentration (shown in the equation below) 
denotes a relative deficit of sodium and/or a rela- 
tive excess of water. Sodium concentration is not 
a measure of total body sodium content. 



[Serum Na + ] 



ECF Na 
ECF H 2 



As seen in the formula above, hyponatremia 
may result from either a decrease in the numera- 
tor or an increase in the denominator. Although 
one might conclude that hyponatremia is more 
likely the result of a decrease in the numerator, in 
clinical practice a relative excess of water most 
commonly causes hyponatremia. Nonosmotic 
release of arginine vasopressin (AVP) is the key 
pathophysiologic process in most cases. The 
regulation of •water homeostasis is dependent on 
(1) an intact thirst mechanism, (2) appropriate 
renal handling of water, and (3) intact AVP release 
and response. 

Renal free water excretion is the major factor 
controlling "water metabolism, and the major factor 
controlling renal free water excretion is AVP. 
Above a plasma osmolality (P osm ) of 283, AVP 
increases by 0.38 pg/mL per 1 mOsm/kg increase 
in P osm . In turn, urine osmolality (U osm ) responds 
to increments in AVP. A rise in AVP of 1 pg/mL 
increases U osm about 225 mOsm/kg. The two 
major afferent stimuli for thirst are an increase in 
plasma osmolality and a decrease in ECF volume. 
Thirst is first sensed when plasma osmolality 
increases to 294 mOsm/kg (the osmolar threshold 



for thirst). At this osmolality AVP is maximally 
stimulated (concentration > 5 pg/mL) and is suffi- 
cient to maximally concentrate urine. Arginine 
vasopressin and angiotensin II directly stimulate 
thirst. 

Osmolality is an intrinsic property of a solu- 
tion and is defined as the number of osmoles of 
solute divided by the number of kilograms of sol- 
vent. It is independent of a membrane. Tonicity 
or "effective osmolality" is equal to the sum of the 
concentration of solutes with the capacity to exert 
an osmotic force across a membrane. It is a prop- 
erty of a solution relative to a membrane. The 
tonicity of a solution is less than osmolality by the 
total concentration of "ineffective solutes" that it 
contains. Solutes that are freely permeable across 
cell membranes such as urea are ineffective 
osmoles. From a cellular viewpoint, tonicity 
determines the net osmolar gradient across the 
cell membrane that acts as a driving force for 
water movement. 

Sodium is the most abundant cation in ECF and 
its concentration is the major determinant of tonic- 
ity and osmolality. Furthermore, water moves freely 
across cell membranes allowing the maintenance of 
osmotic equilibrium between various compart- 
ments, therefore ECF tonicity reflects tonicity of the 
intracellular fluid (ICF). Plasma osmolality is calcu- 
lated from the following formula: 



(mOsm/kg) = 



2 x Na(meq/L) + BUN(mg/dL) 
2.8 
glucose (mg/dL) 
18 



To calculate tonicity one includes only the 
sodium and glucose terms in the equation. It is 
measured directly by freezing point depression or 
vapor pressure techniques. 

Body tonicity, measured as plasma osmolality, is 
maintained within a narrow range (285-295 mOsm/ 
kg). This is achieved via regulation of water intake 
and excretion. Disturbances in body tonicity are 
reflected by alterations in serum sodium concen- 
tration and clinically present as either hypo- or 
hypernatremia. 



32 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



Key Points 

Tonicity and Osmolality 



1 . Changes in serum sodium concentration are 
indicative of a problem in water balance, 
while changes in ECF volume are related to 
total body sodium. 

2. Renal excretion of free water is the major 
factor controlling water metabolism. 

3. The most abundant cation in ECF is 
sodium, therefore its concentration is the 
major determinant of ECF tonicity and 
osmolality. 




Hyponatremia 



Hyponatremia, defined as a serum sodium con- 
centration <135 meq/L, is the most frequent elec- 
trolyte abnormality and is seen in up to 10-15% of 
hospitalized patients. It is especially common in 
critical care units. Hyponatremia is caused by 
either (1) excess water intake (water intoxication) 
with normal renal function or (2) continued 
solute-free water intake with a decreased renal 
capacity for solute-free water excretion. It occurs 
whenever free water intake exceeds free water 
excretion. 

In subjects with normal renal function exces- 
sive water intake alone does not cause hypona- 
tremia unless it exceeds about 1 L/hour. As a 
general rule one's maximal free water excretion is 
equal to about 10-15% of glomerular filtration rate 
(GFR). With a GFR of 180 L/day, maximal free 
water excretion equals approximately 24 L/day or 
1 L/hour. In patients with a normal GFR, hypona- 
tremia due to excessive water intake is observed 
only rarely, such as in psychotic patients who 
drink from faucets or showers. A reduction in 
GFR, however, will limit free water excretion. An 
individual whose GFR is 20% of normal will 



become hyponatremic on drinking over 3.6 L/day. 
Often patients with psychogenic polydipsia have 
some degree of renal impairment. 

Almost all hyponatremic patients have impaired 
renal free water excretion. An understanding of how 
the kidney excretes free water is critical for under- 
standing the pathophysiology of hyponatremia. 

The essential features of renal free water excre- 
tion are the following: 

1 . Normal delivery of tubular fluid to distal 
diluting segments of the nephron. An ade- 
quate GFR without excessive proximal tubular 
reabsorption is required in order to deliver tubu- 
lar fiuid to the diluting segments of the kidney 
(thick ascending limb of the loop of Henle and 
distal convoluted tubule [DCT]). Although tubu- 
lar fluid remains isotonic in the proximal tubule, 
proximal fluid reabsorption is an important 
determinant of water excretion. Normally 70% 
of glomerular filtrate is absorbed in the proximal 
tubule and the remaining 30% is isotonic to 
plasma as it enters the loop of Henle. Thus, if 
proximal tubular reabsorption increases, as in 
volume depletion, free water excreted is limited. 
To use an extreme example, a patient with acute 
renal failure and a GFR of 5 mL/minute forms 
only 7.2 L of glomerular filtrate daily. If 30% is 
delivered to the diluting segments that means a 
total of only 2.2 L is delivered daily. Even if the 
distal nephron were completely impermeant to 
water only 2.2 L of urine is excreted (only part of 
this total is free water). 

2. Normal function of the diluting segments 
(ascending limb of Henle's loop and DCT). 
Tubular fluid is diluted in the water-impermeable 
ascending limb of Henle's loop and DCT by the 
reabsorption of sodium chloride. Sodium is 
transported on the Na + -K + -2Ch cotransporter in 
the thick ascending limb of Henle and the thi- 
azide-sensitive Na-Cl cotransporter in DCT. It is 
in the diluting segments where U osm declines to 
less than P osm that free water is generated. 

3. Absence of AVP. Arginine vasopressin must 
be suppressed in order to prevent solute-free 
water reabsorption in the collecting duct. This 
factor is of primary importance since the renal 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



33 



interstitium remains slightly hypertonic even 
during a water diuresis. Therefore, if the col- 
lecting duct were water-permeable, osmotic 
equilibration of fluid between the tubular 
lumen and interstitium would concentrate the 
urine and impair water excretion. 

Arginine vasopressin is released from the 
posterior pituitary, enters the blood stream, 
binds to its receptor (V 2 ) in the basolateral 
membrane of the collecting duct, and increases 
water permeability. Arginine vasopressin is 
released in response to osmotic and nonos- 
motic stimuli. An increase in ECF osmolality as 
little as 1% stimulates AVP release and the rela- 
tionship of AVP to plasma osmolality is linear 
(Figure 3.1). Nonosmotic stimuli are associated 
with changes in autonomic neural tone such as 
physical pain, stress, hypoxia, and decreases in 
effective circulating volume. The nonosmotic 
pathway is less sensitive and requires a 5-10% 
decrement in blood volume to stimulate AVP 
release. Once the threshold is reached, how- 
ever, the rise in AVP concentration is exponential 



Figure 3-1 



B 35- 




=3 


o 


(arbitrary 

K> 00 

on o 


/ 


1 20- 


/ 


CO 


° Blood volume 


asma vasop 
oi o en 


Osmolality y» 


/j 


Q. 

( 


£-^*—~~^*~~ 


1 i i i i 
) 2 4 8 10 12 




Percent change in blood volume or p osm 



(Figure 3.1). Defense of volume has priority. 
Arginine vasopressin concentration increases 
and stimulates renal water reabsorption pro- 
tecting volume at the expense of hypona- 
tremia. It is more important for the body to 
maintain blood volume than to maintain tonic- 
ity. The volume-depleted patient may become 
profoundly hyponatremic because nonosmotic 
stimuli for AVP release predominate over 
osmotic stimuli. Arginine vasopressin also has 
a pressor effect mediated via the V : receptor, 
contributing perhaps 10% to mean arterial 
pressure during volume depletion. Thus, AVP 
is normally osmoregulatory, but during stress 
becomes a volume regulatory hormone. As a 
general principle the kidney will always act to 
preserve blood and ECF volume at the expense 
of electrolyte and acid-base homeostasis. The 
nonosmotic release of AVP is the key patho- 
physiologic process in the majority of patients 
with hyponatremia. 

AVP binds to the V 2 receptor in the basolat- 
eral membrane of collecting duct. Adenylate 
cyclase is activated, cyclic AMP generated, and 
water channels (aquaporins — AQP2) insert 
into the apical membrane increasing its water 
permeability. 

Adequate solute intake. Although the kidney 
has an enormous capacity to generate free 
"water, it cannot excrete pure water. The lowest 
U osm attainable in humans is 50 mOsm/kg. One 
of the main roles of the kidney is to eliminate 
the osmolar load contained in the diet (approx- 
imately 10 mOsm/kg). The volume of urine 
required to achieve this is expressed in the 
equation below: 



urine volume = 



osmolar intake or excretion 



The changes in plasma AVP induced by alterations in osmolal- 
ity or blood volume. Note that response to changes in osmo- 
lality are linear, whereas response to changes in blood volume 
approximates an exponential curve. 



In the steady state, osmolar intake and excre- 
tion are equal and either can be used. In theory a 
70-kg person with a standard osmolar dietary load 
and a maximally dilute urine could generate 14 L 
of free water per day (700 mOsm/50 mOsm). If 
solute intake is very low, however, as in someone 
drinking only beer (beer drinker's potomania), 



34 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



hyponatremia could develop despite the fact that 
urine is maximally dilute. For example, if solute 
intake were only 150 mOsm/day with a maxi- 
mally dilute urine, urine volume would be only 
3 L. In this situation water intake could exceed 
renal-free water excretion and hyponatremia will 
develop. 



Key Points 



Hyponatremia 



1 . Hyponatremia is denned as a serum sodium 
concentration <135 meq/L and is the most 
common electrolyte abnormality in hospital- 
ized patients. 

2. Hyponatremia occurs whenever free water 
intake exceeds free water excretion. 

3. Almost all patients with hyponatremia have 
impaired renal free water excretion. 

4. The essential features of renal free water 
excretion are delivery of tubular fluid to 
distal diluting segments of the nephron, 
normal function of the diluting segments, 
suppression of AVP, and adequate solute 
intake. 




Etiology 



Hyponatremia most commonly results from an 
inability to maximally dilute the urine coupled with 
continued water intake. Before implicating a defect 
in renal free water excretion as the cause of 
hyponatremia, the presence of hypoosmolality 
must be documented because hyponatremia can 
occur with an elevated or normal serum osmolality. 
Hyponatremia with a normal serum osmolality 
or "pseudohyponatremia" is a laboratory artifact. 
Serum is made up of two fractions, an aqueous 
fraction and a particulate fraction. Pseudohy- 
ponatremia results from a decrease in the aqueous 



fraction. The hame photometry method of sodium 
analysis measures sodium per liter of total serum. 
Conditions that reduce the aqueous fraction 
below the usual 93% of serum (the remaining 7% 
is the particulate fraction made up of proteins and 
lipids) decrease the total amount of sodium per 
aliquot of serum. Sodium concentration, how- 
ever, in the aqueous fraction is normal. Three 
conditions that reduce the aqueous fraction are 
hyperlipidemia, hypercholesterolemia, and hyper- 
proteinemia. This is not a common problem. A 
clue to the presence of hyperlipidemia is a report 
from the lab of lipemic serum. Lipemic serum 
means that after centrifugation of whole blood 
the supernatant is cloudy. Elevations in choles- 
terol concentration do not result in lipemic 
serum. Excess production of paraproteins as in 
multiple myeloma and the administration of 
intravenous immunoglobulin also increase the 
particulate fraction and may result in pseudohy- 
ponatremia. Measurement of serum sodium con- 
centration by ion-sensitive electrodes yields a 
normal value provided the sample is not diluted 
prior to measurement. If the sample is diluted 
(indirect potentiometry), the error is reintroduced 
and pseudohyponatremia can occur. For each 
100 mg/dL rise in glycine concentration the serum 
sodium concentration falls by 3-8 meq/L. 

Translocational hyponatremia is due to a shift of 
water out of cells in response to a nonsodium 
solute. Serum osmolality is elevated. Water moves 
down an osmotic gradient from ICF to ECF when 
nonsodium solute increases ECF osmolality and 
creates a driving force for water movement. The 
most common cause is hyperglycemia. Mannitol 
and glycine infusion also cause translocational 
hyponatremia. For each increase in serum glucose 
of 100 mg/dL above its normal concentration, 
serum sodium concentration falls by 1.6 meq/L. 
This is a calculated correction factor. In practice this 
rule of thumb works well for glucose concentra- 
tions up to 400 mg/dL. At higher concentrations the 
correction factor is likely larger (2.4—2.8 meq/L). For 
each 460 mg/dL increase in triglyceride concen- 
tration the serum sodium concentration falls by 
1 meq/L. 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



35 



The remaining causes of hyponatremia alter 
the external balance of water and are associated 
with low serum osmolality (true hyponatremia). 
True hyponatremia is caused by either (1) excess 
water intake (water intoxication) with normal 
renal function or (2) continued solute-free water 
intake with a decreased renal capacity for solute- 
free water excretion. The most common patho- 
physiologic mechanism is the nonosmotic release 
of AVP that prevents maximal urinary dilution. 
Rarely, severely depressed urine flow rate, as with 
low GFR, increased proximal tubule fluid reab- 
sorption, or decreased solute intake limits urine 
dilution resulting in positive water balance and 
hyponatremia. 

A clue to the source of the increased AVP con- 
centration lies in the evaluation of the patient's 
volume status. Common causes are edematous 
states, extrarenal and renal sodium and water 
losses, syndrome of inappropriate ADH (SIADH), 
and psychogenic polydipsia. The presence of 
edema is indicative of increased total body sodium. 
Hyponatremia results because the increase in 
total body water exceeds the increase in total 
body sodium. In these circumstances, effective 
circulating volume is decreased and volume/ 
pressure receptors are activated releasing AVP. 
Thus a decreased effective circulating volume is 
sensed despite an absolute increase in total 
body salt and water. The increase in AVP is 
"appropriate" to the sensed signal. Major causes 
of hyponatremia with increased total body 
sodium are congestive heart failure, hepatic cir- 
rhosis, nephrotic syndrome, and advanced chronic 
or acute renal failure. The hallmark of these disor- 
ders on physical examination is dependent 
edema. 

Renal and extrarenal salt and water losses are 
characterized by signs and symptoms of decreased 
ECF volume such as thirst, orthostatic hypoten- 
sion, tachycardia, and decreased skin turgor. In 
this setting AVP release is "appropriate" to defend 
ECF volume. Loss of total body sodium exceeds 
the loss of total body water. Common etiologies 
of hyponatremia with decreased ECF volume 
include gastrointestinal losses (excessive salt and 



•water loss causes sufficient hypovolemia to stim- 
ulate baroreceptors to increase AVP release); third 
spacing of fluids; burns; pancreatitis; diuretic 
overuse or abuse; salt-wasting nephropathy; 
adrenal insufficiency; and osmotic diuresis. With 
extrarenal fluid loss the sodium concentration of 
the lost fluid is less than the serum sodium con- 
centration. If this is the case, how does the patient 
become hyponatremic? The answer lies in the fact 
that thirst is intact and that the replacement fluid 
has a lower sodium concentration than the fluid 
lost. 

Hyponatremia from diuretics is almost always 
a result of thiazide rather than loop diuretics, since 
thiazides interfere with dilution of urine but not 
urinary concentrating ability. By contrast, loop 
diuretics interfere with both diluting and concen- 
trating ability, and result in medullary washout of 
solute and diminished AVP-induced free water 
reabsorption. Diuretic-induced volume depletion 
decreases GFR and increases proximal tubular salt 
and water reabsorption, thereby decreasing water 
delivery to distal segments. Potassium depletion 
may result in intracellular shifts of sodium, and 
alters the sensitivity of the osmoreceptor mecha- 
nism leading to AVP release. Most patients have 
an associated hypokalemic metabolic alkalosis. 
Older women are at highest risk and this gener- 
ally occurs in the first 2-3 weeks of therapy. 
Mineralocorticoid and glucocorticoid deficient 
states lead to volume depletion with enhanced 
proximal tubular reabsorption and nonosmotic 
stimulation of AVP release. 

Hyponatremia in the presence of a clinically 
normal ECF volume is most commonly the result 
of SIADH or psychogenic polydipsia. The term 
"clinically normal" should be stressed. If total 
body sodium and total body water were truly 
normal then serum sodium concentration must 
also be normal. In reality, total body water is 
increased as a result of the "inappropriate" release 
of AVP. "Inappropriate" implies that AVP is 
released despite the absence of the two physio- 
logic stimuli for its release: increased serum osmo- 
lality and decreased effective circulating volume. 
This state of mild volume expansion results in 



36 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



3.1 



Disease Processes Causing 


SIADH 




Carcinomas 


Pulmonary Diseases 


CNS Disorders 


Lung (small cell) 


Viral pneumonia 


Encephalitis 


Duodenum 


Bacterial pneumonia 


Meningitis 


Pancreas 


Pulmonary abscess 


Acute psychosis 




Tuberculosis 


Stroke 




Aspergillosis 


Porphyria (AIP) 




Mechanical ventilation 


Tumors 
Abscesses 
Subdural injury 
Guillain-Barre syndrome 
Head trauma 



Abbreviations: CNS, central nervous system; AIP, acute intermittent porphyria. 



urinary sodium wasting and a clinically unde- 
tectable decrease in total body sodium. SIADH is 
characterized by hyponatremia, a low serum 
osmolality, and an inappropriately concentrated 
urine (less than maximally dilute). Urine sodium 
concentration is generally increased but it can be 
low if the patient develops ECF volume depletion. 
The patient must be clinically euvolemic with no 
evidence of adrenal, renal, or thyroid dysfunc- 
tion; and not taking a drug that stimulates AVP 
release or action. SIADH is caused by malignan- 
cies, pulmonary, or central nervous system dis- 
ease (Table 3.1). This is an important disorder to 
diagnose because hyponatremia will worsen if 
normal saline is administered. 

A variety of drugs impair renal free water 
excretion by potentiating the action or release of 
AVP. A partial list is shown in Table 3.2. In 
hypothyroidism the ability of the kidney to 
excrete free water is impaired by a decrease in 
GFR, an increase in proximal tubular reabsorp- 
tion, and an increase in AVP secretion. In second- 
ary adrenal insufficiency hyponatremia results 
since glucocorticoids are required to maximally 
suppress AVP release. 



Psychogenic polydipsia or water intoxication is 
the result of excess water intake with normal renal 
function. It is differentiated from SIADH in that 
the U osm is maximally or near maximally dilute. 



Table 3-2 

Drugs That Result in Arginine Vasopressin (AVP) Release 



Stimulate AVP 




Release 


Other Mechanisms 


Nicotine 


Chlorpropamide: enhance 


Clofibrate 


renal effect of AVP 


Vincristine 


Tolbutamide 


Isoproterenol 


Cyclophosphamide 


Chlorpropamide 


Morphine 


Antidepressants 


Barbiturates 


(SSRIs) 


Carbamazepine 


Antipsychotic 


Acetaminophen 


agents 


NSAIDs: inhibits PG which 


Ecstacy 


antagonize AVP 



Abbreviations: PG, prostaglandins; SSRI, selective serotonin reuptake 
inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs. 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



37 



This commonly occurs in patients with psychiatric 
disease on psychotropic medications that result in 
dry mouth and increased water intake. It is also 
seen in those "with beer drinker's potomania 
whose renal free water excretion is limited by 
solute intake. 



Key Points 

Etiology of Hyponatremia 



1 . Hyponatremia with a normal serum osmo- 
lality is known as "pseudohyponatremia" 
and is a laboratory artifact. 

2. Translocational hyponatremia is due to a 
shift of water out of cells in response to a 
nonsodium solute. Serum osmolality is ele- 
vated. Hyperglycemia is the most common 
cause. 

3. The remaining causes of hyponatremia are 
associated with a low serum osmolality 
(true hyponatremia). True hyponatremia is 
caused by either (1) excess water intake 
with normal renal function or (2) contin- 
ued solute free water intake with a 
decreased renal capacity for solute free 
water excretion. 

4. The most common pathophysiologic 
mechanism is the nonosmotic release of 
AVP. 

5. Edematous states, extrarenal and renal 
sodium and water losses, SIADH, and psy- 
chogenic polydipsia are the most common 
causes of true hyponatremia. 

6. Hyponatremia from diuretics is almost 
always a result of thiazide diuretics since thi- 
azides interfere with urinary dilution but not 
urinary concentrating ability. 

7. SIADH is characterized by hyponatremia, 
low serum osmolality, and an inappropri- 
ately concentrated urine (less than maxi- 
mally dilute) in the absence of renal, 
adrenal, or thyroid disease. 




Signs and Symptoms 



Gastrointestinal complaints of anorexia, nausea, 
and vomiting occur early, as do headaches, muscle 
cramps, and weakness. Thereafter, altered senso- 
rium develops. There may be impaired response 
to verbal and painful stimuli. Inappropriate behav- 
ior, auditory and visual hallucinations, asterixis, 
and obtundation can be seen. Seizures develop 
with severe or acute hyponatremia. In far advanced 
hyponatremia the patient may exhibit decorticate 
or decerebrate posturing, bradycardia, hyper- or 
hypotension, respiratory arrest, and coma. The 
severity of symptoms correlates both with the 
magnitude and rapidity of the fall in serum sodium 
concentration and the rapidity of its onset. Central 
nervous system pathology is due to cerebral 
edema. 

Central nervous system symptoms result from 
a failure in cerebral adaptation. When plasma 
osmolality falls acutely, osmotic equilibrium is 
maintained by either extrusion of intracellular 
solutes (regulatory volume decrease, RVD) or 
water influx into the brain. Neurologic symptoms 
result when osmotic equilibrium is achieved via 
the latter process. Since the brain is surrounded 
by a rigid case small increases in its volume result 
in substantial morbidity and mortality. If solute 
extrusion is successful and osmotic equilibrium 
maintained, the patient remains asymptomatic 
despite low serum sodium concentration and 
osmolality. Sodium extrusion from the brain by 
Na + -K + -ATPase and sodium channels is the first 
pathway activated (minutes) in regulatory volume 
decrease. If this is not adequate to lower brain 
osmolality then calcium-activated stretch recep- 
tors are stimulated. This activates a potassium 
channel that leads to potassium extrusion (hours). 

In contrast to acute hyponatremia, chronic 
hyponatremia is characterized by fewer and 
milder neurologic symptoms. This is due to addi- 
tional regulatory mechanisms. Studies in rats after 
21 days of hyponatremia show that brain water 



38 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



content is normal. In this setting loss of organic 
osmolytes from the brain such as glutamate, gluta- 
mine, taurine, and myoinositol play an important 
role. 



Key Points 

Signs and Symptoms of Hyponatremia 



The severity of hyponatremic symptoms 
correlates with the magnitude and rapidity 
of the fall in serum sodium concentration. 
Central nervous system pathology is due to 
cerebral edema and a failure in cerebral 
adaptation. 

Chronic hyponatremia is characterized by 
fewer and milder neurologic symptoms. 




Diagnosis 



The diagnostic approach to the hyponatremic 
patient is divided into three steps. 

STEP 1: WHAT IS THE SERUM OSMOLALITY? The first 

question one needs to answer in the evaluation of 
the hyponatremic patient is: What is the serum 
osmolality? This does not necessarily mean that 
one needs to directly measure serum osmolality 
but one at least needs to think of the question. 
The answer divides hyponatremic patients into 
three broad categories. 

a. Isoosmolar or pseudohyponatremia results when 
the aqueous fraction of plasma is decreased and 
the particulate fraction is increased. This may 
result from hyperlipidemia (TG > 1500 mg/dL), 
hypercholesterolemia, or hyperproteinemia 
(multiple myeloma, Waldenstrom's macroglob- 
ulinemia, administration of intravenous immu- 
noglobulin). 

b. Hyperosmolar or translocational hyponatremia 
due to infusions of glucose, mannitol, or glycine. 



The most common cause of translocational 
hyponatremia is hyperglycemia, 
c. Hypoosmolar or "true hyponatremia" makes 
up the vast majority of cases, further subdi- 
vided by Steps 2 and 3- 

STEP 2: WHAT IS THE ECF VOLUME (TOTAL BODY SODIUM 

content)? is dependent edema present? In the 

patient with true hyponatremia the second ques- 
tion one asks is what is the apparent ECF volume 
status. An approach to the evaluation of true 
hyponatremia is shown in Figure 3-2. States of 
increased ECF volume are relatively easy to iden- 
tify on physical examination because they are 
characterized by the presence of dependent edema. 
If edema is present then the diagnosis must be 
congestive heart failure, cirrhosis, nephrotic 
syndrome, acute renal failure, or chronic kidney 
disease. 

step 3: what is the urine sodium concentration? 

In the absence of dependent edema the next step 
is to determine if the patient's ECF volume is 
decreased or normal. States of severe ECF volume 
depletion are often clinically apparent. Milder 
degrees of ECF volume depletion, however, may 
be difficult to distinguish from euvolemia on physi- 
cal examination. In the patient with decreased ECF 
volume a urine sodium concentration less than 20 
meq/L and a urine osmolality greater than 400 
mOsm/kg suggests extrarenal sodium loss. The 
fractional excretion of sodium (FE Na ) can also be 
used to assess renal sodium handling. The FE Na is 
that fraction of the filtered sodium load that is 
excreted by the kidney. It is calculated using the 
formula: 



FIv 



urine [Na] x serum [Cr] 
serum [Na]x urine [Cr] 



X100 



Sodium concentrations are expressed in meq/L 
and creatinine concentrations are expressed in 
mg/dL. A FE Na less than 1% suggests ECF volume 
depletion. A urine sodium concentration greater 
than 20 meq/L, a FE Na greater than 2%, and a urine 
osmolality less than 400 mOsm/kg suggests renal 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



39 



Figure 3-2 



Hyponatremia (associated with decreased serum osmolality) 



ECF volume clinically 
decreased 



||TBNa 
|TB 



water 



Renal 
Diuretics 



Extrarenal 
Gl losses 



Urine Na | Urine Na^ 



ECF volume clinically 
apparently normal 



| TBNa 



f TB water 



SIADH 



Urine Na | 



ECF volume clinically 
increased 



| TBNa 



|f TB water 



CHF 

Cirrhosis 

Nephrotic syndrome 

Urine Na| 



Clinical approach to the patient with true hyponatremia. Patients with true hyponatremia (associated with 
a low serum osmolality) can be subdivided into three categories baseci on ECF volume status. 



sodium loss. If the patient appears euvolemic one 
should consider SIADH, drugs, psychogenic poly- 
dipsia, and hypothyroidism. 



Key Points 



Diagnosis of Hyponatremia 



Hyponatremia may be associated with a 
normal, elevated, or decreased serum osmo- 
lality. 

In patients with decreased serum osmolality 
(true hyponatremia) an evaluation of ECF 
volume status subdivides patients into three 
groups: increased; normal; or decreased 
ECF volume (total body sodium). 
Increased ECF volume and total body 
sodium is identified by the presence of 
dependent edema on physical examination. 
Patients with decreased ECF volume are fur- 
ther subdivided baseci on urinary sodium 
excretion into those with renal and 
extrarenal losses of salt and water. 



5. The most common cause of hyponatremia 
in the "clinically euvolemic" patient is 
SIADH. 




Treatment 



The major sequelae of hyponatremia are neuro- 
logic. Neurologic injury is secondary to either 
hyponatremic encephalopathy or improper ther- 
apy (too rapid or overcorrection). Clinical studies 
show that in >90% of cases neurologic injury is 
secondary to hyponatremic encephalopathy. 
Hypoxia is the major factor contributing to neuro- 
logic injury. Since RVD involves active ion trans- 
port that is ATP-dependent, it is blunted by 
hypoxia. As a result sodium accumulates in the 
brain and worsens cerebral edema. Hypoxia is 
also a major stimulus for AVP secretion. Arginine 
vasopressin directly stimulates water entry into 



40 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



neurons. In addition, AVP decreases ATP genera- 
tion and decreases intracellular pH that further 
decreases Na + -K + -ATPase activity. Respiratory 
arrest and seizures often occur suddenly in 
hyponatremic encephalopathy and patients who 
suffer a hypoxic event rarely survive without per- 
manent neurologic injury. Predictive factors for 
neurologic injury include young age, female sex, 
reproductive status (premenopausal women), 
and the presence of encephalopathy. 

Premenopausal women are at 25-fold increased 
risk for permanent neurologic injury from 
hyponatremic encephalopathy compared to post- 
menopausal women or men. This led to specula- 
tion that RVD is not as efficient in young women. 
Both estrogen and progesterone inhibit brain Na + - 
K + -ATPase. In addition, AVP decreases brain ATP 
in women but not men. In one study, pre- 
menopausal women had a respiratory arrest at 
higher serum sodium concentrations compared to 
postmenopausal women, 117 ± 7 meq/L versus 
107 + 8 meq/L, respectively. 

Treatment is dependent on the acuity and 
severity of hyponatremia, as well as the patient's 
ECF volume status. Caution is exercised not to 
raise the serum sodium concentration too quickly 
as a devastating neurologic syndrome, central 
pontine myelinolysis (CPM), can result from over- 
aggressive correction. Destruction of myelin 
sheaths of pontine neurons results in flacid quad- 
riplegia, dysarthria, dysphagia, coma, and death. 
The consequences are catastrophic and no treat- 
ment is currently available. Demyelination may 
be the result of excessive neuronal dehydration. 
Oligodendrocytes in the pons are particularly sus- 
ceptible to osmotic stress. It is associated with 
increases in serum sodium concentration to 
normal within 24-48 hours, an increase in the 
serum sodium concentration greater than 25 
meq/L in the first 48 hours, and elevation of serum 
sodium concentration to hypernatremic levels in 
patients with liver disease. 

Since the neurologic insult may result from a 
rapid shift of water out of brain cells, it is possible 
that it could be interrupted at an early stage by 
shifting water back into brain cells. This was done 



successfully in an animal model. The optimal pro- 
tective effect was obtained provided that the final 
sodium correction gradient was reduced below 
25 meq/L/24 hours and •was effective up to 12-24 
hours after the onset of osmotic injury. The quick- 
est way to do this is through the administration of 
dD-AVP (a synthetic analogue of AVP, 1-deamino- 
8-D-arginine vasopressin, also known as desmo- 
pressin). The risk of relowering the serum sodium 
concentration may be low in the first few days of 
the correction process. As serum sodium concen- 
tration rises during the correction phase, the brain 
regains extruded osmolytes. This process takes 
up to 5-7 days to complete. 

Severe symptomatic hyponatremia with or 
without seizures is treated emergently with the 
goal of raising serum sodium concentration 
above 120 meq/L. Serum sodium concentration 
should not be raised faster than 1 meq/L/hour in 
the absence of seizures or signs of increased 
intracranial pressure. If seizures are present the 
serum sodium concentration can be increased by 
4—5 meq/L in the first hour. One should admit the 
symptomatic patient to the intensive care unit 
and precautions should be taken to ensure a 
secure airway. Serum sodium concentration is 
increased with either the infusion of 3% saline 
(513 meq Na/L) or a combination of a loop 
diuretic and normal saline. Hypertonic saline is 
discontinued when the serum sodium concentra- 
tion increases above 120 meq/L or when symp- 
toms resolve. Serum electrolytes are monitored 
every 2 hours. In the first 48 hours the clinician 
should avoid increasing the serum sodium con- 
centration more than 25 meq/L and correcting the 
serum sodium concentration to or above normal. 
Water restriction alone has no role in the man- 
agement of the symptomatic patient since it 
corrects the serum sodium concentration too 
slowly. In the absence of severe symptoms, serum 
sodium concentration is raised more slowly 
(0.5 meq/L/hour) until above 120 meq/L, and 
then slowly thereafter. 

The patient evolving hyponatremia chroni- 
cally (>48 hours) is not corrected faster than 8— 
12 meq/L in the first 24 hours. If liver disease and 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



41 



hypokalemia are present the rate of correction 
should be closer to 6 meq/day because these 
patients are at high risk for CPM. 

A variety of formulas can be used to calculate 
the sodium requirement. They allow one to calcu- 
late the amount of sodium that would need to be 
added or water that would need to be removed in 
order to return the serum sodium concentration 
to normal. Although both sodium and water have 
either been removed or added in the process of 
generating the hyponatremia, these formulas 
work well in clinical practice. The most com- 
monly employed formula is 

[Na] requirement = total body water x (desired serum [Na] 
- current serum [Na]) 

Total body water is equal to 0.6 times the body 
weight in men and 0.5 times the body weight in 
women. Based on the requirement one then cal- 
culates the infusion rate of 3% saline solution. 
Alternatively, one can estimate the effect on 
serum sodium concentration of 1 L of any infused 
solution using the following formula: 

infusate [Na + 1- serum [Na + ] 



total body water + 1 



One can then adjust the rate of infusate to 
achieve the desired increase in serum sodium 
concentration. 

In the hypovolemic patient one discontinues 
diuretics, corrects gastrointestinal fluid losses, and 
expands the ECF with normal saline. Replacing 
the ECF volume deficit is important because this 
eliminates the stimulus for the nonosmotic release 
of AVP and leads to the production of a maximally 
dilute urine. To calculate the sodium deficit one 
can use the following equation: 

Na deficit = (total body water) x (140 

- current serum sodium concentration) 

One can replace one-third of the deficit over 
the first 12-24 hours and the remainder over the 
ensuing 48-72 hours. If vomiting, diarrhea, or 
diuretics caused the volume depletion, potassium 
deficits also must be corrected. 



In the asymptomatic euvolemic patient one 
often begins treatment by restricting "water. The 
following example illustrates the degree of reduc- 
tion in total body water required to restore the 
serum sodium concentration to normal. A 75-kg 
man has a total body water of 45 L and a serum 
sodium concentration of 115 meq/L. The formula 
below is used to calculate the desired total body 
water. 



Actual serum [Na] 
Normal serum [Na] 



x current TBW = desired TBW 



The desired total body water is 36.9 L. Sub- 
tracting the desired from the current total body 
water reveals that 8.1 L of water must be removed 
to restore the serum sodium concentration to 
140 meq/L. Fluid restriction rarely increases the 
serum sodium concentration by more than 1.5 meq/ 
L/day. When the cause of SIADH is not reversible, 
demeclocycline can be used (600-1200 mg/day) 
providing that the patient has normal liver 
function. 

The hypervolemic patient is managed with salt 
and water restriction. Negative water balance is 
achieved if daily fluid intake is less than the excre- 
tion of free water in urine. If congestive heart fail- 
ure is the cause, an increase in cardiac output will 
suppress AVP release. 

Common management errors in the treatment 
of the hyponatremic patient and recommenda- 
tions include the following: 

1 . A fear of CPM often leads to a delay in correc- 
tion or too slow a rate of correction of hypona- 
tremia. Neurologic sequelae are far more 
commonly related to too slow a rate of correc- 
tion rather than rapid correction. 

2. The belief that 3% saline can be used only in a 
patient who is seizing. Hypertonic saline should 
be employed in hyponatremic encephalopathy. 
Every effort should be made to prevent seizure 
and respiratory arrest, once these sequelae 
develop permanent neurologic injury is the 
rule. 

3. Be cognizant of patients at high risk for CPM 
especially those with abrupt withdrawal of a 



42 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



stimulus that inhibits free water excretion such 
as liver transplantation, and elderly women on 
thiazides (diuretic is discontinued and ECF 
volume repleted). Magnetic resonance imaging 
is the study of choice to diagnose CPM but may 
take up to 1-2 weeks after the onset of signs and 
symptoms to show characteristic abnormalities. 

4. Be aware of patients at high risk for hypona- 
tremic encephalopathy such as premenopausal 
women in the postoperative setting. Postoper- 
ative patients should never receive free water. 
The intravenous fluid of choice in this setting is 
normal saline or Ringers lactate. Electrolytes 
are monitored daily. 

5. Patients with SIADH should never be treated 
with normal saline alone. Normal saline admin- 
istration in this setting results in a further fall in 
serum sodium concentration. The kidney is 
capable of generating free water from normal 
saline. For example, a patient with SIADH and 
a urine osmolality of 600 mOsm/kg, who is 
administered 1 L of normal saline (approxi- 
mately 300 mOsm), will excrete that osmolar 
load in 500 mL of urine (300 mOsm given/600 
mOsm/kg — urine osmolality = 500 mL final 
urine volume). This results in the generation of 
500 mL of free water (the remainder of the 1 L 
given) and a further fall in serum sodium con- 
centration. 



4. Severe symptomatic hyponatremia is treateci 
emergently with the goal of raising serum 
sodium concentration above 120 meq/L. 
The clinician should avoid increasing the 
serum sodium concentration more than 

25 meq/L and correcting the serum sodium 
concentration to or above normal in the first 
48 hours. 

5. Every effort should be made to prevent 
seizure and respiratory arrest, once these 
sequelae develop permanent neurologic 
injury is the rule. 

6. Chronic hyponatremia (>48 hours) is not 
corrected faster than 8-12 meq/L in the first 
24 hours. If liver disease and hypokalemia 
are present the rate of correction should be 
closer to 6 meq/day because these patients 
are at high risk for CPM. 

7. Postoperative patients should not receive 
free water. 

8. Patients with SIADH should never be treated 
with normal saline alone. 




Hypernatremia 



Key Points 

Treatment of Hyponatremia 



1 . The morbidity and mortality of hypona- 
tremia are related to neurologic injury that 
occurs as a result of hyponatremic 
encephalopathy or improper therapy (too 
rapid or overcorrection). 

2. The major factor contributing to neurologic 
injury is hypoxia. Premenopausal women 
are at highest risk. 

3. Treatment is dependent on the acuity and 
severity of hyponatremia, and the patient's 
ECF volume status. 



Pathophysiologic Mechanisms 

Hypernatremia is defined as a serum sodium con- 
centration greater than 145 meq/L. It occurs when 
AVP concentration or effect is decreased or water 
intake is less than insensible, gastrointestinal and 
renal water losses. Therefore, hypernatremia results 
when there is a failure to take in enough free water 
in either the presence or absence of a urinary con- 
centrating defect. This is most commonly seen in 
those patients who depend on others for access to 
water or lack thirst sensation. Infrequently, hyper- 
natremia results from salt ingestion or administra- 
tion of hypertonic saline solutions. 

With free water loss the serum osmolality 
and sodium concentration increase as shown in 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



43 



Figure 33 



Net water loss 

1 


f Osmolality 


f[Na] 


/ 


\ 


f Thirst 


fAVP 


1 


I 


f Water intake ' 


Water reabsorption 


\ 


/ 


| Osmolality 


*[Na] 



Normal response to water loss. The normal 
response to water loss involves the stimula- 
tion of thirst and increased renal water 
reabsorption. 



Figure 3.3. The rise in serum osmolality stimulates 
thirst and AVP release from the posterior pituitary. 
Stimulation of thirst results in increased free water 
intake. Arginine vasopressin binds to its receptor 
in the basolateral membrane of collecting duct 
and stimulates water reabsorption. 

The normal renal concentrating mechanism in 
humans allows for excretion of urine that is as 
much as four times as concentrated as plasma 
(1200 mOsm/kg H 2 0). Since the average daily 
solute load is approximately 600 mOsm, this 
solute is excreted in as little as 0.5 L of urine. Note 
that even under maximal antidiuretic conditions, 
one must drink at least this volume of water per 
day in order to maintain water balance. Thirst is 
an integral component of the water regulatory 
system. The normal function of the renal concen- 
trating mechanism requires that its various com- 
ponents be intact. These include the following: 

1. The ability to generate a hypertonic inter- 
stitium. Henle's loop acts as a countercurrent 
multiplier with energy derived from active 



chloride transport in the water-impermeable 
thick ascending limb of the loop (mediated via 
the Na + -K + -2Cl" cotransporter). The transporter 
serves the dual process of diluting tubular fluid 
and rendering the interstitium progressively 
hypertonic from cortex to papilla. 

2. AVP secretion. This hormone renders the col- 
lecting duct permeable to water and allows 
fluid delivered from the distal tubule to equili- 
brate with the concentrated interstitium. 
Arginine vasopressin is a nonapeptide pro- 
duced by neurons originating in the supraoptic 
and paraventricular nuclei of the hypothala- 
mus. These neurons cross the pituitary stalk 
and terminate in the posterior pituitary. Arginine 
vasopressin is processed and stored in neu- 
rosecretory granules along with neurophysin 
and copeptin. 

3. Normal collecting duct responsiveness to 
arginine vasopressin. Abnormalities in the 
renal concentrating process obligate excretion 
of a larger volume of urine to maintain solute 
balance, e.g., with 600 mOsm of solute to be 
excreted and the inability to increase urine 
osmolality above plasma, a urine flow of 2 L/day 
is obligated. Failure to replace these water 
losses orally leads to progressive water deple- 
tion and hypernatremia. 



Key Points 

Hypernatremia 



Hypernatremia results when there is a fail- 
ure to take in enough free water in either 
the presence or absence of a concentrating 
defect. It is most commonly seen in those 
who depend on others for access to water 
or who lack thirst. 

Thirst is an integral component of the water 
regulatory system. 

Normal concentrating mechanism function 
requires the ability to generate a hypertonic 
interstitium, AVP secretion, and normal col- 
lecting duct responsiveness to AVP. 




Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



Etiology 



Diabetes insipidus (DI) is the result of decreased 
pituitary production of AVP (central) or decreased 
renal responsiveness to AVP (nephrogenic). 
Central DI does not occur until greater than 
80% of vasopressin-producing neurons are de- 
stroyed. 

Central DI may be idiopathic or secondary to 
head trauma, surgery, or neoplasm. Urine volume 
ranges from 3 to 15 L/day. Patients tend to be 
young with nocturia and a preference for cold 
water. The kidneys should respond to exogenous 
AVP with a rise in urine osmolality of 100 mOsm/kg 
above the value achieved following water depri- 
vation. Patients with complete central DI are 
unable to concentrate urine above 200 mOsm/kg 
with dehydration, whereas patients with partial 
DI are able to concentrate urine but not maxi- 
mally. Treatment consists of administering AVP. 
The best therapy is long-acting, nasally adminis- 
tered dD-AVP. An important point is that thirst is 
stimulated by the increased P osm so effectively that 
serum sodium concentration is only slightly ele- 
vated and the most common clinical presentation 
is polyuria. Psychogenic polydipsia also presents 
with polyuria; however, the serum sodium con- 
centration is often mildly decreased rather than 
increased. 

One-third to one-half of central DI cases are 
idiopathic. A lymphocytic infiltrate is present in 
the posterior pituitary and pituitary stalk. Some of 
these patients have circulating antibodies directed 
against vasopressin-producing neurons. 

Familial central DI is rare and inherited in 
three ways. The most common is an autosomal 
dominant disorder resulting from mutations in 
the coding region of the AVP gene. The mutant 
protein fails to fold properly and accumulates 
in the endoplasmic reticulum resulting in neu- 
ronal death. Because neurons die slowly vaso- 
pressin deficiency is not present at birth but 
develops over years. It often gradually progresses 



from a partial to complete defect. A similar clin- 
ical presentation is seen with X-linked inheri- 
tance, although the evidence for this mode of 
inheritance is "weak. Autosomal recessive cen- 
tral DI is a very rare disorder caused by a single 
amino acid substitution resulting in the produc- 
tion of an AVP with little to no antidiuretic 
activity. 

In nephrogenic DI the collecting duct does not 
respond appropriately to AVP. The most common 
inherited form of nephrogenic DI is an X-linked 
disorder in which cyclic AMP is not generated in 
response to AVP. It is caused by a number of muta- 
tions in the V 2 receptor. Aquaporin-2 gene muta- 
tions also result in nephrogenic DI and may be 
inherited in an autosomal dominant or recessive 
fashion. In dominant cases heterotetramers form 
between mutant and wild type aquaporin-2 water 
channels that are unable to traffic to the plasma 
membrane. This usually results in complete resis- 
tance to the effects of AVP. 

Acquired nephrogenic DI is much more 
common but often less severe. Chronic renal fail- 
ure, hypercalcemia, lithium treatment, obstruc- 
tion, and hypokalemia are its causes. Aquaporin-2 
expression in principal cells of the collecting duct 
is markedly reduced. Lithium is the most common 
treatment for manic-depressive psychosis. Ap- 
proximately 0.1% of the population is receiving 
lithium and 20-30% develop severe side effects. 
In rats administered lithium for 25 days, aquaporin- 
2 and -3 expression decreases to 5% of control 
levels. Both hypokalemia and hypercalcemia are 
associated with a significant downregulation 
of aquaporin-2. Rats treated with a potassium- 
deficient diet for 1 1 days show a 30% decrease in 
aquaporin-2 expression. Aquaporin-2 expres- 
sion normalizes after 7 days of a normal potas- 
sium diet. Hypercalcemia induced by excessive 
vitamin D administration in rats results in a con- 
centrating defect that is caused by downregula- 
tion of both aquaporin-2 and the Na + -K + -2C1" 
cotransporter. 

A number of drugs may cause a renal concen- 
trating defect. Ethanol and phenytoin impair AVP 
release resulting in a water diuresis. Lithium and 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



45 



demeclocycline cause tubular resistance to AVP 
while amphotericin B and methoxyflurane injure 
the renal medulla. Thus, a concentrating defect 
(inability to conserve •water) can be secondary to 
a lack of AVP, unresponsiveness to AVP, or renal 
tubular dysfunction. Other specific causes and 
mechanisms for concentrating defects include 
sickle cell anemia or trait (medullary vascular 
injury), excessive water intake or primary poly- 
dipsia (decreased medullary tonicity), severe pro- 
tein restriction (decreased medullary urea), and a 
variety of disorders affecting renal medullary ves- 
sels and tubules. 

Recently, DI caused by peripheral degradation 
of AVP was reported in peripartum women. 
Vasopressinase is an enzyme produced by the pla- 
centa that degrades AVP and oxytocin. It appears 
in plasma of women early in pregnancy and 
increases in activity throughout gestation. After 
delivery, which is curative due to loss of the pla- 
centa, vasopressinase rapidly becomes unde- 
tectable. Although only case reports of diabetes 
insipidus from vasopressinase are published to 
date, it is unclear how frequently this condition 
actually occurs. These patients often respond to 
desmopressin (dD-AVP), which is not degraded 
by vasopressinase. 



Key Points 

Etiology of Hypernatremia 



Diabetes insipidus may be central due to 
decreased pituitary production and release 
of AVP or nephrogenic secondary to 
decreased renal responsiveness to AVP. 
Central DI is idiopathic or secondary to 
head trauma, surgery, or neoplasm. 
Acquired nephrogenic DI occurs most com- 
monly with lithium administration. 
Aquaporin-2 expression in principal cells of 
collecting duct is markedly reduced. 
A variety of drugs cause renal concentrating 
defects. 




Signs and Symptoms 



Cellular dehydration occurs as water shifts out of 
cells. This results in neuromuscular irritability 
with twitches, hyperreflexia, seizures, coma, and 
death. In children, severe acute hypernatremia 
(serum sodium concentration >160 meq/L) has a 
mortality rate of 45%. Two-thirds of survivors 
have permanent neurologic injury. In adults, 
acute hypernatremia has a reported mortality as 
high as 75% and chronic hypernatremia 60%. 
Hypernatremia is often a marker of serious under- 
lying disease. Of note, the brain protects itself 
from the insult of hypernatremia by increasing its 
own osmolality, in part due to increases in free 
amino acids. The mechanism is unclear, but the 
phenomenon is referred to as the generation of 
"idiogenic osmoles." The therapeutic corollary is 
that water repletion must be slow with chronic 
hypernatremia to allow inactivation of these 
solutes and thus avoid cerebral edema. 



Key Points 

Signs and Symptoms of Hypernatremia 



1 . Symptoms of hypernatremia result from a 
shift of water out of brain cells. 

2. In chronic hypernatremia the brain gener- 
ates "idiogenic osmoles" that reduce the gra- 
dient for water movement. 




Diagnosis 



Although hypernatremia can occur in association 
with hypovolemia, hypervolemia, and euvolemia, 
patients most commonly present with hypo- 
volemia. Those that are euvolemic may be mildly 



46 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



Figure 3.'. 



Hypernatremia (always associated with increased serum osmolality) 



Decreased total body Na 
JTBNa 



Normal total body Na Increased total body Na (rare) 
TB Na | TB Na 



II TB 



water 



| TB water 



TB water 



/ \ 



Renal 

Diuretics 
Solute diuresis 



NoAVP 
Gl losses Nephrogenic Dl Central Dl 



Extrarenal No response 
toAVP 



Intake of exogenous 
hypertonic fluid 
Usually Na bicarbonate 



Clinical approach to the patient with hypernatremia. Patients with hypernatremia can also be cate- 
gorized based on ECF volume status. The majority have decreased or normal ECF volume (total 
body sodium). 



hypernatremic but their most common complaint 
is polyuria. Many disorders may result in hyper- 
natremia; however, decreased thirst, inability to 
gain access to water, and drugs are the most 
common causes (Figure 3.4). 

A high serum sodium concentration results 
from free water loss that is not compensated for 
by an increase in free water intake. Free water loss 
may be renal or extrarenal in origin. Extrarenal 
losses originate from skin, respiratory tract, or 
from the gastrointestinal tract. Renal losses are the 
result of a solute (osmotic) or water diuresis. A 
solute or osmotic diuresis most commonly results 
from excretion of glucose in uncontrolled dia- 
betes mellitus. A water diuresis is secondary to 
central or nephrogenic Dl. If thirst is intact, 
patients with renal losses present with the chief 
complaint of polyuria, defined as the excretion of 
more than 3 L of urine daily. 

An increased serum sodium concentration is a 
potent stimulus for thirst and AVP release. After a 
thorough history and physical examination are 
performed the clinician must answer several 



questions in the hypernatremic patient. First, is 
thirst intact? If the serum sodium concentration is 
elevated above 147 meq/L the patient should be 
thirsty. Second, if the patient is thirsty, is he 
capable of getting to water? The next step is to 
evaluate the hypothalamic-pituitary-renal axis. 
This involves an examination of urine osmolality. 
If the hypothalamic-pituitary-renal axis is intact a 
rise in serum sodium concentration above 147 
meq/L maximally stimulates AVP release and 
results in a urine osmolality greater than 700 
mOsm/kg. If urine osmolality is greater than 700 
mOsm/kg then free water losses are extrarenal. A 
urine osmolality less than plasma indicates that 
the kidney is the source of free water loss as a 
result of either central or nephrogenic DL These 
disorders are differentiated by the response to 
exogenous AVP. Either 5 units of aqueous vaso- 
pressin subcutaneously or 10 |0.g of dD-AVP 
intranasally increases urine osmolality by 50% or 
more in central Dl but has no effect on urine 
osmolality in nephrogenic DL In central Dl the 
onset is generally abrupt, urine volume remains 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



47 



fairly constant over the course of the day, nocturia 
is common, and patients have a preference for 
drinking cold water. 

Urine osmolality in the intermediate range 
(300-600 mOsm/kg) may be secondary to psy- 
chogenic polydipsia, an osmotic diuresis, and par- 
tial central or nephrogenic DI. Psychogenic 
polydipsia is generally associated with a mildly 
decreased rather than increased serum sodium 
concentration. Partial central and nephrogenic DI 
may require a water deprivation test to distin- 
guish. In the water deprivation test water is pro- 
hibited and urine volume and osmolality measured 
hourly and serum sodium concentration and 
osmolality every 2 hours. The test is stopped if 
either the urine osmolality reaches normal levels, 
the plasma osmolality reaches 300 mOsm/kg, or 
the urine osmolality is stable on two successive 
readings despite a rising serum osmolality. In the 
last two circumstances exogenous vasopressin is 
administered and the urine osmolality and 
volume measured. In partial central DI the urine 
osmolality generally increases by greater than 
50 mOsm/kg. In partial nephrogenic DI the urine 
osmolality may increase slightly but generally 
remains below serum osmolality. An osmotic 
diuresis is suspected if the total osmolar excretion 
exceeds 1000 mOsm/day. Total osmolar excretion 
is calculated by multiplying the urine osmolality 
by the urine volume in a 24-hour collection. 



Key Points 

Diagnosis of Hypernatremia 



1 . Hypernatremia occurs most commonly in 
association with hypovolemia. 

2. The euvolemic patient is only mildly hyper- 
natremic but will complain of polyuria. 

3. A high serum sodium concentration results 
from free water loss that is not compensated 
for by an increase in free water intake. Free 
water loss is renal or extrarenal in origin. 

4. The clinician should first examine whether 
thirst and access to free water are intact. 



5. The next step is to evaluate the hypothalamic- 
pituitary-renal axis. This involves an exami- 
nation of the urine osmolality. If urine 
osmolality is greater than 700 mOsm/kg 
then free water losses are extrarenal. 

6. A urine osmolality less than plasma indi- 
cates that the kidney is the source of free 
water loss from either central or nephro- 
genic DI. These disorders are differentiated 
by the response of urine osmolality to 
exogenous AVP. 




Treatment 



Treatment of hypernatremia is divided into two 
parts: restoring plasma tonicity to normal and cor- 
recting sodium imbalances, and providing spe- 
cific treatment directed at the underlying disorder. 
When restoring plasma tonicity to normal and 
correcting sodium imbalances, sodium may need 
to be added or removed while providing water. A 
formula to calculate the total amount of water 
needed to lower serum sodium concentration 
from one concentration to another can be used. 
This does not take into account, however, changes 
in sodium balance as it is based on a rough esti- 
mate of total body water as 60% of weight (kg) in 
men and 50% of weight (kg) in women: 

water needed (L) = (total body water) 

x ((actual sodium/desired sodium) 
-1) 

Water deficits are restored slowly in order to 
avoid sudden shifts in brain cell volume. Water 
deficits are corrected preferably with increased 
oral intake or with intravenous administration of 
hypotonic solution. The serum sodium concentra- 
tion should not be lowered faster than 8-10 meq/ 
day. The formula above calculates the amount of 
free water replacement needed at the time the 
patient is first seen. It does not take into account 



48 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



ongoing free water losses that may be occurring 
from the kidney while one is attempting to correct 
the deficit. If urine volume is high or urine osmo- 
lality low then one must add ongoing renal free 
water losses to the replacement calculation. 

In order to determine ongoing renal free water 
losses one must calculate the electrolyte-free 
water clearance. For this purpose urine is divided 
into two components: an isotonic component (the 
volume needed to excrete sodium and potassium 
at their concentration in serum), and an electrolyte- 
free water component. This is shown in the formula 
below: 



Urine Volume = CElectrolytes + C uo 

urine [Na]+[K] 



CElectrolytes 



serum [Na] 



x urine volume 



where C H is the volume of urine from which the 
electrolytes were removed during the elaboration 
of a hypotonic urine. 

♦ CASE 31 

This is best illustrated with a case. A 70 kg male with 
a history of nephrogenic DI is found unconscious at 
home and is brought to the Emergency Department. 
The serum sodium concentration is 160 meq/L. A 
Foley catheter is placed and urine output is 500 mL/ 
hour. Urine electrolytes reveal a sodium concen- 
tration of 60 meq/L, a potassium concentration of 
20 meq/L, and a urine osmolality of 180 mOsm/kg. 
How much water must be administered in order to 
correct the serum sodium concentration to 140 meq/L? 



Water needed (L) = (0.6 x body weight in kg) 

x ((actual [Nal/desired [Na]) 
-1) 
= (0.6 x 70) x ((160/140) - 1 ) 
= 42 X 0.14 or 6 L 

One next determines the time frame over 
which the deficit will be corrected. If the serum 
sodium concentration were decreased by 8 meq/L 
in the first 24 hours, then 2.4 L of water is admin- 
istered at a rate of 100 mL/hour. If water were 
given at this rate in the form of D5W, serum sodium 
concentration would increase not decrease. The 



reason for this is that the replacement calculation 
did not include the large ongoing free water loss 
in urine. 

To include renal free water losses one must 
calculate the electrolyte -free water clearance as 
illustrated below: 



urine [Na]+[K] 

CElectrolytes = x urine volume 

serum [Na] 

60 + 20 rn 

= x 500 ml/hour 

160 

80 



160 



x 500 = 250 mL/hour 



C H 



•■ Urine Volume - CElectrolytes 

= 500-250 = 250 ml/hour 



The ongoing renal free water losses of 250 mL/ 
hour must be added to the replacement solution, 
100 mL/hour, in order to correct the serum 
sodium concentration. 

Treatment is also directed at the underlying dis- 
order. In the patient with nephrogenic DI signifi- 
cant hypernatremia will not develop unless thirst 
is impaired or the patient lacks access to water. 
The goal of treatment is to reduce urine volume 
and renal free water excretion. As discussed ear- 
lier, urine volume is equal to osmolar excretion or 
intake (they are the same in the steady state) 
divided by the urine osmolality. Urine volume can 
be reduced by decreasing osmolar intake with 
protein or salt restriction or by increasing urine 
osmolality. Thiazide diuretics inhibit urinary dilu- 
tion and increase urine osmolality. Nonsteroidal 
anti-inflammatory agents (NSAIDs) by inhibiting 
renal prostaglandin synthesis increase concentrat- 
ing ability. Prostaglandins normally antagonize 
the action of AVP. Their effects are partially addi- 
tive to those of thiazide diuretics. Electrolyte dis- 
turbances such as hypokalemia or hypercalcemia 
should be corrected. Early in the course of 
lithium-induced nephrogenic DI, amiloride may 
be of some benefit. Amiloride prevents the entry 
of lithium into the cortical collecting duct princi- 
pal cell and can limit its toxicity. 

The patient with central DI and a deficiency of 
AVP secretion is treated with hormone replacement 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



49 



Table 33 

Treatment of Central DI 



Condition 


Drug 


Dose 


Complete 








dD-AVP 


5-20 \l% intranasally q 12-24 hours 
0.1-0.4 mg orally q 12-24 hours 


Incomplete 








Chlorpropamide 


125-500 mg/day 




Carbamazepine 


100-300 mg bid 




Clofibrate 


500 mg qid 



Abbreviations: bid, twice a day; qid, four times a day. 



(Table 3.3). Intranasal desmopressin is most 
commonly used. The initial dose is 5 (J-g at bed- 
time and is titrated upward to a dose of 5-20 (J.g 
once or twice daily. Desmopressin can also be 
administered orally. In general a 0.1 mg tablet is 
equivalent to 2.5-5.0 (J.g of the nasal spray. Serum 
sodium concentration must be followed carefully 
during dose titration to avoid hyponatremia. 
Desmopressin is expensive. As a consequence 
drugs that increase AVP release or enhance its 
effect can be added to reduce cost. These drugs 
can also be used in patients •with partial central 
DI. Chlorpropamide and carbamazepine enhance 
the renal action of AVP. Clofibrate may increase 
AVP release. As with nephrogenic DI thiazide 
diuretics and NSAIDs can also be employed. 



KEY POINTS 



Treatment of Hypernatremia 



Treatment of hypernatremia is directed at 
restoring plasma tonicity to normal, correct- 
ing sodium imbalances, and providing spe- 
cific treatment directed at the underlying 
disorder. 

Water deficits are restored slowly to avoid 
sudden shifts in brain cell volume. The 
serum sodium concentration is not lowered 
faster than 8-10 meq/day. 



If urine volume is high or urine osmolality 
low then one must account for ongoing 
renal free water losses. 
In the patient with nephrogenic DI urine 
volume is reduced by decreasing osmolar 
intake with protein or salt restriction or by 
increasing urine osmolality with thiazide 
diuretics. 

Hormone replacement therapy with desmo- 
pressin (dD-AVP) is the cornerstone of treat- 
ment of central DI. 



Additional Reading 

Adrogue, H.J., Madias, N.E. Hypernatremia. N Engl J 

Med 342:1493-1499, 2000. 
Adrogue, H.J., Madias, N.E. Hyponatremia. N Engl J 

Med 342:1581-1589, 2000. 
Bedford, J.J., Leader, J. P., Walker, R.J. Aquaporin 

expression in normal human kidney and in renal 

disease. J Am Soc Nephrol 14:2581-2587, 2003. 
Calakos, N., Fischbein, N., Baringer, J.R., Jay, C. Cortical 

MRI findings associated with rapid correction of 

hyponatremia. Neurology 55:1048-1051, 2000. 
Fraser, C.L., Arieff, A.I. Epidemiology, pathophysiology, 

and management of hyponatremic encephalopathy. 

Am J Med 102:67-77, 1997. 
Goldszmidt, M.A., Iliescu, E.A. DDAVP to prevent rapid 

correction in hyponatremia. Clin Nephrol 53:226- 

229, 2000. 



so 



Chapter 3 ♦ Disorders of Water Balance (Hypo- and Hypernatremia) 



Kumar, S., Berl, T. Sodium. Lancet 352:220-228, 1998. 

Milionis, H.J., Liamis, G.L., Elisaf, M.S. The hypona- 
tremia patient: a systematic approach to laboratory 
diagnosis. CMAJ 166:1056-1062, 2002. 

Moran, S.M., Jamison, R.L. The variable hyponatremia 
response to hyperglycemia. West J Med 142:49-53, 
1985. 



Nielsen, S., Froklaer, J., Marples, D., Kwon, T.-H., Agre, 
P., Knepper, M.A. Aquaporins in the kidney: from 
molecules to medicine. Physiol Rev 82:205-244, 
2002. 

Zarinetchi, R, Berl, T. Evaluation and management of 
severe hyponatremia. Adv Intern Med 41:251-283, 
1996. 



Mark A. Perazella 



Diuretics 




Recommended Time to Complete: 1 day 

1. What is the difference between diuresis and natriuresis? 

2. How do diuretics reach their site of action? 
Z. Where do diuretics act in the nephron? 

(+. Which diuretics act in the proximal tubule and what is their 
mechanism of action? 

5. What transporter in the loop of Henle reabsorbs NaCl? 

6. Which diuretics act in the distal convoluted tubule (DCT) ? 

7. How do diuretics that act in cortical collecting duct (CCD) induce 
natriuresis? 

$. What are some of the common adverse effects of various 

diuretics? 
e \. What is diuretic resistance and how does one assess for the cause of 

resistance? 

10. How does diuretic resistance develop in the setting of chronic loop 
diuretic therapy? 

11. How does one treat various causes of diuretic resistance? 



51 




Chapter 4 



Diuretics 



Introduction 



The primary renal effect of diuretics is to increase 
the amount of urine formed or diuresis (water, 
sodium, urea, and other substances). A large part 
of this effect is due to enhanced natriuresis, which 
is defined as an increase in renal sodium excre- 
tion. Diuretics were initially described as a useful 
therapy to reduce edema in the sixteenth century. 
The first agent known to increase urine output 
was mercurous chloride. In 1930, the antimicro- 
bial sulfanilamide was noted to increase renal Na + 
excretion and reduce edema formation in patients 
with congestive heart failure (CHF). It is interest- 
ing that most diuretics were discovered serendip- 
itously when they were noted to increase urine 
output and change urine composition. These 
changes in urine were considered an adverse 
effect of drugs intended for other purposes. 
Targeted disruption of various renal transporters 
was not part of the development of these drugs as 
the mechanism of transport was unknown; rather 
diuretics were developed empirically. Diuretics 
are the most commonly prescribed medications in 
the United States. They are used to treat a variety 
of clinical disease states including hypertension, 
edema, congestive heart failure, hyperkalemia, and 
hypercalcemia. 

To understand the actions of diuretics, one must 
first appreciate renal handling of sodium and water. 
This subject is reviewed in detail in Chapter 2, but 
will be briefly reviewed here. The kidneys regulate 
extracellular fluid (ECF) volume by modulating 
NaCl and water excretion. Sodium intake is bal- 
anced by the renal excretion of sodium. A normal 
glomerular filtration rate (GFR) is important for the 
optimal excretion of sodium and water. Following 
formation and passage of glomerular ultrafiltrate 
into Bowman's space, delivery of sodium and 
water to the proximal tubule is the first site of tubu- 
lar handling. Along the nephron sodium is reab- 
sorbed by several different transport mechanisms. 
Sodium absorption is regulated by a number of dif- 
ferent factors. For example, various hormones 



(renin, angiotensin II, aldosterone, atrial natriuretic 
peptide (ANP), prostaglandins, and endothelin) 
and physical properties (mean arterial pressure, 
peritubular capillary pressure, and renal interstitial 
pressure) modify renal handling of sodium and 
water. Direct effects on tubular transport along the 
nephron underlie the major influence of these fac- 
tors on renal sodium and water handling. Sodium 
reabsorption is driven primarily by Na + -K + -ATPase 
located on the basolateral membrane of all tubular 
epithelial cells. This pump provides energy required 
by transporters located on the apical (luminal) 
membrane that reabsorb sodium from glomerular 
filtrate. Cell-specific transporters are present on 
these tubular cells. 

Diuretics act to enhance renal sodium and 
water excretion by inhibiting these transporters at 
different nephron sites (Figure 4.1). They act to 
reduce sodium entry into the tubular cell. With the 
exception of spironolactone and eplerenone, all 
diuretics exert their effects from the luminal side of 
the cell. Thus, most diuretics must enter tubular 
fluid to be effective. Secretion across the proximal 
tubule via either organic acid or base transport 
pathways is the primary mode of entry (except for 
mannitol, which undergoes glomerular filtration). 
Diuretic potency depends significantly on drug 
delivery to its site of action, as well as the nephron 
site where it acts. Other factors that influence 
diuretic action are level of kidney function 
(glomerular filtration rate), state of the effective 
arterial blood volume (congestive heart failure, cir- 
rhosis, and nephrosis), and treatment with certain 
medications such as nonsteroidal anti-inflammatory 
drugs (NSAIDs) and probenecid. Diuretics may 
also have a variety of adverse effects, some that 
are common to all diuretics and others that are 
unique to specific agents (Table 4.1). 



Key Points 

Diuretics 



1 . Diuretics increase renal sodium and water 
excretion. 



Chapter 4 



Diuretics 



53 



Figure 4.1 



Proximal 
tubule 




Acetazolamide 
Mannitol 
Dopamine 
Fenoldopam 



Hydrochlorothiazide Amiloride 



Metolazone 

Chlorthalidone 

Chlorothiazide 



Spironolactone 

Triamterene 

Eplerenone 



Loopl 
of | 

Henle 1 



X 



Distal 
tubule 






Furosemide 
Torsemide 
Bumetamide 
Ethacrynic acid 



Nesiritide 

Vasopressin 

antagonists 



/ 



Collecting 
duct 



Sites of diuretic action in the nephron. Sodium chloride reabsorption is reduced by 
various diuretics in proximal tubule, loop of Henle, distal tubule, and collecting duct. 



Diuretics were developed empirically based 
on observed effects on urine volume and 
change in urine composition. 
Several hormones control renal sodium and 
water excretion through effects on tubular 
transport. 

The majority of diuretics enter the urine by 
tubular secretion and act on the luminal sur- 
face to reduce sodium reabsorption. 




Sites of Diuretic Action 
in the Kidney 



Proximal Tubule 

The initial site of diuretic action in the kidney is 
the proximal tubule. Transport of sodium in the 
proximal tubular cell is driven by Na + -K + -ATPase 



activity, which drives sodium reabsorption by the 
Na + -H + exchanger on the apical membrane. The 
Na + -K + -ATPase uses energy derived from ATP to 
extrude three Na + ions in exchange for two potas- 
sium ions. This results in a reduction of intracellu- 
lar Na + concentration. Sodium can then move 
down its electrochemical gradient from tubular 
lumen into the cell via the Na + -H + exchanger in 
exchange for an H + that moves out of the cell 
against its electrochemical gradient. Secretion of 
H + by this exchanger is associated with reclama- 
tion of filtered bicarbonate. Two diuretics that 
impair sodium reabsorption in this nephron seg- 
ment are mannitol and acetazolamide. Each acts 
differently to reduce sodium reclamation. Mannitol, 
an osmotic diuretic, is mainly employed for pro- 
phylaxis to prevent ischemic or nephrotoxic renal 
injury and to reduce cerebral edema. It is a non- 
metabolizable osmotic agent that is freely filtered 
by the glomerulus and enters the tubular space 
where it raises intratubular fluid osmolality. This 
effect drags water, which is accompanied by sodium 
from tubular cells into the tubular fluid. Mannitol is 
poorly absorbed with oral administration and is 



54 



Chapter 4 



Diuretics 



Table 4.1 

Adverse Effects of Diuretic Drugs 



Proximal tubule diuretics 

Carbonic anhydrase inhibitors (acetazolamide) 

Hypokalemia, metabolic acidosis 

Drowsiness, fatigue, lethargy, paresthesias 

Bone marrow suppression 

Osmotic diuretics (mannitol) 

Hypokalemia, hyperkalemia (cell shift) 

Expansion of the ECF, CHF 

Nausea and vomiting, headache 

Loop diuretics (furosemide, bumetanide, 
torsemide, ethacrynic acid) 

Hypokalemia, hypomagnesemia, hyponatremia 

Metabolic alkalosis, hypovolemia 

Ototoxicity, diarrhea 

Blood dyscrasia (thrombocytopenia, agranulo- 
cytosis) 

DCT diuretics (thiazides, metolazone) 

Hypokalemia, hypomagnesemia, hyponatremia 

Hypercalcemia, hyperuricemia 

Metabolic alkalosis, hypovolemia 

Mild hyperglycemia, hyperlipidemia 

Hypersensitivity, interstitial nephritis 

Leukopenia, thrombocytopenia, aplastic and 
hemolytic anemia 

CCD diuretics 

Mineralocorticoid receptor antagonists 
(spironolactone*, eplerenone) 

Hyperkalemia 

Gynecomastia*, hirsutism*, menstrual irregulari- 
ties*, testicular atrophy* 

Sodium channel inhibitors (amiloride*, tri- 
amterenes) 

Hyperkalemia 

Glucose intolerance*, megaloblastic anemia ♦ , 
urinary crystals ♦ 



Abbreviations: ECF, extracellular fluid; CHF, congestive heart failure. 



active only when given intravenously. It acts in 



the kidney within 10 minutes and has 



of 



approximately 1.2 hours in patients with normal 
renal function. Toxicity develops when filtration 
of mannitol is impaired, as in renal failure. 



Retained mannitol causes increased plasma 
osmolality, •which can exacerbate CHF, induce 
hyponatremia, and causes a hyperoncotic syn- 
drome. As a result of these effects, mannitol is 
contraindicated in patients with CHF and moder- 
ate-to-severe kidney disease. 

The carbonic anhydrase (CA) inhibitor acetazo- 
lamide is prescribed to alkalinize the urine (certain 
drug overdoses), prevent and treat altitude sick- 
ness, and decrease intraocular pressure in certain 
forms of glaucoma. The CA inhibitors disrupt bicar- 
bonate reabsorption by impairing the conversion of 
carbonic acid (H 2 C0 3 ) into C0 2 and H 2 in tubular 
fluid. Excess bicarbonate in the tubular lumen asso- 
ciates with Na + , the most abundant cation in tubular 
fluid, and exits the proximal tubule. Acetazolamide 
and other CA inhibitors exert their effect within 
half an hour and maintain a t U2 of approximately 
13 hours. Over time, the effect of these drugs dimin- 
ishes due to the reduction in plasma and fil- 
tered bicarbonate. Metabolic consequences of 
CA inhibitors include metabolic acidosis and 
hypokalemia. Hypokalemia results from enhanced 
delivery of sodium and bicarbonate to the principal 
cell, which promotes potassium secretion through a 
change in membrane potential. These drugs should 
be avoided in patients with cirrhosis (increases 
serum NH 3 ) and those with uncorrected hypo- 
kalemia. Because downstream nephron segments 
such as the loop of Henle, distal convoluted tubule 
(DCT), and CCD avidly reabsorb sodium, these two 
drugs are relatively weak diuretics. 



Thick Ascending Limb of the Loop of Henle 

In this nephron segment, the Na + -K + -2Ch cotrans- 
porter on the apical surface of tubular cells, pow- 
ered by Na + -K + -ATPase on the basolateral 
membrane reabsorbs significant amounts of NaCl 
(20-30% of the filtered sodium load). In addition to 
NaCl, potassium, calcium, and magnesium are 
reclaimed in this tubular segment. It is not surpris- 
ing that the most potent diuretics, the loop diuret- 
ics, retard the action of this transporter. Loop 
diuretics consist of those that are sulfonamide 



Chapter 4 



Diuretics 



55 



derivatives (furosemide, bumetanide, and torse- 
mide) and ethacrynic acid, a non-sulfa-containing 
loop diuretic. These drugs are used primarily to 
treat states of volume overload refractory to other 
diuretics including CHF, cirrhosis-associated ascites 
and edema, and nephrotic syndrome. Other indi- 
cations are hypercalcemia and hypertension asso- 
ciated with moderate-to-severe kidney disease, 
which is often a sodium retentive state. Rarely, 
these drugs are employed to help correct hypona- 
tremia in patients with the syndrome of inappro- 
priate antidiuretic hormone (SIADH). 

Loop diuretics can be administered as either 
oral or intravenous (IV) preparations. They are 
well absorbed orally, unless significant bowel 
edema is present as in severe CHF, cirrhosis, and 
nephrotic syndrome. Loop diuretics act within 
20-30 minutes and have a t in of approximately 
1—1.5 hours. In healthy subjects given intravenous 
furosemide or an oral dose twice the IV dose, 
there was no difference in cumulative urine 
volume, natriuresis, or potassium and chloride 
excretion. The major difference between the two 
modes of administration was a 30-minute peak 
natriuretic action with IV furosemide compared 
with a 75-minute peak for oral therapy. This dif- 
ference is likely due to the rapid increase in 
plasma levels with IV dosing. In patients with 
chronic kidney disease, the dose of loop diuretic 
to promote effective natriuresis is higher than 
patients with normal kidney function. This is due 



to several factors. Most important is that a reduced 
GFR is associated "with a reduction in filtered sodium 
load. For example, the filtered sodium for a patient 
with a GFR of 100 mL/minute is 15 meq/minute, 
"whereas it is only 0.15 meq/minute in a patient 
with kidney disease and a GFR of 10 mL/minute. 
In advanced chronic kidney disease (creatinine 
clearance = 17 mL/minute), the maximal diuretic 
response to intravenous furosemide occurs at 
160-200 mg, much higher than required in sub- 
jects with normal renal function. Decreased deliv- 
ery of loop diuretic to its site of action is another 
factor in renal failure that limits efficacy at lower 
administered doses. 

In normal subjects, the dose equivalency for 
the various loop diuretics is as follows: 

bumetanide 1 mg = torsemide 10 mg 
= furosemide 40 mg 

The maximum dose of each drug varies based 
on the indication and the underlying disease state. 
Table 4.2 notes the approximate ceiling doses for 
the loop diuretics based on the associated clinical 
condition. Ceiling dose is defined as the dose that 
provides maximal inhibition of NaCl reabsorption, 
reaching a plateau in the diuretic dose-response 
curve. Adverse effects from loop diuretics are 
related in part to their therapeutic effect on 
natriuresis and changes in urine composition. 
These include hypokalemia, hypocalcemia, hypo- 
magnesemia, volume contraction (which can 



Table 4.2 



Ceiling Doses of Intravenous and Oral Loop Diuretics 


in Various Clinical Conditions 








Clinical Condition 


Furosemide (mg) 


Bumetanide (mg) 
rv PO 


Torsemide (mg) 


IV 


PO 


IV 


PO 


Kidney disease 














GFR 20-50 mL/minute 


80 


60-80 


2-3 


2-3 


20-50 


20-50 


GFR <20 mL/minute 


200 


240 


8-10 


8-10 


50-100 


50-100 


Congestive heart failure 


40-80 


160-240 


2-3 


2-3 


20-50 


20-50 


Nephrotic syndrome 


120 




3 




50 


50 


Cirrhosis 


40-80 


80-160 


1 


1-2 


10-20 


20-50 



Abbreviations: IV, intravenous; PO, oral; GFR, glomerular nitration rate. 



56 



Chapter 4 



Diuretics 



result in hypotension and shock), and metabolic 
alkalosis. Groups most susceptible to these unto- 
ward effects, in particular volume contraction, are 
the elderly and patients with hypertension who lack 
clinical edema. Loop diuretics must also be used 
cautiously in patients with cirrhosis, to avoid pre- 
cipitation of the hepatorenal syndrome and in 
patients treated with digoxin that are at high risk for 
lethal arrhythmias when hypokalemia develops. 
Ototoxicity is another complication of high plasma 
drug levels. Ethacrynic acid is associated with 
severe ototoxicity and is rarely employed except in 
patients with sulfonamide allergy. Furosemide, 
torsemide, and bumetanide are contraindicated in 
patients with sulfonamide allergy. Rarely, mild 
hyperglycemia occurs in patients due to inhibition 
of insulin release by loop diuretics. 



Distal Convoluted Tubule 

The DCT contains the thiazide-sensitive Na + -Cl" 
cotransporter (NCC), which reabsorbs sodium 
and chloride delivered from the loop of Henle. 
This segment reabsorbs approximately 5-10% of 
the filtered sodium load. Thiazide and thiazide- 
like diuretics inhibit NCC. Common drugs include 
hydrochlorothiazide (HCT2), metolazone, and 
the intravenous preparation chlorothiazide. 
Through inhibition of NCC, this class of drugs is 
used primarily to treat hypertension, particularly 
in patients with salt-sensitive hypertension. 
Additional uses include treatment of osteoporosis 
and nephrolithiasis. While not intuitively obvious 
as a therapy for these states, thiazide-type diuret- 
ics increase calcium reabsorption in proximal 
tubule and DCT. This increases total body calcium 
to enhance bone density in patients with osteo- 
porosis and decreases urinary calcium concentra- 
tion, thereby reducing renal stone formation. 
Finally, as will be discussed later, thiazides are 
used in combination with loop diuretics to 
enhance diuresis and natriuresis in patients who 
develop diuretic resistance. 

Thiazide diuretics are less potent than loop 
diuretics. They are available as both oral (HCTZ 



and metolazone) and intravenous (chlorothiazide) 
preparations. They are well absorbed following 
oral administration with an onset of action within 
approximately 1 hour. The t 1/2 is variable between 
drugs and they have a duration of action from 6 to 
48 hours depending on the drug. The HCTZ dose 
ranges from 12.5 to 50 mg/day, however, most of 
the benefit occurs with 25 mg/day. Adverse effects 
develop more frequently with higher doses. 
Metolazone dosing ranges from 2.5 mg/day up to 
10 mg twice daily. Patients treated with metola- 
zone should measure their weight daily to avoid 
excessive diuresis and volume contraction. 
Bioavailability is reduced in patients with kidney 
disease, liver disease, and CHF. Patients with 
kidney disease, especially those with a GFR less 
than 25^0 mL/minute, have limited drug delivery 
to its site of action. Metolazone, however, appears 
to maintain efficacy at lower levels of GFR. 

Adverse effects associated with thiazide-type 
diuretics include hypokalemia, hypomagnesemia, 
hyponatremia, and metabolic alkalosis. As with 
loop diuretics, hypokalemia can be life threatening 
in patients with heart disease and those on digoxin. 
Patients with cirrhosis are at risk for encephalopa- 
thy from associated hypokalemia and elevated 
plasma NH 3 levels. Hypercalcemia can develop in 
patients at risk such as those with primary hyper- 
parathyroidism and bed bound patients. Hypona- 
tremia occurs in patients with excessive ADH 
concentrations that are treated with a thiazide 
diuretic. This results from the thiazide's effect to 
diminish the kidney's diluting capacity without 
affecting concentrating ability, allowing ADH to 
enhance •water reabsorption. Hypersensitivity reac- 
tions are noted including pancreatitis, hemolytic 
anemia, and thrombocytopenia. Finally, due to 
increased proximal uric acid reabsorption pro- 
moted by thiazide diuretics, patients can develop 
hyperuricemia and clinical gout. 



Cortical Collecting Duct 

The CCD reabsorbs approximately 1-3% of the fil- 
tered sodium load. Reabsorption of NaCl and 



Chapter 4 



Diuretics 



57 



secretion of potassium is controlled primarily by 
aldosterone and the prevailing plasma potassium 
concentration. Intratubular flow rate and sodium 
concentration also participate in this process. The 
CCD principal cell is constructed to perform this 
function based on the presence of an apical 
epithelial Na + channel (ENaC) and potassium 
channel (ROMK) and a basolateral Na + -K + -ATPase. 
Sodium is reabsorbed through ENaC and potas- 
sium secreted through ROMK following stimula- 
tion of the Na + -K + -ATPase (and opening of ENaC 
and ROMK) by aldosterone and an increased 
plasma potassium concentration. Medications that 
inhibit either ENaC transport or Na + -K + -ATPase 
function increase NaCl excretion while minimiz- 
ing potassium loss. Potassium-sparing diuretics 
such as spironolactone and eplerenone competi- 
tively inhibit the mineralocorticoid receptor and 
blunt aldosterone-induced NaCl reabsorption and 
potassium secretion. These drugs are indicated to 
treat hypertension, especially due to either pri- 
mary or secondary aldosteronism. They are also 
useful to reduce edema and ascites in patients with 
cirrhosis and improve cardiac dysfunction in 
patients with CHF characterized by an ejection 
fraction less than 40%. In contrast, amiloride and 
triamterene reduce NaCl reabsorption and potas- 
sium secretion by blocking ENaC. They are 
employed to reduce potassium losses associated 
with non-potassium-sparing diuretics and thereby 
prevent hypokalemia. Most often, they are given 
in combination with thiazide diuretics (HCTZ and 
amiloride, HCTZ and triamterene). They may also 
be added to a regimen that includes loop diuretics. 
The potassium-sparing diuretics, in particular 
spironolactone and eplerenone, work best when 
aldosterone concentrations are elevated. Spirono- 
lactone, which is available only in oral form, is 
well absorbed. The drug undergoes hepatic 
metabolism. It has a t 1/2 of approximately 20 hours 
and requires up to 2 days to become effective. The 
dose range is 25-200 mg/day. Eplerenone is a rel- 
atively new oral potassium-sparing diuretic that 
has similar renal effects as spironolactone. It dif- 
fers from spironolactone in that it has a shorter t 1/2 
(4-6 hours), is metabolized by the liver (CYP3A4), 



and excreted primarily (67%) by the kidneys. It is 
most effective when dosed twice per day. The 
dose range is 25-100 mg/day. Amiloride is well 
absorbed with oral administration. It has a t l/2 of 
6 hours and is excreted by the kidney. Triamterene 
is similar to amiloride except for a shorter t ]/2 
(3 hours). All drugs that act in the CCD are weak 
diuretics, not unexpected due to the limited 
Na + reabsorption that occurs in this nephron 
segment. 

The most common and concerning adverse 
effect of these drugs is hyperkalemia. The groups 
at highest risk are patients with moderate-to- 
severe kidney disease and those taking either 
potassium supplements or medications that 
impair potassium homeostasis such as the 
angiotensin converting enzyme (ACE) inhibitors, 
angiotensin receptor blockers (ARBs), and 
NSAIDs. Other patients at risk include those with 
diabetes mellitus (hyporeninemic hypoaldostero- 
nism) and tubulointerstitial kidney disease. 
Spironolactone therapy is complicated by gyneco- 
mastia and amenorrhea. This occurs because it 
binds to estrogen and androgen receptors, espe- 
cially "when the dose equals or exceeds 100 mg/day. 
Eplerenone is specific for the mineralocorticoid 
receptor and is free of these adverse effects. In 
addition to hyperkalemia, amiloride causes a mild 
metabolic acidosis. Nausea and vomiting can 
also develop with either amiloride or triamterene 
therapy. Rarely, hyponatremia may occur in the 
elderly. 



Key Points 

Sites of Diuretic Action 



1 . Mannitol and acetazolamide reduce sodium 
reabsorption in proximal tubule. Due to 
increases in sodium reabsorption at down- 
stream sites, they are weak diuretics. 

2. In thick ascending limb of Henle, loop 
diuretics induce a significant natriuresis by 
inhibiting the Na + -K + -2C1~ cotransporter. Loop 
diuretics are employed to treat volume 



58 



Chapter 4 



Diuretics 



overload (CHF, cirrhosis, and nephrotic syn- 
drome), hypertension complicated by 
chronic kidney disease, hypercalcemia, and 
some forms of hyponatremia. 

3. Hypokalemia, volume contraction, and 
metabolic alkalosis are relatively common 
adverse effects of loop diuretics. 

4. Thiazide-type diuretics are used primarily to 
treat hypertension; however, they are also 
useful for osteoporosis, nephrolithiasis, and 
combination therapy for patients with loop 
diuretic resistance. 

5. Hypokalemia, hyponatremia, hypomagne- 
semia, and hyperuricemia are common side 
effects of the thiazide diuretics. 

6. In CCD, the principal cell reabsorbs sodium 
and secretes potassium under the stimula- 
tion of aldosterone, plasma potassium con- 
centration, urinary flow rate, and sodium 
delivery. 

7. Spironolactone and eplerenone reach the 
mineralocorticoid receptor from the peri- 
tubular (blood) side, while amiloride and 
triamterene block apical ENaC from the uri- 
nary space. Despite different mechanisms of 
action, these drugs ultimately enhance NaCl 
excretion and inhibit potassium excretion. 

8. Hyperkalemia is the primary adverse effect 
of diuretics that act in CCD. Patients with 
moderate-to-severe kidney disease and dia- 
betes mellitus, as well as patients on med- 
ications that impair renal potassium 
excretion are at highest risk. 




Diuretic Resistance 



The desired goal of diuretic therapy is typically to 
reduce ECF volume in disorders such as CHF 
(peripheral and pulmonary interstitial edema), 
cirrhosis (ascites and peripheral edema), and 



nephrotic syndrome (peripheral and renal edema) 
and control blood pressure in patients with hyper- 
tension. Inability to achieve these goals despite 
appropriate diuretic therapy (standard doses) is 
the definition of diuretic resistance. Identification 
of the problem is the first step. Assessing diuretic 
resistance requires a logical approach to the prob- 
lem (Table 4.3). The second step requires appro- 
priate diagnosis of the cause of edema. It is 
essential to ensure that the patient has general- 
ized renal-related edema rather than localized 
edema from venous or lymphatic obstruction. 
Cyclic edema, a problem generally found only 
in women and interstitial edema due to fluid 

Table 43 

Approach to Patients with Diuretic Resistance 



Step 1: Define diuretic resistance as failure to 
resolve edema or hypertension with standard 
diuretic doses. 

Step 2: Identify cause of edema as renal-related 
edema vs. edema due to other causes 
(obstruction of veins or lymphatics, cyclic 
edema, calcium channel blocker therapy). 

Step 3: Examine for incomplete therapy of the 
primary disorder requiring diuretic therapy. 

Step 4: Assess patient compliance with salt 
restricted diet and diuretic regimen. 

Step 5: Consider pharmacokinetic alterations of 
the diuretic including incomplete or delayed 
medication absorption and/or impaired kidney 
function (acute or chronic renal failure). 

Step 6: Consider pharmacodynamic alterations 
of the diuretic regimen including severity of 
the edema state, activation of the renin- 
angiotensin-aldosterone system and sympa- 
thetic nervous system, and compensatory 
hypertrophy of distal nephron sites (particu- 
larly the DCT). 

Step 7: Explore for adverse drug interactions 
including concurrent traditional NSAID or 
selective COX-2 inhibitor therapy. 



Abbreviations: DCT, distal convoluted tubule; NSAID, nonsteroidal 
anti-inflammatory drug; COX-2, cyclooxygenase-2. 



Chapter 4 



Diuretics 



59 



redistributed from the plasma compartment, as 
seen with calcium channel blocker therapy, are 
other forms of edema not amenable to diuretic 
treatment. 

The next step (step 3) is to examine whether 
the primary disorder requiring diuretic therapy is 
adequately treated. Clinical disorders associated 
with impaired diuretic response include CHF, cir- 
rhosis with ascites, nephrotic syndrome, hyper- 
tension, and kidney disease. These disease states 
and their specific causes of diuretic resistance are 
covered in more detail later in the chapter, but an 
example of resistance due to inadequate therapy 
of the primary disorder includes suboptimal man- 
agement of CHF. These patients often require 
afterload reduction with an antagonist of the 
renin-angiotensin-aldosterone system (RAAS) in 
addition to diuretic therapy. In patients with 
severe congestive cardiomyopathies and decom- 
pensated heart failure, an intravenous inotropic 
agent such as dobutamine or milrinone may be 
indicated to improve cardiac pump function and 
renal perfusion. Excessive reductions in arterial 
blood pressure may also induce diuretic resis- 
tance. Allowing the blood pressure to increase 
can be beneficial in this situation. 

A common cause of diuretic resistance that 
should not be overlooked is poor compliance with 
dietary salt restriction or the actual diuretic regi- 
men. Step 4 mandates a thorough history to iden- 
tify either of these problems. Direct questioning 
about diet, in particular ingestion of canned foods 
or fast foods, is often illuminating. Many patients 
also believe that drinking large amounts of certain 
beverages (gatorade, powerade) is healthy. This 
behavior can overcome diuretic effect on edema 
formation. Adverse effects from diuretics, such as 
impotence and muscle cramps, may promote non- 
compliance. These symptoms should be inquired 
about in all patients. 

Step 5 requires a search for alterations in phar- 
macokinetics as the source of diuretic resistance. 
One common cause of ineffective diuresis is poor 
absorption of the agent. Patients with edematous 
states may also have bowel edema. This hampers 
gastrointestinal absorption of the oral diuretic, 



causing incomplete or delayed drug absorption. 
In patients with poor cardiac output, vascular dis- 
ease of the intestinal tree, and advanced cirrhosis, 
blood flow to the intestinal absorptive sites may 
be inadequate to allow appropriate drug absorp- 
tion. The presence of kidney disease (reduced 
GFR) decreases the concentration of diuretic that 
is secreted in active form into the tubular lumen, 
the site of their action. It also increases the frac- 
tion that is eliminated by hepatic excretion or 
glycosylation. 

Pharmacodynamic causes of diuretic resistance 
are included in step 6. The most important cause 
in this category is extreme renal sodium retention 
from various mechanisms. Pronounced activation 
of the RAAS and sympathetic nervous system 
(SNS) reduces diuretic response by lowering GFR 
(reduced filtered load of sodium) and increasing 
NaCl reabsorption along all nephron segments. 
Angiotensin II enhances NaCl reabsorption in 
proximal tubule, loop of Henle, and DCT, while 
aldosterone increases NaCl reabsorption in DCT 
and CCD. Stimulation of the RAAS and SNS occurs 
for two basic reasons. First, the underlying dis- 
ease state, which includes conditions such as CHF, 
cirrhosis, and nephrotic syndrome, decreases 
effective arterial blood volume. This activates the 
RAAS, SNS, and other pathways that enhance 
renal sodium reabsorption. Second, diuretics also 
may reflexively activate the RAAS and SNS, per- 
petuating diuretic resistance. An important partic- 
ipant in the development of diuretic resistance is 
compensatory changes in distal nephron tubular 
cells following chronic therapy with loop diuret- 
ics. Increased delivery of NaCl to the DCT induces 
hypertrophy and hyperplasia of tubular cells 
(Figure 4.2) and increases the density of both Na + - 
K + -ATPase pump sites and NCC cotransporters. 
This intranephronal adaptation enhances the 
intrinsic capacity of the DCT to reabsorb Na + and 
CI". Experimental animal data suggests that treat- 
ment with loop diuretics increases reabsorption 
of NaCl threefold in DCT. As will be discussed 
later, these changes in the DCT underlie the 
enhanced natriuretic response noted when a thi- 
azide diuretic is added to a loop diuretic. 



60 



Chapter 4 



Diuretics 



Figure 4.2 



Hypertrophy and increase in 
metabolic activity of distal tubule 
cells resulting in increased 
sodium reabsorption 





ilWftfr 



n=;i i i 




Intranephronal adaptation of distal tubular (DT) cells with chronic loop diuretic therapy. 
Hypertrophy and hyperplasia of DT cells and increased density of Na + -K + -ATPase pump sites 
and NCC cotransporters induce diuretic resistance. Abbreviation: TAL, thick ascending limb. 



The final step in the assessment of diuretic 
resistance is to inquire about use of medications 
that may blunt diuretic action. Two particularly 
important culprits are the traditional NSAIDs and 
selective cyclooxygenase-2 inhibitors (COX-2). 
These drugs impair intrarenal prostaglandin syn- 
thesis by the COX-2 isoenzyme, which is impor- 
tant in the kidney to maintain renal blood flow 
and GFR and to block NaCl reabsorption in all 
nephron segments. Reduced natriuresis and 
increased blood pressure, as well as diuretic 
resistance results in patients with at risk physiol- 
ogy (hypertension, CHF, cirrhosis, nephrotic syn- 
drome, and chronic kidney disease). Other drugs 
that impair diuretic response do so by reducing 
delivery of active diuretic to the site of action by 
competing for secretion through proximal tubular 
cell transport pathways. Probenecid, cimetidine, 
and trimethoprim are examples of drugs that com- 
pete for these pathways and reduce secretion of 
diuretic into urine, where they reach their site of 
action. 



All of these factors need to be considered to 
adequately diagnose and successfully treat the 
patient suffering from either uncontrolled hyper- 
tension or refractory edema (or both) associated 
with diuretic resistance. 



Key Points 

Diuretic Resistance 



1 . Diuretic resistance is defined as the inability 
to control blood pressure or reduce edema 
formation ciespite appropriate diuretic ther- 
apy (standard doses). 

2. The logical approach to diuretic resistance 
includes assessment of variables such as 
verification of renal-related edema, appro- 
priate therapy of the primary disorder, 
dietary and diuretic compliance, pharmaco- 
kinetic and pharmacodynamic issues, and 
therapy with antinatriuretic medications. 



Chapter 4 



Diuretics 



61 



Activation of the RAAS and SNS promote 
renal sodium retention, while intranephronal 
adaptation by DCT cells with chronic 
loop diuretic therapy blunts diuretic 
response. 

Concomitant therapy with NSAIDs and 
selective COX-2 inhibitors reduce 
prostaglandin-induced NaCl excretion and 
perpetuate diuretic resistance. 




Clinical Conditions Associated 

with Specific Causes of Diuretic 

Resistance 



In addition to the previously noted general causes 
of diuretic resistance, certain clinical conditions that 
can be associated with poor diuretic response are 
encountered in practice. Each of these disease 
states induces diuretic resistance through effects on 
circulatory and renal hemodynamics and/or tubular 
transport function in various nephron segments. 



Congestive Heart Failure 

The hemodynamics associated with CHF results 
in sodium and water retention from reduced renal 
perfusion, activated RAAS and SNS, and enhanced 
arginine vasopressin (AVP) release. The severity 
of cardiac dysfunction dictates the degree of tubu- 
lar NaCl and fluid reabsorption. It is therefore 
intuitive that the ideal treatment of CHF is directed 
at improving cardiac function. When this fails or is 
only partially successful, assessment of other fac- 
tors of diuretic resistance in this clinical condition 
need to be considered. Impaired absorption of 
diuretic across the gastrointestinal (GI) tract con- 
tributes to suboptimal response to the drug. A 50% 
decrease in peak urinary diuretic concentrations 



following oral administration was noted in 
patients with CHF. Bowel edema, reduced bowel 
wall perfusion, and disturbed GI motility can alter 
GI tract absorption. 



Nephrotic Syndrome 

Sodium and fluid retention in patients with 
nephrotic syndrome develops from activated 
RAAS and SNS, increased concentrations of AVP, 
and direct stimulation of NHE3 transport activity 
in proximal tubule by excessive urinary protein 
concentration. The presence of renal dysfunction 
exacerbates nephrotic syndrome as it reduces the 
filtered load of NaCl. Primary renal sodium reten- 
tion is an important cause of edema formation in 
a subgroup of these patients. Either complete or 
partial remission of the primary renal lesion 
(reduce proteinuria) and ACE inhibitors or ARBs 
are basic steps to improve renal sodium and fluid 
excretion. Diuretic resistance occurs by several 
mechanisms. Because loop and thiazide diuretics 
are highly protein bound, the volume of distribu- 
tion of drug increases due to hypoalbuminemia. 
This reduces the concentration of drug in the cir- 
culation and the amount delivered to the kidney. 
Also, albumin directly stimulates the organic 
anion transport pathway that transports these 
drugs from blood into the proximal tubular cell. 
Thus, hypoalbuminemia hampers urine diuretic 
concentrations independent of renal delivery. 
Collecting duct resistance to ANP-associated natri- 
uresis also contributes to diuretic resistance. 
Finally, since albumin binds diuretics, excessive 
concentrations of albumin in the tubule fluid 
blunt the ability of these drugs to inhibit NaCl 
transport in the loop of Henle. 



Cirrhosis 

Edema formation and ascites occur most commonly 
with advanced cirrhosis or during acute decompen- 
sation of chronic liver disease. Enhanced proximal 
tubular NaCl and fluid reabsorption, stimulated 



62 



Chapter 4 



Diuretics 



by an activated RAAS and SNS, reduces NaCl 
delivery to more distal sites where loop diuretics 
act. In addition, secondary aldosteronism stimulates 
avid NaCl uptake by the DCT and CCD. These 
mechanisms are integral to reduced diuretic 
response in patients with early cirrhosis. Patients 
with advanced cirrhosis and gross ascites have, in 
addition to the aforementioned factors, other 
causes of diuretic resistance. Intestinal edema 
limits drug absorption, while the volume of distri- 
bution of drug is increased significantly with 
hypoalbuminemia and a markedly expanded ECF 
volume. Unrecognized reductions in GFR also 
contribute to suboptimal diuresis. Finally, sponta- 
neous bacterial peritonitis, hypotension, and 
bleeding from varices can exacerbate the tenuous 
hemodynamics in the cirrhotic and underlie the 
development of diuretic resistance. 



Hypertension 

Essential hypertension remains primarily a distur- 
bance in renal salt handling. Thereby, salt restric- 
tion and diuretic therapy are the most appropriate 
initial management options. While dietary sodium 
restriction and diuretics are successful in many 
patients, as much as a third of patients remain 
resistant to therapy. In this situation, a lapse in 
dietary salt restriction, usually from ingestion of 
processed, canned, or fast foods that contain 
excessive amounts of sodium, is present. In some 
patients, the RAAS is activated prior to diuretic 
therapy. Treatment of these patients with a 
diuretic further activates the RAAS as well as the 
SNS, promoting renal NaCl retention and periph- 
eral vasoconstriction. These effects can induce 
hypertension resistant to standard diuretic ther- 
apy. The addition of moderate-to-severe kidney 
disease to hypertension is a frequent cause of 
diuretic resistance. Salt restriction alone or with a 
diuretic is typically insufficient to control blood 
pressure. This is particularly true if the GFR is 
below the 25—40 mL/minute and the patient is 
receiving a thiazide diuretic. Reduced drug deliv- 
ery and limited diuretic effect on natriuresis 



underlies resistance to thiazides, although meto- 
lazone maintains fairly good efficacy in these 
patients. 

Kidney Disease 

As GFR declines, the diuretic and natriuretic effect 
of diuretics diminishes. Thiazide diuretics with the 
exception of metolazone are generally ineffective 
with a GFR below 30 mL/minute, while escalating 
doses of loop diuretics are required to promote an 
adequate, albeit reduced diuresis. Reduction in 
filtered sodium, reduction in delivered drug, and 
accumulation of endogenous organic anions with 
uremia are responsible for diuretic resistance. 
Endogenous organic anions compete with diuret- 
ics for the organic anion transport pathway, 
thereby reducing secretion of drug into tubular 
fluid. Thus, the diuretic can't reach its site of 
action in a concentration sufficient to inhibit 
NaCl reabsorption. 



Key Points 

Clinical Conditions Associated with Specific Causes 
of Diuretic Resistance 



1. Diuretic resistance in CHF is due to multiple 
factors. The hemodynamics of cardiac dys- 
function, as well as reduced drug absorption 
from bowel wall edema, GI dysmotility, and 
reduced perfusion contribute to NaCl reten- 
tion and impaired diuretic response. 

2. Nephrotic syndrome promotes diuretic 
resistance due to hypoalbuminemia and 
albuminuria. Activation of the RAAS and 
SNS, as well as direct stimulation of NH 3 in 
proximal tubule induces NaCl retention. 
Reduced drug delivery to renal sites of 
action, decreased collecting duct respon- 
siveness to ANP, and binding of diuretic in 
tubular fluid reduces efficacy. 

3. Extreme activation of the RAAS anci SNS 
promote diuretic resistance in cirrhosis. 



Chapter 4 



Diuretics 



63 



Bowel edema, an expanded volume of dis- 
tribution, and reduced GFR also contribute 
to NaCl retention and diuretic resistance. 
Renal failure causes suboptimal response to 
diuretics from a reduction in filtered sodium 
and impaired delivery of diuretics to their 
respective sites of action. Thiazide diuretics 
with the exception of metolazone become 
ineffective at a GFR less than 30 mL/minute. 




Treatment of Diuretic 
Resistance 



Once diuretic resistance is identified and appro- 
priate steps to assess the cause of the resistant 
state are undertaken, a number of maneuvers can 
be used to improve diuretic response. Therapy is 
based on the recognized cause of diuretic resis- 
tance and the underlying clinical condition. 



Intravenous Diuretic Therapy 

Initial treatment of patients with diuretic resis- 
tance is escalation of the oral dose of loop diuretic 
(assuming the patient was switched from a thi- 
azide-type diuretic previously). Ceiling doses for 
oral loop diuretics are noted in Table 4.2. The 
dosing interval for loop diuretics must be no 
longer than 8 hours (based on time of drug effect), 
or a rebound increase in sodium reabsorption 
(postdiuretic NaCl retention) will occur. Intravenous 
therapy is often required to restore diuretic effi- 
cacy in patients with absorptive problems such as 
bowel edema, altered GI motility, and reduced 
bowel perfusion. Ceiling doses for IV diuretics are 
also noted in Table 4.2. The major limitation of 
high-dose loop diuretic therapy is drug-related 
toxicity. Ototoxicity occurs in patients receiving 



very high-dose or prolonged high-dose therapy. 
This adverse effect is typically reversible, but is 
rarely associated with an irreversible defect. 
Myalgias may complicate high-dose bumetanide 
therapy; while thiamine deficiency was described 
in patients receiving chronic furosemide for CHF. 



Continuous Diuretic Infusion 

Patients who are failing or responding marginally 
to high-dose IV loop diuretics may benefit from 
continuous diuretic infusion. This therapy has 
several potential advantages. Trough concentra- 
tions of loop diuretic are avoided and postdiuretic 
NaCl retention is averted. Continuous infusions 
are also more efficient, achieving approximately 
30% more natriuresis for the same IV bolus dose. 
The efficacy is greatest for bumetanide (which has 
the shortest t y2 ) and least for torsemide (which 
has the longest f 1/2 ). Titration of diuretic dose is 
more easily achieved with continuous infusion. 
Finally, toxicity is reduced with continuous infu- 
sion as the spike in peak concentrations is obvi- 
ated. Thus, the occurrence of ototoxicty and 
myalgias is lessened. Table 4A reviews the start- 
ing bolus dose and continuous infusion dose 
range for loop diuretics. Careful observation to 
avoid overdiuresis and other electrolyte abnor- 
malities is required. 



Table 4.4 



Dosing Guidelines for Continuous Infusions of Loop Diuretics 




Bolus Dose 


Infusion Rate 


Diuretic 


(mg) 


(mg/hour) 


Furosemide 


20-80 


2-100 (up to 
1.0 mg/kg/hour) 


Torsemide 


25 


1-50 (up to 
0.5 mg/kg/hour) 


Bumetanide 


1.0 


0.2-2 (up to 

0.02 mg/kg/hour) 



64 



Chapter 4 



Diuretics 



Combination Diuretic Therapy 

The addition of a second class of diuretics can 
often overcome diuretic resistance. In general, the 
patient who is failing the ceiling dose of a loop 
diuretic benefits from addition of a thiazide 
diuretic. While the combination of a loop and 
proximal tubule diuretic increases efficacy, addi- 
tion of a DCT diuretic to a loop diuretic is syner- 
gistic and more potent. This enhanced efficacy 
results from several effects, none of "which is due 
to a change in the bioavailability or pharmacoki- 
netics of either drug. The longer half-life of thi- 
azide diuretics attenuates the postdiuretic NaCl 
retention of loop diuretics. High-dose IV chloro- 
thiazide improves delivery of sodium from the 
proximal tubule to the loop of Henle by inhibiting 
carbonic anhydrase. The most important effect of 
thiazides in improving loop diuretic efficacy is 
their ability to blunt NaCl reabsorption by the 
hypertrophic and hyperplastic DCT cells (Figure 
4.3). Patients with CHF, cirrhosis, and nephrotic 
syndrome are likely to gain benefit from a CCD 



diuretic like spironolactone or eplerenone. This 
diuretic class modulates the activated RAAS in 
these patients and reduces the development of 
potentially harmful hypokalemia. 

Thiazide diuretics should be added to loop 
diuretics that are at their ceiling dose. Also, either 
proximal tubule or CCD diuretics can be added 
depending on the underlying clinical condition 
and desired effect. For example, patients with a 
severe metabolic alkalosis and edema may benefit 
from acetazolamide, as long as hypokalemia is 
corrected prior to administration. In patients with 
an activated RAAS and concurrent hypokalemia 
(without advanced kidney disease), a CCD diuretic 
should be considered. Patients with CHF have 
improved heart failure management and survival 
with the addition of spironolactone or eplerenone. 
Table 4.5 notes the diuretic doses that are appro- 
priate for use in combination with a loop diuretic. 
Combination diuretic therapy can promote vigor- 
ous diuresis with severe hypovolemia, as well as 
electrolyte disturbances. Cautious prescription 
and close monitoring for adverse effects is 



Figure 4.3 




Initiation of a thiazide diuretic blocks distal tubular 
sodium reabsorption and reverses cellular 
hypertrophy restoring the natriuretic response. 



ti 



Thiazide 
diuretic 

ij- Furosemide 



■■ ; :- ■ ■ ..-KZZ':.'.:*:: 



La. 
v 



® 



Chronic 
furosemide 




Acute 
furosemide 



Combination therapy with a thiazide-type diuretic and loop diuretic improves 
diuretic response. Enhanced NaCl reabsorption by hypertrophic and hyper- 
plastic distal tubular (DT) cells is inhibited by the addition of a thiazide-type 
diuretic to a loop diuretic. Abbreviation: TAL, thick ascending limb. 



Chapter 4 



Diuretics 



65 



Table 4.5 



Dosing Guidelines for Diuretics Added to Loop Diuretics 
for Combination Therapy 



Class of Diuretic 


Dose Range (mg/day) 


Proximal tubule 




diuretics 




Acetazolamide 


250-375; up to 500 (IV) 


Distal convoluted 




tubule diuretics 




Chlorothiazide 


500-1000 (IV) 


Metolazone 


2.5-10 (oral) 


Hydrochlorothiazide 


25-100 (oral) 


Collecting tubule 




diuretics 




Amiloride 


5-10 (oral) 


Spironolactone 


100-200 (oral) 


Eplerenone 


25-100 (oral) 



Abbreviation: IV, intravenous. 



required. Patients should be counseled to perform 
daily weights and contact their physician with any 
changes greater than 2 lb/day. In addition, elec- 
trolytes and renal function should be measured 
within 5-7 days of initiating combination therapy. 



Cardiovascular Agents 

Several drugs available as an infusion increase renal 
blood flow, GFR, and natriuresis through both car- 
diovascular and direct renal effects. Acute dopamine 
infusion at very low doses (1-3 u.g/kg/minute) stim- 
ulates renal dopamine receptors (DAj and DA 2 ) and 
stimulates natriuresis. A dose of 5 u,g/kg/minute 
stimulates beta-adrenergic receptors and increases 
cardiac output, thereby enhancing renal perfusion 
and diuresis. Doses greater than 5 u,g/kg/minute 
are associated with tachycardia and increased sys- 
temic vascular resistance, and potentially reduce 
natriuresis. After 24 hours of dopamine infusion, 
however, natriuresis wanes. The addition of 
dopamine to diuretics is of limited benefit and is 
associated with potentially serious tachyarrhyth- 



mias. Fenoldopam is a selective DA a receptor ago- 
nist that is approved to treat severe (urgent or malig- 
nant) hypertension. It lowers blood pressure by 
vasodilating the vasculature. It also induces a natri- 
uresis by binding renal DAj receptors and inhibit- 
ing the action of NHE3. Its renal effects are six times 
more potent than dopamine. 

Dobutamine is an inotropic agent and dopamine 
derivative that does not cause systemic or mesen- 
teric vasoconstriction. It increases cardiac output 
and reflexively reduces systemic vascular resis- 
tance. These effects improve renal blood flow in 
the patient with congestive cardiomyopathy and 
enhance urinary sodium and fluid excretion fol- 
lowing diuretic administration. The combination 
of dopamine and dobutamine produces synergis- 
tic effects, providing a rationale for combining 
low doses of dopamine (2—5 u.g/kg/minute) and 
dobutamine in critically ill patients with impaired 
cardiac pump function. 

Atrial natriuretic peptide (ANP) is a hormone 
produced by myocardial atrial (and ventricular 
less commonly) cells when volume expansion 
increases cardiac wall stress. Brain natriuretic 
peptide (BNP) is similar to ANP. Although it was 
initially identified in the brain, it is also synthe- 
sized in the heart, particularly the ventricles. Both 
peptides are released in response to the high fill- 
ing pressures associated with heart failure. These 
hormones have natriuretic and diuretic effects 
and also lower blood pressure by reducing RAAS, 
SNS, and endothelin activity. Diuresis and natri- 
uresis occurs through increases in GFR (increased 
Na + filtration), stimulation of cyclic GMP in the 
inner medullary collecting duct (closing nonspe- 
cific cation channels), stimulation of dopamine 
secretion in the proximal tubule, and inhibition of 
All and aldosterone production. Based on these 
characteristics, ANP and in particular, BNP 
(nesiritide) are infused intravenously to treat 
heart failure resistant to other medical manage- 
ment. Nesiritide is administered as an IV bolus 
of 2 fig/kg, followed by a continuous infusion of 
0.01 |J.g/kg/minute titrated up to a maximum dose 
of 0.03 |ag/kg/minute. This therapy often increases 
natriuresis, increases cardiac index, lowers 



66 



Chapter 4 



Diuretics 



cardiac filling pressure, and reduces blood pres- 
sure. The major adverse effect is hypotension, 
which is reversible with drug discontinuation. 

Vasopressin (V 2 ) receptor antagonists represent 
a class of agents that target the AVP receptor in 
kidney. Since AVP increases water reabsorption in 
CCD by increasing the number of aquaporins 
(water channels) in the apical membrane, V 2 
antagonists facilitate a water diuresis. Orally active 
V 2 antagonists are available for experimental use. 
They will likely be beneficial to enhance free 
water clearance and treat various forms of hypona- 
tremia, including that induced by diuretics. 



Key Points 

Treatment of Diuretic Resistance 



1 . High-dose intravenous diuretics overcome 
decreased GI absorption that can occur with 
oral agents. Ototoxicity needs to be monitored 
in patients receiving high-dose loop diuretics. 

2. Combining a loop diuretic with an agent 
that acts at another nephron segment effec- 
tively overcomes diuretic resistance. Certain 
clinical conditions warrant choice of one 
class of diuretic over another. For example, 
a patient with edema and metabolic alkalo- 
sis may benefit from the addition of acetazo- 
lamide to a loop diuretic. 

3. Combination diuretic therapy must be moni- 
tored closely for hypovolemia and elec- 
trolyte disturbances. Hypokalemia is a 
particular concern when loop diuretics are 
combined with either proximal tubule 
diuretics or DCT diuretics. 

4. Dopamine and fenoldopam increase diure- 
sis and natriuresis through increases in renal 
blood flow, GFR, and direct tubular effects. 
Low doses are effective, while higher doses 
add little benefit but are associated with 
dangerous tachyarrhythmias. 

5. Dobutamine is an inotropic agent that 
improves cardiac output and lowers 



systemic vascular resistance. These effects 
improve renal blood flow and GFR, thereby 
enhancing response to diuretics. The combi- 
nation of dobutamine and dopamine is 
more effective in increasing natriuresis than 
either drug alone. 

6. Atrial natriuretic peptide and nesiritide 
increase diuresis and natriuresis through 
multiple effects along the nephron. They are 
used in CHF refractory to routine medical 
management. 

7. V 2 antagonists are experimental agents with 
great potential for treatment of hypona- 
tremia from SIADH and diuretic therapy. 
They act by blocking the binding of antidi- 
uretic hormone to the V, receptor, reducing 
the number of aquaporins available to reab- 
sorb water in CCD. 



Additional Reading 

Denton, M.D., Chertow, G.M., Brady, H.M. "Renal- 
dose" dopamine for the treatment of acute renal fail- 
ure: scientific rationale, experimental studies and 
clinical trials. Kidney Int 49:4-14, 1996. 

Ellison, D.H. The physiologic basis of diuretic syner- 
gism: its role in treating diuretic resistance. Ann 
Intern Med 114:886-894, 1991. 

Ellison, D.H. Diuretic drugs and the treatment of 
edema: from clinic to bench and back again. Am J 
Kidney Dis 23:623-643, 1994. 

Ellison, D.H., Okusa, M.D., Schrier, R.W. Mechanisms of 
ciiuretic action. In: Schrier, R.W. (ed.), Diseases of the 
Kidney and Urinary Tract, 7th ed. Lippincott Williams 
&Wilkins, Philadelphia, PA 2001, pp. 2423-2454. 

Martin, S.J., Danziger, L.H. Continuous infusion of loop 
diuretics in the critically ill: a review of the literature. 
Crit Care Med 22: 1323-1329, 1994. 

Rose, B.D. Diuretics. Kidney Int 39 :336-352, 1991. 

Wilcox, C.S. Diuretics. In: Brenner, B.M. (ed.), The 
Kidney, 5th ed. W.B. Saunders, Philadelphia, PA, 
1996, pp. 2299-2330. 



Robert F. Reilly, Jr. 



Intravenous Fluid 
Replacement 




Recommended Time to Complete: 1 day 



QuiMj+C Quettlew* 



1. How are sodium and water distributed across body fluid compart- 
ments and what forces govern their distribution? 

2. What options are available for volume resuscitation? 

1. What are the guiding principles behind intravenous fluid 

replacement? 
fy. How does one assess the degree of intravascular and extracellular 

fluid volume depletion? 
S. How does one manage the critically ill patient with extracellular fluid 

(ECF) volume depletion? 




Introduction 



Every physician and physician in training must 
master the ability to use intravenous solutions for 
the expansion of the intravascular and ECF 
volume. Proper understanding of solutions available 



(colloid vs. crystalloid), their space of distribution, 
their cost and potential adverse effects, as well as 
an assessment of the patient's volume status are 
essential for their proper use. Mistakes are made 
when there is improper understanding of the 
patient's volume and electrolyte status. 

Hypovolemia is a common problem in hospi- 
talized patients, especially those in critical care 
units. It can occur in a variety of clinical settings 



67 



68 



Chapter 5 ♦ Intravenous Fluid Replacement 




including those characterized by obvious fluid 
loss as with hemorrhage or diarrhea, as well as in 
patients without obvious fluid loss as a result of 
vasodilation with sepsis or anaphylaxis. In one 
study, inadequate volume resuscitation was 
viewed as the most common management error 
in patients who died in the hospital after admis- 
sion for treatment of injuries. 



Understanding Body Fluid 
Compartments 



Total body water constitutes 60% of lean body 
weight in men and 50% of lean body weight in 
women. It is distributed between intracellular fluid 
(ICF) (66.7%) and ECF (33.3%) compartments (see 
Figure 5.1). The ECF compartment is further sub- 
divided into intravascular and interstitial spaces. 
Twenty-five percent of the ECF compartment con- 
sists of the intravascular space, with the remaining 
75% constituted by the interstitial space. 



Osmotic forces govern the distribution of water 
between ICF and ECF. The ECF and ICF are in 
osmotic equilibrium, and if an osmotic gradient is 
established, "water will flow from a compartment 
of low osmolality to a compartment of high osmo- 
lality. For example, if a solute is added to the ECF 
such as glucose that raises its osmolality, water 
will flow out of the ICF until the osmotic gradient 
is dissipated. Water movement into and out of 
cells, particularly in the brain, with resultant cell 
swelling or shrinking is responsible for the symp- 
toms of hyponatremia and hypernatremia. 

Urea distributes rapidly across cell membranes 
and equilibrates throughout total body water and 
is with one exception, an ineffective osmole. 
Equilibration of urea across the blood-brain bar- 
rier can take several hours. If urea is rapidly 
removed from the ECF with the initiation of 
hemodialysis in a patient with end-stage renal 
disease, the potential exists for the development 
of "dialysis disequilibrium syndrome." Patients at 
increased risk are those with a blood urea nitro- 
gen (BUN) >100 mg/dL that have rapid rates of 
urea removal during their first or second 
hemodialysis session. As urea concentration falls 
during hemodialysis a transient osmotic gradient 



Figure 5-1 



Starling forces 



Osmolar forces 



► 


¥■ 


Intra- 


Interstitial fluid 




vascular 


15% 




fluid 






5% 







Extracellular fluid 
20% 



Intracellular fluid 
40% 



Body fluid compartments. Total body water consists of intracellular fluid and extracellular 
fluid. Intracellular fluid is 40% of lean body weight and extracellular fluid is 20% of lean 
body weight. The major driving force for fluid movement between these compartments is 
osmosis. The extracellular fluid can be further subdivided into the intravascular and inter- 
stitial spaces that constitute 5 and 15% of total body weight, respectively. The major driv- 
ing force for fluid movement between these compartments are Starling's forces. 



Chapter 5 ♦ Intravenous Fluid Replacement 



69 



for water movement into the brain is established. 
This results in headache, nausea, vomiting, and in 
some cases generalized seizures. Dialysis disequi- 
librium can be minimized by initiating hemodial- 
ysis with low blood fiow rates and for short 
periods of time. 

Each compartment has one major solute that 
acts to hold water within it: ECF — Na salts; ICF — K 
salts; and intravascular space — plasma proteins. It 
is important to appreciate that the serum sodium 
concentration is a function of the ratio of the 
amounts of sodium and water present and does 
not correlate with ECF volume, which is a func- 
tion of total body sodium. This is illustrated by the 
three examples below where ECF volume is 
increased in all three cases but serum sodium con- 
centration is high, low, and normal. 

If one adds NaCl to the ECF, it remains within 
the ECF increasing its osmolality resulting in water 
movement out of cells. Equilibrium is character- 
ized by hypernatremia, an increase in ECF osmo- 
lality (NaCl addition), and ICF osmolality (water 
loss). As a result ECF volume increases and ICF 
volume decreases. Therefore, even though sodium 



is restricted to the ECF, its administration results in 
an increase in osmolality of both ECF and ICF, and 
a reduction in ICF volume. The osmolar effects of 
NaCl administration are distributed throughout 
total body water even though NaCl is confined to 
the ECF. If one adds 1 L of water to the ECF there 
is an initial fall in ECF osmolality promoting water 
movement into cells. Equilibrium is characterized 
by hyponatremia and an expansion of both ECF 
and ICF volumes. One-third of the water remains 
in the ECF and only 8% in the intravascular space. 

Finally, if one adds 1 L of isotonic saline to the 
ECF, the saline is confined to the ECF and it will 
increase by 1 L. The intravascular volume will 
increase by 250 mL. Since there is no change in 
osmolality there is no shift of water between the 
ECF and ICF and serum sodium concentration 
remains unchanged. 

Starling's forces govern movement of water 
between intravascular and interstitial spaces 
(Figure 5.2). Expansion of the interstitial space 
results in the clinical finding of edema. Edema 
fluid resembles plasma in electrolyte content, 
although its protein content may vary. The interstitial 



Figure 5-2 



From 
arteriole 






Capillary 



m44 




To 

venule 



^> 



Forces moving fluid out- 
intravascular hydrostatic pressure 
interstitial oncotic pressure 



Forces moving fluid in- 
travascular oncotic pressure 
interstitial hydrostatic pressure 



a 



Lymphatic drainage 



D^ 



To venous circulation 



Starling's forces across the capillary bed. Starling's forces that move fluid out of the capillary 
are intravascular hydrostatic pressure (most important) and interstitial oncotic pressure. 
Forces acting to move fluid into the capillary are the intravascular oncotic pressure (most 
important) and interstitial hydrostatic pressure. Fluid in the interstitial space drains back to 
the venous system via lymphatics. 



70 



Chapter 5 ♦ Intravenous Fluid Replacement 



Table 5.1 

Mechanism of Edema Formation 



Increased 
Hydrostatic Pressure 



Decreased Capillary 
Oncotic Pressure 



Venous obstruction 
Congestive heart failure 
Cirrhosis of the liver 



Nephrotic syndrome 
Malabsorption 
Cirrhosis of the liver 



space must be expanded by 3-5 L before edema in 
dependent areas is detected. Edema may be local- 
ized due to vascular or lymphatic injury or it may 
be generalized as in congestive heart failure. Forces 
governing edema formation are summarized by the 
equation below where K c reflects the surface area 
and permeability of the capillary. LR is the lym- 
phatic return. P c and P t are the hydrostatic pres- 
sures in the capillary and tissue, respectively, 
whereas K c and 7t t are the oncotic pressures in the 
capillary and tissue, respectively. 

Net accumulation = K c X [(P c - K c ~) - (P t - K t ~)] - LR 

The most common abnormalities leading to 
edema formation are an increase in capillary 
hydrostatic pressure or a decrease in capillary 
oncotic pressure. In CHF, for example, the P c 
increases. In cirrhosis, the P c increases (secondary 
to portal hypertension) and the n c declines. The 
major specific causes of edema, classified accord- 
ing to the major mechanism(s) responsible are 
shown in Table 5.1. The final common pathway 
maintaining generalized edema is renal retention 
of excess sodium and water. 



Key Points 

Body Fluid Compartments 



1 . Total body water constitutes 60% of lean 
body weight in men and 50% of lean body 
weight in women. It is distributed between 
ICF (67.7%) and ECF (33-3%) compartments. 



6. 



7. 



Twenty-five percent of the ECF compart- 
ment consists of the intravascular space, 
with the remaining 75% constituted by the 
interstitial space. 

Osmotic forces determine the distribution 
of water between ICF and ECF. 
Each compartment has one major solute that 
acts to hold water within it: ECF-Na salts; 
ICF-K salts; and intravascular space-plasma 
proteins. 

The serum sodium concentration is a func- 
tion of the ratio of sodium to water and does 
not correlate with ECF volume, which is a 
function of total body sodium. 
Starling's forces govern movement of water 
between intravascular and interstitial spaces. 
The most common abnormalities leading to 
edema formation are an increase in capillary 
hydrostatic pressure or a decrease in capil- 
lary oncotic pressure. 




Replacement Options— Colloid 
Versus Crystalloid 



Despite the fact that adequate volume replace- 
ment is essential in the management of critically 
ill patients, the optimal replacement fluid remains 
a focus of considerable debate. The clinician can 
choose between a wide array of crystalloids and 
colloids. Crystalloid solutions consist of water 
and dextrose and may or may not contain other 
electrolytes. The composition varies depending 
on the type of solution. Some of the more com- 
monly used crystalloid solutions and their com- 
ponents are shown in Table 5.2 and include 
dextrose in water (D 5 W), normal saline (0.9%), 
one-half normal saline (0.45%)), and Ringer's lac- 
tate. Ringer's lactate is used more commonly on 
surgical services and normal saline on medical 
services. 



Chapter 5 ♦ Intravenous Fluid Replacement 



71 



Table 5.2 

Commonly Used Crystalloid Solutions 





Osmolality 


Glucose 


Sodium 


Chloride 


Lactate 


Preparation 


(mOsm/L) 


(g/L) 


(meq/L) 


(meq/L) 


(meq/L) 


D 5 W 


252 


50 


— 


— 


— 


0.9% NS 


308 


— 


154 


154 


— 


0.45% NS 


154 


— 


77 


77 


— 


Ringer's lactate 


272 


— 


130 


109 


28 



Abbreviations: D 5 W, 5% dextrose in water; NS, normal saline. 



Colloid solutions consist of large molecular 
weight molecules such as proteins, carbohy- 
drates, or gelatin. Colloids increase osmotic pres- 
sure and remain in the intravascular space longer 
compared to crystalloids. Osmotic pressure is 
proportional to the number of particles in solu- 
tion. Colloids do not readily cross normal capil- 
lary walls and result in Uuid translocation from 
interstitial space to intravascular space. 

Colloids are referred to as monodisperse, like 
albumin, if the molecular weight is uniform, or 
polydisperse, if there is a range of different molec- 
ular weights, as with starches. This is important 
because molecular weight determines the dura- 
tion of colloidal effect in the intravascular space. 
Smaller molecular weight colloids have a larger 
initial oncotic effect but are rapidly renally 
excreted and, therefore, have a shorter duration 
of action. Hydroxyethyl starch (HES), dextran, 
and albumin are the most commonly used col- 
loids. Gelatins are not commercially available in 
the United States. 

Hydroxyethyl starch is a glucose polymer 
derived from amylopectin. Hydroxyethyl groups 
are substituted for hydroxyl groups on glucose. 
The substitution results in slower degradation and 
increased water solubility. Naturally occurring 
starches are degraded by circulating amylases and 
are insoluble at neutral pH. Hydroxyethyl starch 
has a "wide molecular weight range. Duration of 
action is dependent on rates of elimination and 
degradation. Smaller molecular "weight species 



are eliminated rapidly by the kidney. The rate of 
degradation is determined by the degree of sub- 
stitution (the percentage of glucose molecules 
having a hydroxyethyl group substituted for a 
hydroxyl group). Substitution occurs at positions 
C2, C3, and C6 of glucose and the location of the 
hydroxyethyl group also affects the rate of degra- 
dation. Characteristics associated with a longer 
duration of action include larger molecular weight, 
a high degree of substitution, and a high C2/C6 
ratio. 

Hetastarch is a HES with a large molecular 
weight (670 kDa), slow elimination kinetics, and 
is associated with an increase in bleeding compli- 
cations after cardiac and neurosurgery. The larger 
the molecular weight and the slower the rate of 
elimination, the more likely that HES will cause 
clinically significant bleeding. Newer HES prepa- 
rations with lower molecular weights and more 
rapid elimination kinetics may be associated with 
fewer complications. Hetastarch use is also asso- 
ciated with an increased risk of acute renal failure 
in septic patients and in brain-dead kidney 
donors. Given these findings, Hetastarch cannot 
be recommended in patients with impaired 
kidney function. The threshold level of glomeru- 
lar filtration rate below which Hetastarch should 
be avoided is unknown. A comparison between 
albumin and Hetastarch is shown in Table 5.3. 
Hetastarch is available as a 6% solution in normal 
saline. One liter of Hetastarch will initially expand 
the intravascular space by 700-1000 mL. 



72 



Chapter 5 ♦ Intravenous Fluid Replacement 



Table 5.3 

Albumin vs. Hetastarch 





Albumin 


Hetastarch 


MW 


69,000 


670,000 


Made from 


Human sera 


Starch 


Compound 


Protein 


Amylopectin 


Preparations 


25 and 5% 


6% 



Abbreviation: MW, molecular weight. 

Dextrans are glucose polymers with an average 
molecular weight of 40-70 kDa produced by bac- 
teria grown in the presence of sucrose. In addition 
to expanding the intravascular volume, dextrans 
also have anticoagulant properties. Several studies 
show that they decrease the risk of postoperative 
deep venous thrombosis and pulmonary 
embolism. Dextran infusion decreases levels of 
von Willebrand factor and factor VIILc more than 
can be explained by plasma dilution alone. 
Dextrans also enhance fibrinolysis and protect 
plasmin from the inhibitory effects of a-2 antiplas- 
min. In clinical studies comparing dextran to unfrac- 
tionated heparin, low-molecular weight heparin, 
and heparinoids in the prophylaxis of postopera- 
tive deep venous thrombosis, dextran was associ- 
ated with increased blood loss after transurethral 
resection of the prostate and hip surgery. Dextran 
40 use is also associated with acute renal failure in 
the setting of acute ischemic stroke. 

Two large meta-analyses by the Cochrane 
Injuries group and by Wilkes and Navickis 
evaluated albumin as an intravascular volume 
expander. The Cochrane group compared albu- 
min to crystalloid in critically ill patients with 
hypovolemia, burns, and hypoalbuminemia. The 
pooled relative risk of death was increased by 
68% in the albumin group. The authors found no 
evidence that albumin reduced mortality and 
a strong suggestion that it increased risk of death. 
Wilkes and Navickis showed that the relative risk 
of death was increased with albumin adminis- 
tration in patients with trauma, burns, and 
hypoalbuminemia but the increase in all cases 



was not statistically significant. Given these con- 
cerns and the higher cost of albumin compared to 
crystalloids and other synthetic colloids, routine 
use of albumin as a plasma volume expander 
cannot be supported. Albumin is available in two 
concentrations. A 5% solution that contains 12.5 g 
of albumin in 250 ml of normal saline and has a 
colloid osmotic pressure of 20 mmHg and a 25% 
solution that contains 12.5 g of albumin in 50 mL 
of normal saline and has a colloid osmotic pres- 
sure of 100 mmHg. After 1 L of 5% albumin is 
infused the intravascular space is expanded by 
500-1000 mL. 

Advocates of colloids argue that crystalloids 
excessively expand the interstitial space and pre- 
dispose patients to pulmonary edema. Crystalloid 
advocates point out that colloids are more expen- 
sive, have the potential to leak into the interstitial 
space in clinical conditions where capillary walls 
are damaged, as in sepsis, and increase tissue 
edema. Despite decades of research, however, in 
most clinical situations there is no difference in 
pulmonary edema, mortality, or length of hospital 
stay between colloids and crystalloids. 



Key Points 

Replacement Options 



1 . Crystalloids contain water and dextrose and 
may or may not contain other electrolytes. 
The most commonly used crystalloids are 
normal saline and Ringer's lactate. 

2. Colloid solutions consist of large molecular 
weight molecules. Colloids increase osmotic 
pressure and remain in the intravascular 
space longer compared to crystalloids. 

3. Hetastarch is associated with an increased 
risk of acute renal failure in septic patients 
and in brain-dead kidney donors. Its use 
cannot be recommended in patients with 
impaired kidney function. Further studies 
are needed to establish the threshold level 
of glomerular filtration rate below which 
Hetastarch should be avoided. 



Chapter 5 ♦ Intravenous Fluid Replacement 



73 



Given the higher cost of albumin compared 
to crystalloids and other synthetic colloids 
and the possible association with higher 
mortality rates, the routine use of albumin as 
an intravascular plasma volume expander 
cannot be recommended. 
In critically ill patients there is no difference 
in pulmonary edema, mortality, or length of 
hospital stay with either colloid or crystal- 
loid use. 




General Principles 



One must first decide on the amount of sodium and 
volume to be replaced based on the physical exam- 
ination and clinical situation. As a general rule the 
fluid deficit is 3-5 L in the patient with a history of 
volume loss, 5-7 L in the patient with orthostatic 
hypotension, and 7-10 L in the septic patient. Since 
colloids are initially confined to the intravascular 
space, about one-fourth of these volumes are 
required if colloids are used. For most clinical indi- 
cations crystalloids and colloids are equivalent. In 
the bleeding patient crystalloids are preferred. In the 
patient with total body salt and water excess (CHF, 
cirrhosis, nephrosis) colloids minimize sodium over- 
load. Albumin should only be used in specialized 
situations such as large volume paracentesis. 



In the hypotensive patient a solution must be 
employed that "will remain in the intravascular 
and/or extracellular space. Dextrose in water 
(D 5 W) should not be used since only 8% of the 
administered volume remains intravascularly. 
Crystalloids such as normal saline and Ringer's lac- 
tate or colloids are the replacement fluid of choice. 

In patients with identifiable sources of fluid 
loss, it is important to be aware of the electrolyte 
content of body fluids (shown in Table 5.4). Of 
note, sweat and gastric secretions are relatively 
low in sodium and potassium, whereas colonic 
fluids are high in potassium and bicarbonate. 

Normal maintenance requirements for fluids 
and electrolytes must also be considered and 
added to deficits. Insensible water losses average 
500-1000 mL/day or approximately 10 mL/kg/day. 
Insensible water losses are less in the ventilated 
patient breathing humidified air. The average 
maintenance requirements for sodium, potas- 
sium, and glucose are 50-100 meq/day; 40-80 
meq/day; and 150 g/day, respectively. Potassium 
should be repleted carefully in patients •with 
chronic kidney disease. 



Key Points 

General Principles 



1 . The amount of sodium and fluid replaced is 
based on the physical examination and clin- 
ical situation. 



Table 5.4 

Electrolyte Content of Body Fluids 





Sodium 


Potassium 


Chloride 


Bicarbonate 




(meq/L) 


(meq/L) 


(meq/L) 


(meq/L) 


Sweat 


30-50 


5 


50 


— 


Gastric 


40-60 


10 


100 





Pancreatic 


150 


5-10 


80 


70-80 


Duodenum 


90 


10-20 


90 


10-20 


Ileum 


40 


10 


60 


70 


Colon 


40 


90 


20 


30 



74 



Chapter 5 ♦ Intravenous Fluid Replacement 



2. For most clinical indications crystalloids and 
colloids are equivalent. 

3. Dextrose in water must not be used in the 
hypotensive patient. 

4. One needs to be aware of normal daily 
losses of water and electrolytes. 

5. Caution should be exercised in repleting 
potassium in patients with chronic kidney 
disease. 




Assessing ECF Volume 



ECF volume is notoriously difficult to assess based 
on history and physical examination. Signs 
and symptoms such as dry mouth, thirst, diminished 
axillary sweat, decreased capillary refill, and 
decreased skin turgor are often unreliable. Axillary 
sweat is more commonly related to the patient's 
anxiety level than volume status. Decreased skin 
turgor is also seen with aging and rapid loss of 
body weight, as well as the rare genetic disorder 
pseudoxanthoma elasticum. Perhaps the most 
reliable physical finding of ECF volume depletion is 
orthostatic hypotension. The American Autonomic 
Society and the American Academy of Neurology 
define orthostatic hypotension as a decline in sys- 
tolic blood pressure of greater than or equal to 
20 mmHg or a decrease in diastolic blood pres- 
sure of greater than or equal to 10 mmHg. An 
increase in pulse was not included in their defini- 
tion, although this commonly occurs in patients 
without autonomic dysfunction. 

Fluid resuscitation is initiated with boluses of 
crystalloid or colloid with periodic reassessment 
of clinical end points such as heart rate, urine 
output, and blood pressure. In patients with 
advanced chronic kidney disease or end-stage 
renal disease one cannot use urine output as a 
measure of the adequacy of fluid resuscitation. 
Patients who do not respond or who have 
severe comorbid illness of the heart or lungs are 



considered for invasive monitoring. Central 
venous pressure and pulmonary artery occlu- 
sion pressure measurements via a central venous 
or pulmonary artery catheter are used as the 
gold standard of left ventricular preload and 
response to fluid therapy. In most patients car- 
diac output is optimized at filling pressures of 
12-15 mmHg. 

This approach, however, has several limita- 
tions especially in ventilated patients. In the 
mechanically ventilated patient pulmonary artery 
occlusion pressure and left ventricular end dias- 
tolic pressure are affected by factors other than 
left ventricular end diastolic volume such as 
intrathoracic pressure and myocardial compli- 
ance. This has led to a search for more reliable 
markers of intravascular volume status. Although 
these approaches may be more accurate, they are 
also more invasive. For example, measurement of 
intrathoracic blood volume, total end diastolic 
volume, and extravascular lung water require an 
intraaortic fiberoptic catheter in addition to a pul- 
monary artery catheter. Analysis of changes in 
aortic blood velocity requires transesophageal 
echocardiography and heavy sedation to sup- 
press spontaneous ventilation. The measurement 
of respiratory changes in arterial pulse pressure in 
response to volume repletion appears promising 
but also requires sedation to completely suppress 
spontaneous respiratory activity. A less invasive 
method to predict the response of the critically ill 
ventilated patient to volume resuscitation is 
needed. 



Key Points 

Assessing ECF Volume 



1 . ECF volume is difficult to assess based on 
history and physical examination. 

2. Orthostatic hypotension may be the most 
reliable sign of volume depletion. 

3. Volume repletion is initiated with boluses of 
crystalloid or colloid with periodic reassess- 
ment of clinical end points such as heart 



Chapter 5 ♦ Intravenous Fluid Replacement 



75 



rate, urine output, and blood pressure. 
Nonresponders or those with severe comor- 
bid illness of the heart or lungs are candi- 
dates for invasive monitoring. 
4. Pulmonary artery occlusion pressure mea- 
surement via a pulmonary artery catheter is 
used as the gold standard of left ventricular 
preload and response to fluid therapy. In 
most patients cardiac output is optimized at 
filling pressures of 12-15 mmHg. This 
approach, however, has several limitations, 
especially in ventilated patients. 




The Septic Patient 



In septic shock cardiac output is generally high 
and systemic vascular resistance low. Tissue per- 
fusion is compromised by both systemic hypoten- 
sion and maldistribution of blood flow in the 
microcirculation. Septic shock is more complex 
than other forms of shock that are related to 
global hypoperfusion. With global hypoperfu- 
sion, as in cardiogenic shock or hypovolemic 
shock, a decrease in cardiac output results in 
anaerobic metabolism. In septic shock, however, 
maldistribution of a normal or increased cardiac 
output impairs organ perfusion, and inflammatory 
mediators disrupt cellular metabolism. In this set- 
ting adenosine triphosphate (ATP) stores are 
depleted despite maintenance of tissue oxygena- 
tion and lactic acid levels can be elevated despite 
normal tissue P0 2 . 

Shock is characterized by hypotension, which 
is defined as a mean arterial pressure <60 mmHg. 
The primary goals of fluid resuscitation in septic 
shock are normalization of tissue perfusion and 
oxidative metabolism. Large fluid deficits are pres- 
ent in the septic patient. As many as 2-A L of col- 
loid and 5-10 L of crystalloid are required. Survival 
in the septic patient is associated with increased 
cardiac output, and blood and plasma volumes. 



Volume repletion significantly improves cardiac 
output and enhances tissue perfusion. Fluid resus- 
citation alone, in the absence of inotropic agents, 
increases cardiac index by 25-40%. In as many as 
50% of septic patients with hypotension, shock is 
reversed with volume replacement alone. When 
crystalloids and colloids are titrated to the same 
filling pressure they are equally effective. 

Acute respiratory distress syndrome develops 
in one-third to two-thirds of patients with septic 
shock. A major challenge for the clinician manag- 
ing the patient with septic shock is balancing the 
potential benefits of intravascular volume expan- 
sion on vital organ perfusion, such as the brain 
and kidney, with the potentially adverse impact of 
worsening pulmonary edema. On theoretical 
grounds both crystalloids and colloids could 
worsen pulmonary edema. With crystalloid infu- 
sion plasma oncotic pressure may fall acting as a 
driving force for water movement out of the 
intravascular space and lung water accumulation. 
With colloid infusion if microvascular permeabil- 
ity is increased, colloid particles could migrate 
into the interstitium, thereby acting as a driving 
force for water movement, and worsen pul- 
monary edema. Despite these potential problems 
studies have shown that there is no significant dif- 
ference in the development of pulmonary edema 
between crystalloids and colloids when lower fill- 
ing pressures are maintained. 



Key Points 

The Septic Patient 



1 . In septic shock tissue perfusion is compro- 
mised by systemic hypotension and maldis- 
tribution of blood flow. 

2. Large fluid deficits are present in the septic 
patient. As many as 2-4 L of colloid and 
5-10 L of crystalloid may need to be admin- 
istered in the first 24 hours. 

3. Fluid resuscitation is initiated with boluses 
of crystalloid or colloid with periodic 
reassessment of clinical end points. 



76 



Chapter 5 ♦ Intravenous Fluid Replacement 



When crystalloids and colloids are titrated to 
the same filling pressure they are equally 
effective. 

A major challenge for the clinician manag- 
ing the patient with septic shock is balanc- 
ing the benefits of intravascular volume 
expansion on vital organ perfusion with the 
potential adverse impact of worsening pul- 
monary edema. 



function. This process is inhibited by albumin. 
Albumin also coats the surface of the extracorpo- 
real circuit decreasing the polymer surface affinity 
for platelets and reducing platelet granule release. 
HES reduces von Willebrand factor more than can 
be explained by hemodilution alone. Platelet dys- 
function is mediated in part by the HES-induced 
fall in von Willebrand factor coupled "with the 
decrease in von Willebrand receptor function 
induced by cardiopulmonary bypass. 




The Cardiac Surgery Patient 



Patients undergoing cardiac surgery are at risk for 
intraoperative and postoperative bleeding. Cardio- 
pulmonary bypass induces multiple platelet 
abnormalities including decreased platelet count, 
decreased von Willebrand factor receptor, and 
desensitization of platelet thrombin receptors. 
Several studies indicate that increased postcar- 
diopulmonary bypass blood loss requiring reoper- 
ation is an independent risk factor for prolonged 
intensive care unit stay and death. 

Trials comparing HES to albumin show 
increased postoperative bleeding and higher 
transfusion requirements in those receiving HES. 
One large retrospective study revealed a 25% 
lower mortality in those receiving albumin versus 
HES. In this study, the authors estimated that albu- 
min use would save 5-6 lives per 1000 patients 
undergoing cardiopulmonary bypass. Other stud- 
ies showed increased blood loss with HES even in 
low-risk patients. 

Whether this is related to a beneficial effect of 
albumin or a deleterious effect of HES is unknown. 
Cardiopulmonary bypass activates inflammatory 
mediators and complement. There is an increase 
in free radical generation and lipid peroxidation. 
Albumin has significant antioxidant properties 
and inhibits apotosis in microvascular endothe- 
lium. Free fatty acid production contributes to 
erythrocyte crenation that in turn inhibits platelet 



Key Points 



The Cardiac Surgery Patient 



There is an increased risk of bleeding in 

patients undergoing cardiopulmonary 

bypass. 

Cardiopulmonary bypass inciuces multiple 

platelet abnormalities. 

Increased postoperative bleeding and 

higher transfusion requirements are noted in 

cardiopulmonary bypass patients receiving 

HES. Whether this is related to a beneficial 

effect of albumin or a deleterious effect of 

HES remains to be determined. 



Additional Reading 

Boldt, J. New light on intravascular volume replace- 
ment regimens: what did we learn from the past 
three years? Anestb Analg 97:1595-1604, 2003. 

Boussat, S, Jacques, T., Levy, B., Laurent, E., Gache, A., 
Capellier, G., Neidhardt, A. Intravascular volume 
monitoring and extravascular lung water in septic 
patients with pulmonary edema. Intensive Care 
Med 28:712-718, 2002. 

Choi, P.T., Yip, G., Quinonez, L.G., Cook, D.J. Crystalloids 
vs. colloids in fluid resuscitation: a systematic 
review. Crit Care Med 27:200-210, 1999. 

Cittanova, M.L., Leblanc, I., Legendre, C, Mouquet, C, 
Riou, B., Coriat, P. Effect of hydroxyethylstarch in 
brain-dead kidney donors on renal function in kidney- 
transplant recipients. Lancet 348:1620-1622, 1996. 



Chapter 5 ♦ Intravenous Fluid Replacement 



77 



Cochrane Injuries Group Albumin Reviewers. Human 
albumin administration in critically ill patients: sys- 
tematic review of randomized controlled trials. BMJ 
317:235-240, 1998. 

de Jonge, E., Levi, M. Effects of different plasma substi- 
tutes on blood coagulation: a comparative review. 
Crit Care Med 29:1261-1261, 2001. 

Evans, P.A., Heptinstall, S., Crowhurst, E.C., Davies, T., 
Glenn, J. R., Madira, W., Davidson, S.J., Burman, J.F., 
Hoskinson, J., Stray, CM. Prospective double-blind 
randomized study of the effects of four intravenous 
fluids on platelet function and hemostasis in elective 
hip surgery. / Thromb Haemost 1:2140-2148, 2003. 

Feissel, M., Michard, E, Mangin, I., Ruyer, O., Faller, 
J. P., Teboul, J.L. Respiratory changes in aortic blood 
velocity as an indicator of fluid responsiveness in 
ventilated patients with septic shock. Chest 119:867- 
873, 2001. 

Kramer, G.C. Hypertonic resuscitation: physiologic 
mechanisms and recommendations for trauma care. 
/ Trauma 54(5 Suppl.):S89-S99, 2003. 

Matejovic, M., Krouzecky, A., Rokyta, R. Jr., Novak, I. 
Fluid challenge in patients at risk for fluid loading- 
induced pulmonary edema. Acta Anaesthesiol 
Scand 48:69-73, 2004. 

Michard, E, Boussat, S., Chemla, D., Anguel, N, Mercat, 
A., Lecarpentier, Y., Richard, C, Pinsky, M.R., 
Teboul, J.L. Relation between respiratory changes in 



arterial pulse pressure and fluid responsiveness in 
septic patients with acute circulatory failure. Am J 
Respir Crit Care Med 162:134-138, 2000. 

Schortgen, E, Lacherade, J.C., Bruneel, E, Cattaneo, I., 
Hemery, F., Lemaire, F., Brochard, L. Effects of 
hydroxyethylstarch and gelatin on renal function in 
severe sepsis: a multicentre randomised study. 
Lancet 357:911-916, 2001. 

Sedrakyan, A., Gondek K., Paltiel, D., Elefteriades, J.A. 
Volume expansion with albumin decreases mortal- 
ity after coronary artery bypass graft surgery. Chest 
123:1853-1857, 2003. 

Task Force of the American College of Critical Care 
Medicine, Society of Critical Care Medicine. Practice 
parameters for hemodynamic support of sepsis in 
adult patients in sepsis. Crit Care Med 27:639-660, 
1999. 

Treib, J., Baron, J.E, Grauer, M.T., Strauss, R.G. An inter- 
national view of hydroxyethyl starches. Intensive 
Care Med 25:258-268, 1999. 

Wilkes, M.M., Navickis, R.J. Patient survival after human 
albumin administration. A meta-analysis of random- 
ized, controlled trials. Ann Intern Med 135:149-164, 
2001. 

Wilkes, MM., Navickis, R.J., Sibbald, W.J. Albumin 
versus hydroxyethyl starch in cardiopulmonary 
bypass surgery: a meta-analysis of postoperative 
bleeding. Ann Thome Surg 72:527-533, 2001. 



Mark A. Perazella 



Potassium Homeostasis 




Recommended Time to Complete: 2 days 

1. What role does potassium (K + ) play in cellular function? 

2. How does the body avoid a lethal cardiac arrhythmia following the 
ingestion of a potassium rich meal? 

I. What are the major factors that influence cellular shift of potassium 

and how do they accomplish their effect? 
k- What is the major site of K + secretion by the kidney? 
S. What are the four key factors that modulate renal K + excretion? 
i. Does diet play a major role in the development of either hypo- or 

hyperkalemia? 
7. What are the general categories of causes of hypokalemia? 
9. What are the three general categories of causes of hyperkalemia? 
e j. Treatment of clinical disorders of potassium balance is best guided 

by what two factors? 

10. What is the most appropriate method of potassium supplementation 
in patients with severe hypokalemia? 

11. What three treatment steps are employed to treat patients with severe 
hyperkalemia? 



78 




Potassium Homeostasis 



Introduction 



Potassium (K + ) is found in nearly all food sources. 
It is the predominant intracellular cation in the 
body. A high cellular concentration is required to 
maintain normal function of a number of cellular 
processes. These include nucleic acid and protein 
synthesis, regulation of cell volume and pH, cell 
growth, and enzyme activation. In particular, a 
high intracellular K + concentration is necessary 
for the maintenance of the resting membrane 
potential. The resting membrane potential, in 
concert with the threshold membrane potential, 
sets the stage for generation of the action poten- 
tial. This process is ultimately required for proper 
functioning of excitable tissues. Hence, these 
actions allow normal functioning of cardiac and 
skeletal muscles. Regulation of K + homeostasis is 
achieved mainly through cellular shifts of potas- 
sium, as well as renal K + excretion. These two reg- 
ulatory mechanisms are under the control of a 
variety of factors that are reviewed in subsequent 
sections. Disturbances in these homeostatic 
mechanisms result in either hypokalemia or 
hyperkalemia. Both of these disturbances in K + 
balance promote a variety of clinical symptoms 
and physical findings that are predominantly 
caused by disruption of action potential forma- 
tion, leading to neuromuscular dysfunction and 
inhibition of normal cell enzymatics. Rapid recog- 
nition and treatment of these disorders are 
required to avoid serious morbidity and mortality. 



Potassium Homeostasis 



Total body K + stores in an adult are between 3000 
and 4000 meq (50-60 meq/kg body weight). Total 
body K + content is also influenced by age and sex. 
As compared with a young male, an elderly man 




79 



has 20% less total body K + content. Also, age- 
matched females have 25% less total body K + than 
males. Potassium is readily absorbed from the 
gastrointestinal (GI) tract and subsequently dis- 
tributed in cells of muscle, liver, bone, and red 
blood cells. Maintenance of total body K + stores 
within narrow limits is achieved by zero net bal- 
ance between input and output, as well as by reg- 
ulation of K + between the extracellular fluid (ECF) 
and intracellular fluid (ICF). The bulk (90%) of 
dietary potassium is excreted in urine and the rest 
in feces (10%) in an adult. In contrast to sodium 
(Na + ), K + is predominantly an intracellular cation, 
with 98% of body K + located inside the cell. 
Hence, only 2% of K + is present in the ECF. As a 
result, there is a dramatic difference in K + concen- 
tration intracellularly (145 meq/L) versus extracel- 
lularly (4-5 meq/L). Despite this fact, however, 
the serum K + concentration is employed as an 
index of potassium balance, since it is the most 
readily available clinical test. In general, it is a rea- 
sonably accurate reflection of total body potas- 
sium content. In disease states, however, the 
serum potassium concentration may not always 
represent total body K + stores. The clinician must 
keep this in mind when assessing patients with 
abnormal laboratory values. 



Key Points 

Potassium (K + ) 



1. Potassium is the most abunciant intra- 
cellular cation in the body. It plays a key 
role in cell growth, nucleic acid, and protein 
synthesis. 

2. Proper functioning of these various cellular 
processes depends on maintenance of high 
K + concentration within cells. 

3. Generation of an action potential in neuro- 
muscular tissue is a key function of K + 
movement between ICF and ECF. 

4. Total body K + stores range between 3000 
and 4000 meq and are determined by age, 
sex, and body size. 



80 



Chapter 6 



Potassium Homeostasis 



To maintain net zero K + balance, approxi- 
mately 90% of K + is excreted by the kidneys, 
while 10% is excreted by the GI tract. 
Serum K + concentration is the marker used 
to estimate total body K + balance. 



potential. Any change in serum K + concentration 
alters the action potential and excitability of the cell. 
Thus, regulation of K + distribution must be efficient, 
since a small movement of K + from the ICF or ECF 
results in a potentially fatal change in serum K + con- 
centration. Physiologic and pathologic factors influ- 
ence K + distribution between ICF and ECF. 




Role of K + in the Resting 
Membrane Potential 




Cellular Distribution of t 



Movement of cations, such as K + and Na + , into 
their respective compartments requires active and 
passive cellular transport mechanisms. The loca- 
tion of K + and Na + in their respective fluid com- 
partments is maintained predominantly by the 
action of the Na + -K + -ATPase pump in the cell 
membrane. This enzyme hydrolyzes ATP to create 
the energy required to pump Na + out of the cell 
and K + into the cell in a 3:2 ratio. Potassium moves 
out of the cell at a rate dependent on the electro- 
chemical gradient, this creates the resting mem- 
brane potential (E ). As seen below, the 
Goldman-Hodgkin-Katz equation calculates the 
membrane potential on the inside of the mem- 
brane using Na + and K + concentrations. Three fac- 
tors determine the E : (1) the electrical charge of 
each ion; (2) the membrane permeability to each 
ion; and (3) the concentration of the ion on each 
side of the membrane. Inserting the intracellular 
K + (145) and Na + (12) concentrations and extra- 
cellular K + (4.0) and Na + (140) concentrations into 
the formula results in a resting membrane potential 
of -90 mV. The cell interior is -90 mV, largely due 
to the movement of Na + out of the cell via the 
Na + -K + - ATPase pump. 



: -61 log 



3/2 (140) + 0.01 (12) 
3/2 (4.0) + 0.01 (145) ' 



-90 mV 



The resting potential sets the stage for membrane 
depolarization and generation of the action 



Many foods have a high K + content that can raise 
serum K + concentration, sometimes to levels that 
significantly disturb cell function and, as a result, 
are potentially lethal. In order to maintain the 
serum K + concentration within a safe range, 
movement of K + into cells is the first response of 
the body following ingestion of a potassium rich 
meal. This is a key feature of K + homeostatic 
mechanisms because renal excretion of K + 
requires several hours. The critical importance of 
this process is illustrated in the following case. 

♦ CASE 6.1 

A 70-kg man drinks three glasses of orange juice 
(40 meq of K + ). In the absence of cellular shift, the K + 
would remain in the ECF (17 L) and raise the serum 
K + concentration by 2.4 meq/L. The excess K + , how- 
ever, is rapidly shifted into cells and gradually 
excreted by the kidneys over the next several hours. 
This prevents a potentially lethal acute rise in serum 
K + concentration. 



Not surprisingly, insulin, which is secreted fol- 
lowing a meal to maintain proper glucose bal- 
ance, is also integral to cellular K + homeostasis. As 
such, serum K + concentration is maintained in the 
normal range by the physiologic effects of insulin. 
This role of insulin to move K + into cells is "well 
suited since renal K + excretion does not occur 
immediately following ingestion of a meal con- 
taining large amounts of potassium. Movement of K + 



Chapter 6 



Potassium Homeostasis 



81 



into cells allows rapid lowering of the serum K + 
concentration until the K + load is fully excreted by 
the kidneys. Insulin stimulates K + uptake into cells 
by increasing the activity and number of Na + -K + - 
ATPase pumps in the cell membrane. Two K + ions 
are transported into the cell while three Na + ions 
are moved out of the cell by this energy-requiring 
transporter. The intracellular shift of K + is inde- 
pendent of glucose transport. A deficiency of 
insulin, as occurs in many patients with type 1 dia- 
betes mellitus, is associated with hyperkalemia 
from impaired cellular uptake of K + . The follow- 
ing clinical experiment illustrates the effect of 
insulin on cellular K + homeostasis. 

Infusion of somatostatin, an inhibitor of pan- 
creatic insulin release, in normal subjects reduced 
basal insulin concentrations to very low levels. 
Serum K + concentrations were measured with KC1 
infusion during baseline, infusion with somato- 
statin, and infusion with somatostatin plus insulin. 
An exaggerated rise in serum K + concentration 
developed with somatostatin, this effect was com- 
pletely reversed by insulin infusion. 

As noted with insulin, endogenous cate- 
cholamines and /^-adrenergic agonists promote K + 
movement into cells through stimulation of the Na + - 
K + -ATPase. Activation of the P 2 receptor underlies 
the effect on this active enzyme pump to move K + 
into cells. Receptor activation is signaled through 
adenylate cyclase to generate cyclic AMP. This 
second messenger system ultimately stimulates the 
Na + -K + -ATPase pump to shift K + into cells. 
Medications such as albuterol, a /^-adrenergic ago- 
nist used for asthma, can lower serum K + concen- 
tration through stimulation of cell uptake while 
propranolol, an antihypertensive medication which 
blocks /^-adrenergic receptors, may cause hyper- 
kalemia through inhibition of K + movement into 
cells. Intoxication with a medication such as 
digoxin may raise serum K + concentration by dis- 
rupting the Na + -K + -ATPase, thereby blocking cellu- 
lar K + uptake. The clinical observation described 
below demonstrates the effect of digoxin on Na + - 
K + -ATPase function and serum K + concentration. 

An elderly male with a history of heart disease 
presents to the emergency department with 



severe weakness, nausea, and vomiting. Severe 
digoxin intoxication is documented on blood 
testing. Serum K + concentration is 7.1 meq/L, pre- 
vious serum K + concentration was 4.9 meq/L. This 
case shows the effect of digoxin intoxication on 
cellular K + balance, an effect mediated through 
inhibition of the Na + -K + -ATPase. 

Other physiologic factors that modulate cellu- 
lar K + movement include exercise, changes in 
extracellular pH, in particular metabolic acidosis 
and alkalosis, as well as changes in plasma osmo- 
lality. Exercise has a dual effect on cellular K + 
movement. A transient rise in serum K + concen- 
tration occurs primarily to increase blood flow to 
muscle. This homeostatic effect occurs because 
local release of K + vasodilates vessels and 
improves perfusion of ischemic muscles (pro- 
vides more oxygen). A counterbalancing effect of 
endogenous catecholamine secretion also devel- 
ops with exercise; this moves K + back into the ICF 
(activation of /^-adrenergic receptors) and 
restores the serum K + concentration to normal. 
The level of exercise influences the cellular 
release of K + . For example, a 0.3-0.4 meq/L rise 
with slow walking, a 0.7-1.2 meq/L rise with mod- 
erate exercise, and as much as a 2.0 meq/L rise 
with exercise to the point of exhaustion. Rest is 
associated with rapid correction of the rise in 
serum K + concentration, mainly through the 
actions of the Na + -K + -ATPase. Physical condition- 
ing reduces the rise in K + concentration presum- 
ably through an improvement in pump activity. 

Changes in pH also influence serum K + con- 
centration. Metabolic acidosis is associated with 
an exit of K + from cells in exchange for protons 
(H + ) as the cells attempt to buffer the ECF pH. The 
exchange of K + for H + maintains electroneutrality 
across membranes. In this setting, up to 60% of 
excess protons are buffered within cells. An oppo- 
site effect is observed with metabolic alkalosis as 
K + enters the ICF to allow H + to enter the ECF and 
reduce alkalemia. In general, the serum K + con- 
centration increases or decreases by 0.4 meq/L 
for every 0.1 decrease or increase in pH. There is 
a wide variability, however, in the change in 
serum K + concentration with pH change in 



82 



Chapter 6 



Potassium Homeostasis 



metabolic acidosis (0.2-1.7 meq/L for every 
0.1 fall in pH). Furthermore, this effect is more 
prominent with mineral (nonanion gap) metabolic 
acidoses than organic anion acidoses. The expla- 
nation for the differential effects of these types of 
acidoses on cellular K + movement is based on the 
ability of the accompanying anion to cross cell 
membranes. In mineral metabolic acidosis, the 
anion chloride is unable to cross the membrane, 
therefore K + must exit the cell to maintain elec- 
troneutrality. In contrast, the anion lactate is able 
to cross the membrane and less K + is required to 
exit the cell to maintain electroneutrality. 

An increase in plasma osmolality, as occurs with 
hyperglycemia in diabetes mellitus, raises serum K + 
concentration as a result of a shift of K + out of cells. 
Potassium movement from cells is induced by sol- 
vent drag as K + accompanies water that is diffusing 
from the ICF into the ECF. Also, as water leaves the 
cell, the intracellular K + concentration rises, result- 
ing in an increased driving force for passive diffu- 
sion of K + out of the cell. In general, the serum K + 
concentration rises by 0.4—0.8 meq/L for every 
10 mOsm/kg increase in the effective osmolality. 
As will be discussed later, other hyperosmolar sub- 
stances can cause a shift of K + out of cells. There 
exists a small amount of data suggesting that aldo- 
sterone may increase cellular uptake of K + through 
stimulation of the Na + -K + -ATPase pump. The role 
of aldosterone on cellular K + movement, however, 
is controversial and probably of only minor impor- 
tance. As will be noted later, aldosterone has its 
major effect to enhance renal K + excretion. 



Key Points 

Cellular Distribution of K + 



Potassium is distributed between ECF and 
ICF by a number of physiologic factors. 
Insulin and /^-adrenergic agonists act to 
move K + into cells by stimulating the activity 
of Na + -K + -ATPase. 

Metabolic alkalosis and acidosis shift K + into 
and out of cells in exchange for H + to buffer 
pH changes. 



4. Hyperosmolality increases serum K + concen- 
tration through the effects of both solvent 
drag on intracellular K + and creation of a dif- 
fusional driving force for K + to exit the cell. 




K + Handling by the Kidney 



Proximal Tubule 

Potassium handling in the kidney occurs through 
the processes of glomerular filtration and both 
tubular reabsorption and secretion. In proximal 
nephron, 100% of K + reaches the tubule as K + is 
freely filtered by the glomerulus. Approximately 
60-80% of filtered K + is reabsorbed by proximal 
tubule. Uptake of K + occurs via passive rather 
than active transport mechanisms. Potassium is 
reabsorbed by a K + transporter and through para- 
cellular pathways coupled with Na + and water. 
Any process that affects Na + and water movement 
in the proximal tubule will also influence K + reab- 
sorption. For example, volume depletion will 
increase Na + and water reabsorption, also increas- 
ing K + uptake while volume expansion will inhibit 
passive diffusion of K + . 



Loop ofHenle 



In the loop of Henle, K + is both secreted and reab- 
sorbed. Ultimately, 25% of the filtered K + is reab- 
sorbed in this nephron segment. Potassium is 
secreted into the lumen and the K + concentration 
at the tip of the loop of Henle may exceed the 
amount filtered. In contrast, K + is actively and pas- 
sively reabsorbed in the medullary thick ascend- 
ing limb. Active K + transport occurs by the 
lNa + -lK + -2Ch cotransporter (Figure 6.1), which is 
powered by the enzymatic activity of Na + -K + - 
ATPase on the basolateral membrane. Secondary 
active cotransport is driven by the steep Na + 



Chapter 6 



Potassium Homeostasis 



Figure 6. 1 



Lumen 



Na + 
K + 

2Cr 




Blood 

Na + -K + ATPase 
— 2K + 



K + channel 



3Na + 




K + channel 



Cell model of the thick ascending limb of Henle. The Na + -K + -ATPase on the baso- 
lateral membrane provides the energy required to drive secondary active K + transport 
by the lNa + -lK + -2Cl~ cotransporter in the thick ascending limb of Henle. 



gradient across the apical membrane created by 
this enzyme pump. To allow continued cotrans- 
port, K + must recycle across the apical membrane 
from the cell into the tubular lumen. This provides 
a continuous supply of K + ions for cotransport 
with Na + and Cl~ and negates the limiting effect of 
low luminal K + . Medications such as loop diuret- 
ics and certain genetic disorders impair the trans- 
port function of this cotransporter resulting in Na + 
and K + "wasting. 



Distal Nephron 

Following K + handling in the previously described 
nephron segments, approximately 10% of filtered 
K + reaches the distal tubule. In contrast to the 
other nephron segments, net K + secretion occurs 
in the distal tubule. This develops because of the 
high luminal Na + concentration and low luminal 
Cl~ concentration, which stimulates the K + -Cb 
cotransporter to secrete K + . In cortical collecting 
duct (CCD), K + is both secreted and reabsorbed. The 
CCD is the major site of K + secretion in the kidney. 
Two major cell types modulate K + movement in 



this nephron segment. The principal cell is uniquely 
designed to secrete K + (Figure 6.2). The apical 
membrane of this cell contains epithelial Na + 
channels (ENaC) and K + channels, which act in 
concert with basolateral Na + -K + -ATPase to reab- 
sorb Na + and secrete K + . Reabsorption of Na + 
through ENaC increases K + secretion through its 
channel by creating an electrochemical gradient 
for K + movement from cell to tubular lumen. An 
electrical gradient develops as a result of Na + entry 
into the principal cell without an accompanying 
anion, creating a lumen negative charge that stim- 
ulates K + secretion. Also, the entry of Na + into cells 
increases basolateral Na + -K + -ATPase activity to 
lower intracellular Na + . Transporting three Na + 
ions out of the cell and two K + ions into the cell 
increases intracellular K + concentration and cre- 
ates a diffusional gradient favoring K + exit from 
cells through apical K + channels into the tubular 
lumen. Blockade of the Na + channel (amiloride, 
trimethoprim) reduces renal K + excretion by 
blocking generation of the electrochemical gradient. 
Administration of an aldosterone receptor antago- 
nist (spironolactone, eplerenone) reduces apical 
Na + channel function, as well as Na + -K + -ATPase 



84 



Chapter 6 



Potassium Homeostasis 



Figure 6.2 



Lumen 






Blood 
Na+-K + -ATPase 




3Na + 3 


Na + 










Na + channel 
















1 K 1 




K + channel 


K + channel 









Cell model of the principal cell. The principal cell functions to regulate renal K + 
excretion. Reabsorption of Na + through ENaC increases K + secretion via ROMK by 
creating an electrochemical gradient for K + movement from cell to tubular lumen. 



activity, which limits K + secretion from cells to urine. 
The other cell in the distal nephron involved in K + 
movement is the intercalated cell. There are two 
types of intercalated cells a and p. The a intercalated 



cell pictured below (Figure 6.3) excretes K + . An 
H + -K + -ATPase on the apical surface of this cell 
reabsorbs K + in exchange for H + . The ft intercalated 
cell excretes HCO;r and is not pictured. 



Figure 6.3 



Lumen 




H + -ATPase 



K + 



3Na 




Blood 

Na + -K + -ATPase 
2K + 




H + -K + -ATPase 



Cell model of the a intercalated cell. The intercalated cell promotes K + reabsorption via the 
H + -K + -ATPase located on the apical surface. This action stimulates K + reabsorption in 
exchange for H + ion. 



Chapter 6 



Potassium Homeostasis 



85 



Table 6.1 

Factors That Influence Renal Potassium Excretion 



Aldosterone 

Plasma potassium concentration 
Tubular flow rate 
Tubular sodium concentration 
Antidiuretic hormone 
Glucocorticoids 
Metabolic alkalosis 
Metabolic acidosis 

Impermeant anions in the urine (sulfate, bicar- 
bonate, carbenicillin) 



Factors Controlling Renal K + Excretion 

Although a number of factors influence renal K + 
excretion (Table 6.1), this discussion focuses on 
four clinically relevant factors that control K + 
secretion in principal cells. Most important is the 
mineralocorticoid aldosterone, which acts through 
binding its steroid receptor. This hormone stimu- 
lates Na + entry through apical channels and 
enhances basolateral Na + -K + -ATPase activity. This 
dual effect on the cell creates both an electrical 
potential for K + secretion (lumen negative charge 
stimulates K + movement from cell to urine), as well 
as a diffusional gradient for K + secretion (raising 
intracellular K + concentration). The plasma K + 
concentration also influences K + secretion by the 
kidney. As the plasma K + concentration rises 
above 5 meq/L, it produces effects on the princi- 
pal cell that are similar to aldosterone as described 
above. This likely represents a protective mecha- 
nism to maintain renal K + excretion even when 
aldosterone is deficient or absent. On the luminal 
side (urinary space), both urine flow rate and Na + 
delivery influence K + secretion. High flow rates 
enhance K + secretion by maintaining a low urine 
K + concentration and a favorable diffusional gradi- 
ent for intracellular K + . Urinary Na + delivery to the 
principal cell promotes K + secretion by enhancing 
the entry of Na + ions through ENaC and creating a 
favorable electrochemical gradient. Thus, an 



increase in urine flow rate and Na + delivery, as cre- 
ated by use of a loop diuretic will increase K + 
excretion. In contrast, disease states such as con- 
gestive heart failure or true intravascular volume 
depletion reduce urine flow rate or Na + delivery, 
and as a result impair renal K + excretion. The 
impact of urine flow rates and Na + delivery on 
renal K + excretion are less important, however, 
than aldosterone or the plasma K + concentration. 



Key Points 

K + Handling by the Kidney 



1. Potassium is freely filtered by the glomerulus. 

2. The proximal tubule reabsorbs 60-80% of 
filtered K + , the loop of Henle reabsorbs 
approximately 25%, while the distal 
nephron is the primary site of renal K + 
secretion. 

3. In distal nephron, the principal cell in CCD 
is the primary regulator of K + excretion. 

4. Several factors modulate K + excretion. 

5 . Aldosterone and plasma K + concentration 
primarily influence K + secretion by the prin- 
cipal cell. 

6. Urinary Na + concentration and urine flow 
rate also regulate K + secretion by the princi- 
pal cell, but are less important than aldos- 
terone and plasma K + concentration. 




Clinical Disorders of K + 
Homeostasis 



Clinical disorders of potassium balance are 
common problems in patients with a variety of 
medical conditions, especially those that require 
therapy with certain medications. In general, the 
causes of these disturbances promote K + imbal- 
ance by interrupting cell shift or renal excretion 



86 



Chapter 6 



Potassium Homeostasis 



of K + . Other factors that contribute include varia- 
tions in dietary K + intake and disturbed gastroin- 
testinal K + handling. 



Hypokalemia 

Hypokalemia is typically defined as a serum (or 
plasma) K + concentration less than 3.5 meq/L. 
Causes of hypokalemia (Table 6.2) can be 
broadly categorized as (1) reduced dietary intake, 
(2) increased cellular uptake, (3) increased renal 
excretion, and (4) excessive GI losses. Inadequate 
ingestion of K + alone is rarely a cause of hypo- 
kalemia due to the ubiquitous presence of this 
cation in foods. More often, diet only contributes 
to another primary cause of serum K + deficiency 
and rarely causes hypokalemia alone. Hypo- 
kalemia may develop from a shift of K + into cells 
from the effects of excessive production of endoge- 
nous insulin or catecholamines. Exogenous admin- 
istration of insulin induces shift of K + into cells 
and precipitates hypokalemia. A classic example 
is the patient with diabetes mellitus who presents 
with ketoacidosis and is administered a continu- 
ous insulin infusion. Serum K + concentration 
often falls dramatically due to the effect of insulin 
on cellular K + uptake, as well as correction of the 
hyperosmolar state, /^-adrenergic agonists used 
for asthma (albuterol) or labor (ritodrine) can 
lower serum K + concentration through cell uptake 
mediated by fi 2 receptors. A clinical scenario where 
hypokalemia may develop from a /^-adrenergic 
agonist is the patient with severe asthma who 
requires frequent nebulized treatments to correct 
bronchospasm. Metabolic alkalosis may also pro- 
mote cell shift of K + and precipitate hypokalemia. 
Typically, this acid-base disorder is precipitated by 
vomiting and diuretic use, both of which con- 
tribute to hypokalemia through renal K + losses. 
Hypokalemic periodic paralysis is an inherited dis- 
order associated with severe hypokalemia from 
cellular uptake of K + , a phenomenon often pre- 
cipitated by stress, exercise, or a large carbohy- 
drate meal. The mutation is in the a 1 subunit of 
the dihydropyridine-sensitive calcium channel. 



Table 6.2 



Causes of Hypokalemia 



Reduced dietary intake 

Inadequate oral intake (in combination with 

other factors) 
Increased cellular uptake 

Insulin 

Catecholamines (J3 ? adrenergic) 

Endogenous catecholamines 

Epinephrine 

Dopamine 

Aminophylline 

Isoproterenol 
Chloroquine intoxication 
Metabolic alkalosis 
Hypokalemic periodic paralysis 
Hypothermia 

Cell growth from B, 2 therapy 
Increased renal excretion 
Aldosteronism (primary or secondary) 
Corticosteroid excess 
High urine flow rate from diuretics 
High distal delivery of sodium 
Renal tubular acidosis 
Drugs 

Amphotericin B 

Diuretics 

Aminoglycosides 

Lithium 

Cisplatinum 

Some penicillins 
Genetic renal diseases 

Barrier's syndrome 

Gitelman's syndrome 

Liddle's syndrome 

Apparent mineralocorticoid excess 
syndrome 
Gastrointestinal potassium loss 
Vomiting 
Diarrhea 
Ostomy losses 
Skin loss of potassium 
Strenuous exercise 
Severe heat stress 



Chapter 6 



Potassium Homeostasis 



87 



Hypothermia and chloroquine intoxication are 
rare causes of hypokalemia secondary to the shift 
of potassium into cells. Finally, rapid synthesis of 
red blood cells induced by B or iron therapy 
may cause hypokalemia. This phenomenon 
occurs because newly formed cells use available 
K + to develop the high intracellular K + concentra- 
tion common to all cells. 

Renal K + losses contribute significantly to the 
development of hypokalemia. A number of med- 
ications promote K + excretion by the kidney via 
actions in various nephron segments. In proximal 
tubule, K + reabsorption is impaired by different 
mechanisms. For example, acetazolamide, through 
blocking carbonic anhydrase induces bicarbona- 
turia and promotes K + wasting. Osmotic diuretics 
increase flow through the proximal tubule, reducing 
Na + and water reabsorption and thus paracellular 
K + reabsorption. Drugs such as aminoglycosides 
and cisplatin injure proximal tubular cells and 
cause K + wasting. The loop of Henle reabsorbs K + 
via the lNa + -lK + -2Cl" transporter. Loop diuretics 
inhibit the function of this transporter and reduce 
K + reabsorption significantly. In distal tubule, thi- 
azide diuretics block the activity of the Na + -Ch 
cotransporter, thereby increasing delivery of Na + 
and urine volume to principal cells in CCD. As dis- 
cussed previously, these luminal effects increase 
K + secretion. Fludrocortisone, a mineralocorticoid 
agonist, binds the aldosterone receptor and stim- 
ulates renal K + secretion in principal cells. The 
antifungal agent amphotericin B causes K + loss 
from the kidney through a rather unique mecha- 
nism. Through interactions with membrane 
sterols, it disrupts cell membranes and allows K + 
to leak out of the principal cell into the urinary 
space following its diffusional gradient. Primary 
or secondary aldosteronism, as well as corti- 
costeroid excess, may induce severe hypokalemia 
through stimulation of mineralocorticoid recep- 
tors and associated K + secretion in CCD. Primary 
or acquired forms of renal tubular acidosis (RTA) 
cause hypokalemia through tubular dysfunction 
proximally (type 2 RTA) or distally (type 1 RTA). 
Nonreabsorbable anions, by increasing lumen 
negative charge, increase the driving force for K + 



secretion in the CCD. These include carbenicillin, 
hippurate in patients who sniff glue (toluene), 
and jS-hydroxybutyrate in patients with diabetic 
ketoacidosis. Inherited renal disorders also cause 
hypokalemia. In the loop of Henle, various muta- 
tions cause dysfunction of the lNa + -lK + -2Cb 
cotransporter, the apical K + channel, the basolat- 
eral Cl" channel, or the /3 subunit (Barttin) that 
traffics the Cl" channel to the basolateral mem- 
brane. An activating mutation in the calcium sens- 
ing receptor on the basolateral membrane of the 
loop of Henle causes inhibition of ROMK and 
renal Na + and K + wasting. Various Bartter's syn- 
drome phenotypes accompany each mutation, 
ultimately leading to K + wasting and hypokalemia. 
A mutation of the gene encoding the thiazide sen- 
sitive Na + -Cl~ cotransporter causes the inherited 
disorder known as Gitelman's syndrome. As seen 
with a thiazide diuretic, Gitelman's syndrome 
causes renal K + wasting and hypokalemia. Liddle's 
syndrome promotes severe hypokalemia by caus- 
ing overactivity of the epithelial Na + channel in 
the principal cell, an effect that favors unregulated 
renal potassium secretion. Mutations in subunits 
of the epithelial Na + channel (fi and f) underlies 
this genetic disorder. 

Hypomagnesemia causes renal potassium 
"wasting for unknown reasons. Gastrointestinal 
losses of K + , such as vomiting, diarrhea, and 
excessive ostomy output may cause excessive K + 
losses from the body. In rare cases, excessive skin 
K + losses from extreme heat or strenuous exercise 
may cause hypokalemia. 

A practical algorithm to assess the cause of 
hypokalemia is described in Figure 6.4. After 
excluding pseudohypokalemia and cell shift, 
hypokalemia is first evaluated by measuring the 
patient's blood pressure. Hypokalemia associated 
with hypertension is then classified based on con- 
centrations of renin and aldosterone. In patients 
with hypokalemia that is associated with normal 
or low blood pressure, the next step in evaluation 
entails measuring urinary K + concentration to 
identify renal or extrarenal causes. Finally, acid- 
base status determines further classification of 
hypokalemia. Most have hypokalemia that is 



Figure 6.4 



GO 
00 



Pseudohypokalemia 



■ K + uptake by leukemic 
cells in test tube 




Cell shift 



• Insulin 

• p 2 -adrenergic stimulation 

• Alkalemia 

• Hypothermia 

• Periodic paralysis 

• Cesium chloride/barium 



Normal/low BP 




■ Renal artery stenosis 

■ Renin-secreting tumor 

■ HTN + diuretic 

■ Malignant HTN 



Urine K + >20mEq/day 



Urine K + < 20 mEq/day 
_A 



Extra-renal 



T Aldosterone 



Renal 



• Cushing's 

• AME 

• Licorice ingestion 

• Liddle's syndrome 



• Primary hyperaldosteronism 
•GRA 



Metabolic 
alkalosis 



Metabolic 
Alkalosis 




Metabolic 
acidosis 



■ Vomiting 

■ NG drainage 

■ Sweat 



■ Diarrhea 

■ Laxative 

■ Colostomy 



Normal 
pH 



Metabolic 
acidosis 



• Bartter's syndrome 

■ Gitelman's syndrome 

• Diuretic 



• Hypomagnesemia 

• Aminoglycosides 

• Cisplatin 



• Distal RTA 

• Proximal RTA 

• Toluene 

• DKA 



Clinical algorithm to evaluate hypokalemia. After excluding pseudohypokalemia and cell shift, blood pressure and various serum and urine tests 
are employed to classify hypokalemia. Abbreviations: HTN, hypertension; NG, nasogastric; AME, apparent mineralocorticoid excess; GRA, 
glucorticoid remediable aldosteronism; RTA, renal tubular acidosis; DKA, diabetic ketoacidosis. 



Chapter 6 



Potassium Homeostasis 



89 



associated with either a metabolic acidosis or 
alkalosis. 

The clinical manifestations of hypokalemia 
represent the effects of serum K + deficits on action 
potential generation in excitable tissues, protein 
synthesis, enzyme function, and regulation of cell 
pH and volume. Impaired neuromuscular func- 
tion precipitates a spectrum of clinical findings 
ranging from muscle weakness to frank paralysis. 
Respiratory failure results from diaphragmatic 
muscle weakness while ileus is a GI manifestation 
of disturbed smooth muscle contractility. Cardiac 
disturbances include a variety of atrial and ven- 
tricular arrhythmias, as well as abnormal myocar- 
dial contractile function. Arrhythmias that develop 
from hypokalemia are a major clinical concern as 
they may be fatal in patients on digoxin or in those 
with underlying cardiac disease. Renal manifesta- 
tions of hypokalemia include impaired urinary 
concentration (polyuria), increased renal ammo- 
nia production and bicarbonate reabsorption 
(perpetuating metabolic alkalosis), and renal 
failure from either tubular vacuolization (hypo- 
kalemic nephropathy) or myoglobinuria (rhabdomy- 
olysis). Finally, other metabolic perturbations 
associated with hypokalemia include hyper- 
glycemia from decreased insulin release, and 
impaired hepatic glycogen and protein synthesis. 

Treatment of hypokalemia is guided by two 
factors. First, the physiologic effects of the K + 
deficit need to be determined and second, the 
cause of hypokalemia (cell shift versus renal or GI 
excretion) and approximate K + deficit need to be 
estimated. Physiologic effects of hypokalemia are 
best judged by (1) physical examination of neuro- 
muscular function and (2) electrocardiographic 
(ECG) interrogation of the cardiac conduction 
system. Muscle weakness is often present with 
significant hypokalemia, while paralysis signals 
severe hypokalemia. The presence of prominent 
u waves on ECG (Figure 6.5) suggests a serum K + 
concentration in the 1.5-2.0 meq/L range. The K + 
deficit is approximated by the knowledge of the 
underlying mechanism of hypokalemia (less with 
cell shift, more with renal/GI losses) and the pre- 
vailing serum K + concentration. Potassium 



concentrations in the 3.0-3.5 meq/L range usually 
represent a total body deficit in the 200-400 meq 
range. Correction with oral potassium chloride 
(KC1 — 40-80 meq/day) is preferred with mild- 
to-moderate deficits such as these. In the 
2.0-3.0 meq/L range, K + deficits can reach 
400-800 meq. Intravenous KC1 (20-40 meq/L in 
1 L of 0.45 normal saline) at a rate of no more than 
20 meq/hour, in addition to oral KC1, is often 
required to correct severe K + deficits. Faster rates 
may injure veins (sclerosis) and cause cardiac dys- 
rhythmias and must be avoided. Obviously, cor- 
rection of the underlying etiology of hypokalemia 
is part of the treatment strategy. 

Key Points 

Hypokalemia 



1 . The multiple causes of hypokalemia are 
related to both disturbances in cellular K + 
homeostasis and renal K + excretion. 
Reduced dietary K + intake rarely causes 
hypokalemia. 

2. Clinical manifestations of hypokalemia are 
due primarily to neuromuscular and cardiac 
effects of potassium on excitable cells. 
Findings include muscle weakness and car- 
diac arrhythmias. 

3. The significance of the total K + deficit is 
determined by the combination of the 
mechanism of hypokalemia (cell shift versus 
renal/GI K + loss) and the serum (or plasma) 
K + concentration. 

4. Electrocardiographic evidence of hypokalemia 
is confirmed by the presence of u waves. 

5. Treatment of hypokalemia is determined by 
severity of the K + deficit. Intravenous KC1 is 
given with severe deficits, while oral KC1 is 
employed for mild-to-moderate deficits. 



Hyperkalemia 

Hyperkalemia is defined as a serum (or plasma) K + 
concentration greater than 5.5 meq/L. Rarely, the 



90 



Chapter 6 



Potassium Homeostasis 



Figure 6.5 




1-. i r -< « 

i }■"■-: ] 


: -■. .-.;•• :-.r.: i 

II | 


(• | 


, pi::::;:.:' •: .. 
.1. Up:::]! " : .■ 




fT":! : : | 



ECG of a patient with hypokalemia. The presence of prominent u waves on ECG signals pro- 
found hypokalemia. The u waves are illustrated by the arrows. 



serum K + concentration may be falsely elevated 
(pseudohyperkalemia) due to release of K + from 
cells in the test tube. Lysis of cells following 
prolonged tourniquet application during venipunc- 
ture, and release of K + from large cell numbers 
(white blood cells >100,000 cells/mm 3 ; platelets 
>1, 000,000 cells/mm 3 ) are examples of spurious 
hyperkalemia. As with hypokalemia, causes of 
hyperkalemia (Table 6.3) are broadly categorized 
as (1) increased dietary intake, (2) decreased cel- 
lular uptake, and (3) decreased renal excretion. 
Excessive K + intake alone does not cause hyper- 
kalemia but does contribute to other more impor- 
tant causes of K + overload, such as those with 



renal excretory defects. Shift of K + from the intra- 
cellular space to the ECF occurs in a variety of 
clinical states. As will be seen, disturbances in 
insulin, /^-adrenergic actions, acidemia, and ele- 
vations in plasma osmolality all promote the shift 
of K + from ICF to ECF. Deficient concentration of 
either endogenous or exogenous insulin reduces 
K + entry into cells. This is a frequent cause of 
hyperkalemia in patients with insulin-dependent 
diabetes mellitus. Therapy with /^-adrenergic 
antagonists (propranolol, carvedilol) to treat 
hypertension and heart disease can raise serum 
K + concentration through inhibition of /^-receptor- 
mediated cell uptake. Nonanion gap (mineral.) 



Chapter 6 



Potassium Homeostasis 



91 



Table 6.3 

Causes of Hyperkalemia 



Increased dietary intake 

Excessive oral or intravenous intake (in combination 

with other factors) 
Cellular release of potassium 

Lack of insulin (fasting, diabetes mellitus) 
/^-adrenergic blockade 

Propranolol 

Labetolol 

Carvedilol 
Metabolic acidosis 
Hyperkalemic periodic paralysis 
Succinylcholine 
Hyperosmolality 

Hyperglycemia 

Mannitol 
Aminocaproic acid, lysine 
Digoxin toxicity 

Cell lysis (hemolysis, rhabdomyolysis, tumor lysis) 
Severe exercise 
Decreased renal excretion 
Hypoaldosteronism 

Hypoadrenalism 

Hyporeninemic hypoaldosteronism 

Heparin 

ACE-inhibitors, angiotensin receptor blockers 

NSAIDs 
Low urine flow rate 
Low distal delivery of sodium 
Renal tubular resistance to aldosterone 

Obstructive uropathy 

Systemic lupus erythematosis 

Sickle cell disease 
Drugs 

Amiloride 

Triamterene 

Spironolactone 

Trimethoprim 

Pentamidine 

Calcineurin inhibitors 
Genetic renal diseases 

Pseudohypoaldosteronism type 1 

Pseudohypoaldosteronism type 2 (Gordon's 
syndrome) 
Reduced GFR 



Abbreviations: ACE, angiotensin-converting enzyme; NSAIDS, non- 
steroidal anti-inflammatory drugs. 



metabolic acidosis also promotes shift of K + out of 
cells and hyperkalemia. Hyperkalemic periodic 
paralysis is an inherited disorder associated with 
impaired cellular uptake of K + and hyperkalemia. 
The mutation is in the a subunit of the skeletal 
muscle sodium channel. Hyperosmolality, as 
develops in diabetes mellitus with hyperglycemia 
and in patients treated with certain hyperosmolar 
substances (mannitol, dextran, hydroxyethyl- 
starch), can shift K + out of cells via solvent drag 
and elevate serum K + concentration. Severe lysis 
of red blood cells (hemolysis), muscle cells (rhab- 
domyolysis), and tumor cells (tumor lysis) causes 
hyperkalemia from massive release of K + from 
these cells. 

Decreased K + excretion by the kidneys con- 
tributes significantly to the development of hyper- 
kalemia. Several medications reduce renal K + 
excretion. The major action of these drugs is to 
blunt the kaliuretic mechanisms of the principal 
cell. Drugs such as the nonsteroidal anti-inflam- 
matory drugs (including selective cyclooxyge- 
nase-2 inhibitors), angiotensin-converting enzyme 
inhibitors, angiotensin receptor antagonists, and 
heparin reduce aldosterone synthesis. Spironolac- 
tone and eplerenone compete with aldosterone 
for its steroid receptor and diminish K + secretion. 
Amiloride, triamterene, trimethoprim, and pen- 
tamidine all block the apical Na + channel on the 
principal cell and reduce the electrochemical gra- 
dient for K + secretion. Inhibition of Na + -K + -ATPase 
by digoxin, cyclosporine, and tacrolimus also 
impair renal K + secretion. Several clinical dis- 
eases affect the ability of the kidneys to excrete 
potassium. Advanced renal failure limits K + secre- 
tion by reduction in the number of functioning 
nephrons. Aldosterone deficiency from adrenal 
dysfunction, diabetes mellitus, or other forms of 
hyporeninemic hypoaldosteronism also impairs 
renal K + excretion. This has been called a type 4 
renal tubular acidosis. Hyperkalemia also devel- 
ops from tubular resistance to aldosterone or cel- 
lular defects in tubular K + secretion (obstructive 
uropathy, systemic lupus erythematosis, and 
sickle cell nephropathy). Inherited renal disorders 
such as pseudohypoaldosteronism types 1 and 2 



92 



Chapter 6 



Potassium Homeostasis 



manifest a K + secretory defect, hyperkalemia, and 
hypertension. Finally, limited distal delivery of 
Na + and sluggish urine flow rates, as seen with 
severe volume depletion may impair K + secretion 
by the principal cell. 

A practical clinical algorithm to assess the 
cause of hyperkalemia is described in Figure 6.6. 
After excluding pseudohyperkalemia and shift of 
K + out of cells, hyperkalemia is evaluated by mea- 
suring urinary K + excretion and the transtubular 
K + gradient (TTKG). The TTKG provides a more 
accurate assessment of the tubular fluid K + con- 
centration at the end of the cortical collecting 
tubule and whether hyperkalemia is due to a 
defect in renal excretion or other process. The 
TTKG is calculated by measuring urinary and serum 
K + and osmolality (osm), respectively and plugging 
the values into the following formula: 

TTKG = Urine [K] + -s- (urine osm/serum osm) 
-5- serum [K] + 

Reduced urine K + excretion and a TTKG less 
than 5 suggest a renal defect in K + excretion. 
Patients who fall into this category are evaluated 
further by measuring serum aldosterone and renin 
concentrations to determine the ultimate cause of 
hyperkalemia. Those with an elevated K + excretion 
and TTKG greater than 5 are categorized as non- 
renal causes of hyperkalemia as noted in Figure 6.6. 

The clinical manifestations of hyperkalemia are 
derived from the pathologic effects of high serum 
K + concentration on the generation of action 
potentials in excitable tissues, in particular heart 
and neuromuscular tissues. Hyperkalemia pro- 
motes various cardiac conduction disturbances 
that ultimately affect the rate and rhythm of the 
heart. These include various AV nodal blocks, ven- 
tricular tachycardia and fibrillation, and asystole. 
Myocardial contractility is also impaired in this set- 
ting and contributes to hypotension and shock. 
Various degrees of muscle weakness and paralysis 
are also important clinical signs of hyperkalemia. 

Hyperkalemia is potentially lethal and must be 
promptly identified and treated. As with hypo- 
kalemia, treatment of hyperkalemia should be 
guided by two factors. First, the physiologic 



effects of the excess K + state need to be deter- 
mined and second, the cause of hyperkalemia 
(cell shift versus impaired renal excretion) should 
be identified and aggressively treated. Physiologic 
effects of hyperkalemia are noted by signs of neu- 
romuscular dysfunction and ECG evidence of the 
cardiac conduction disturbances. Significant 
hyperkalemia often manifests as muscle weak- 
ness of varying severity. Well-characterized ECG 
changes suggest the presence of hyperkalemia. 
One of the earliest changes is tenting of the t 
waves. As the serum K + concentration increases, 
the QRS complex widens (Figure 6.7), the p wave 
disappears, and a sine wave pattern develops, 
ultimately leading to ventricular fibrillation or 
asystole. Aggressive therapy is required to pre- 
vent a fatal outcome (Table 6.4). Treatment of 
hyperkalemia should include three main objec- 
tives: stabilize excitable tissues; shift K + into cells 
to lower serum K + concentration; and remove K + 
from the body. Stabilization of excitable mem- 
branes, in particular cardiac tissues, is the first pri- 
ority. This is best accomplished by administering 
intravenous calcium (Ca 2+ ) as either Ca 2+ glu- 
conate or Ca 2+ chloride under cardiac monitoring. 
For patients on digoxin, the calcium should be 
given as a slower drip. Following Ca 2+ therapy, 
the serum K + concentration is lowered rapidly 
employing methods to shift K + into cells. Effective 
therapies include intravenous regular insulin 
(10-20 units) with 25-50 g of glucose in nondiabet- 
ics (to prevent hypoglycemia). Insulin acts within 
30 minutes and lasts approximately 4—6 hours. It 
lowers the serum K + concentration by approxi- 
mately 0.5-1.0 meq/L. High-dose /^-adrenergic 
agonists (albuterol 20 mg nebulized) will lower 
serum K + concentration by approximately 0.6 meq/L 
within 30 minutes. Its effect lasts for 1-2 hours. In 
patients who can tolerate a sodium load and have 
a severe nonanion gap metabolic acidosis, sodium 
bicarbonate shifts K + into cells. The cation- 
exchange resin, sodium polystyrene sulfonate, 
mixed with sorbitol and given either orally or as a 
retention enema is used to increase GI K + excre- 
tion. High-dose loop diuretics increase renal K + 
excretion in patients with reasonably good kidney 



Figure 6. 6 






Pseudohyperkalemia 



Hyperkalemia 



• Test tube hemolysis 

• Thrombocytosis 

• Leukocytosis 



Cell shift 



Urine K + excretion 
TTKG 



• Insulinopenia 

• B 2 -adrenergic blockade 
■ Acidemia 

• Hyperkalemic periodic 
paralysis 

• Succinylcholine 

• Hyperosmolality 

• Arginine HCI 

• Exercise 



4 Urine K + excretion 
TTKG < 5 



t Urine K + excretion 
TTKG > 5 



Normal Aldo 



• Gordon's syndrome 

■ Tubulointerstitial 
disease 

■ Drugs 

- Aldosterone 
Antagonists 

- Triamterene 

- Amiloride 

- Trimethoprim 

- Pentamidine 





4 Aldo 




/ 


/ 




\ 


\ 


4 Renin 




T Renin 



Internal 



Drugs 



Diet 



• Tissue necrosis • K + penicillin 



■ Diabetic 
nephropathy 

■ Obstruction 

■ Elderly 

■ Drugs 

- NSAIDs 

- Calcineurin 
inhibitors 

- COX-2 inhibitors 



Primary adrenal disease 

- Addison's disease 

- Congenital enzyme defects 
Drugs 

- ACE inhibitors 
-ARBs 

- Heparin 



Hematoma 
Tumor lysis 
Hemolysis 
Rhabdomyolysis 



■ Stored blood 

■ Collin's solution 
(organ 
preservation) 



■ Salt substitutes 

■ Herbal products 

■ Low-sodium 
canned foods 



Clinical algorithm to evaluate hyperkalemia. After excluding pseudohyperkalemia and cell shift, urine K + excretion and TTKG are used to ini- 
tially classify hyperkalemia. Renin and aldosterone are used to further classify renal causes of hyperkalemia. Abbreviations: Aldo, aldosterone; 
NSAIDs, nonsteroidal antiinflammatory drugs; COX-2, cyclooxygenase-2; ACE, angiotensin converting enzyme; ARBs, angiotensin receptor 
blockers. 



94 



Chapter 6 



Potassium Homeostasis 



Figure 6. 7 






.^.•-.-. rf^ j ^A j. j. ;/V- r 4.|-'i " ii ^jKi" 1-, !-■' ■*' ' 




ECG of a patient with hyperkalemia. Peaked T waves, widening of the QRS complex, and loss of the p wave (shown here) are ECG 
changes consistent with hyperkalemia. The development of a sine wave indicates imminent cardiac arrest. 



Table 6.4 

Treatment of Hyperkalemia 



Treatment 


Dose 


Onset 


Duration 


Mechanism 


Calcium gluconate (10%) 


10-20 mL IV 


1-5 minutes 


30—60 minutes 


Stabilize excitable 
membranes 


Insulin and glucose 


10 U of IV insulin 
and 25 g of glucose 


30 minutes 


4-6 hours 


Cell uptake 


Albuterol 


20 mg in 4 mL of 


30 minutes 


1-2 hours 


Cell uptake 


(/} agonist) 


normal saline for 
nebulization 








Sodium bicarbonate 


50-75 meq IV 


30-60 minutes 


1-6 hours 


Cell uptake 


Sodium polystyrene 


30-45 g oral 


2-4 hours 


4-12 hours 


GI excretion 


sulfonate 


50-100 g enema 








Hemodialysis 


1-2 meq/L 
potassium bath 


Immediate 


2-8 hours 


Removal from 
the blood 



Abbreviations: TV, intravenous; TJ, units; GI, gastrointestinal. 



Chapter 6 



Potassium Homeostasis 



95 



function. Hemodialysis is an efficient modality to 
quickly remove K + from the body in patients with 
significant renal impairment. Correction of the 
primary cause of hyperkalemia and adjustment in 
dietary K + intake should also be undertaken. 



Key Points 



Hyperkalemia 



Hyperkalemia is caused principally by the 
combination of disturbances in cellular K + 
uptake and impaired renal K + excretion. 
Excessive dietary K + intake contributes to 
hyperkalemia when renal K + excretion is 
decreased. 

Clinical manifestations of hyperkalemia are 
ciue primarily to the disruption of the 
normal generation of the resting membrane 
potential in excitable tissues. Thus, neuro- 
muscular and cardiac functions are 
impaired, resulting in muscle weakness and 
life-threatening cardiac arrhythmias. 
Electrocardiographic evidence of hyper- 
kalemia is confirmed by the presence of 
peaked (tented) t waves, widening of the 
QRS, loss of the p wave, and formation of 
the ominous sine wave. 
Treatment of hyperkalemia is based on the 
principles of stabilization of excitable cell 
membranes, shifting of K + into cells, and 
removal of K + from the body using renal 
excretion, colonic excretion, or dialysis. 
Rapid recognition and treatment of hyper- 
kalemia is required to avoid serious morbid- 
ity and mortality. 



Giebisch, G.H. A trail of research on potassium. Kidney 
Int 62:1498-1512, 2002. 

Good, D.W, Wright, E.S. Luminal influences on potas- 
sium secretion: sodium concentration and fluid flow 
rate. Am J Physiol Z56-$192-V2Q)5, 1979. 

Perazella, M.A., Brown, E. Electrolyte and acid-base 
ciisorders associateci with AIDS: an etiologic review. 
/ Gen Intern Med 9:232-236, 1994. 

Perazella, M.A., Mahnensmith, R.L. Hyperkalemia in the 
elderly: drugs exacerbate impaired potassium 
homeostasis. / Gen Intern Med 12:646-656, 1997. 

Perazella, MA. Hyperkalemia in the end-stage renal 
disease patient in the emergency department. Conn 
Med 63:131-136, 1999. 

Perazella, MA. Drug-induced hyperkalemia: old cul- 
prits and new offenders. Am J Med 109:307-314, 
2000. 

Perazella, M.A., Rastegar, A. Disorders of potassium and 
acid-base metabolism in association with renal dis- 
ease In: Schrier, R.W. (ed.)., Diseases of the Kidney, 
7th ed. Little, Brown & Company, New York, NY, 
2001, pp. 2577-2605. 

Smith, J.D., Perazella, M.A., DeFronzo, RA. 
Hypokalemia: clinical disorders. In: Arief, A. A., 
DeFronzo RA. (eds.), Fluid, Electrolyte and Acid- 
Base Disorders, 2nd ed. Churchill Livingstone, New 
York, NY, 1995, pp. 387-426. 



Additional Reading 



Biswas, P., Perazella, M.A. Acute hyperkalemia associ- 
ated with intravenous epsilon-aminocaproic acid 
therapy. Am J Kidney Dis 33:782-785, 1999. 

Cruz, D.N, Perazella, M.A. Hypertension and hypo- 
kalemia: unusual synciromes. Conn Med 61:67-75, 
1997. 



Dinkar Kaw and 
Joseph I. Shapiro 



Metabolic Acidosis 




Recommended Time to Complete: 2 days 

1. Why is evaluation of acid-base status important? 

2. What is "buffering?" 

1. What determines the pH in the intracellular and extracellular spaces? 
fy. How does one assess acid-base balance? 

S. What processes are involved in renal acid excretion? 
i. What stepwise approach can be used to identify acid-base 

disturbances? 
7- What is metabolic acidosis and how does it occur? 

2. What are the compensatory mechanisms for metabolic acidosis? 
€ \. What are the biochemical and physiologic effects of metabolic 

acidosis? 

10. What is the serum anion gap (SAG) and how is it used in the 
differential diagnosis of metabolic acidosis? 

11. What is the urine anion gap and what is it used for? 

12. How does one diagnostically approach metabolic acidosis? 
11. What is the treatment of metabolic acidosis? 



96 



Chapter 7 




Acid-Base Chemistry 
and Biology 



Acid-base disorders are one of the most common 
problems encountered by the clinician. Although 
the degree of acidosis or alkalosis that results is 
rarely life threatening, careful evaluation of the 
patient's acid-base status often provides insight 
into the underlying medical problem. Moreover, 
the pathophysiology and differential diagnosis of 
these disorders can be approached logically with a 
minimum of laboratory and clinical data. 

Acid-base homeostasis consists of the precise 
regulation of C0 2 tension by the respiratory 
system and plasma bicarbonate (HCOj) concen- 
tration [HCOj] by the kidney. The kidney regulates 
the plasma [HCOj] by altering HCO^ reabsorption 
and elimination of protons (H + ). The pH of body 
fluids is determined by C0 2 tension and [HCOj]. 
These body fluids can generally be readily sam- 
pled and analyzed with a blood gas instrument 
that determines C0 2 tension (in arterial blood, 
PaC0 2 ), pH, and [HCO3], the latter is generally 
calculated (see below). Primary abnormalities of 
C0 2 tension are considered respiratory distur- 
bances, whereas primary derangements of [HCO3] 
are referred to as metabolic disturbances. 

Understanding clinical acid-base chemistry 
requires an appreciation of buffers. For diagnostic 
purposes, we can define an acid as a chemical that 
donates a H + , and a base as a H + acceptor. For an 
acid (HA) and its conjugate base (A^>, we describe 
its strength (or tendency to donate a H + ) by its dis- 
sociation constant K eq and the formula: 



[HA] = K X [H + ][A- 



(1) 



If we rearrange this equation and apply a log 
transformation, we arrive at the following: 



pH = pK + log 10 



[A~] 

[HA] 



(2) 



We use the term buffering to describe the 
capacity of a solution to resist a change in pH 



97 



when a strong (i.e., highly dissociated) acid or 
alkali is added. As a concrete example, say we 
added 100 mL of 0.1 M HC1 to 900 mL of distilled 
water. The [H + ] of what was previously distilled 
water would increase from 10~ 7 to 10~ 2 M. In other 
words, the pH would fall from 7.0 to 2.0. In con- 
trast, if we added 100 mL of 0.1 M HC1 to 900 mL 
of a 1 M phosphate buffer (pK = 6.9 at pH 7.0), 
most of the dissociated H + from HC1 would asso- 
ciate with dibasic phosphate (HPOp and the ratio 
of dibasic to monobasic (H 2 POp phosphate 
would only be slightly changed. As a result, the 
pH would fall by only 0.1. In this latter example, 
the hydrochloric acid (HCl) was buffered by the 
phosphate solution, whereas in the case where 
hydrochloric acid was added to distilled water, no 
such buffering occurred. 

In higher animals such as mammals, the most 
important buffer in the extracellular space is the 
bicarbonate buffer system. Inorganic phosphate 
and proteins are less important buffers in the 
extracellular space. Inorganic phosphate is quan- 
titatively the most important buffer followed 
by bicarbonate and intracellular proteins in 
the intracellular or cytosolic space (Figure 7.1). 



Figure 7. 1 




H 2 C0 3 

H 2 P0 4 " 

HPr 



HCO3" 
HPO4 
Pr" 



Extracellular space 



Relative importance of different buffers in intracellular and extra- 
cellular spaces. Note that in the intracellular space, phosphate 
and proteins play a greater role than they do in the extracellular 
space where the bicarbonate buffer system is most important. 



98 



Chapter 7 



While cytosolic or intracellular pH (pHi) is proba- 
bly more important in predicting physiologic and 
clinical consequences than extracellular pH, it is 
extremely difficult to measure in vivo. Because 
extracellular acid-base status is still informative, 
we focus our clinical efforts on classifying disease 
states using this information that can readily be 
obtained. Specifically, we focus our attention on 
the bicarbonate buffer system (Figure 7.1). It is 
generally assumed that equilibrium conditions 
apply to the bicarbonate buffer system in blood 
because of the abundance of carbonic anhydrase 
(CA) in red blood cells and the high permeability 
of the red blood cell membrane to components of 
the bicarbonate buffer system. Therefore, we can 
express the following equations: 



or 



H + +HCOT 



[H + ] = iT,, x 



4HXO, 



[H,CQ 3 ] 
[HCO^ ] 



(3) 



(4) 



Furthermore, H 2 C0 3 is defined by the partial pres- 
sure of C0 2 and the solubility of C0 2 in physio- 
logic fluids that is, for all intents and purposes, a 
constant S. We can, therefore, rearrange equation 
(4) to read 



[H*] = Kx 



S x PCO, 



[HCO3 ] 

Taking the antilog of both sides we get 

[HCO" ] 



pH = pK + log 1( 



S x PCO, 



(5) 



(6) 



that is called the Henderson-Hasselbalch equa- 
tion. In blood (at 37°C), the pK referred to in equa- 
tion (6) is 6.1 and the solubility coefficient for C0 2 
(5) is 0.03- Therefore, we can simplify this expres- 
sion to 



pH = 6.1 + log 10 



[HCO, 



0.03xPaCO, 



(7) 



This formula allows us to view acid-base disor- 
ders as being attributable to the numerator of the 



ratio (metabolic processes), the denominator (res- 
piratory processes), or both (mixed or complex 
acid-base disorders). 



Key Points 



Acid-Base Chemistry and Biology 



Evaluation of acid-base status provides 
insight into underlying medical problems. 
Many cellular functions are dependent on 
optimum pH of body fluids. 
The pH is defined as the negative logarithm 
of [H + ], 

Interplay among body buffers, lungs, and 
kidneys is responsible for maintaining pH 
within normal limits. 

The most important buffer in the extracellu- 
lar space is bicarbonate and in the intracel- 
lular space is inorganic phosphate. 
Lungs excrete CO z and kidneys excrete H + 
to maintain serum bicarbonate and pH in 
the normal range. 




Assessing Acid-Base Balance 



A myriad of enzymatic reactions involve the loss 
or gain of protons that occur with ongoing catab- 
olism and anabolism. To understand whether 
acid or base is produced; however, one simply 
examines the initial substrates and final prod- 
ucts. To do this, it is helpful to think of acids and 
bases as "Lewis" acids and bases; in other words, 
to consider acids as electron acceptors rather 
than as proton donors. In concrete terms, when 
a substrate is metabolized to something more 
anionic (e.g., glucose is metabolized to lactate 
through the Embden-Meyerhoff glycolytic path- 
way), acid is generated. Conversely, if a substrate 
is metabolized to something more cationic 



Chapter 7 ♦ 

Figure 7.2 



99 





Substrate 

1 

Product " 

+ 

H + 






Substrate 

1 

Product + 

+ 

HC0 3 - 





"Black box'' approach to acid-base metabolism. 
The left panel shows that when a substrate is 
metabolized to a more electronegative product, a 
proton is generated. Conversely, the right panel 
demonstrates that when a substrate is metabolized 
to a more electropositive product, a proton is con- 
sumed and bicarbonate is generated. 



Key Points 

Assessing Acid-Base Balance 



When a substrate is metabolized to some- 
thing more anionic (e.g., glucose is metabo- 
lized to lactate through the Embden- 
Meyerhoff glycolytic pathway), acid is 
generated. 

If a substrate is metabolized to something 
more cationic (e.g., lactate is metabolized to 
C0 2 and H 2 via the TCA cycle), acid is 
consumed. 

The kidneys regulate serum [HCOj] and 
acid-base balance by reclaiming filtered 
HCOj and generating new HCOj to 
replace that lost internally (in titrating meta- 
bolic acid) and externally (e.g., from the 
gastrointestinal tract). 



(e.g., lactate is metabolized to C0 2 and H 2 via 
the tricarboxylic acid [TCA] cycle), acid is con- 
sumed (Figure 7.2). Because of the importance 
of the bicarbonate buffer system in overall acid- 
base homeostasis, we generally consider the 
addition of a proton as equivalent to the 
decrease in total body HCO J and loss of a proton 
as a gain in HCOj. 

The classic normal values for an arterial blood 
gas are pH: 7.4; [HCOj]: 24 meq/L; and PaC0 2 : 
40 mmHg. The kidneys regulate serum [HCOj] 
and acid-base balance by reclaiming filtered 
HCOj and generating new HCOj to replace that 
lost internally (in titrating metabolic acid) and 
externally (e.g., from the gastrointestinal tract). 
Approximately 1 mmol of H + /kg body weight per 
day is generated from the metabolism of a normal 
"Western diet." To maintain acid-base homeostasis 
the kidney must excrete this acid load. The role 
of the kidney in acid-base homeostasis can be 
divided into two basic functions: (1) the reab- 
sorption of filtered bicarbonate and (2) the excre- 
tion of the acid load derived from dietary 
metabolism. 




Acid Excretion by the Kidney 



Our understanding of renal acid excretion has 
evolved considerably in the past decade. In par- 
ticular, we have identified the specific ion pumps 
and transporters that are involved in tubular 
proton secretion in different portions of the 
nephron. It is clear that the major ion transporters 
and pumps include the sodium-proton exchanger 
(Na + -H + exchanger, which exchanges one H + for 
one sodium ion), the sodium-phosphate cotrans- 
porter (which transports three sodium ions with 
one dibasic phosphate molecule), and the vacuo- 
lar H + ATPase (which pumps H + directly into the 
tubular lumen). Other important transport pro- 
teins include the chloride-bicarbonate exchanger, 
the "colonic" H + -K + ATPase, and the Na + -K + 
ATPase. These transport proteins are expressed 
to varying degrees in different cell types and 
nephron segments of the kidney, depending on 
the specific functions of these cells. 



100 



Chapter 7 



Regarding overall acid-base handling by the 
kidney, there is a strong relationship between 
acid secretion and the reclamation of filtered 
bicarbonate, as well as the production of new 
bicarbonate by the kidney as one would antici- 
pate based on our earlier discussion. First, 
plasma is filtered at the glomerulus and HCOj 
enters the tubular lumen. Each HCOj molecule 
that is reclaimed requires the epithelial secretion 
of one H + . This H + secretion occurs via the Na + -H + 
exchanger on the luminal membrane or through 
an electrogenic H + ATPase. On an integrated 
physiologic level, we can think of the HCOj 
reabsorption processes establishing a plasma 
threshold for bicarbonate, i.e., that level of 
plasma HCOj at which measurable HCOj 
appears in urine. This concept of a plasma 
threshold is well established for renal glucose 
handling, historically, the appearance of glucose 
in urine was used as a surrogate for elevated 
blood glucose levels before blood glucose mon- 
itoring became widespread. Continuing this 
analogy to renal glucose handling, we can also 
define the maximal net activity of tubular HCOj 
reabsorption as the T* max . The T mxt and plasma 
threshold for HCOj are, of course, intimately 
related. As the !T max for HCOj increases, the 
plasma threshold for HCOj increases. Conversely, 
decreases in 7* max result in decreases in the 
plasma threshold. Quantitatively, to eliminate 
HCOj from urine with a glomerular filtration 
rate of 100 mL/minute and a plasma [HCOj] of 
24 meq/L, the tubules must secrete about 2.4 mmol 
of H + per minute. Ergo, HCOj reclamation by the 
tubules involves a considerable amount of H + 
secretion. 

Bicarbonate reclamation is closely related to 
sodium reabsorption and is, therefore, sensitive 
to a number of other influences that impact 
sodium reabsorption. In particular, states of 
extracellular fluid (ECF) volume expansion and 
decreases in PaC0 2 decrease the apparent T max 
for HCOj , whereas ECF volume contraction and 
increases in PaC0 2 increase the apparent T max 
for HCOj . Parathyroid hormone inhibits proxi- 
mal tubule HCOj reabsorption and lowers the 



apparent 7* max and plasma threshold for HCOj . 
The majority of HCOj reabsorption (approxi- 
mately 80-90%) takes place in the proximal 
tubule. The enzyme carbonic anhydrase is 
expressed intracellularly, as well as on the lumi- 
nal membrane of the proximal tubule cell, 
which allows the secreted H + to combine with 
tubular fluid HCOj to form H 2 CO,. This H 2 CO, 
rapidly dissociates to form H 2 and C0 2 , which 
then can reenter the proximal tubule cell. 
Intracellularly, water dissociates into H + and 
OH~. Intracellular carbonic anhydrase catalyzes 
the formation of HCOj from CO, and OH~. 
Bicarbonate leaves the cell via several bicarbon- 
ate transport proteins including the sodium- 
bicarbonate cotransporter, as well as the 
Ch-HCOj exchanger. In the proximal tubule, 
where the reclamation of HCOj filtered from the 
blood occurs, HCOj is formed inside the renal 
tubular cells when either H + secretion or ammo- 
nium (NH4O synthesis occurs. The HCOj is then 
transported back into blood predominantly via 
the basolateral Na + -3HCOj cotransporter. 

Proton secretion by the distal nephron is aided 
by the production of an electrogenic gradient. 
This gradient, which is produced by removal of 
sodium from the luminal fluid in excess to anion 
reabsorption, favors H + secretion. There is also 
direct pumping of H + into the tubular lumen. Na + - 
H + exchange, as well as the activities of the vac- 
uolar H + ATPase and the Na + -K + ATPase in 
intercalated and principal cells, accomplish these 
tasks. Chloride exchange "with bicarbonate on the 
basolateral side of these distal tubular cells allows 
for proton secretion to be translated into bicar- 
bonate addition to blood as discussed earlier. The 
epithelial membrane in the distal nephron must 
not allow backleak of H + or loss of the electro- 
genic gradient. Under normal circumstances, 
urine pH can be as low as 4.4. This represents a 
1000:1 gradient of [H + ] between tubular and extra- 
cellular fluids. 

Net acid excretion (NAE) is the total amount of 
H + excreted by the kidneys. Quantitatively, we 
can calculate NAE to be the amount of H + (both 
buffered and free) excreted in urine minus the 



Chapter 7 



101 



amount of HCOj that failed to be reclaimed and 
was lost in the urine. Because H + secretion into 
the tubule lumen results in a 1:1 HCOj addition to 
the ECF, NAE equals the amount of new HCOj 
generated. 

Net acid excretion is accomplished through 
two processes that are historically separated on 
the basis of a colorimetric indicator (phenol- 
phthalein) that detects pH changes effectively 
between pH 5 and 8. That acid, which can be 
detected by titrating sufficient alkali into urine 
to achieve color changes with this indicator, is 
called titratable acid and is mostly phosphate in 
the monobasic (H 2 PO~) form. Nontitratable 
acid excretion occurs primarily in the form of 
NH4" 1 ; This form of acid excretion is not detected 
by phenolphthalein since the pK (approxi- 
mately 9) for ammonium is too high. Even though 
most clinicians equate NAE with an acidic urine, 
it is important to recognize that a low urine pH 
does not necessarily mean that NAE is 
increased. For example, at a urine pH of 4.0 the 
free H + concentration is only 0.1 mmol. In a 70-kg 
person on an average Western diet one can see 
that free protons would make up only a small 
fraction of the approximately 70 mmol of net acid 
that need to be excreted per day. The majority 
of NAE is in the form of protons bound to 
buffers, either phosphate or ammonium. This 
makes it possible to elaborate a much less acid 
urine but still achieve adequate NAE. In fact, 
there are several pathologic conditions (dis- 
cussed later) in which the urine pH is relatively 
acid but NAE is insufficient. In subjects that 
consume a typical Western diet, adequate NAE 
occurs through the functions of both the proxi- 
mal tubule to synthesize NH 4 + (which generates 
HCOp and distal and collecting tubules where 
H + and NH 4 + secretion occur. 

Net acid excretion is influenced by several fac- 
tors including the serum potassium concentration 
(serum K + elevations decrease NH/ excretion, 
while decreases enhance distal nephron H + 
secretion), PaC0 2 , and the effects of aldos- 
terone. Quantitatively, NAE is usually evenly 
divided between titratable acid and ammonium 



excretion, however, our capacity to increase NAE 
is mostly dependent on enhanced ammoniagen- 
esis and NH 4 + excretion. The older view that NH 4 + 
excretion "was accomplished by simple passive 
trapping of NH 4 + in the tubular lumen has been 
revised. We now understand that the excretion of 
NH 4 + is more "active." First, in proximal tubule 
cells, there is deamination of glutamine to form 
alphaketoglutarate (aKG) and two NH^ The fur- 
ther metabolism of aKG to C0 2 and H 2 gener- 
ates two new HCO3 molecules as discussed 
earlier. Proximal tubule cells actively secrete NH 4 
into the lumen, probably via the luminal Na + -H + 
exchanger. NH 4 + can substitute for H + and be 
transported into the urine in exchange for 
sodium. NH4" is subsequently reabsorbed in the 
medullary thick ascending limb of Henle where it 
can be transported instead of K + via the Na + -K + - 
2C1~ cotransporter. This increases medullary inter- 
stitial concentrations of NH 4 + Interstitial NH4" 
enters the collecting duct cell, substituting for K + 
on the basolateral Na + -K + ATPase. The NH 4 + is 
next secreted into the tubular lumen, possibly by 
substitution for H + in the apical Na + -H + exchanger 
or H + -K + ATPase and is ultimately excreted into 
the final urine. It is important to note that the net 
generation of any HCO3 from aKG metabolism is 
dependent on this excretion of NH.^ Quite 
simply, if this NH/ molecule is not excreted in 
urine, it is returned via the systemic circulation to 
the liver, where it will be used to form urea at the 
expense of generating two protons. In this case, 
the HCO3 molecules that were generated by the 
metabolism of aKG are neutralized and no net 
generation of HCO3 will result. 

Because routine clinical measurement of uri- 
nary NH 4 + concentrations never became stan- 
dard, our appreciation of NH^ in net acid-base 
balance during pathophysiologic conditions 
was delayed until recently, however, assessment 
of NH4" is key in understanding NAE. It turns out 
that urinary [NH^] is estimated by calculations 
based on urinary electrolyte concentrations 
(either urinary anion gap or urinary osmolar 
gap) that are routinely measured. This will be 
discussed later. 



102 



Chapter 7 



Key Points 

Acid Excretion by the Kidney 



1 . Each HC0 3 ~ reclaimed from the proximal 
tubular lumen requires the epithelial secre- 
tion of one H + Largely, a Na + -H + exchanger 
on the luminal membrane accomplishes 
this, although an electrogenic H + ATPase is 
also involved. 

2. Net acid excretion by the kidney is the 
amount of H + (both buffered and free) 
excreted in the urine minus the amount of 
HCO^ excreted in the urine. 

3. Net acid excretion is accomplished primarily 
through elimination of titratable acid (which 
is mostly phosphate) and nontitratable acid 
(in the form of NH|). 

4. An acidic urine (low urine pH) does not 
necessarily mean that NAE is increased. 

5. Proton secretion by distal nephron is facili- 
tated by the production of an electrogenic 
gradient that is produced by removal of 
sodium from the luminal fluid. 




Clinical Approach to the Patient 
with an Acid-Base Disorder 



The approach to acid-base disorders often con- 
founds practitioners of medicine, however, if one 
follows a fairly standard algorithm, acid-base 
disorders can be dissected fairly easily. We sug- 
gest the following seven steps when confronting 
a suspected acid-base disorder. The information 
necessary to approach a suspected acid-base 
disorder involves a blood gas (which gives pH, 
Pa0 2 , PaC0 2 , and calculated [HC0 3 1 values) and 
serum chemistry panel (which gives serum Na + , 
K + , Cl~ and total C0 2 content). It is these data on 
which subsequent decisions are based. The total 



C0 2 content (TC0 2 ), which is the sum of the serum 
[HCOjl and dissolved C0 2 (usually determined on 
a venous serum sample) is often referred to as the 
"C0 2 ", however, it must not be confused with the 
PaC0 2 , which refers to the partial pressure of C0 2 
in arterial blood. Since the serum [HCO,1 or TC0 2 
includes a component of dissolved C0 2 , it is often 
1-2 meq/L higher than the calculated [HC0 3 i 
derived from arterial blood gases. 

1. What is the blood pH (is the patient acidemic 
or alkalemic)? Based on a normal sea level pH 
of 7.40 ± 0.02, a significant decrease in pH or 
acidemia means that the primary ongoing 
process is an acidosis. Conversely, an increase 
in pH or alkalemia indicates that the primary 
ongoing process is an alkalosis. 

2. Identify the primary disturbance. In order to 
accomplish this one must examine the direc- 
tional changes of PaC0 2 and serum [HC0 3 i 
from normal. If pH is low and [HC0 3 ~] is low, 
then metabolic acidosis is the primary distur- 
bance. Conversely, if pH is high and [HCO^] is 
high, then metabolic alkalosis is the primary 
disturbance. 

3. Is compensation appropriate? This step is 
essential for one to understand whether the 
disturbance is simple (compensation appropri- 
ate) or complex (mixed). With metabolic aci- 
dosis, the PaC0 2 (in mmHg) must decrease, 
conversely, with metabolic alkalosis the PaC0 2 
must increase. Inadequate compensation is 
equivalent to another primary acid-base distur- 
bance. It is important to recognize that com- 
pensation is never complete. Compensatory 
processes cannot return one's blood pH to 
what it was before one suffered a primary dis- 
turbance. 

4. What is the serum anion gap (discussed in 
detail later in this chapter)? Calculating the 
serum anion gap provides insight into the 
differential diagnosis of metabolic acidosis 
(anion gap and non-anion gap metabolic aci- 
dosis) and can also indicate that metabolic 
acidosis is present in the patient with metabolic 
alkalosis. 



Chapter 7 



103 



5 . Compare the change in serum anion gap to the 
change in serum bicarbonate concentration 
(discussed more fully in Chapter 9). If the 
change in the serum anion gap is much larger 
than the fall in serum bicarbonate concentra- 
tion, one can infer the presence of both an 
anion gap metabolic acidosis and metabolic 
alkalosis. If the fall in serum bicarbonate con- 
centration is, however, much larger than the 
increase in the serum anion gap (and the serum 
anion gap is significantly increased), one can 
infer the presence of both an anion gap and 
non-anion gap metabolic acidosis. 

6. Identify the underlying cause of the distur- 
bance. This is the whole purpose of analyzing 
acid-base disorders. One must remember that 
acid-base disorders are merely laboratory signs 
of an underlying disease. The pathologic cause 
of the acid-base disorder is usually obvious 
once the individual primary disturbances are 
identified. 

7. Initiate appropriate therapy. The acid-base 
disturbance must be directly addressed in several 
clinical situations. Ultimately, treatment of the 
underlying cause is most important. 




Metabolic Acidosis 



Pathophysiologic Mechanisms 
and Compensation 

Metabolic acidosis is characterized by a primary 
decrease in [HCOj]. This systemic disorder may 
occur in several •ways: 

1 . Addition of a strong acid that consumes HCO3 . 

2. Loss of HCO3 from the body (usually through 
the gastrointestinal [GI] tract or kidneys). 

3. Rapid addition of non-bicarbonate-containing 
solutions to ECF, also called dilutional acidosis. 

In the latter two situations where HCO3 is lost 
or diluted, an organic anion is not generated. In 



this case, electroneutrality is preserved by recip- 
rocal increases in serum chloride concentration. 
These forms of metabolic acidosis are generally 
referred to as hyperchloremic or non-anion gap 
metabolic acidosis, however, when an organic 
acid consumes HCO3, the organic anion that is 
produced is often retained in ECF and serum. In 
this circumstance, the serum chloride concentra- 
tion does not increase. This important concept is 
discussed in detail below. 

The first line of defense against the fall in pH 
resulting from metabolic acidosis is the participa- 
tion of buffer systems. This always occurs to some 
degree. As a general rule, nonbicarbonate buffers 
buffer about one-half of an acid load, however, 
with more severe acidosis, the participation of 
nonbicarbonate buffers can become even more 
important. Bone contributes importantly to buffer- 
ing in chronic metabolic acidosis. The attendant 
loss of calcium from bone that results in reduced 
bone density and increased urinary calcium 
excretion are major deleterious consequences of 
chronic metabolic acidosis. 

The second line of defense is the respiratory 
system. The PaC0 2 declines in the setting of meta- 
bolic acidosis. This is a normal, compensatory 
response. Failure of this normal adaptive res- 
ponse indicates the concomitant presence of 
respiratory acidosis. An excessive decline in 
PaC0 2 , producing a normal pH, indicates the 
presence of concomitant respiratory alkalosis. 
Both situations are considered to be complex or 
mixed acid-base disturbances (Chapter 9). The 
respiratory response to metabolic acidosis is 
mediated primarily by pH receptors in the central 
nervous system (CNS). Peripheral pH receptors 
probably play a smaller role. This explains the 
small time delay prior to the establishment of res- 
piratory compensation observed in animals and 
humans subjected to experimental metabolic 
acidosis. The normal, compensatory fall in PaC0 2 
(in mmHg) should be between 1 and 1.5 times 
the fall in serum [HCO3] (in meq/L). Even with 
extremely severe metabolic acidosis, how- 
ever, the PaC0 2 cannot be maintained below 
10-15 mmHg. 



104 



Chapter 7 



The kidney provides the third and final line of 
pH defense. This mechanism is, however, rela- 
tively slow compared to the immediate effect of 
buffering and respiratory compensation, which 
begins within 15-30 minutes. In contrast, the renal 
response requires 3-5 days to become complete. 
In the presence of normal renal function, acidosis 
induces increases in NAE by the kidney. This 
increase in NAE is due primarily to increases in 
NH + excretion rather than the minimal changes in 
phosphate (titratable acid) excretion. Acidosis 
increases the deamination of glutamine that gen- 
erates NH^ Excretion of the NH^ and the ultimate 
catabolism of aKG, leads to generation of new 
HCO3. In fact, there is both transcriptional and 
translational upregulation of key enzymes involved 
in glutamine metabolism that are induced by 
acidosis. Chronic metabolic acidosis also increases 
renal endothelin-1 that activates the Na + -H + 
exchanger on the proximal tubule brush border. 
Therefore, acidosis induces both the generation 
of new HCOj via the glutamine system and the 
enhancement of HCO3 reabsorption and titrat- 
able acid formation. Interestingly, the decreases 
in PaC0 2 that occur from respiratory compensa- 
tion, actually limit renal correction in metabolic 
acidosis. 



Key Points 

Metabolic Acidosis 



1. Metabolic acidosis is a systemic disorder 
characterized by a primary decrease in 
serum [HC0 3 i. 

2. This occurs in three ways: the addition of 
strong acid that is buffered by (i.e., con- 
sumes) HCOj"; the loss of HCO^ from body 
fluids, usually through the GI tract or kid- 
neys; and the rapid addition to the ECF of 
nonbicarbonate-containing solutions (dilu- 
tional acidosis). 

3. In hyperchloremic or normal anion gap 
metabolic acidosis no organic anion is 
generated. 



4. Organic anions are generated when an 
organic acid consumes bicarbonate leading 
to increased anion gap metabolic acidosis. 

5. Fall in PaCO, is a normal compensatory 
response to simple metabolic acidosis. 

6. Increases in NAE by the kidney develop in 
response to metabolic acidosis. The increase 
in NAE is due mostly to increases in NHJ 
excretion that take up to 5 days to become 
maximal. 




Biochemical and Physiologic 
Effects of Metabolic Acidosis 



In the short term, mild degrees of acidemia are 
often well tolerated. In fact, some physiologic 
benefit such as increased P 50 for hemoglobin 
favoring 2 delivery to tissues occurs. If acidosis 
is severe (pH less than 7.10), however, myocar- 
dial contractility and vascular reactivity are 
depressed; in this setting, hypotension often pro- 
gresses to profound shock. These consequences 
of acidosis result from well-described molecular 
mechanisms. First, acidosis depresses both vascular 
and myocardial responsiveness to catecholamines. 
In the case of the vasculature, supraphysiologic 
concentrations of catecholamines may restore 
reactivity, but the myocardial depression created 
by acidosis will eventually overcome this effect as 
pH continues to fall. 

Metabolic acidosis induces an intracellular aci- 
dosis, and this appears to be particularly deleteri- 
ous to physiologic function in cardiac myocytes. 
In addition, metabolic acidosis impairs the ability 
of cardiac myocytes to use energy. Some of this 
results from a blockade of glycolysis at the level of 
phosphofructokinase, but direct inhibition of 
mitochondrial respiratory function also occurs. On 
a physiologic level, intracellular acidosis impairs 
contractile responses to normal and elevated 



Chapter 7 



105 



cytosolic calcium concentrations. Specifically, intra- 
cellular acidosis significantly shifts the sensitivity 
of Troponin C to calcium. Perhaps even more 
important, acidosis induces impairment of actin- 
myosin cross-bridge cycling. This results directly 
from increases in inorganic phosphate concentra- 
tion in the monovalent form (HjPO^). This 
increase in H 2 PC>4 results both from the acidic 
environment, as well as an impairment of myocar- 
dial energy production that increases the total 
intracellular concentration of inorganic phos- 
phate. Metabolic acidosis and hypoxia synergisti- 
cally impair myocardial myocyte metabolism, a 
phenomenon consistent with the monovalent 
inorganic phosphate hypothesis. 

With mild degrees of acidosis, it may be diffi- 
cult to discern an increase in ventilatory effort. 
More severe metabolic acidosis, pH < 7.20, increases 
the ventilatory effort. This is readily apparent as 
respirations become extremely deep and rapid, a 
clinical sign known as Kussmaul respiration. Mild 
degrees of acidosis do not markedly impair hemo- 
dynamic stability in subjects with otherwise 
normal cardiovascular function, but severe 
metabolic acidosis often leads to hypotension, 
pulmonary edema, and ultimately, ventricular stand- 
still. Bone effects of even mild chronic metabolic 
acidosis are prominent. This acid-base disturbance 
leaches calcium from bone, resulting in hypercal- 
ciuria and bone disease. Treatment of renal tubu- 
lar acidosis (RTA) or the acidosis of chronic kidney 
disease hinges on these important effects. 

Decreased blood pH (acidemia), serum 
[HCO3] (primary response), and PaC0 2 (compen- 
satory response) are the laboratory findings that 
are the hallmark of simple metabolic acidosis. 
We reiterate that if the PaC0 2 does not fall by 
1-1.5 times the decline in serum [HCOj], this 
implies the coexistence of respiratory acidosis. 
We would argue that the profound clinical impli- 
cations of this make this more than a semantic 
argument. It is, in fact, common for subjects with 
profound metabolic acidosis to eventually tire of 
their extraordinary respiratory effort. In this set- 
ting, the PaC0 2 rises to a level consistent with 
inadequate compensation, often just prior to 



respiratory arrest. Ergo, this must be considered 
as respiratory acidosis in order to mobilize the 
appropriate, emergent clinical response (Chapter 9). 
Normal or increased serum potassium in the face 
of decreased total body potassium stores occurs 
commonly with metabolic acidosis. This occurs 
because acidosis shifts potassium from the intra- 
cellular fluid to the extracellular fluid and renal 
potassium excretion increases in many states of 
metabolic acidosis. As is discussed in the next 
section, metabolic acidosis is classified as an 
anion gap (organic) or non-anion gap (hyper- 
chloremic) metabolic acidosis. In general, meta- 
bolic acidosis states are characterized by the 
retention of an organic anion generated in con- 
cert with HCO3 consumption (organic acidosis) 
and others are not (hyperchloremic). As screen- 
ing of serum for such organic anions is not prac- 
tical on a routine, immediate basis, a calculation 
performed on the serum electrolytes called the 
anion gap is employed. 



Key Points 

Biochemical and Physiologic Effects of Metabolic Acidosis 



1. With marked acidemia (pH less than 7.10), 
myocardial contractility is depressed and 
peripheral resistance falls. 

2. Acidosis depresses both vascular and 
myocardial responsiveness to cate- 
cholamines, as well as innate myocardial 
contractility. Both myocardial beta-receptor 
density, as well as physiologic responses to 
beta-agonists, are decreased by metabolic 
acidosis. 

3. Decreased myocardial calcium sensitivity 
results in contractile dysfunction. 

4. Metabolic acidosis and hypoxia act 
synergistically to impair myocardial 
function, a phenomenon consistent with 
the monovalent inorganic phosphate 
hypothesis. 

5. Chronic metabolic acidosis causes hypercal- 
ciuria and bone disease. 




Chapter 7 ♦ 



Use of the Serum and Urine 

Anion Gap in the Differential 

Diagnosis of Metabolic Acidosis 



The serum anion gap is used to determine 
whether an organic or mineral acidosis is present. 
This very simple concept that we will discuss in 
some detail allows the clinician to use simple elec- 
trolyte determinations to accurately infer whether 
an organic anion is present in high concentration. 
We calculate the serum anion gap as 



SAG = [Na + ] - [C11 - [TCO, 



(8) 



In this equation, we use the TC0 2 as an index 
of serum [HCOj], We rather arbitrarily define 
"unmeasured" as not being in the equation (8). In 
other words, unmeasured cations (UC) are those 
cations that are not Na + (e.g., K + , Mg 2+ , Ca 2+ ) and 
unmeasured anions (UA) as anions that are not 
Cl" or HCO; (e.g., SO", H 2 PO,-- HPO", albumin, 
and organic anions). The SAG, UA, and UC are 
expressed in units of meq/L. Equation (9) is writ- 
ten as such to maintain electroneutrality. 



[Na + ] + UC = [C11 + [TCOJ + UA 



(9) 



When we combine equations (8) and (9), the 
following equation for SAG is derived: 



SAG = UA - UC 



(10) 



For ease of computation, we consider a normal 
SAG to be about 10 meq/L; actually it is somewhere 
between 6 and 10 meq/L. We further assume that 
every proton generated causes a stoichiometric 
reduction in serum [HCO3]. With these assump- 
tions, it is clear that the addition of organic acid 
will cause an increase in the SAG, whereas addi- 
tion of mineral acid (HCl) will not (Figure 7.3). 

The SAG is extremely useful in the differential 
diagnosis of metabolic acidosis. We stress, how- 
ever, that it must be interpreted with some caution. 
While an organic acidosis should theoretically pro- 
duce anions in concert with protons (discussed 



Figure 


7.3 






HA 


HCl 


;ih + ] 


t[Al 


*[H + ] 


t [CIl 


\ 


\ / 


1 [HCO3-] 


1 [HCO3I / 






\ / 


|SAG 


Normal SAG 



Organic acidosis is associated with an increase in 
serum anion gap (SAG) (left panel) whereas min- 
eral acidosis is not (right panel). Note that addition 
of organic acid (HA) causes an increase in [H + ] 
which, in turn, results in a decrease in [HCO3]. Since 
[Cli and [Na + ] do not change, the SAG defined as 
[Na + ] - [Cli - [HCO3] increases. In contrast, when 
HCl is added, the decrease in [HCO3I is matched by 
an increase in [Cli and the SAG does not change. 



above), note that the relationship between the 
increase in SAG and fall in bicarbonate concentra- 
tion depends primarily on the clearance mecha- 
nisms for the anion and the volume of distribution 
for both bicarbonate and the anion. In general, 
the SAG is most useful when it is extremely ele- 
vated. A major increase in the anion gap (e.g. SAG 
>25 meq/L) always reflects the presence of an 
organic acidosis. 

Unmeasured anions include SOf", H 2 PO~, 
HPOf~, albumin and organic anions. LJnmeasured 
cations include K + , Mg 2+ , and Ca 2+ . A low SAG is 
seen in four clinical circumstances: (1) a reduction 
in the concentration of unmeasured anions (pri- 
marily albumin); (2) underestimation of the serum 
sodium concentration; (severe hypernatremia); 
(3) overestimation of the serum chloride concen- 
tration (bromide intoxication and marked hyper- 
lipidemia); and (4) increased non-sodium cations 



Chapter 7 



107 



(hyperkalemia, hypermagnesemia, hypercalcemia, 
lithium toxicity, or a cationic paraprotein). For 
each 1 g/dL decrease in serum albumin concen- 
tration the SAG will decrease by 2.5 meq/L. 
Therefore, in patients with hypoalbuminemia the 
SAG should be adjusted upward based on this 
correction factor. 

As discussed earlier, one cannot routinely mea- 
sure urinary ammonium concentration. Therefore, 
we must use the same type of reasoning employed 
for the SAG to develop a method to estimate NH^ 
concentration based on the electrolyte content of 
urine. Because of electroneutrality we presume 



[Na + ] + [K + ] + UC = [CM + UA 



(11) 



Furthermore, when urine pH is <6, the urine 
does not contain appreciable amounts of bicar- 
bonate. More relevant, the UC is made up mostly 
of NH 4 t Therefore, we can define the urinary 
anion gap (UAG) as 



UAG = [Na + ] + [K + ] - [Ch 



(12) 



It is clear that the UAG will be negative when 
urinary [NH.+] is high. It turns out that low concen- 
trations of urinary NH^" are associated with a pos- 
itive UAG. While the SAG is useful in many 
settings of clinical acid-base diagnosis and ther- 
apy, we must stress that the UAG is limited to a 
few clinical situations, specifically, it is used to dif- 
ferentiate renal (principally tubular acidosis) from 
non-renal causes of non-anion gap metabolic aci- 
dosis (such as diarrhea). 



3. The addition of organic acid will cause an 
increase in the SAG, whereas addition of 
mineral acid (HC1) will not. 

4. The urinary anion gap is used to estimate 
the quantity of NH 4 + in urine. 

5. The UAG is used in the differentiation of 
renal from non-renal causes of non-anion 
gap metabolic aciciosis. 




The first step in the differential diagnosis of meta- 
bolic acidosis is examination of the SAG. An anion 
gap metabolic acidosis is characterized by reten- 
tion of an organic anion (elevated anion gap). In 
contrast, a hyperchloremic or non-anion gap 
metabolic acidosis is not associated with retention 
of an organic anion (normal anion gap). 



Increased Anion Gap Metabolic 
Acidosis 




Key Points 

Use of the Serum and Urine Anion Gap in the Differential 
Diagnosis of Metabolic Acidosis 



The serum anion gap is a concept used in 
acid-base pathophysiology to infer whether 
an organic or mineral acidosis is present. 
Venous serum electrolytes are used to calcu- 
late the serum anion gap as 

SAG = [Na + ] - [CM - lTGO,] 



There are three forms of anion gap metabolic aci- 
dosis that are characterized by ketonemia or 
ketonuria and these include diabetic ketoacidosis, 
starvation ketosis, and alcoholic ketoacidosis 
(AKA) (Table 7.1). In all of these disorders, 
impaired lipid metabolism leads to generation 
and accumulation of short chain fatty ketoacids, 
specifically, beta-hydroxybutyric and acetoacetic 
acids. These ketoacids are relatively strong acids 
that produce acidosis, as "well as an increase in the 
anion gap. The initial step in the evaluation of the 
patient with anion gap metabolic acidosis is an 
examination of blood and urine for ketones. 



108 



Chapter 7 



Table 7. 1 



Causes of Increased Anion Gap (Organic) Metabolic Acidosis 



Increased acid production 

Lactic acidosis 
Ketoacidosis 

Diabetic ketoacidosis 

Starvation 

Alcoholic ketoacidosis 
Inborn errors of metabolism 
Toxic alcohol ingestions 
Salicylate overdose 

Other intoxications (e.g., toluene, isoniazid) 
Failure of acid excretion 
Acute renal failure 
Chronic kidney disease 



alcohol intoxication that is characterized by ketosis 
without significant acidosis. 



Starvation 

Starvation produces some metabolic processes 
that are similar to those seen with DKA. As carbo- 
hydrate availability becomes limited, hepatic 
ketogenesis is accelerated and tissue ketone 
metabolism is reduced. This produces increases 
in the serum (and urine) concentration of 
ketoacids and ketones. At first, there is minimal 
associated acidosis as renal NAE maintains bal- 
ance. With more prolonged starvation the serum 
[HCO3] often declines, however, it does not gen- 
erally fall below 18 meq/L since ketonemia pro- 
motes insulin release. 



Diabetic Ketoacidosis 

Diabetic ketoacidosis is a common form of anion- 
gap metabolic acidosis. This entity results from a 
nearly absolute deficiency of insulin along with 
increases in glucagon. We should stress that the 
amount of insulin needed for catabolism of short 
chain fatty acids is significantly less than that neces- 
sary for glucose homeostasis, ergo, DKA is a 
common presentation in patients with insulin 
dependent diabetes mellitus but is rather unusual in 
patients with non-insulin dependent diabetes melli- 
tus. Patients with non-insulin dependent diabetes 
mellitus present with marked increases in serum 
glucose concentrations without ketosis (non-ketotic 
hyperglycemic coma). This entity is also associated 
with an increase in the anion gap, but the chemical 
nature of the accumulated anion(s) has, surprisingly, 
not yet been well characterized. 

DKA is diagnosed by the combination of anion 
gap metabolic acidosis, hyperglycemia, and 
demonstration of increased serum (or urine) 
ketones, however, the presence of serum and 
urine ketones is not specific for DKA. In fact, ele- 
vated ketones may accompany starvation and 
alcoholic ketoacidosis, where there may be some 
associated acidosis (see below), as well as isopropyl 



Alcoholic Ketoacidosis 

AKA is a relatively common form of acidosis seen 
in inner city hospitals. The acid-base disturbance 
results from the combination of alcohol toxicity 
and starvation. Ethanol itself leads to an increase 
in cytosolic NAD + , but without glucose (the star- 
vation component), ketogenesis and decreased 
ketone usage results. The serum glucose concen- 
trations can actually range over a wide spectrum. 
In some cases they are very low (i.e., <50 mg/dL), 
but occasionally they may be moderately high 
(e.g., 200-300 mg/dL). In the latter circumstance, 
clinicians may confuse AKA with DKA. Patients 
with AKA often present with complex acid-base 
disorders (Chapter 9) rather than simple meta- 
bolic acidosis. A marked increase in the SAG is a 
hallmark of this disorder. 

Alcoholic ketoacidosis may be a difficult diag- 
nosis to make. Sometimes it is confused with DKA 
(discussed above). When the acidosis is severe, 
however, the majority of ketoacids circulating in 
the serum may not be detected by the Acetest 
assay, which is relatively insensitive to /3-hydroxy- 
butyric acid. Therefore, a high index of suspicion 
must be held in the appropriate clinical setting. 



Chapter 7 



109 



Lactic Acidosis 

Anaerobic metabolism results in the production 
of lactic acid. Aerobic tissues metabolize carbohy- 
drates to pyruvate that then enters an oxidative 
metabolic pathway (TCA) in mitochondria. This 
results in the regeneration of NAD + that was con- 
sumed in the TCA cycle, as "well as in the gly- 
colytic pathway. When tissues perform anaerobic 
glycolysis, however, NAD + cannot be regenerated 
from electron transport. In order to regenerate 
NAD + , the reaction catalyzed by lactate dehydro- 
genase (LDH), 



H + + pyruvate + NADH -> lactate + NAD + 



(13) 



must proceed and lactate is generated. Despite 
consumption of an H + , the net effect of glycolysis 
is to generate lactic acid from carbohydrates and 
as discussed earlier, generate H + . Normally, lac- 
tate (L isomer) production is closely matched by 
lactate metabolism to glucose (Cori cycle) or aer- 
obic metabolism to C0 2 and H 2 0, and circulating 
concentrations are maintained in a very low 
range. Under certain pathologic conditions, there 
may be a substantial increase in lactate concentra- 
tions and a concomitant development of meta- 
bolic acidosis, known as lactic acidosis. These 
include those with local or systemic decreases in 
oxygen delivery, impairments in oxidative metab- 
olism, or impaired hepatic clearance. Of these, 
local or systemic decreases in 2 delivery as a 
result of hypotension are most common. 

Lactic acidosis is one of the most common 
forms of anion gap metabolic acidosis. It must be 
considered as a possible cause of any anion gap 
metabolic acidosis, particularly if the clinical cir- 
cumstances include hemodynamic compromise, 
sepsis, tissue ischemia, or hypoxia. Measurement 
of the serum lactate concentration employs a 
spectrophotometric assay using the LDH reaction. 
Please note that D-lactic acidosis will be missed 
with this approach since LDH does not recognize 
D-lactate. D-lactic acidosis occurs with blind intes- 
tinal loops colonized with D-lactate-producing 
organisms. The clinician must suspect this diag- 
nosis in the appropriate clinical setting and 



confirm n-lactic acidosis with alternate measure- 
ment methods (e.g., *H NMR spectroscopy, HPLC, 
specific enzymatic method for D-lactate). 



Renal Failure 

After eliminating ketoacidosis and lactic acidosis 
as potential causes for an anion gap metabolic 
acidosis one next examines the serum blood urea 
nitrogen (BUN) and creatinine concentrations to 
determine if organic anion accumulation is the 
result of kidney failure. Normally, the kidney 
is responsible for excretion of the approximately 
1 meq/kg/day of H + generated by dietary protein. If 
the kidney fails to do this, one develops metabolic 
acidosis. With both acute and chronic renal fail- 
ure, there is some retention of anions (including 
phosphate, sulfate, and some poorly character- 
ized organic anions), and the SAG is typically ele- 
vated, however, it is common to find that the 
increase in SAG is less than the fall in bicarbonate 
concentration. In short, renal failure typically 
gives a mixed anion gap and non-anion gap meta- 
bolic acidosis. Metabolic acidosis in the setting of 
acute and chronic renal failure is generally not 
severe unless a marked catabolic state occurs, or 
another acidotic condition (e.g., non-anion gap 
acidosis from diarrhea) supervenes. 



Toxic Alcohol Ingestions 

Toxic alcohol ingestion should be considered in 
all patients with an unexplained anion gap meta- 
bolic acidosis. Delays in diagnosis and therapy of 
these intoxications are likely to be accompanied 
by permanent organ damage and death. These 
entities are also important to recognize because 
they often require hemodialysis to remove the 
offending agent and their metabolites. The most 
important toxic alcohols include methanol and 
ethylene glycol. These are often taken as a suicide 
attempt, but they may be inadvertently ingested 
by children or inebriated adults. While the clinical 
syndrome ultimately results in very severe 



no 



Chapter 7 



metabolic acidosis, it must be stressed that the 
patient's acid-base status may initially be normal 
if they present to the hospital early after ingestion. 
Because these toxic alcohols are osmotically 
active, the serum osmolar gap (defined as the dif- 
ference between measured serum osmolarity and 
calculated serum osmolarity) is used to identify 
these patients. 



[glucose] 
18 



Calculated serum osmolarity = 2 [Na + ] + 

[BUN] 
2.8 

where [Na + ] is in meq/L and [glucose] and [BUN] 
are in mg/dL. 

This osmolar gap is generally elevated soon 
after ingestion because of the presence of the 
toxic alcohol in serum, however, if the ingestion is 
remote, it may not be substantially elevated. 
Although useful in suggesting this diagnosis, ele- 
vations in serum osmolar gap are neither sensitive 
nor specific for toxic alcohol ingestions. In fact, 
ethanol is the most common cause of an elevated 
serum osmolar gap. Therefore, it should be mea- 
sured and its contribution to the osmolar gap cal- 
culated. The contribution of ethanol to the 
osmolar gap is estimated by dividing its concen- 
tration in mg/dL by 4.6. 

Methanol intoxication typically presents with 
abdominal pain, vomiting, headache, and visual 
disturbances. This latter symptom derives from 
the toxicity of formic acid, a methanol metabolite 
to the optic nerve. Metabolism is folic acid 
dependent. Methanol toxicity can be seen with 
ingestions as small as 30 ml, and more than 100 mL 
of methanol is generally fatal unless treated 
promptly. Ethylene glycol is a major component 
of antifreeze. It apparently has a sweet taste that 
makes it appealing to children and inebriated 
adults. Ethylene glycol intoxication presents very 
similarly to that of methanol; both produce CNS 
disturbances and severe anion gap metabolic aci- 
dosis. In contrast to methanol, however, ethylene 
glycol does not usually produce retinitis, but it 
may cause both acute and chronic renal failure. 
The clinical presentation often consists of three 



stages: (1) CNS depression that lasts for up to 
12 hours associated "with metabolic acidosis; 
(2) cardiopulmonary failure; and (3) oliguric acute 
renal failure that may be heralded by flank pain. 
Detection of oxalate crystals in urine is common 
in cases of ethylene glycol ingestion but may take 
up to 8 hours to appear. Oxalate monohydrate 
crystals may be erroneously interpreted as hippu- 
rate crystals by the clinical laboratory. The lethal 
dose may be as little as 100 mL. 

Consideration of either ethylene glycol or 
methanol ingestion is important because they 
require very similar and immediate treatment. 
Neither ethylene glycol nor methanol are particu- 
larly toxic in their own right. It is the metabolism 
of these agents through the enzyme alcohol dehy- 
drogenase that produces toxic metabolites. 
Therefore, blockade of their metabolism by the 
administration of agents that block alcohol dehy- 
drogenase (ethanol or fomepizole) should be 
considered early. Moreover, since both the parent 
compounds and metabolites are low molecular 
weight and have small volumes of distribution, 
hemodialysis is generally employed. It is impor- 
tant to note that if ethanol is used to block metab- 
olism of the parent compound and dialysis is also 
prescribed, the dose of ethanol must be adjusted 
to compensate for its concomitant removal by the 
dialysis procedure. As with ethanol, fomepizole 
requires dose adjustment during hemodialysis. 
With ethylene glycol intoxication pyridoxine and 
thiamine promote the conversion of glyoxalate to 
the less toxic metabolites glycine and beta 
hydroxyketoadipate, respectively. 



Salicylate Intoxication 

Salicylate overdoses are also common. Salicylate 
intoxication may occur as a suicide attempt, but 
often, especially in the elderly, may result from 
routine use. Aspirin or methylsalicylate intoxica- 
tion may lead to serious and complex acid-base 
abnormalities. In younger subjects with salicylate 
intoxication, metabolic acidosis may be simple, 
whereas in older subjects a complex acid-base 



Chapter 7 



111 



disturbance involving respiratory alkalosis and 
metabolic acidosis is more likely. Elderly subjects 
often demonstrate a major discordance between 
blood concentrations and symptoms. CNS toxicity 
almost always accompanies extremely elevated 
blood concentration (serum salicylate concentra- 
tions >50 mg/dL). 

Salicylates stimulate respiration and produce a 
component of respiratory alkalosis, especially 
early in the course of toxicity in adults. The acids 
responsible for the metabolic acidosis and 
increase in the SAG are primarily endogenous 
acids (e.g., lactate and ketoanions) whose metab- 
olism is affected by toxic amounts of salicylates 
that uncouple oxidative phosphorylation. Salicylic 
acid contributes to a minor degree. 

The diagnosis of salicylate toxicity should be 
considered when a history of aspirin use, nausea, 
and tinnitis are present. Suspicion should also be 
raised by clinical findings of unexplained respira- 
tory alkalosis, anion gap metabolic acidosis, or 
noncardiogenic pulmonary edema. Advanced age 
and a delay in the diagnosis of salicylate toxicity 
are associated with significant morbidity and mor- 
tality. Efforts to remove the salicylate include 
urine alkalinization to a urine pH of 8.0 with 
sodium bicarbonate in milder cases. Systemic pH 
should be carefully monitored and kept below 
7.6. Hemodialysis is indicated if the salicylate level 
is >100 mg/dL, or if the patient has altered mental 
status, a depressed GFR, is fluid overloaded, or has 
pulmonary edema. Glucose should be adminis- 
tered because CSF glucose concentrations are 
often low despite normal serum glucose concen- 
tration. Acetazolamide should be avoided because 
it is highly protein bound and may increase free 
salicylate concentration. 



Other Intoxications 

Several other intoxications produce anion gap 
metabolic acidosis. These include toluene, strych- 
nine, paraldehyde, iron, isoniazid, papaverine, 
tetracyclines (outdated), hydrogen sulfide, and 
carbon monoxide. These substances interfere with 



oxidative metabolism and produce lactic acidosis. 
Citric acid (present in toilet bowl cleaner) is an 
exception; the citrate itself causes an increase in 
SAG. Citric acid toxicity is associated with marked 
hyperkalemia. Toluene is another exception; it 
may produce a distal renal tubular acidosis in 
concert with an elevation of serum hippuric acid 
(a metabolite of toluene) concentration. Hippurate 
is rapidly eliminated from the body by the kidney, 
and as a consequence the anion does not accu- 
mulate, leading to a non-anion gap metabolic aci- 
dosis. This — rather than a distal renal tubular 
acidosis is — the likely mechanism of the normal 
SAG metabolic acidosis seen with toluene ingestion. 



Inborn Errors of Metabolism 

Inborn errors of metabolism represent an unusual 
but important cause of organic acidosis. In some 
cases (e.g., mitochondrial myopathies, some glyco- 
gen storage diseases), lactic acidosis develops 
"without evidence for hypoxia or hypoperfusion. 
In other conditions (e.g., maple syrup urine dis- 
ease, methylmalonic aciduria, propionic acidemia, 
and isovaleric acidemia), the accumulation of 
other organic acids occurs in concert with meta- 
bolic acidosis. Although many of these diseases 
present shortly after birth, some conditions may 
be first suspected in adulthood. 



Key Points 

Causes of Anion Gap Metabolic Acidosis 



1 . The diagnosis of lactic acidosis must be con- 
sidered in all forms of metabolic acidosis 
associated with an increased anion gap, par- 
ticularly those cases associated with local or 
systemic decreases in oxygen delivery, 
impairments in oxidative metabolism, or 
impaired hepatic clearance. 

2. Diabetic ketoacidosis results from lack of 
sufficient insulin necessary to metabolize 
glucose anci excess glucagon that causes the 



112 



Chapter 7 



generation of short chain fatty ketoacids. 
The diagnosis of diabetic ketoacidosis is 
made by finding the combination of anion 
gap metabolic acidosis, hyperglycemia, and 
demonstration of serum (or urine) 
ketoacids. 

3. Ethylene glycol and methanol ingestion are 
important causes of an anion gap metabolic 
acidosis that are associated with an elevated 
osmolar gap. 

4. Metabolic acidosis in the setting of acute 
and chronic renal failure is generally not 
severe. 




Table 1.2 



Hyperchloremic Metabolic 
Acidosis 



Causes of Hyperchloremic Metabolic Acidosis 



Gastrointestinal loss of HCOj 

Diarrhea 

Gastrointestinal drainage and fistulas 

Urinary diversion to bowel 

Chloride containing anion-exchange resins 

CaCl, or MgCl, ingestion 

Renal loss of HCO, 

Renal tubular acidosis 

Carbonic anhydrase inhibitors 

Potassium sparing diuretics 

Miscellaneous causes of hyperchloremic 

acidosis 
Recovery from ketoacidosis 
Dilutional acidosis 
Addition of HC1 
Parenteral alimentation 
Sulfur ingestion 



In contrast to SAG acidosis, hyperchloremic meta- 
bolic acidosis is not associated with accumulation 
of organic anions (Table 7.2). Rather, loss of HCO3 
(renal or GI), as well as some miscellaneous 
causes, add HCl to blood and lower serum HCO3 
and raise serum CI" concentration. The urinary 
anion gap can be used to differentiate renal from 
GI causes of non-anion gap metabolic acidosis if 
the diagnosis is not obvious based on history and 
physical examination. The urinary anion gap is 
equal to the sum of urinary sodium and potassium 
concentrations minus urine chloride concentration. 
It will be negative in situations where urinary 
[NH 4 + ] is elevated and the kidney is responding 
appropriately to metabolic acidosis (nonrenal 
causes). The urinary anion gap is negative 
because NH/ when excreted in urine is accompa- 
nied by Cl~ to maintain charge neutrality. In situa- 
tions where the kidney is responsible for the 
metabolic acidosis the urinary anion gap will be 
positive. This may occur "with either renal tubular 
acidosis or renal failure. Renal failure is identified 
by elevated serum concentrations of BUN and 



creatinine. The urinary anion gap can be mislead- 
ing in two clinical circumstances. The first is when 
decreased sodium delivery compromises distal 
acid excretion. Therefore, in order to use the uri- 
nary anion gap urine sodium concentration must 
be greater than 20 meq/L. Decreased distal 
sodium delivery impairs collecting duct H + secre- 
tion and the UAG cannot be used if delivery of 
sodium to this segment is decreased. The second 
occurs when an anion (usually a ketoanion or 
hippurate) is excreted with sodium or potassium. 
Urinary sodium and potassium may be elevated 
leading to a positive urine anion gap and the 
impression that the kidney is not responding 
appropriately. The urinary osmolar gap (UOG) is 
not affected by the excretion of other anions and 
may need to be used in this situation. 

UOG = 2(Na + K) + [BUN]/2.8 + [glucose]/18 

The UOG is not affected by unmeasured anions in 
the urine since they are associated with cations 
(sodium or potassium). Dividing the UOG by 2 
will approximate the urinary [NH 4 + ]. A value less 



Chapter 7 



113 



than 20 implies that the kidney is not responding 
appropriately to metabolic acidosis. 




Gastrointestinal Loss of HCO; 



Diarrhea 

The concentration of HCOj in diarrheal fluid is 
usually greater than the concentration of HCO3 in 
serum. Although it seems like it should be obvi- 
ous, the diagnosis of diarrhea to explain non- 
anion gap metabolic acidosis may be difficult in 
the very young or very old who are unable to pro- 
vide historical details. In children, the distinction 
between diarrhea and an underlying RTA may be 
very important. In this situation, the UAG provides 
helpful information. When diarrhea causes meta- 
bolic acidosis, a significantly negative UAG (i.e., 
<10 meq/L) reflecting the presence of ample uri- 
nary NH 4 + concentrations is present. In contrast, 
patients with all forms of distal RTA have positive 
UAGs reflecting the relatively low urinary [NH 4 + ] 
present in these conditions. Some patients with GI 
bicarbonate losses will have a urine pH >6.0 due 
to complete titration of NH 3 to NH^ The urine 
anion gap in these patients will be negative, help- 
ing to distinguish those with renal tubular acidosis. 



Gastrointestinal Drainage and Fistulas 

Intestinal, pancreatic, and biliary secretions have 
high HCO3 and relatively low CI" concentrations. 
The intestine produces approximately 600-700 mL 
of fluid per day, but this may be increased in states 
of disease. Biliary secretions amount to more than 
lL/day. This fluid usually contains HCO3 concen- 
trations as high as 40 meq/L. Pancreatic secretions 
are an even greater potential source of bicarbon- 
ate loss, as the volume may exceed 1-2 L/day and 
contain [HCO,] up to 100 meq/L. 



Because of the high [HCOj], drainage of these 
fluids or fistulas can cause significant metabolic 
acidosis. One interesting variation to this phe- 
nomenon occurs with kidney pancreas transplan- 
tation when the exocrine pancreas is drained 
through the bladder. This procedure almost uni- 
versally leads to substantial metabolic acidosis as 
the NAE of the transplanted kidney is essentially 
nullified by the combination with pancreatic 
secretions. For this reason, most kidney pancreas 
transplants are now performed with intestinal 
drainage of the exocrine pancreas. 

Urinary Diversion to Bowel 

Surgical approaches to bladder and ureteral disease 
include creation of alternative drainage of urine 
through in situ bowel and or conduits produced 
from excised bowel. In both of these settings, active 
CIVHCO3 exchange by bowel mucosa can impair 
renal NAE. Because of this, a non-anion gap meta- 
bolic acidosis may complicate both of these proce- 
dures. In fact, metabolic acidosis is almost certain 
when an ureterosigmoidostomy is performed. It is 
less common with ureteroileostomies and is gener- 
ally only seen when contact time between the urine 
and the intestinal mucosa is increased, as occurs 
with stomal stenosis. 



Chloride Containing Anion-Exchange Resins 

Cholestyramine, a resin used to bind bile acids, 
can also bind HCOj. Because of this, Ch/HCOj 
exchange across bowel mucosa may be facili- 
tated, and metabolic acidosis may develop. This is 
most likely in conditions of chronic kidney dis- 
ease where new HCO3 generation is impaired. 



CaCl 2 or MgCl 2 Ingestion 

Calcium and magnesium are not absorbed com- 
pletely in the gastrointestinal tract. As was the case 
for cholestyramine, unabsorbed Ca 2+ or Mg 2+ may 
bind HCO3 in the intestinal lumen and facilitate 



114 



Chapter 7 




Cl / HC0 3 exchange. In this way, a non-anion gap 
metabolic acidosis may result. 



Renal Loss of HCO; 



Renal Tubular Acidosis 

There is no topic in nephrology that confuses stu- 
dents and clinicians more than RTA. The RTAs are a 
group of functional disorders that are characterized 
by impaired renal HCO3 reabsorption and H + 
excretion. We distinguish these conditions from the 
acidosis of renal failure by requiring that the impair- 
ment in NAE is out of proportion to any reduction in 
glomerular filtration rate (GFR) that may be present. 
In most cases, RTAs occur in patients with a com- 
pletely normal or near normal GFR. 

Renal tubular acidoses can be approached in 
several different ways. We prefer to separate them 
based on whether the proximal (bicarbonate reab- 
sorption) or distal (NAE) nephron is primarily 
involved. From a clinical standpoint, it is then most 
simple to divide the distal RTAs into those that are 
associated •with hypokalemia and those that are 
associated with hyperkalemia. The hyperkalemic 
type can then be further divided into those due to 
hypoaldosteronism and those characterized by a 
general defect in sodium reabsorption. We prefer 
this approach to the confusing numbering system 
that has been used: proximal RTA (type II); distal 
RTA (type I) and distal RTA secondary to hypoal- 
dosteronism (type IV). 



Proximal RTA 

Proximal RTA is a relatively uncommon disease. 
In proximal RTA, bicarbonate reabsorption in 
proximal tubule is impaired, and the plasma 
threshold for HCO3 is decreased. When plasma 
[HCO3] exceeds the plasma threshold for HCO3, 
the delivery of HCOj-rich fluid to distal nephron 



sites leads to substantial bicarbonaturia. This is 
associated "with profound urinary losses of both 
potassium and sodium. When plasma [HCO,] falls 
below the plasma threshold for HCO3, however, 
NAE increases and a steady state is achieved. 
Thus, patients with proximal RTA typically mani- 
fest a mild metabolic acidosis with hypokalemia. 
The serum [HCO3] is generally between 14 and 
20 meq/L. If one treats patients with sodium bicar- 
bonate, however, bicarbonaturia recurs, and urinary 
potassium losses become severe. Diagnostically, 
patients with suspected proximal RTA undergo an 
infusion with bicarbonate to correct the serum 
[HCO3]. Proximal RTA can be diagnosed in this 
setting when fractional HCO3 excretion (i.e., the 
fraction of filtered HCO3 that is excreted in the 
urine) exceeds 15%. 

Proximal RTA may occur as an isolated distur- 
bance of HCOj reabsorption, but more commonly 
coexists with other defects in proximal nephron 
function (e.g., reabsorption of glucose, amino 
acids, phosphate, and uric acid). In the situation 
where proximal tubule function is deranged for 
these other substances, the term "Fanconi's syn- 
drome" is used. In addition to the mild metabolic 
acidosis usually associated with proximal RTA, 
Fanconi's syndrome is complicated by osteomala- 
cia and malnutrition. Proximal RTA may occur as 
an inherited disorder (Lowe's syndrome, cystinosis, 
and Wilson's disease) and present in infancy. 
Alternatively, it may be acquired in the course of 
other diseases, following exposure to proximal 
tubular toxins (heavy metals), or in the setting of 
drug therapy. In the past, mercurial diuretics were 
commonly associated with the development of 
Fanconi's syndrome. Now the most common 
acquired causes include medications (nucleotide 
analogues) and multiple myeloma (light chains 
cause proximal tubular dysfunction). 



Distal RTAs 

Although classic hypokalemic distal RTA was ini- 
tially characterized by an impairment in urinary 
acidification, all distal RTAs result in an impairment 
in NAE. This impairment in NAE is largely due to 



Chapter 7 



115 



reduced urinary NH 4 + excretion. Distal RTA may be 
associated with either hypokalemia or hyper- 
kalemia. Distal RTA associated with hyperkalemia 
is the most common form of RTA, and generally 
results from hypoaldosteronism. All distal RTAs are 
characterized by a positive UAG in the setting of 
acidosis, reflecting inadequate NH 4 + excretion. 

Hypokalemic distal RTA is best considered a dis- 
order of collecting duct capacity for effective 
proton secretion such that patients cannot achieve 
the necessary NAE to maintain acid-base balance. 
Patients with hypokalemic distal RTA usually pres- 
ent with hyperchloremic metabolic acidosis but are 
unable to acidify their urine (below pH 5.5) despite 
systemic acidosis. We stress that the failure to acid- 
ify the urine does not fully explain the defect in 
NAE, which is primarily due to an associated defect 
in NH/j 1 " excretion. The two mechanisms that were 
suggested for impaired acidification by distal 
nephron in hypokalemic distal RTA are (1) back- 
leak of acid through a "leaky" epithelium and 
(2) proton pump failure (i.e., the H + ATPase cannot 
pump sufficient amounts of H + ). Hypokalemic 
distal RTA may be inherited or may be associated 
with other acquired disturbances. Some of the 
same conditions that can cause hypokalemic distal 
RTA (e.g., urinary obstruction, autoimmune disor- 
ders) can also cause hyperkalemic distal RTA 
due to a defect in sodium reabsorption, suggesting 
that the mechanistic analysis discussed above 
might be somewhat artificial. In its primary form, 
hypokalemic distal RTA is quite unusual, and gen- 
erally is diagnosed in young children. The afflicted 
children typically present with extremely severe 
metabolic acidosis, growth retardation, nephrocal- 
cinosis, and nephrolithiasis. Hypokalemia, which 
is usually present, may actually be caused by the 
associated sodium depletion and stimulation of the 
renin-angiotensin-aldosterone axis. Therefore, 
renal potassium losses decrease considerably 
when appropriate therapy with sodium bicarbon- 
ate is instituted. This is completely different from 
patients with proximal RTA where urinary potas- 
sium losses increase during therapy because of the 
bicarbonaturia associated urinary potassium losses. 

Hyperkalemic distal RTAs can develop from 
several mechanisms. These include (1) a defect in 



sodium reabsorption where a favorable trans- 
epithelial voltage cannot be generated and/or 
maintained, and (2) hypoaldosteronism. Hyper- 
kalemic distal RTA from decreased sodium reab- 
sorption is more common than either classic 
hypokalemic distal RTA or proximal RTA. Urinary 
obstruction is the most common cause of this form 
of distal RTA. Other causes include cyclosporin 
nephrotoxicity, renal allograft rejection, sickle cell 
nephropathy, and many autoimmune disorders 
such as lupus nephritis and Sjogren's syndrome. 
In contrast to hypoaldosteronism, urinary acidifi- 
cation is impaired in these subjects. Also, hyper- 
kalemia plays a less significant role in the 
pathogenesis of the impaired NH 4 + excretion that 
is more closely tied to impaired distal nephron 
function. 

Hyperkalemic distal RTA from hypoaldostero- 
nism results from either selective aldosterone defi- 
ciency or complete adrenal insufficiency. Probably 
the most common form of RTA is a condition 
called hyporeninemic hypoaldosteronism that is 
most often seen in patients afflicted with diabetic 
nephropathy. In patients with this form of RTA, 
urinary acidification assessed by urine pH is 
normal but NAE is not. The defect in NAE in some 
of these patients can be explained by impaired 
NHf synthesis in the proximal nephron resulting 
directly from the hyperkalemia. Hyperkalemia 
also interferes with NH ( + recycling in the thick 
ascending limb of Henle where it competes with 
NH 4 + for transport on the potassium site of the Na-K- 
2C1 cotransporter. Other patients with hyporenine- 
mic hypoaldosteronism have a more complex 
pathophysiology. 

Another contrasting point between proximal 
RTA and hypokalemic distal RTA is the amount of 
alkali therapy needed. Patients with hypokalemic 
distal RTA only need enough alkali to account for 
the amount of acid generated from diet and 
metabolism. Therefore, approximately 1 mmol/ 
kg/day is generally sufficient in these patients, 
whereas patients with proximal RTA require 
enormous amounts of bicarbonate and potas- 
sium supplementation. Some authors actually 
discourage trying to treat such patients with 
alkali. 



116 



Carbonic Anhydrase Inhibitors 

CA inhibitors (e.g., acetazolamide) inhibit both 
proximal tubular luminal brush border and cellu- 
lar carbonic anhydrase. This disruption of CA 
results in impaired HCOj reabsorption similar to 
that of proximal RTA. Topiramate is an anti- 
seizure medication used in children that causes a 
mild-to-moderate proximal RTA through this 
mechanism. 



Potassium Sparing Diuretics 

Aldosterone antagonists (e.g., spironolactone 
and eplerenone) or sodium channel blockers 
(e.g., amiloride and triamterene) may also pro- 
duce a hyperchloremic acidosis in concert with 
hyperkalemia. Trimethoprim and pentamidine 
may also function as sodium channel blockers 
and cause hyperkalemia and hyperchloremic 
metabolic acidosis. This is most often seen in 
human immunodeficiency virus (HlV)-infected 
patients. 



Chapter 7 



Key Points 

Causes of Hyperchloremic Acidosis 



Gastrointestinal loss of bicarbonate and 
renal tubular acidosis are two main causes 
of non-anion gap metabolic acidosis. 
In the setting of non-anion gap metabolic 
acidosis, a negative urine anion gap 
would reflect gastrointestinal bicarbonate 
loss, whereas, in all forms of distal renal 
tubular acidosis the urine anion gap will 
be positive. 

Proximal renal tubular acidosis is due to 
impairment in proximal tubular reabsorp- 
tion of bicarbonate. 
Distal renal tubular acidosis is due to 
impaired net acid excretion and can be 
either hypokalemic or hyperkalemic. 




Miscellaneous Causes of 
Hyperchloremic Acidosis 



Recovery from Ketoacidosis 

Patients with DKA generally present with a "pure" 
anion gap metabolic acidosis. In other words, the 
increase in the anion gap roughly parallels the fall 
in bicarbonate concentration, however, during 
therapy, renal perfusion is often improved, and 
substantial loss of ketoanions in urine may result. 
Therefore, many patients afflicted with DKA may 
eliminate the ketoanions faster than they correct 
their acidosis, leaving them with a non-anion gap 
or hyperchloremic metabolic acidosis. Rarely, this 
phenomenon may even occur in patients who 
drink enough fluid to maintain glomerular filtra- 
tion rate (GFR) close to normal as they develop 
DKA. 



Dilutional Acidosis 

The rapid, massive expansion of ECF volume with 
fluids that do not contain HCOj (e.g., 0.9% saline) 
can dilute the plasma and cause a mild, non-anion 
gap metabolic acidosis. This is occasionally seen 
with trauma resuscitation or during treatment of 
right ventricular myocardial infarction. 



Addition of Hydrochloric Acid (HCl) 

Therapy with HCl or one of its congeners (e.g., 
ammonium chloride or lysine chloride) will rap- 
idly consume HCOj, and thus, cause a hyper- 
chloremic metabolic acidosis. 



Parenteral Alimentation 

Amino acid infusions may produce a hyper- 
chloremic metabolic acidosis in a manner similar 



Chapter 7 



117 



to addition of HC1. In fact, this is actually quite 
common if alkali-generating compounds (e.g., 
acetate or lactate) are not administered concomi- 
tantly with amino acids, however, replacement of 
the chloride salt of these amino acids with an 
acetate salt easily avoids this problem. It turns out 
that it is metabolism of sulfur containing amino 
acids that obligates excretion of acid since neu- 
trally charged sulfur is excreted as sulfate. In gen- 
eral, 1 g of amino acid mixture generally requires 
1 meq of acid to be excreted. Ergo, the acetate 
content of parenteral alimentation should proba- 
bly match the amino acid content on a meq/g 
basis. 




Treatment of Metabolic Acidosis 



As stated earlier, the reason we analyze acid-base 
disorders is to obtain information as to the clinical 
condition underlying the acid-base abnormality. 
The fundamental principles of acid-base therapy 
are that a diagnosis must be made and treatment 
of the underlying disease state initiated. That said, 
some direct therapy of the acidosis is sometimes 
indicated. With most of the hyperchloremic states 
of metabolic acidosis, gradual correction of the 
acidosis is effective and beneficial. Oral bicarbon- 
ate or an anion that can be metabolized to bicar- 
bonate is generally preferred. One gram of 
sodium bicarbonate is equivalent to 12 meq of 
HCOj. In order to administer 1 meq/kg/day, 
doses will generally exceed 5 g/day in adults. 
Commercially available sodium or mixed sodium 
and potassium citrate solutions (e.g., Shohl's solu- 
tion, Bicitra or Polycitra) contain 1-2 meq of HCO3 
equivalent per mL. Citrate solutions may be better 
tolerated than sodium bicarbonate tablets or 
powder (baking soda), however, citrate can 
increase GI absorption of aluminum and should, 
therefore, not be administered along with alu- 
minum-based phosphate binders. 



The acute treatment of metabolic acidosis 
associated •with an increased anion gap "with 
intravenous sodium bicarbonate is controversial. 
Unfortunately, there is little in the form of ran- 
domized clinical data to guide us. Based primarily 
on experimental models, it appears that bicar- 
bonate therapy may actually be deleterious in this 
setting, especially if the acidosis is associated 
with impaired tissue perfusion. The so-called 
"paradoxical" intracellular acidosis which results 
when bicarbonate is infused during metabolic 
acidosis probably accounts for a portion of these 
deleterious effects. This "paradoxical" intracellu- 
lar acidosis is a direct consequence of the greater 
permeability of cell membranes to C0 2 than 
HCO3. The addition of HCO3 to blood (or an 
organism) produces C0 2 . When metabolic acido- 
sis is present, more C0 2 is produced for a given 
dose of sodium bicarbonate than if there were no 
acidosis. In fact, recent studies performed in a 
closed, human blood model demonstrate that the 
production of C0 2 from administered HCOj is 
directly dependent on the initial pH. When venti- 
lation is normal, the lungs rapidly eliminate this 
extra C0 2 . When pulmonary ventilation, or more 
commonly tissue ventilation however, is impaired 
(by poor tissue perfusion) this C0 2 generated by 
infused HCOj may diffuse into cells (far more 
rapidly than the original HCO, molecule) and 
paradoxically decrease the intracellular pH 
(Figure 7.4). Experimentally, administration of 
sodium bicarbonate in models of metabolic aci- 
dosis is associated with a fall in intracellular pH 
in several organs including the heart. Bicarbonate 
infusion in these settings also causes hemody- 
namic compromise. In addition to this "paradox- 
ical" intracellular acidosis, hypertonic sodium 
bicarbonate therapy in the form of 50 mL 
ampules of 1 M NaHC0 3 may promote hyper- 
tonicity. The hypertonic state itself may impair 
cardiac function, especially in patients undergo- 
ing resuscitation for cardiac arrest. Based on 
these data, we do not support therapy with intra- 
venous sodium bicarbonate for acute anion gap 
metabolic acidosis in the emergency situation. 
This area, however, remains controversial. 



118 



Chapter 7 



Figure 7.4 



Extracellular space 



i 

/ 



CA 
HoCO, < ► CO, + H ? 




HC0 3 " 

Intracellular space 




Mechanism of "paradoxical" intracellular acidosis following 
administration of sodium bicarbonate. Note that the sudden 
addition of bicarbonate causes increases in PaC0 2 accom- 
panying the increase in [HCOj], This occurs, in part, because 
abundant carbonic anhydrase (CA) allows for the virtually 
instantaneous dehydration of H 2 C0 3 in blood. Because most 
cell membranes are permeable to CO, but are not nearly as 
permeable to HCOj, the intracellular PC0 2 increases faster 
than [HCOj] and the intracellular pH transiently falls. 



To address the concerns for sodium bicarbonate 
discussed above, alternatives have been developed 
including non-C0 2 generating buffers such as 
trishydroxymethyl aminomethane (THAM) and 
Carbicarb (a 1:1 mixture of disodium carbonate and 
sodium bicarbonate). Dichloroacetate, which is 
specifically designed to decrease lactate production 
in lactic acidosis, •was used in animals with some 
success. Clinical data with these agents are limited, 
and these agents are not Food and Drug 
Administration (FDA) approved for routine clinical 
use. Perhaps, more concerning is that none of these 
agents are still protected by patents, and it is unclear 
who (if anyone) will bear the cost of studies neces- 
sary to demonstrate their clinical safety and efficacy. 



Key Points 

Treatment of Metabolic Acidosis 



1. Hyperchloremic metabolic acidosis is usually 
effectively treated by gradual correction of 
acidosis with administration of bicarbonate. 



2. Acute treatment of an anion gap metabolic 
acidosis with intravenous sodium bicarbon- 
ate may be deleterious, especially in condi- 
tions associated with impaired tissue 
perfusion. 

3. The administration of sodium bicarbonate in 
animals with metabolic acidosis is associ- 
ated with a fall in intracellular pH in several 
organs, as well as additional hemodynamic 
compromise. 



Additional Reading 

Adrogue, H.J., Madias, N.E. Management of life- 
threatening acid-base disorders. Second of two parts. 
N Engl J Med 338:107-111, 1998. 

Adrogue, H.J., Eknoyan, G., Suki, W.K. Diabetic 
ketoacidosis: role of the kidney in the acid-base 
homeostasis re-evaluated. Kidney Int 25:591-598, 
1984. 

Adrogue, H.J., Madias, N.E. Management of life -threat- 
ening acici-base disorders. First of two parts. N Engl 
J Med 338:26-34, 1998. 

Batlle, D.C., Arruda, J.A.L., Kurtzman, N.A. Hyper- 
kalemic distal renal tubular acidosis associated with 
obstruction. N Engl J Med 304:373-379, 1981. 

Batlle, DC, Hizon, M., Cohen, E., Gutterman, C, 
Gupta, R. The use of the urinary anion gap in the 
diagnosis of hyperchloremic metabolic acidosis. 
N Engl J Med 318:594-599, 1988. 

Filley, G.F. Acid-Base and Blood Gas Regulation. 1st 
edition. Lea & Febiger, Philadelphia, PA, 1971. 

Gabow, PA., Kaehny, W.D., Fennessey, P.V., Goodman, 
S.I., Gross P.A., Schrier, R.W. Diagnostic importance 
of an increased serum anion gap. N Engl J Med 
303:854-858, 1980. 

Halperin, M.L., Bear, R.A., Hannaford, M.C., Goldstein, 
M.B. Selected aspects of the pathophysiology of 
metabolic acidosis in diabetes mellitus. Diabetes 
30:781-787, 1981. 

Oh, M.S., Carroll, H.J. The anion gap. N Engl J Med 
297:814-817, 1977. 

Reilly, R.F., Anderson, R.J. Interpreting the anion gap. 
Crit Care Med 26:1771-1772, 1998. 

Shapiro, J.I. Pathogenesis of cardiac dysfunction during 
metabolic acidosis: therapeutic implications. Kidney 
IntSuppl6lM7-S51, 1997. 



Dinkar Kaw and 
Joseph I. Shapiro 



Metabolic Alkalosis 




Recommended Time to Complete: 1 day 



Qi*lAli*6 Qi*t^t^04^t 



1. What is metabolic alkalosis and how does it occur? 

2. What are the compensatory mechanisms for metabolic alkalosis? 
I. How is metabolic alkalosis maintained? 

ty. What are the clinical features of metabolic alkalosis? 

S. How does one differentiate various causes of metabolic alkalosis? 

i. How does one treat metabolic alkalosis? 




Pathophysiology of Metabolic 
Alkalosis 



Metabolic alkalosis is an acid-base disorder that 
occurs as the result of a process that increases pH 
(alkalemia) from a primary increase in serum 
[HCO3]. The primary elevation of serum [HCO3] is 
caused by the pathophysiologic processes out- 
lined below. 



Net H + Loss from ECF 



A loss of protons from the body occurs primarily 
through either the kidneys or the gastrointestinal 
(GI) tract. When H + losses exceed the daily H + load 
produced by metabolism and diet a net negative H + 
balance results. Because the loss of H + results in the 
generation of a HCO3, increases in serum [HCO^] 
result. Gastrointestinal loss of protons generally 
occurs in the stomach; in this setting, H + secretion 
by the luminal gastric parietal cell H + ATPase leaves 
a HCOj to be reclaimed at the basolateral surface. 



119 



120 



Chapter! 



Metabolic Alkalosis 



In the kidney, the coupling between net acid 
excretion (NAE) and bicarbonate generation was 
discussed at length in Chapter 7. Finally, shifting of 
H + into cells may accompany significant potassium 
depletion. Again, this should produce a rise in extra- 
cellular fluid (ECF) [HCO3]. Regarding this last 
mechanism, we should point out that evidence of 
intracellular acidosis developing during experi- 
mental potassium depletion has not been consis- 
tently observed in experimental settings. 



Key Points 

Pathophysiology of Metabolic Alkalosis 



Metabolic alkalosis is a systemic disorder char- 
acterized by increased pH due to a primary 
increase in serum bicarbonate concentration. 
Primary elevation of serum bicarbonate con- 
centration is due to net H + loss or net addi- 
tion of bicarbonate precursors to the ECF. 



Net Bicarbonate or Bicarbonate 
Precursor Addition to ECF 

HCO3 administration or addition of substances 
that generate HCOj (e.g., lactate, citrate) at a rate 
greater than that of metabolic H + production also 
leads to an increase in ECF [HCO3]. In the pres- 
ence of normal kidney function, however, ECF 
[HCO3] will not increase significantly. This occurs 
because as serum [HCOj] exceeds the plasma 
threshold for HCOj reabsorption, the kidney 
excretes the excess HCOj. As a result serum bicar- 
bonate concentration will not rise unless there is 
a change in renal bicarbonate handling (mainte- 
nance factor). The need for maintenance factors 
in the pathogenesis of metabolic alkalosis is 
discussed in more detail below. 



Loss of Fluid From the Body That Contains 
Chloride in Greater Concentration and 
Bicarbonate in Lower Concentration 
Than Serum 

If this type of fluid is lost ECF volume must con- 
tract. If this contraction is substantial enough, a 
measurable increase in serum [HCOj] develops. 
Protons are not lost in this setting in contrast to 
losses noted with vomiting or nasogastric suction. 
Bicarbonate is now distributed in a smaller 
volume, however, resulting in an absolute increase 
in ECF [HCO3I. This is referred to as contraction 
alkalosis. 




The normal kidney has a powerful protective 
mechanism against the development of significant 
increases in ECF [HCOj], namely the plasma 
threshold for [HCOj] above which proximal reab- 
sorption fails and HCOj losses in urine begin. 
Because of this, in almost all cases of metabolic 
alkalosis, the kidney must participate in the 
pathophysiology of the metabolic alkalosis. 
Exceptions to this rule occur when renal function 
is dramatically impaired (e.g., renal failure) 
and/or when the ongoing alkali load truly over- 
whelms the renal capacity for bicarbonate elimi- 
nation. These exceptional situations are both 
uncommon and easily identified. Therefore, we 
usually approach the pathophysiology of meta- 
bolic alkalosis by addressing initiation factors 
(i.e., factors that initiate the process) and mainte- 
nance factors (those that prevent renal excretion 
of excess bicarbonate). In some cases, as will be 
seen, the same factor may be responsible for both 
initiation and maintenance. 

The first line of pH defense during metabolic 
alkalosis is, again, buffering. When HCOj is 
added to ECF, protons react with some of this 
HCO3 to produce C0 2 that is normally exhaled by 
the lungs. Through this chemical reaction, the 
increase in serum and ECF [HCO,] is attenuated. 



Chapter! 



Metabolic Alkalosis 



121 



It has been shown that the ICF contributes the 
majority of H + used in this buffering process. 

Respiratory compensation also occurs with 
metabolic alkalosis. Under normal conditions, 
control of ventilation occurs in the brainstem and 
is most sensitive to interstitial H + concentration 
(Chapter 9). Respiratory compensation to meta- 
bolic alkalosis follows the same principles as res- 
piratory compensation to metabolic acidosis. Of 
course, the direction of the change of PaC0 2 is 
different (i.e., hypercapnia due to hypoventila- 
tion rather than hypocapnia due to hyperventila- 
tion occurs) and constraints regarding oxygenation 
must limit the magnitude of this hypoventilatory 
response. With metabolic alkalosis, the PaC0 2 
should increase 0.6-1.0 times the increase in 
serum [HCOj]. Absence of compensation in the 
setting of metabolic alkalosis constitutes the coex- 
istence of a secondary respiratory disturbance. 

The third line of defense is kidney. In a manner 
analogous to tubular reabsorption of glucose, we 
can consider the maximal amount of tubular 
bicarbonate reabsorption (T* max ) as the plasma 
threshold (PT) above which bicarbonaturia 
occurs. Once the PT is exceeded, bicarbonate 
excretion in urine is proportional to the glomeru- 
lar filtration rate (GFR). If a patient has a GFR of 
100 mL/minute and the bicarbonate concentra- 
tion is 10 meq/L above the PT, bicarbonate will be 
lost in the urine initially at a rate of 1 meq/minute! 
Therefore, the corrective response by the kidney 
to excrete excessive HCOj in urine will usually 
correct metabolic alkalosis unless there is a main- 
tenance factor that prevents this. 



Key Points 

Compensatory Mechanisms for Metabolic Alkalosis 



1. The first line of defense is buffering. 
When HCOj is added to ECF, H + reacts 
with HCOj to produce CO, that is nor- 
mally exhaled in expired gas. Most of the 
H + used in this buffering comes from the 
ICF. 



Rise in PaC0 2 is the normal compensatory 
response to simple metabolic alkalosis. 
In virtually all cases of metabolic alkalosis, 
the kidney participates in the pathogenesis 
by not excreting the excess bicarbonate. 




The Maintenance of Metabolic 
Alkalosis 



A number of factors increase the apparent 7" max for 
HCOj. As a result, they increase net HCOj reab- 
sorption by the kidney. This is shown schemati- 
cally in Figure 8.1. 



Arterial Blood Volume Decrease 

Volume depletion either absolute (e.g., salt losses 
through vomiting or bleeding) or effective (e.g., 

Figure 8. 1 



Initiation factor 


Maintenance factor 


Loss of H + 


• T max HCO3 






~^THC0 3 " excretion 






' Filtered HC0 3 " 


■[HCO3I - 


T PaC0 2 


(pH 


— iv;" 



Importance of maintenance factors in the pathophysiology of 
metabolic alkalosis. In this figure, we see that proton loss (e.g., 
from vomiting) leads to increases in pH and [HCOj]. These 
increases in [HCOj] will be accompanied by increases in HCOj 
filtration and loss in urine. If a maintenance factor (e.g., volume 
depletion, primary mineralocorticoid excess) is present, how- 
ever, that raises the tubular transport of HCOj (r max ), increased 
renal losses of HCOj are prevented, and metabolic alkalosis is 
maintained. Note that the higher pH causes a decrease in alve- 
olar ventilation (V A , Chapter 9) and the PaCO, increases. 



122 



Chapter! 



Metabolic Alkalosis 



congestive heart failure, nephrotic syndrome, 
hepatic cirrhosis) increases the 7 max and plasma 
threshold for HCOg. This occurs through both prox- 
imal (increased proximal tubule reabsorption of Na 
and water) and distal (mineralocorticoid effect) 
mechanisms. Catecholamines and angiotensin II 
stimulate the Na + -H + exchanger isoform in the 
luminal membrane of proximal tubule (NHE3). 
Proton excretion into urine generates intracellular 
bicarbonate that is transported across the basolateral 
membrane into blood. Mineralocorticoids act 
distally to directly stimulate the H + ATPase, and 
indirectly raise the driving force for proton excretion 
by increasing lumen electronegativity (through 
stimulation of the epithelial sodium channel). 



Chloride Depletion 

Sodium and chloride losses result in ECF volume 
depletion. Studies have shown that chloride is 
independently (i.e., besides being a marker for 
extracellular fluid volume) involved in HCOj 



reabsorption. In fact, even despite ECF expan- 
sion, chloride depletion increases the plasma 
threshold for HCOr, thereby raising ECF [HCO^]. 



Aldosterone 

Mineralocorticoids increase distal sodium reab- 
sorption which, in turn, increases renal HCO3 gen- 
eration and effectively raises the plasma threshold 
and T max for HCO3. These effects can occur in the 
absence of decreases in effective arterial blood 
volume. Aldosterone's predominant effect is in the 
distal nephron. Shown in Figure 8.2 is a model of 
two of the three major cell types in the collecting 
duct, the principal cell and the alpha intercalated 
cell. The principal cell, is responsible for sodium 
reabsorption and potassium secretion. The alpha 
intercalated cell mediates acid secretion and, there- 
fore, bicarbonate reabsorption and generation. 
Potassium secretion is passive and dependent 
strictly on the electrochemical gradient. Potassium 
secretion can be increased by raising intracellular 



Figure 8.2 



Lumen 




<f 



11|3HSD 



Principal cell 



I 



Blood 



Aldosterone 



n 



3Na + 
2K + 



Na + -K + ATPase 

cr 



-XT" <^4 Aldo: 

*z£f~ «»» ir 3 r 

K + — f \ * M=+-k'+ ATP= 

H + - ^ 1 ^ 



Aldosterone 



H+-K+ ATPase 



Intercalated cell " J 



xn 



Na + -K + ATPase 
HCO.," 



cr 



CI -HCO3 exchanger 



Collecting duct cell model. Proteins involved in sodium, potassium, and acid-base 
homeostasis are shown in both principal cells and alpha intercalated cells. 



Chapter! 



Metabolic Alkalosis 



123 



potassium, lowering luminal potassium, or making 
the lumen more electronegative. Indeed the major 
factors that control distal potassium secretion 
operate by changing these driving forces. Stimu- 
lation of the Na + -K + ATPase by aldosterone in- 
creases intracellular potassium. Aldosterone also 
increases distal sodium reabsorption by causing 
the insertion of sodium channels, as well as syn- 
thesis of new sodium channels. In the long term 
aldosterone also increases the expression of the 
Na + -K + ATPase in most epithelial cells, and directly 
stimulates the H + ATPase present in the luminal 
membrane of the intercalated cell. It also acts indi- 
rectly by increasing lumen electronegativity 
(through sodium reabsorption). Aldosterone binds 
to its receptor in the cytoplasm; this complex then 
translocates to the nucleus and stimulates gene 
transcription. 

Surprisingly, it was found that glucocorticoids 
have similar affinity to that of aldosterone for the 
mineralocorticoid receptor. In addition glucocor- 
ticoids circulate at many times the concentration 
of aldosterone. So how could aldosterone ever 
have an effect? The answer to this question lies in 
the fact that target tissues for aldosterone, such as 
collecting duct cells, possess the enzyme type II 
11/3-hydroxysteroid dehydrogenase (HSD) that 
degrades active Cortisol to inactive cortisone. If 
this enzyme is congenitally absent (apparent min- 
eralocorticoid excess), inhibited (licorice), or 
overwhelmed (Cushing's syndrome), then gluco- 
corticoids can exert a mineralocorticoid-like effect 
in the collecting duct. 



Potassium Depletion 

Potassium depletion also may increase the appar- 
ent r max and plasma threshold for HCOj and, thus, 
act as a maintenance factor for metabolic alka- 
losis. One potential mechanism for this is that 
potassium depletion may promote a relative intra- 
cellular acidosis and that this relative intracellular 
acidosis makes renal H + excretion more favorable; 
however, there is considerable evidence against 
this appealing concept. For one, there are orders 
of magnitude concentration differences involved 



when we compare protons to potassium ions. 
The [H + ] in ECF is only about 40 nM (although 
intracellular concentrations may be slightly 
higher), whereas potassium concentrations may 
change by 1.0-2.0 mmol/L. More problematic is 
the observation that investigators failed to detect 
a decrease in renal intracellular pH during exper- 
imental potassium depletion with 31 P NMR spec- 
troscopy. Moreover, in human studies, metabolic 
alkalosis can be corrected almost completely 
without correction of potassium depletion. More 
likely mechanisms for the increased T max for 
HCO3 resulting from K depletion follow. First, 
potassium depletion results in cellular potassium 
depletion in proximal tubule. This, in turn, 
would be expected to hyperpolarize the basolat- 
eral membrane and increase the driving force for 
bicarbonate exit via the Na-3HCC>3 cotrans- 
porter. Second, potassium depletion upregulates 
H + -K + ATPase in the collecting duct intercalated 
cell. It is likely that this upregulation results in 
increased H + secretion in this segment. This, in 
turn, would result in HCOj generation and addi- 
tion to ECF. 



Hypercapnia 

The apparent T m3Ji andplasma threshold for HCO3 
are raised by increases in PaC0 2 . This is probably 
related to the decreases in intracellular pH that 
occur during acute and chronic hypercapnia. 
Analogous to our discussion in Chapter 7, 
increases in PaC0 2 that occur during metabolic 
alkalosis as part of normal respiratory compensa- 
tion, impair the ability of the kidney to return 
serum bicarbonate concentration to normal. 



Key Points 

Maintenance of Metabolic Alkalosis 



1. Pathogenesis of metabolic alkalosis requires 
factors, that initiate or generate it and those 
that maintain it. 



124 



Chapter! 



Metabolic Alkalosis 



Several factors increase the apparent T mix 
for HCOj and thus, increase net HCO, reab- 
sorption by the kidney. These include 
decreases in effective arterial blood volume, 
chloride depletion, increases in aldosterone, 
potassium depletion, and hypercapnia. 
The most important maintenance factor is 
volume depletion. 




Clinical Features of Metabolic 
Alkalosis 



increases in lactate concentration resulting from 
enhanced glycolysis secondary to disinhibition of 
phosphofructokinase. The majority of the increase 
in SAG, however, is due to the increased elec- 
tronegativity of albumin with elevated pH. 

Key Points 



Clinical Features of Metabolic Alkalosis 



There are no specific signs or symptoms of 
metabolic alkalosis. Many of the symptoms 
may be related to associated hypocalcemia. 
Severe alkalosis (pH >7.6) can cause malig- 
nant arrhythmias, as well as seizures. 



Signs and symptoms of metabolic alkalosis are non- 
specific. Patients who present with muscle cramps, 
weakness, arrhythmias, or seizures, especially in 
the setting of diuretic use and vomiting, should 
prompt consideration of metabolic alkalosis. Most 
signs and symptoms are due to decreases in ionized 
calcium that occur as the increased pH causes 
plasma proteins to bind calcium more avidly. At a 
pH above 7.6, malignant ventricular arrhythmias 
and seizures may be seen. It is interesting to note 
that humans tolerate alkalosis less well than acidosis. 
Examination of arterial blood gases will demon- 
strate an increased pH, increased [HCOj], and 
increased PaC0 2 with the increase in PaC0 2 being 
between 0.6 and 1 times the increase in [HCOj]. 
Serum electrolytes reveal increased total C0 2 con- 
tent (TC0 2 ), which is the sum of the serum [HCOj] 
and dissolved C0 2 , decreased chloride concentra- 
tion and, typically, decreased potassium concen- 
tration. Hypokalemia occurs predominantly from 
enhanced renal losses. Renal potassium excretion 
results from maintenance factors involved in the 
pathogenesis of the metabolic alkalosis. Elevated 
concentrations of mineralocorticoids (or sub- 
stances with mineralocorticoid-like activity) are 
almost always involved as a maintenance factor. 
Severe metabolic alkalosis may also be associated 
with an increased serum anion gap (SAG) 
(increases up to 10-12 meq/L). This is due to small 




Differential Diagnosis 



The first step in evaluation of the patient with meta- 
bolic alkalosis is to subdivide them into those that 
have ECF chloride depletion as a maintenance factor 
(chloride responsive) (Table 8.1) from those that do 
not (chloride resistant) (Table 8.2). This is accom- 
plished by measuring urinary chloride. At first 

Table 8.1 

Causes of Chloride-Responsive Metabolic Alkalosis 



Gastrointestinal causes 

Vomiting or gastric drainage 
Villous adenoma of the colon 
Chloride diarrhea 
Renal causes 
Diuretic therapy 
Posthypercapnia 
Poorly reabsorbable anions 
Exogenous alkali administration or ingestion 
Bicarbonate administration 
Milk-alkali syndrome 
Massive transfusion of blood products 
(sodium citrate) 



Chapter! 



Metabolic Alkalosis 



125 



9.2 



Causes of Chloride-Resistant Metabolic Alkalosis 



With hypertension 

Primary aldosteronism 

Renal artery stenosis 

Renin-producing tumor 

Cushing's syndrome 

Licorice or chewing tobacco 

Apparent mineralocorticoid excess 

Congenital adrenal hyperplasia 

Liddle's syndrome 

Without hypertension 

Banter's syndrome and Gitelman's syndrome 

Current diuretic use 

Profound potassium depletion 

Hypercalcemia (nonhyperparathyroid etiology) 

Poststarvation (refeeding alkalosis) 



glance this might be surprising since urinary 
sodium concentration and fractional excretion of 
sodium are examined most commonly as indica- 
tors of volume depletion. These may be mislead- 
ing in metabolic alkalosis, however, especially if 
the kidney is excreting bicarbonate that will obli- 
gate increased sodium excretion. Urine chloride 
concentration allows one to classify patients into 
chloride-responsive and chloride-resistant cate- 
gories (Figure 8.3). In general, chloride-responsive 
metabolic alkalosis corrects when volume expan- 
sion or improvement of hemodynamics occur. In 
contrast, chloride-resistant metabolic alkalosis 
does not correct with these maneuvers. Patients 
with chloride-responsive metabolic alkalosis typi- 
cally have urine chloride concentrations less than 
20 meq/L, whereas patients with chloride-resistant 
metabolic alkalosis have urine chloride concen- 
trations exceeding 20 meq/L. 



Figure 8.3 



Metabo 


ic alkalosis 


sistant 




\ 
Chloride-responsive 


\ 
Chloride-re: 


(urine [CI ] < 20 meq/L) 


(urine [CI ] > 20 meq/L) 




• Renal 








Post diuretic therapy 








Post hypercapnia 








Poorly reabsorbable anions 






• Gastrointestinal 






Villous adenoma 






Congenital chloridorrhea 






Vomiting or gastric drainage 






• Exogenous alkali 






Bicarbonate administration 






Milk-alkali syndrome 


With hypertension 


Without hypertension 


Massive transfusion 


• Primary aldosteronism 


• Bartter's syndrome 




• Renin-producing tumor 


• Gitelman's syndrome 




• Congenital adrenal hyperplasia 


• Current diuretic use 




• Type II 1 1 fi-hydroxylase deficiency (AME) 


• Hypercalcemia 




• Cushing's syndrome 


• Poststarvation 




• Renal artery stenosis 


• Profound K + depletion 




• Liddle's syndrome 






• Licorice ingestion 





Differential diagnosis of metabolic alkalosis. The differential diagnosis of metabolic alkalosis based on the urine [Cli is 
demonstrated. The urine [Cli is used to separate chloride-responsive causes of metabolic alkalosis (where the urine [Cli 
is <20 meq/L) from the chloride resistant causes of metabolic alkalosis where the urine [Cli is generally >20 meq/L. These 
chloride-resistant causes can be further separated by whether the patient is hypertensive (volume expanded) or not. 
Abbreviation: AME, apparent mineralocorticoid excess. 




Chloride-Responsive Metabolic 



Chapter! 



Metabolic Alkalosis 



mutation in the downregulated in adenoma 
(DRA) gene. DRA functions as a Cl-bicabonate 
and Cl-sulfate exchanger and is expressed in the 
apical membrane of colonic epithelium. 



Vomiting and Gastric Drainage 

Patients with persistent vomiting or nasogastric 
suctioning may lose up to 2 L/day of fluid con- 
taining a proton concentration of 100 mmol/L. 
Given that for each H + secreted a HCOj molecule 
is generated, gastric parietal cells can excrete up 
to 200 mmol of HCOj per day. This constitutes a 
very significant initiation factor; however, it is the 
sodium, chloride, and potassium losses that allow 
metabolic alkalosis to be maintained. It is notable 
that potassium losses are more significant in urine 
than in vomitus, which generally contains only 
about 10 meq/L of potassium. 

Metabolic alkalosis that develops "with vomit- 
ing is often mild. Similar to protracted vomiting, 
gastric drainage, generally via a nasogastric tube, 
also causes a metabolic alkalosis. 



Colonic Villous Adenoma 

Rarely, a colonic villous adenoma has significant 
secretory potential. This type of adenoma may pro- 
duce profound diarrhea that contains excessive 
amounts of protein, sodium, potassium, and chlo- 
ride. These diarrheal losses of sodium, potassium, 
and chloride and the relatively low HCO3 concen- 
tration in the fluid may lead to metabolic alkalosis — 
in contrast to the typical metabolic acidosis that 
more commonly complicates diarrheal states. 



Congenital Chloridorrhea 

Congenital chloridorrhea is a rare congenital syn- 
drome arising from a defect in small and large 
bowel chloride absorption causing chronic diar- 
rhea with a fluid that is rich in chloride leading to 
metabolic alkalosis. This disorder is the result of a 



Diuretic Therapy 

Loop diuretics that exert their effects in the thick 
ascending limb of Henle (e.g., furosemide, 
bumetanide) and thiazide diuretics that act in the 
distal tubule (e.g., hydrochlorothiazide and metola- 
zone) may facilitate volume depletion, as well as 
directly stimulate renin secretion (loop diuretics). 
These diuretics can, thus, provide both initiation and 
maintenance factors and produce metabolic alkalo- 
sis. If the diuretic is still active urinary chloride con- 
centration is typically elevated. If the diuretic is 
cleared from the circulation and is no longer active 
(typically 24-48 hours after a dose) urinary chloride 
concentration is low, reflecting a normal renal 
response to volume depletion. Metabolic alkalosis 
associated with hypokalemia is a common compli- 
cation of diuretic use, and should suggest the possi- 
bility of diuretic abuse. Diuretics are commonly 
abused in patients with anorexia nervosa. 



Posthypercapnia 

The kidney responds to chronic elevations in PaC0 2 
by raising the plasma HCOj concentration. If hyper- 
capnia is subsequently corrected rapidly, as occurs 
with intubation and mechanical ventilation, the ele- 
vated serum HCO3 concentration will persist for at 
least several hours until renal correction is complete. 
Note that sufficient chloride must be present to allow 
for this renal correction, and many patients with dis- 
eases leading to hypercapnia are also treated with 
diuretics that may cause chloride depletion. 



Poorly Reabsorbable Anions 

Large doses of some beta-lactam antibiotics, such 
as penicillin and carbenicillin, may result in 



Chapter! 



Metabolic Alkalosis 



127 



hypokalemic metabolic alkalosis. The initiation 
and maintenance factor is the delivery of large 
quantities of poorly reabsorbable anions to the 
distal nephron with attendant increases in H + and 
potassium excretion. 



Cystic Fibrosis 

Metabolic alkalosis may develop in children with 
cystic fibrosis due to chloride losses in sweat that 



secretion contribute to the maintenance of meta- 
bolic alkalosis. The resulting hypercalcemia also 
decreases renal blood flow and glomerular filtra- 
tion, further impairing renal correction of meta- 
bolic alkalosis. Nephrocalcinosis may develop 
with chronic antacid ingestion, a pathologic factor 
that decreases GFR further, and thus more pro- 
foundly reduces the kidney's ability to excrete an 
alkali load. 



has a low [HCOj], The maintenance factor is the Transfusion of Blood Products 



resultant volume depletion caused by these 
losses. 



Alkali Administration 

As discussed earlier, the normal kidney rapidly 
excretes alkali. Ergo, a sustained metabolic alka- 
losis requires a maintenance factor. In these set- 
tings continuous and/or massive administration 
of alkali may cause metabolic alkalosis. This alkali 
load may be in the form of HCO^ or, more com- 
monly, substances "whose metabolism yields 
HCOj as with citrate or acetate. In particular, it is 
clear that patients with chronic kidney disease 
whose ability to excrete a HCOj load is decreased 
may develop sustained metabolic alkalosis fol- 
lowing alkali administration. Baking soda is the 
richest source of exogenous alkali containing 60 
meq of bicarbonate per teaspoon. Many patients 
ingest baking soda as a "home remedy" to treat 
dyspepsia and various GI problems. 



Milk-Alkali Syndrome 

The milk-alkali syndrome is classically noted in 
patients with GI upset who consume large amounts 
of antacids containing calcium and absorbable 
alkali. Calcium carbonate or Turns is the drug 
most often ingested for this purpose. Volume 
depletion (or at least the lack of ECF volume 
expansion) along with hypercalcemia-mediated 
suppression of parathyroid hormone (PTH) 



Infusion of more than 10 units of blood contain- 
ing the anticoagulant citrate can produce a mod- 
erate metabolic alkalosis, analogous to alkali 
administration discussed earlier. In many cases, 
some degree of prerenal azotemia may contribute 
to the maintenance of metabolic alkalosis. 
Through an identical mechanism, patients given 
parenteral hyperalimentation with excessive 
amounts of acetate or lactate may also develop 
metabolic alkalosis. 




Chloride-Resistant Metabolic 
Alkalosis 



Renal Artery Stenosis 



Renal artery stenosis is a frequent clinical problem 
that develops in the elderly and those with 
advanced vascular disease. The most common 
cause of a chloride-resistant metabolic alkalosis 
with associated hypertension is renovascular dis- 
ease. This is discussed in more detail in Chapter 21. 



Primary Aldosteronism 

With primary aldosteronism, excess aldosterone 
acts as both the initiation and maintenance factor 



128 



Chapter! 



Metabolic Alkalosis 



for metabolic alkalosis. Several mechanisms are 
involved; some are the result of increased sodium 
reabsorption and potassium secretion, whereas 
others are independent of sodium or potassium 
transport. Increased H + secretion promotes recla- 
mation of filtered HCO3 and generation of new 
HCO3, which is ultimately retained in the ECF. 
Interestingly, although the increased ECF volume 
tends to mitigate the alkalosis by decreasing 
proximal tubular bicarbonate reabsorption, distal 
processes aid in maintenance of an elevated 
plasma HCO3 threshold. In primary aldostero- 
nism, the clinical features of a hypokalemic 
metabolic alkalosis are produced, often in concert 
with hypertension that results from ECF volume 
expansion. 

Primary aldosteronism may be caused by an 
adrenal tumor, which selectively synthesizes 
aldosterone (Conn's syndrome) or hyperplasia 
(usually bilateral) of the adrenal cortex. The diag- 
nosis of a primary mineralocorticoid excess state 
depends on the demonstration that ECF volume is 
expanded (e.g., nonstimulatible plasma renin 
activity) and nonsuppressible aldosterone secre- 
tion is present (e.g., demonstration that exoge- 
nous mineralocorticoids and high salt diet or 
acute volume expansion with saline do not sup- 
press plasma aldosterone concentration). Recent 
data suggest that primary aldosteronism may 
occur in as many as 8% of adult hypertensive 
patients; however, most of these patients do not 
have a significant metabolic alkalosis. In some 
families, glucocorticoid remediable aldosteronism 
(GRA) develops from a gene duplication fusing 
regulatory sequences of an isoform of the 11/3- 
hydroxylase gene to the coding sequence of the 
aldosterone synthase gene. The diagnosis of this 
entity should be entertained in subjects in whom 
family members also have difficult to control hyper- 
tension. Clinical confirmation is generally pursued 
with the measurement of elevated concentrations 
of 18-OH-cortisol and 18-oxocortisol in urine 
prior to genetic analysis. Patients with GRA can 
often be successfully treated with glucocorticoid 
supplementation. 



Cushing's Syndrome 

Cushing's syndrome is characterized by excessive 
corticosteroid synthesis. Tumors that secrete 
ectopic adrenocorticotropic hormone (ACTH) are 
more likely to cause hypokalemia and metabolic 
alkalosis than pituitary tumors. Most cortico- 
steroids (specifically Cortisol, deoxycorticosterone, 
and corticosterone) also have significant miner- 
alocorticoid effects and produce hypokalemic 
metabolic alkalosis. Hypertension typically is 
present. Collecting duct cells contain type II 11/3- 
HSD that degrades Cortisol to the inactive metabo- 
lite cortisone. Cortisol secretion in response to 
ectopic ACTH may be so high, however, that it 
overwhelms the metabolic capacity of the 
enzyme. In addition, type II 11/3-HSD may be 
inhibited by ACTH. 



Bartter's and Gitelman 's Syndrome 

Barrier's syndrome is characterized by hyperrenine- 
mia, hyperaldosteronemia in the absence of hyper- 
tension or sodium retention. This rare condition 
generally presents in childhood. Histologically, 
hyperplasia of the juxtaglomerular apparatus was 
observed, but this is not specific. The disorder is 
caused by an abnormality in thick ascending limb 
chloride reabsorption (cell model shown in 
Figure 8.4). This results in high distal nephron 
sodium and chloride delivery, renin-angiotensin- 
aldosterone system activation, and development 
of hypokalemic metabolic alkalosis. The primary 
disturbance was initially felt to be an abnormality 
in the prostaglandin system; however, it is now 
clear that increased renal prostaglandins in these 
patients is secondary. Recent genetic studies elu- 
cidated the molecular basis of the disease. 
Bartter's syndrome is caused by one of five abnor- 
malities. Specifically, inherited inactivity of the 
apical Na + -K + -2Ch transporter, the ROMK potas- 
sium channel, the basolateral chloride channel 
(CLC-K b ), the beta-subunit of the basolateral 
chloride channel (Barttin) or a gain of function 



Chapter! 



Metabolic Alkalosis 



129 



Figure 8.4 



Lumen 



Blood 



O 



Na + 

K 

2CI" 



la _ ZZ5ZT 



NKCC2 



zn 



3Na + 



2K + 
Na + -K + ATPase 



cr 



Ca 




rr CLC-K b 

- Ca 2+ , Mg 2+ 
Ca 2+ , Mg 2+ sensing receptor 



Paracellin-1 



— ~? -^ L — + 3Na + 
« S^ 2K + 



NKCC2 



cr 



T 



Na + -K + ATPase 



- Ca 2+ , Mg 2+ 
J Ca 2+ , Mg 2+ sensing receptor 



Thick ascending limb cell model. Proteins involved in ion transport in thick ascending 
limb are shown. Abnormalities of five of these proteins result in Banter's syndrome and 
are discussed in the text. 



mutation in the calcium-sensing receptor, proteins 
that are each essential to thick ascending limb of 
Henle function, can each result in Bartter's syn- 
drome. A closely related condition, Gitelman's 
syndrome, is caused by mutations in the thiazide- 
sensitive Na-Cl transporter important in distal 
tubule function. Gitelman's syndrome may present 
in adults and is probably more common than 
Bartter's syndrome. 

Both Bartter's and Gitelman's syndromes can 
closely mimic diuretic abuse. In fact, Bartter's syn- 
drome and Gitelman's syndrome can be function- 
ally imitated by the pharmacologic administration 
of loop and thiazide diuretics, respectively. 
Therefore, it is important to consider surreptitious 
diuretic use as an alternative to these diagnoses, 
especially if patients present de novo as adolescents 
or adults with previously normal serum potassium 



and bicarbonate concentrations. Measuring diuretic 
concentrations in urine is often part of the initial 
workup. 



Liddle's Syndrome 

Liddle's syndrome is a rare autosomal dominant 
disorder resulting from a mutation in either the 
beta- or gamma-subunit of the sodium channel 
expressed in the apical membrane of the collecting 
duct. The mutation increases sodium reabsorption 
by blocking removal of the channel from the mem- 
brane. The molecular mechanism was discussed 
in Chapter 2. Metabolic alkalosis, hypokalemia, 
and severe hypertension characterize this genetic 
disorder. 



130 



Chapter! 



Metabolic Alkalosis 



Licorice 

Glycyrrhizic and glycyrrhetinic acid, which are 
found in both licorice and chewing tobacco, 
may cause a hypokalemic metabolic alkalosis 
accompanied by hypertension, and thus, simulate 
primary aldosteronism. Recent studies demon- 
strate that this chemical inhibits type II 1 1/3- 
hydroxysteroid dehydrogenase activity and 
"uncovers" the mineralocorticoid receptor which 
is normally "protected" by this enzyme from 
glucocorticoid stimulation. As glucocorticoids 
circulate at much higher concentrations than 
mineralocorticoids and produce comparable 
stimulation of the mineralocorticoid receptor, 
the result is a clinical syndrome similar to primary 
aldosteronism without elevated plasma aldosterone 
concentration. 



Profound Potassium Depletion 

Severe hypokalemia (serum [K + ] <2 meq/L) may 
result in metabolic alkalosis. Urine chloride con- 
centration exceeds 20 meq/L in this setting. In 
some reports, affected individuals did not demon- 
strate mineralocorticoid excess, and their alkalo- 
sis did not correct with sodium repletion until 
potassium was repleted. This indicates that severe 
hypokalemia may sometimes convert a chloride 
responsive to a chloride-resistant metabolic alka- 
losis. We should stress, however, that correction of 
metabolic alkalosis without repletion of potassium 
deficits was shown. Therefore, while hypokalemia 
contributes to the maintenance of metabolic alka- 
losis and should be corrected, potassium supple- 
mentation does not appear necessary to correct 
metabolic alkalosis. 



Hypercalcemia (Suppressed PTH) 

Patients with hypercalcemia from malignancy or 
sarcoid, and not from hyperparathyroidism, may 
develop a mild metabolic alkalosis. This is likely 
to be due to the calcium-mediated suppression of 



PTH, which may raise the plasma threshold for 
HCOj. 



Poststarvation (Refeeding Alkalosis) 

After a prolonged fast, administration of carbohy- 
drates may produce a metabolic alkalosis that per- 
sists for weeks. The initiation factor for this form 
of metabolic alkalosis is not known, but increased 
renal sodium reabsorption secondary to ECF 
volume depletion is responsible for maintenance 
of the alkalosis. 



Key Points 

Chloride-Resistant Metabolic Alkalosis 



Metabolic alkalosis is classified based on 
urine chloride concentration into chloride 
responsive and chloride resistant. 
The most common causes of chloride- 
responsive metabolic alkalosis are diuretics 
and vomiting. 

Chloride-resistant metabolic alkaloses are 
due to conditions associated with increased 
aldosterone concentration or an 
aldosterone-like effect (type II 11/3-HSD 
associated disorders or a sodium channel 
mutation). 




Approach to the Patient 

with Chloride-Resistant 

Metabolic Alkalosis 



As shown in Figure 8.3 patients are initially subdi- 
vided based on the presence or absence of hyper- 
tension. Those patients with hypertension can 
then be further categorized based on their renin 



Chapter! 



Metabolic Alkalosis 



131 



Table 8.3 

Renin and Aldosterone Concentrations in Patients With Chloride-Resistant Metabolic Alkalosis and Hypertension 





Renin Concentration 


Aldosterone Concentration 


Primary aldosteronism 


Decreased 


Increased 


Renal artery stenosis 


Increased 


Increased 


Renin-producing tumor 


Increased 


Increased 


Cushing's syndrome 


Decreased 


Decreased 


Licorice ingestion 


Decreased 


Decreased 


Apparent mineralocorticoid excess 


Decreased 


Decreased 


Liddle's syndrome 


Decreased 


Decreased 



and aldosterone concentrations shown in Table 8.3. 
Many of these disorders are discussed in more 
detail in Chapter 21. 




Treatment 



Treatment of metabolic alkalosis, as with all acid- 
base disturbances, hinges on correction of the 
underlying disease state; however, the severity of 
the acid-base disturbance itself may be life threat- 
ening in some cases, and requires specific ther- 
apy. This is especially true in mixed acid-base 
disturbances where pH changes are in the same 
direction (such as a respiratory alkalosis from 
sepsis and a metabolic alkalosis secondary to 
vomiting). In these circumstances increased pH 
may become life threatening resulting in seizures 
or ventricular arrhythmias that require rapid 
reduction in systemic pH through control of ven- 
tilation. In this clinical condition, intubation, seda- 
tion, and controlled hypoventilation with a 
mechanical ventilator (sometimes using inspired 
C0 2 and/or supplemental oxygen to prevent 
hypoxia) is often lifesaving. 

In the past, administration of either HC1, argi- 
nine chloride, or ammonium chloride was used to 



correct metabolic alkalosis, these agents can 
result in significant potential complications. 
Hydrochloric acid may cause intravascular hemol- 
ysis and tissue necrosis, while ammonium chlo- 
ride may result in ammonia toxicity. In addition, 
their effect is not rapid enough to prevent or treat 
life-threatening complications. Therefore, in the 
setting of a clinical emergency, controlled 
hypoventilation must be employed. Once the sit- 
uation is no longer critical, partial or complete 
correction of metabolic alkalosis over the ensuing 
6-8 hours with HCl administered as a 0.15 M solu- 
tion through a central vein is preferred. Generally, 
the "acid deficit" is calculated assuming a bicar- 
bonate distribution space of 0.5 times body 
weight in liters, and about half of this amount of 
HCl is given with frequent monitoring of blood 
gases and electrolytes. 

In less urgent settings, metabolic alkalosis is 
treated after examining whether it is chloride- 
responsive or not. Chloride-responsive metabolic 
alkalosis is responsive to volume repletion. Co- 
existent hypokalemia should also be corrected. 
Chloride-resistant metabolic alkaloses are treated 
by antagonizing the mineralocorticoid (or miner- 
alocorticoid-like substance) that maintains renal 
H + losses. This sometimes can be accomplished 
with spironolactone, eplerenone, or other distal 
K-sparing diuretics like amiloride. 

It is not unusual that the actual cause of metabolic 
alkalosis is due to a therapy that is essential in the 



132 



Chapter! 



Metabolic Alkalosis 



management of a disease state. The hypokalemic 
metabolic alkalosis that develops from loop 
diuretic use in the nephrotic syndrome patient is 
an example where continued diuretic use is 
needed to manage the patient's severe edema. A 
creative approach to such clinical scenarios is the 
addition of the proximal diuretic acetazolamide, 
which will decrease the plasma threshold for 
HCO3 by inhibiting proximal tubule HCO3 reab- 
sorption. The prescription of a proton pump 
inhibitor will decrease gastric H + losses in the 
patient who requires prolonged gastric drainage. 
In those with far advanced chronic kidney disease 
and severe metabolic alkalosis hemodialysis may 
be required. 



Key Points 

Treatment of Metabolic Alkalosis 



1. With life threatening pH elevation (e.g., pH 
>7.6 with seizures and ventricular arrhyth- 
mias), rapid pH reduction is accomplished 
by control of ventilation. 

2. HC1 or its congeners do not work fast 
enough to prevent or treat life-threatening 
complications. 

3. Once the situation is no longer critical, par- 
tial or complete correction of metabolic 
alkalosis over 6-8 hours with HC1 adminis- 
tered as a 0.15 M solution through a central 
vein can be carried out. 



Chloride-responsive metabolic alkalosis cor- 
rects with volume replacement and 
improved hemodynamics. 
Chloride-resistant metabolic alkalosis may 
need treatment with mineralocorticoid 
receptor antagonists or sodium channel 
blockers. 



Additional Reading 

Adrogue, H.J., Madias, N.E. Management of life- 
threatening acid-base disorders. First of two parts. 
N Engl J Med 338:26-34, 1998. 

Adrogue, H.J., Madias, N.E. Management of life- 
threatening acid-base disorders. Second of two parts. 
N Engl J Med 338:107-111, 1998. 

Dell, K.M., Guay-Woodford, L.M. Inherited tubular 
transport disorders. Semin Nephrol 19:364-373, 1999. 

DuBose, T.D. Jr. Reclamation of filtered bicarbonate. 
Kidney Int 38: 584-589, 1990. 

Filley, G.F. Acid-Base and Blood Gas Regulation. Lea & 
Febiger, Philadelphia, PA, 1971. 

Greenberg, A. Diuretic complications. Am J Med Sci 
319:10-24, 2000. 

Galla, J.H. Metabolic alkalosis. / Am Soc Nephrol 
11:369-375, 2000. 

Hebert, S.C. Bartter syndrome. Cnrr Opin Nephrol 
Hypertens 12:527-532, 2003. 

Monnens, L., Bindels, R., Grunfeld, J.P. Gitelman syn- 
drome comes of age. Nephrol Dial Transplant 
13:1617-1619, 1998. 



Youngsook Yoon and 
Joseph I. Shapiro 



Respiratory and Mixed 
Acid-Base Disturbances 




Recommended Time to Complete: 1 day 

1. How is respiration controlled? 

2. What is ventilation? 

Z. What is respiratory acidosis and how does it occur? 

k. What mechanisms are involved in compensation for respiratory 

acidosis? 
S. What is respiratory alkalosis and how does it occur? 
i. What mechanisms are involved in the compensation for respiratory 

alkalosis? 
7- What are clues to the presence of a mixed acid-base disturbance? 
9- How do we approach the patient with a mixed acid-base disorder? 



133 




Chapter 9 ♦ Respiratory and Mixed Acid-Base Disturbances 



Respiratory Disturbances 



Introduction 

Breathing is an automatic, rhythmic, and centrally 
regulated process by which contraction of the 
diaphragm and rib cage moves gas in and out of 
the airways and alveolae of the lungs. Respiration 
includes breathing, but it also involves the circu- 
lation of blood, allowing for 2 intake and C0 2 
excretion. 

Two patterns are involved in the control of 
breathing: automatic and volitional. The auto- 
matic component is largely under the control of 
PaC0 2 . The control center for automatic breathing 
resides in the brainstem within the reticular acti- 
vating system (Figure 9.1). There are two major 
regions that control automatic ventilation: the 
medullary respiratory areas and the pontine respi- 
ratory group. Interestingly, less is known about 
volitional control than automatic control of respi- 
ration, and we will restrict our further discussion 
to automatic breathing. 



Figure 9-1 



Pontine 

respiration 

area 

PaCO, 



Medullary 
respiration 
area 




Diaphragm 



Chest wall 
muscles 



Control of ventilation. Schematic illustrating that central control 
of ventilation is largely through PaC0 2 sensitive chemorecep- 
tors in the pons (A) and medulla (B), whereas peripheral input 
is largely through PaO, sensitive chemoreceptors in the carotid 
body. Output is to the diaphragm via the phrenic nerves and 
thoracic muscles largely via intercostal innervations. 



Two main types of chemoreceptors, central and 
peripheral, are involved in the control of automatic 
breathing. The most important ones are located in 
the medulla of the central nervous system (CNS). 
The main peripheral chemoreceptors are within the 
carotid bodies although less important receptors 
were identified in the aortic arch. Central chemore- 
ceptors respond to changes in PaC0 2 largely 
through changes in brain pH (interstitial and cytoso- 
lic). This is a sensitive system, and PaC0 2 control is 
generally tight. In contrast, respiratory control by 
oxygen tensions is much less important until Pa0 2 
falls to below 70 mmHg. This is a reflection of the 
Hb-0 2 dissociation curve since Hb saturation is 
generally above 94% until the Pa0 2 falls below 
70 mmHg. 2 control of respiration is mediated 
largely through peripheral chemoreceptors which, 
in response to low 2 , close adenosine triphosphate 
(ATP)-sensitive K channels and depolarize glomus 
cells in the carotid body. The two systems interact, 
in that, with hypoxia, the central response to PaC0 2 
is enhanced. As we will discuss later, with chronic 
hypercapnia, control of respiration by C0 2 is 
severely blunted leaving some patients' respiration 
almost entirely under the control of 2 tensions. 

In addition to neural control, the physical 
machinery of breathing is also extremely impor- 
tant in gas exchange. This physical machinery 
involves both the lungs, as well as bones and the 
thorax musculature that interact to move air in and 
out of the pulmonary air spaces. Just as there may 
be neural defects that impair respiration, abnor- 
malities of either the skeleton, musculature, or air- 
ways, air spaces, and lung blood supply may 
impair respiration. To some degree, these abnor- 
malities are assessed and characterized by pul- 
monary function tests. Although it is beyond the 
scope of this chapter to discuss this topic in detail, 
it should be clear to the reader that modern pul- 
monary function tests readily differentiate prob- 
lems with airway resistance (e.g., asthma or 
chronic obstructive pulmonary disease) from 
those of alveolar diffusion (e.g., interstitial fibro- 
sis) or neuromuscular function (e.g., phrenic 
nerve palsy, Guillian-Barre syndrome). Figure 9-1 
shows a simplified schematic of the elements 
involved in controlling ventilation. 



Chapter 9 ♦ Respiratory and Mixed Acid-Base Disturbances 



Pulmonary ventilation refers to the amount of 
gas brought into and/or out of the lung. Pulmonary 
ventilation is expressed as minute ventilation 
(i.e., how much air is inspired and expired 
within 1 minute) or in functional terms as alveo- 
lar ventilation (V A ) since the portion of ventila- 
tion confined to the conductance airways does 
not effectively exchange 2 for C0 2 in alveolae. 
Since 2 uptake and C0 2 excretion are so criti- 
cal, we can reference ventilation with regard to 
either of these gases, however, since C0 2 excre- 
tion is so effective and ambient C0 2 tensions in 
the atmosphere are so low, pulmonary ventila- 
tion generally is synonymous with pulmonary 
C0 2 excretion. Note that C0 2 is much more solu- 
ble than 2 and exchange across the alveolar 
capillary for C0 2 is essentially complete under 
most circumstances, whereas some 2 gradient 
from alveolus to the alveolar capillary is always 
present. 

We should also point out that ventilation 
occurs at the tissue level as well. In this case, 
rather than inspired air removing C0 2 in its 
gaseous form, C0 2 produced by cells is largely 
(about 75%) converted to HCOj and removed 
from the local cellular environment by blood 
flow. Although it is an extreme case, when C0 2 
tensions in expired gases are monitored during 
cardiac arrest, the institution of effective circula- 
tion is accompanied by a sharp increase in 
expired C0 2 . 



Key Points 



135 



Respiratory Disturbances 



1 . CNS respiratory centers receive input from 
chemoreceptors locally (PaC0 2 ) and periph- 
erally (PaO,). 

2. Ventilation is determined by the integration 
of neural inputs, neural outputs, muscular 
responses, flow through airways, and gas 
exchange between alveolae and pulmonary 
capillaries. 




Respiratory acidosis is defined as a primary 
increase in PaC0 2 secondary to decreased effec- 
tive ventilation with net C0 2 retention. This 
decrease in effective ventilation can occur from 
defects in any aspect of ventilation control or 
implementation. These different causes are sum- 
marized in Table 9-1. 

Compensation for respiratory acidosis occurs 
at several levels. Some of these processes are 
rapid, analogous to what is seen with major com- 
pensatory mechanisms for metabolic acidosis or 
alkalosis, whereas others are slower. This latter 
fact allows us to clinically distinguish between 
acute and chronic respiratory acidosis in some 
cases. 

With respiratory acidosis, a rise in [HCOj] is a 
normal, compensatory response. As is the case for 
metabolic disorders, a failure of this normal adap- 
tive response is indicative of the presence of 
metabolic acidosis in the setting of a complex or 
mixed acid-base disturbance. Conversely, an 
exaggerated increase in HCO3 producing a 
normal pH indicates the presence of metabolic 
alkalosis in the setting of a complex or mixed 
acid-base disturbance. 

Mechanisms by which respiratory acidosis 
increases HCO3 concentration are as follows. First 
and probably foremost, increases in PaC0 2 and 
decreases in 2 tension stimulate ventilatory 
drive, in some way antagonizing the process that 
led to C0 2 retention in the first place. Next, mech- 
anisms by which C0 2 transport occurs from tis- 
sues to lungs become operant. In other words, 
increases in PaC0 2 are immediately accompanied 
by a shift to the right of the reaction 

H 2 C0 3 <-» H + + HCO3 

and increases in HCO3 concentration result. The 
amount of this increase in [HCO3] in meq/L is 0.1 
times the increase in PaC0 2 in mmHg (±2 meq/L). 
The kidney provides the mechanism for the 
majority of chronic compensation. Once PaC0 2 



136 



Chapter 9 ♦ Respiratory and Mixed Acid-Base Disturbances 



Table 9.1 

Causes of Respiratory Acidosis 



Acute Airway obstruction — aspiration of foreign body or vomitus, laryngospasm, generalized 

bronchospasm, obstructive sleep apnea 

Respiratory center depression — general anesthesia, sedative overdosage, cerebral trauma or 
infarction, central sleep apnea 

Circulatory catastrophes — cardiac arrest, severe pulmonary edema 

Neuromuscular defects — high cervical cordotomy, botulism, tetanus, Guillain-Barre syn- 
drome, crisis in myasthenia gravis, familial hypokalemic periodic paralysis, hypokalemic 
myopathy, toxic drug agents (e.g., curare, succinylcholine, aminoglycosides, organophos- 
phates) 

Restrictive defects — pneumothorax, hemothorax, flail chest, severe pneumonitis, hyaline 
membrane disease, adult respiratory distress syndrome 

Pulmonary disorders — pneumonia, massive pulmonary embolism, pulmonary edema 

Mechanical underventilation 
Chronic Airway obstruction — chronic obstructive lung disease (bronchitis, emphysema) 

Respiratory center depression — chronic sedative depression, primary alveolar hypoventila- 
tion, obesity hypoventilation syndrome, brain tumor, bulbar poliomyelitis 

Neuromuscular defects — poliomyelitis, multiple sclerosis, muscular dystrophy, amyotrophic 
lateral sclerosis, diaphragmatic paralysis, myxedema, myopathic disease (e.g., polymyositis, 
acid maltase deficiency) 

Restrictive defects — kyphoscoliosis, spinal arthritis, fibrothorax, hydrothorax, interstitial 

fibrosis, decreased diaphragmatic movement (e.g., ascites), prolonged pneumonitis, obesity 



increases and arterial pH decreases, renal acid 
excretion and retention of bicarbonate become 
more avid. Some of this is a direct chemical con- 
sequence of elevated PaC0 2 and mass action facil- 
itating intracellular bicarbonate formation, whereas 
other portions involve genomic adaptations of 
tubular cells involved in renal acid excretion. On 
this latter topic, enzymes involved in renal ammo- 
niagenesis (e.g., glutamine synthetase), as well 
as apical and basolateral ion transport proteins 
(e.g., Na + -H + exchanger, Na + -K + ATPase) are syn- 
thesized in increased amounts at key sites within 
the nephron. In sum, chronic respiratory acidosis 
present for at least 4-5 days will be accompanied 
by a [HCOjT] increase = 0.4 times the increase 
in PaC0 2 (mmHg) (±3 meq/L). Note that renal 
correction also never completely returns the 
arterial pH to the level it was at prior to C0 2 
retention. 



Key Points 

Respiratory Acidosis 



4. 



In respiratory acidosis, the primary distur- 
bance is an increase in PaC0 2 secondary to 
a decrease in effective ventilation with net 
CO, retention. 

Decreases in effective ventilation can result 
from defects in any aspect of ventilation 
control or implementation. 
In respiratory acidosis, the [HCOj] rises as a 
normal, compensatory response. 
A failure of the normal adaptive response 
indicates the presence of metabolic acidosis 
in the setting of a complex or mixed acid- 
base disturbance. 

The kidney provides the mechanism for the 
majority of chronic compensation. 



Chapter 




Respiratory and Mixed Acid-Base Disturbances 



137 



Respiratory Alkalosis 



Respiratory alkalosis is defined as a primary 
decrease in PaC0 2 secondary to an increase in 
effective ventilation with net C0 2 removal. This 
increase in effective ventilation can occur from 
defects in any aspect of ventilation control or 
implementation. These different causes are sum- 
marized in Table 9-2. 

With respiratory alkalosis, a fall in [HCOj] is a 
normal, compensatory response. As was the case 
for respiratory acidosis and the metabolic disor- 
ders, a failure of this normal adaptive response is 
indicative of the presence of metabolic alkalosis 
in the setting of a complex or mixed acid-base 



Table 9.2 

Causes of Respiratory Alkalosis 



Hypoxia 

Decreased inspired oxygen tension 

Ventilation-perfusion inequality 

Hypotension 

Severe anemia 
CNS mediated 

Voluntary hyperventilation 

Neurologic disease-cerebrovascular accident 
(infarction, hemorrhage), infection 
(encephalitis, meningitis), trauma, tumor 

Pharmacologic and hormonal stimulation- 
salicylates, ditrophenol, nicotine, xanthines, 
pressor hormones, pregnancy 
Hepatic failure 
Gram-negative septicemia 
Anxiety-hyperventilation syndrome 
Heat exposure 
Pulmonary disease 

Interstitial lung disease 

Pneumonia 

Pulmonary embolism 

Pulmonary edema 

Mechanical overventilation 



disturbance. Conversely, an exaggerated decrease 
in [HCOj] producing a normal pH indicates the 
presence of metabolic acidosis in the setting of a 
complex or mixed acid-base disturbance. 

The mechanisms by which respiratory alkalosis 
decreases [HCOj] are as follows. First and probably 
foremost, decreases in PaC0 2 will inhibit ventila- 
tory drive, in some way antagonizing the process 
that led to reductions in C0 2 tension in the first 
place. Decreases in PaC0 2 are immediately accom- 
panied by a shift to the left of the reaction 

H 2 C0 3 <-> H + + HC0 3 

and decreases in [HCOj] result. The amount of this 
decrease in [HCOj] is (in meq/L) 0.1 times the 
decrease in PaC0 2 in mmHg (with an error range 
of ±2 meq/L). Again, the kidney provides the 
mechanism for the majority of chronic compensa- 
tion. Once PaC0 2 decreases and arterial pH 
increases, renal excretion of acid and retention of 
bicarbonate are reduced. Some of this is a direct 
chemical consequence of decreased PaC0 2 and 
mass action antagonizing intracellular bicarbonate 
formation, whereas other portions involve genomic 
adaptations of tubular cells involved in renal acid 
excretion. Essentially, the reverse of what we 
described for metabolic compensation for respira- 
tory acidosis occurs. In sum, chronic respiratory 
alkalosis present for at least 4-5 days will be 
accompanied by a [HCOj] decrease (in meq/L) of 
0.4 times the increase in PaC0 2 (mmHg) (with an 
error range of ±3 meq/L). Note that renal correc- 
tion also never completely returns arterial pH to 
the level it was at prior to respiratory alkalosis. 
Moreover, decreases in [HCOj] below 12 meq/L 
are generally not seen from metabolic compensa- 
tion for respiratory alkalosis. 



Key Points 

Respiratory Alkalosis 



Abbreviation: CNS, central nervous system. 



1 . In respiratory alkalosis the primary process is 
a decrease in PaC0 2 secondary to an increase 
in effective ventilation with net CO, removal. 



138 



Chapter 9 ♦ Respiratory and Mixed Acid-Base Disturbances 



2. With respiratory alkalosis, a fall in [HCO,] is 
a normal, compensatory response. 

3. A failure of this normal adaptive response is 
indicative of the presence of metabolic alka- 
losis in the setting of a complex or mixed 
acid-base disturbance. 

4. The kidney provides the mechanism for the 
majority of chronic compensation. 

5. Decreases in [HCO,] below 12 meq/L are 
generally not seen from metabolic compen- 
sation for respiratory alkalosis. 




Mixed Disturbances 



The first clue to the presence of a mixed acid-base 
disorder is the degree of compensation. As dis- 
cussed above, "over compensation" or an absence 
of compensation are certain indicators that a 
mixed acid-base disorder is present. For metabolic 
disorders, the respiratory compensation should be 
immediate; in these settings, it is relatively easy to 
determine whether compensation is appropriate 
(see Chapters 7 and 8). For respiratory disorders, 
however, it is a bit more complex since metabolic 
compensation takes days to become complete. 
Note that mass action will produce about a 0.1 meq/L 
change in [HCO3] for every 1 mmHg change in 
PaC0 2 ; ergo, a complete absence of metabolic 
compensation for respiratory acidosis or alkalosis 
clearly indicates a second primary problem. For 
degrees of compensation between 0.1 and 0.4 
meq/L/mmHg change in PaC0 2 , it is difficult if not 
impossible to distinguish between a failure of 
compensation (e.g., a primary metabolic disorder) 
and an acute respiratory disturbance on the blood 
gas alone. These rules of compensation are illus- 
trated graphically in Figure 92. To further address 
this question, we must return to our description of 
the anion gap in Chapter 7. Recall that the serum 
anion gap can be defined as 



SAG = [NaT - tCl" 



HCO: 



but this can also be interpreted as 

SAG = UA - UC 

To use the SAG in the approach to a complex 
acid-base disorder, we make the stoichiometric 
assumption that for a pure organic acidosis 

ASAG = AlHCOj] 

Since we don't have "pre" and "post" disorder 
values, we further assume that the SAG started at 
10 meq/L and the [HCO3] started at 24 meq/L. 
With these assumptions, we can diagnose simul- 
taneous anion gap metabolic acidosis and meta- 
bolic alkalosis when the SAG is large and the 
decrease in [HCO,] is relatively small. A common 
clinical scenario for this is when vomiting accom- 
panies an anion gap metabolic acidosis such as 
lactic acidosis in the setting of bowel ischemia. 
Conversely, we can also diagnose simultaneous 
non-anion gap metabolic acidosis with anion gap 
metabolic acidosis if the fall in [HCO3] is much 
larger than the modestly but significantly 
increased SAG. Probably the most common exam- 
ple for this would be renal failure where some 
degree of non-anion gap acidosis and anion 
gap acidosis coexist. These situations are shown 
schematically in Figure 9-3. A list of clinical sce- 
narios where complex acid-base disorders often 
occur is shown in Table 93. 

It is appropriate at this point to reiterate the 
reason that one performs analysis of acid-base 
disorders. Quite simply, it is to gain insight into 
the clinical problems that the patient is facing. To 
this end, it is important to realize that the accurate 
diagnosis of a mixed disorder is more than a 
matter of semantics. In some cases, it may even be 
life saving. The following case illustrates this. An 
8-year-old boy presents to an emergency room 
with history of a viral illness followed by progres- 
sive obtundation. His arterial blood gas shows a 
pH of 7.00, PaC0 2 = 38 mmHg, [HCO3] = 9 meq/L. 
The serum glucose concentration is elevated, and 
both urine and blood are positive for ketones. The 
serum anion gap is calculated at 25 meq/L. 

Why is it so important to accurately diagnose 
that the patient above has a mixed respiratory and 



Chapter 9 ♦ Respiratory and Mixed Acid-Base Disturbances 



139 



Figure 9.2 



100 



Metabolic 
acidosis 



Acute respiratory 
acidosis 



Chronic respiratory 
acidosis 




Metabolic 
alkalosis 



Acute respiratory 
alkalosis 
1 



pH = 7.70 



60 



Chronic respiratory 
alkalosis 



[HC0 3 1 meq/L 



Acid-base nomogram. Acid-base nomogram derived from rules of compensation described 
in the text. Regions associated with simple acid-base disorders are identified in the shaded 
regions. A: Mixed respiratory and metabolic acidosis, B: mixed respiratory acidosis and 
metabolic alkalosis, C: mixed respiratory alkalosis and metabolic alkalosis, and D: mixed 
respiratory alkalosis and metabolic acidosis. Regions between acute and chronic respiratory 
acidosis and acute and chronic respiratory alkalosis cannot be uniquely defined (see text). 
Lines of constant pH 7.00 and 7.70, as well as normal range (black box) shown for reference. 



metabolic acidosis (see Figure 9-2) rather than 
"uncompensated" metabolic acidosis? In the sce- 
nario described, it is likely that the child will soon 
stop breathing. Although the PaC0 2 of 38 mmHg 
is a "normal" value, it is not appropriate compen- 
sation and, thus, must be interpreted as another 
primary disorder. Understanding that this truly 
represents respiratory acidosis confers appropri- 
ate urgency to the clinical situation and also may 
prompt a search for potential causes of respira- 
tory acidosis. In this case the respiratory acidosis 
is likely secondary to neuromuscular fatigue, 
however, in other clinical situations it may prompt 
a search for causes of central respiratory depres- 
sion (e.g., sedative administration) or acute 
airway obstruction. 

As was the case for simple acid-base disorders, 
the key reason for analyzing mixed acid-base 



disorders is to create short lists of differential diag- 
noses to further explore clinically. This is gener- 
ally accomplished diagnosis by diagnosis. In other 
words, if a patient were found to have a triple 
acid-base disorder consisting of respiratory alka- 
losis, anion gap metabolic acidosis, and metabolic 
alkalosis, one would examine each of these sepa- 
rately and put them together in the context of the 
patient. 

In Chapters 7 and 8, we stated that the degree 
of acidosis or alkalosis is rarely life threatening by 
itself. Although this is true, the exceptional cases 
generally involve mixed acid-base disorders 
"where both respiratory and metabolic disorders 
change pH in the same direction. For example, 
mixed respiratory acidosis and metabolic acidosis 
that might occur in the setting of cardiac and res- 
piratory arrest may produce low enough pH to 



140 



Chapter 9 ♦ Respiratory and Mixed Acid-Base Disturbances 



Figure 9-3 



l^n 


m K< 






Anion gap-A 

A-[HC0 3 1 


Anion gap-A 

A-[HC0 3 1 


Mixed anion gap metabolic 


Mixed anion-gap metabolic 


acidosis and metabolic 


acidosis and non-anion 


alkalosis 


gap metabolic acidosis 



Diagnosis of hidden mixed acid-base disturbances. Schematic 
illustrating how one can diagnose hidden mixed acid-base dis- 
turbances by comparing the change in anion gap to the change 
in bicarbonate concentration. If the change in anion gap is 
much larger than the fall in bicarbonate concentration this 
implies the coexistence of anion gap metabolic acidosis and 
metabolic alkalosis (left panel). If the change in anion gap is 
much smaller than the change in the bicarbonate concentra- 
tion then this implies the presence of an anion gap and non- 
anion gap metabolic acidosis (right panel). 



Table 9,3 

romes Commonly Associated with Mixed Acid-Base Disorders 



Hemodynamic compromise 

Cardiopulmonary arrest 
Pulmonary edema 
Sepsis 
Liver failure 
Poisonings 

Ethylene glycol intoxication 
Methanol intoxication 
Aspirin intoxication 
Ethanol intoxication 
Metabolic disturbances 
Severe hypokalemia 
Severe hypophosphatemia 
Diabetic ketoacidosis 
Bowel ischemia 
COPD 
Renal failure 



impair cardiac contractile function and/or vascu- 
lar tone. Conversely, respiratory alkalosis in com- 
bination with metabolic alkalosis (e.g., patient 
with pulmonary edema treated with potassium 
wasting diuretics) could develop elevations in pH 
sufficient to cause seizures and/or cardiac 
arrhythmias. When these extreme conditions 
occur, correct therapy is directed at pH control 
through the control of ventilation. Once the pH is 
adjusted to one that is not life threatening, the 
metabolic disturbance(s) are addressed. We reit- 
erate that treatment of the acid-base disorder 
always involves making the correct clinical diag- 
nosis of the underlying causes and appropriate 
specific therapy directed at those causes. 



Key points 

Mixed Acid-Base Disorders 



Abbreviation: COPD, chronic obstructive pulmonary disease 



1 . Mixed acid-base disorders may result from 
the coexistence of primary respiratory and 
metabolic disorders, the coexistence of 
metabolic alkalosis with anion gap meta- 
bolic acidosis, and/or the coexistence of 
non-anion gap metabolic acidosis with 
anion gap metabolic acidosis. 

2. To evaluate compensation, one applies the 
following rules: 

Metabolic acidosis: compensatory change in 
PaCO, (mmHg) = 1-1.5 X the fall in 
[HCO^l (meq/L) or the PaC0 2 (mmHg) 



■■ 1.5 x [HCO, 



i + 2. 



Metabolic alkalosis: compensatory change 
in PaC0 2 (mmHg) = 0.6-1 x the increase 
in [HCO^] (meq/L). 

Acute respiratory acidosis or alkalosis: com- 
pensatory change in [HCOj] (meq/L) = 0.1 x 
the change in PaC0 2 (mmHg) ± 2 (meq/L). 

Chronic respiratory acidosis or alkalosis: com- 
pensatory change in [HCO3] (meq/L) = 0.4 x 
the change in PaC0 2 (mmHg) ± 3 (meq/L). 

Failure to achieve the appropriate degree of 
compensation implies a second primary 
disorder. 



Chapter 9 ♦ Respiratory and Mixed Acid-Base Disturbances 



141 



The most dangerous mixed disturbances 
occur when both metabolic anci respiratory 
alkalosis or metabolic and respiratory aci- 
dosis coexist. 

Stoichiometric equivalence between the 
change in anion gap and the reduction in 
[HCOj] is assumed with anion gap metabolic 
acidosis. A marked discrepancy between these 
measurements implies the coexistence of 
either anion gap metabolic acidosis and meta- 
bolic alkalosis or anion gap metabolic acidosis 
and non-anion gap metabolic acidosis. 
Triple acid-base disorders are diagnosed 
when both respiratory and metabolic distur- 
bances are present and either anion gap 
metabolic acidosis and metabolic alkalosis 
or anion gap metabolic acidosis and non- 
anion gap metabolic acidosis coexist. 



Adrogue, H.J., Madias, N.E. Management of life- 
threatening acid-base disorders. Second of two parts. 
NEnglJMed 338:107-111, 1998b. 

Constable, P.D. Clinical assessment of acid-base status. 
Strong ion difference theory. Vet Clin North Am 
Food AnimPract 15:447-471, 1999. 

Epstein, S.K., Singh, N. Respiratory acidosis. Respir 
Care 46:366-383, 2001. 

Filley, G.F. Acid-Base and Blood Gas Regulation. 1st 
edition. Lea & Febiger, Philadelphia, PA, 1971. 

Kreit, J.W., Eschenbacher, W.L. The physiology of spon- 
taneous and mechanical ventilation. Clin Chest Med 
9:11-21, 1988. 

Mellins, R.B., Haddad, G.G. Respiratory control in 
early life: an overview. Prog Clin Biol Res 136:3-15, 
1983. 

Orr, W.C. Sleep and breathing: an overview. Ear Nose 
Throat J 63:191-198, 1984. 

Stewart, P.A. How to Understand Acid-Base. A Quan- 
titative Primer for Biology and Medicine. 1st edition. 
Elsevier, New York, NY, 1981. 



Additional Reading 



Adrogue, H.J., Madias, N.E. Management of life- 
threatening acid-base disorders. First of two parts. 
NEnglJMed 338:26-34, 1998a. 



Robert F. Reilly, Jr. 



Disorders of Serum 
Calcium 




Recommended Time to Complete: 1 day 



Cf <vv^u*v£ Quei%le/h4 



1. How is extracellular fluid (ECF) ionized calcium regulated? 

2. What roles do parathyroid hormone (PTH) and l,25(OH) 2 vitamin 
D 3 (calcitriol) play in this process? 

1. What three pathophysiologic processes are involved in 
hypercalcemia? 

If. Which two diseases make up the majority of cases of hypercalcemia 
and how do their presentations differ? 

5. Can you devise a rational treatment plan for the hypercalcemic patient? 

6. Why does the hypomagnesemic patient develop hypocalcemia? 

7. How does one approach the patient with hypocalcemia? 

2. What are the keys to successfully treating hypocalcemia? 



142 




Chapter 10 ♦ Disorders of Serum Calcium 



Regulation of ECF Ionized 
Calcium 



Despite the fact that only a small percentage of 
calcium contained in the body resides in ECF, it is 
ECF ionized calcium that is physiologically regu- 
lated. It is regulated by the combined interaction 
between PTH, the calcium-sensing receptor and 
calcitriol in the parathyroid gland, bone, intestine, 
and kidney. Sixty percent of ECF calcium is ultra- 
filterable and is either ionized and thereby free in 
solution (50%) or complexed to anions (10%). The 
other 40% is bound to proteins (mainly albumin). 
The vast majority of total body calcium exists as 
hydroxyapatite in bone (99%). The bone calcium 
reservoir is so large that one cannot become 



143 



hypocalcemic without a decrease in bone calcium 
release due to a defect in either PTH or calcitriol 
action. 

Figure 10.1 illustrates average daily calcium 
fluxes between ECF and the organ systems 
involved in its regulation (bone, intestine, and 
kidney). The average adult takes in 1000 mg and 
absorbs about 20% in intestine. In the steady state, 
intestinal absorption is matched by urinary excre- 
tion. The kidney excretes approximately 2% 
(200 mg) of the filtered calcium load. 

Another important regulator of calcium ho- 
meostasis is the calcium-sensing receptor. The 
calcium-sensing receptor is expressed in the cell 
membrane of the parathyroid gland. It is also 
expressed on the surface of cells in kidney, intes- 
tine, lung, and a variety of other organs. In 
parathyroid gland it couples changes in ECF calcium 
concentration to the regulation of PTH secretion 



Figure 10.1 



1 ,000 mg 
25 mmol 




800 mg 
20 mmol 



200 mg 
5 mmol 



ECF 

(1,000 mg) 

25 mmol 



500 mg 
12.5 mmol 



9,800 mg 
245 mmol 



10,000 mg 
250 mmol 





800,000 mg 
20,000 mmol 



" 
200 mg 
5 mmol 



Calcium homeostasis. Daily calcium fluxes between ECF, intestine, kidney, 
and bone are shown. In the steady state net intestinal absorption and renal 
excretion of calcium are equal. The majority of calcium in the body is in bone. 
(With permission from Schrier, R.W. (ed.). Manual of Nephrology. Lippincott 
Williams & Wilkins, Philadelphia, PA, 2000.) 



144 



Chapter 10 



Disorders of Serum Calcium 



via a complex signaling pathway mediated by 
phospholipase C and phospholipase A,. High cal- 
cium concentration activates the receptor and 
inhibits release of PTH. Low calcium concentra- 
tion stimulates PTH secretion and production, as 
well as increases parathyroid gland mass. This 
system responds within minutes to changes in cal- 
cium concentration. The parathyroid gland does 
not contain a large supply of excess storage gran- 
ules. Basal and stimulated secretion of PTH can 
only be supported for a few hours in the absence 
of new hormone synthesis. There is an inverse 
sigmoidal relationship between calcium concen- 
tration and PTH secretion (Figure 10.2). As can be 
seen in the figure, there is still some basal PTH 
secretion even at high calcium concentrations. 
This is important clinically in the patient with sec- 
ondary hyperparathyroidism and end-stage renal 
disease. As parathyroid gland mass increases 
basal PTH secretion increases to the point where 
it can no longer be suppressed by high dose 



Figure 10.2 





Maximum 




| 100 


\ 






X 

CO 

E 






o 


\ 




V 50 


"Set point" — A 




w 

CO 
CD 
CD 






1 
1- 
CL 






^T~ 






Minimum 


C 


) 1.0 


2.0 


[Ca ++ ], m 


Vl 



PTH-calcium response curve. There is an inverse 
sigmoidal relationship between ionized calcium 
concentration and release of PTH from the 
parathyroid gland. The set point is that ionized 
calcium concentration at which PTH release is 
inhibited by 50%. The minimum arrow illus- 
trates that there is a basal level of PTH release 
even at high calcium concentrations. 



calcitriol therapy and ultimately subtotal parathy- 
roidectomy is required. Calcium-sensing receptor 
knockout mice demonstrate marked parathyroid 
hyperplasia suggesting that the receptor also 
plays a role in parathyroid cell growth and prolif- 
eration. The calcium-sensing receptor is expressed 
in kidney. In the thick ascending limb of Henle it 
is expressed in the basolateral membrane. 
Activation of the receptor here by elevated blood 
calcium concentration results in inhibition of 
apical sodium entry via the furosemide-sensitive 
Na-K-2C1 cotransporter. Inhibition of the apical 
membrane potassium channel by arachidonic 
acid-derived intermediates reduces the lumen- 
positive voltage that drives paracellular calcium 
transport in this segment and increases urinary 
calcium excretion. The ability of the kidney to 
concentrate urine is also impaired. In the inner 
medullary collecting duct the receptor is present 
in the apical membrane in the very same vesicles 
that contain water channels. Perfusion of the 
inner medullary collecting duct with a high cal- 
cium solution reduces vasopressin-stimulated 
water flow by about 40% presumably via activation 
of the receptor. This may provide a mechanism to 
inhibit calcium crystallization in states of hypercal- 
ciuria. The inhibition of water transport may aid in 
increasing the solubility of calcium salts. 

PTH increases ECF calcium concentration via 
effects in bone, intestine, and kidney. In the 
presence of calcitriol, PTH stimulates bone 
resorption through an increase in osteoclast 
number and activity. In the intestine PTH acts 
indirectly through its stimulation of calcitriol for- 
mation to increase calcium and phosphorus 
absorption. Calcitriol increases expression of 
epithelial calcium channels in the intestine. In 
the kidney, PTH increases calcium reabsorption 
in the distal convoluted tubule and connecting 
tubule, stimulates activity of 1-a-hydroxylase in 
the proximal convoluted tubule that converts 
25(OH) vitamin D, to 1,25(0 H) 2 vitamin D,, and 
reduces proximal tubular reabsorption of phos- 
phate and bicarbonate. The end result is an 
increase in ECF calcium concentration without 
an increase in phosphorus concentration. 



Chapter 10 



Disorders of Serum Calcium 



145 



The final step in calcitriol formation is the 1-a- 
hydroxylation of 25(OH) vitamin D (calcidiol) in 
proximal tubule. The biosynthetic pathway for 
calcitriol is shown in Figure 10.3. 7-Dehydrocho- 
lesterol in skin is converted to vitamin D by UV 
light. Vitamin D is then 25 hydroxylated in the liver. 
This step is poorly regulated and in general 25(OH) 
vitamin D ? concentration parallels vitamin D 
intake. Finally, 1-a-hydroxylation takes place in the 
inner mitochondrial membrane of proximal tubu- 
lar cells. Increasing PTH concentration and hypo- 
phosphatemia enhance l-ot-hydroxylase activity. 



Calcitriol stimulates its own catabolism via activa- 
tion of 24 hydroxylase. Twenty-four hydroxylase 
is the major catabolic enzyme in calcitriol target 
tissues. It is upregulated by calcitriol, hypercal- 
cemia, and hyperphosphatemia. 

Calcitriol increases calcium and phosphorus 
availability for bone formation and prevents 
hypocalcemia and hypophosphatemia. In intes- 
tine and kidney, calcitriol plays an important role 
in increasing calcium transport via the stimulation 
of expression of calcium-binding proteins (cal- 
bindins). Calbindins bind calcium and move it 



Figure 10.3 




HO' 
7-dehydrocholesterol 




Vitamin Do 



diet 



UV light 



25-OHase 

liver (not hormonally regulated) 




HO' 
25-OH vitamin D 3 



1-OHase 




24-OHase 



HO-^^OH 
1 ,25-(OH) 2 vitamin D 3 

24-OHase 

1,24,25-(OH) 3 vitamin D 3 




HO' 

24,25-(OH) 2 vitamin D 3 

24-OHase 

1,24,25-(OH) 3 vitamin D 3 



Vitamin D metabolism. The metabolic pathway is illustrated. 



146 



Chapter 10 



Disorders of Serum Calcium 



from the apical to the basolateral membrane, 
thereby allowing calcium to move through the 
cell without an increase in free intracellular cal- 
cium. Calcitriol increases expression of the 
sodium phosphate cotransporter in intestine. In 
bone, calcitriol has a variety of effects: (1) poten- 
tiation of PTH effects; (2) stimulation of osteoclas- 
tic reabsorption; and (3) induction of monocyte 
differentiation into osteoclasts. In parathyroid 
gland, calcitriol binds its receptor in the cytoplasm 
and forms a heterodimer with the retinoid X 
receptor and is translocated to the nucleus. The 
complex binds to the PTH gene promoter and 
decreases PTH expression, as well as inhibits 
parathyroid growth. 

Renal calcium excretion plays an important 
role in calcium homeostasis. Calcium that is not 
bound to albumin is freely filtered at the glomeru- 
lus. The proximal tubule reabsorbs 2/3 of the fil- 
tered load. The majority of reabsorption is passive 
but there is a small active component. Calcium 
transport in the proximal tubule parallels that of 
sodium and water. Therefore, calcium reabsorp- 
tion proximally varies directly with ECF volume. 
The more expanded the ECF volume, the higher 
calcium excretion. Calcium excretion is decreased 
in the setting of volume contraction. The thick 
ascending limb of Henle reabsorbs 25% of the fil- 
tered load. Calcium transport in this segment is 
passive, paracellular, and dependent on the mag- 
nitude of the lumen-positive transepithelial volt- 
age. The lumen-positive voltage is a result of 
potassium exit across the apical membrane via a 
potassium channel. Potassium reenters the cell 
across the apical membrane on the furosemide- 
sensitive Na-K-2Cl cotransporter. If the Na-K-2Cl 
cotransporter is inhibited by furosemide, the 
lumen-positive voltage is dissipated and the driv- 
ing force for paracellular calcium transport is no 
longer present. The result is an increase in urinary 
calcium excretion. This has important clinical rel- 
evance in that cornerstones of the early treatment 
of hypercalcemia are ECF volume expansion and 
inhibition of the Na-K-2C1 cotransporter with 
furosemide in order to increase renal calcium 
excretion. The distal tubule (distal convoluted 



tubule and connecting tubule) reabsorbs 10% of 
the filtered calcium load. This segment is the 
major regulatory site of calcium excretion under 
PTH control. Calcium transport is entirely active 
in this segment. Transport is stimulated by PTH, 
alkalosis and thiazide diuretics and inhibited by 
acidosis and hypophosphatemia. 



Key points 



Regulation of ECF Ionized Calcium 



1. PTH and calcitriol regulate extracellular 
fluid ionized calcium concentration. 

2. Calcium concentration is sensed by the 
calcium-sensing receptor, which plays an 
important role in regulating PTH secretion. 

3. PTH increases calcium concentration via 
actions in bone, intestine, and kidney. 

4. PTH and hypophosphatemia enhance \-a 
hydroxylase activity in the proximal tubule 
leading to calcitriol formation. 

5. Calcitriol increases availability of calcium 
and phosphorus for bone formation and 
prevents hypocalcemia and hypophos- 
phatemia. 

6. Calcitriol is the most potent suppressor of 
PTH gene transcription. 




Etiology 

Hypercalcemia results from increased absorption 
of calcium from the gastrointestinal (GI) tract, 
increased bone resorption, or decreased calcium 
excretion by the kidney (Table 10.1). 

Increased GI calcium absorption is important 
in hypercalcemia that results from the milk- 
alkali syndrome, vitamin D intoxication, and 



Chapter 10 



Disorders of Serum Calcium 



147 



Table 10.1 



Etiologies of Hypercalcemia 



Increased bone resorption 

Hyperparathyroidism (primary and secondary) 

Malignancy 

Thyrotoxicosis 

Immobilization 

Paget's disease 

Addison's disease 

Lithium 

Vitamin A intoxication 

Familial hypocalciuric hypercalcemia 

Increased GI absorption 

Increased calcium intake 

Milk-alkali syndrome 

Renal failure (calcium and vitamin D 
supplements) 
Increased vitamin D concentration 

Vitamin D intoxication 

Granulomatous disease 
Decreased renal excretion 
Thiazide diuretics 



Abbreviation: GI, gastrointestinal. 



granulomatous diseases. Milk-alkali syndrome 
results from excessive intake of calcium and bicar- 
bonate or its equivalent. In addition, alkalosis 
stimulates calcium reabsorption in the distal aibule 
of the kidney. Suppression of PTH secretion by 
hypercalcemia further increases proximal tubular 
bicarbonate reabsorption. The most common 
cause of the milk-alkali syndrome in the past 
was milk and sodium bicarbonate ingestion for 
therapy of peptic ulcer disease. Today the most 
common clinical setting is an elderly woman 
treated with calcium carbonate and vitamin D for 
osteoporosis. Bulemics taking supplemental cal- 
cium or a high calcium diet are also at high risk. 
The classic triad of milk-alkali syndrome is hyper- 
calcemia, metabolic alkalosis, and elevated serum 
blood urea nitrogen (BUN) and creatinine con- 
centrations. Treatment of these patients is often 
complicated by rebound hypocalcemia as a result 



of sustained PTH suppression from hypercal- 
cemia. PTH concentrations in these patients are 
often very low. 

Hypercalcemia from increased calcium inges- 
tion alone rarely occurs in the absence of decreases 
in kidney function or supplementation •with vita- 
min D. Vitamin D intoxication also causes hyper- 
calcemia. Calcitriol stimulates calcium absorption 
in the small intestine; however, bone release of 
calcium may also play an important role in these 
patients. A recent outbreak was reported as the 
result of over fortification of milk from a home 
delivery dairy. Other milk-associated outbreaks 
have resulted from the inadvertent addition of cal- 
citriol to milk. Increased GI calcium absorption 
and hypercalcemia occur with granulomatous dis- 
orders, such as sarcoidosis, mycobacterium tuber- 
culosis, and mycobacterium avium in patients 
with human immunodeficiency virus (HIV) infec- 
tion. Macrophages express 1-a-hydroxylase when 
stimulated and convert calcidiol to calcitriol. 
Hypercalcemia may be the initial manifestation of 
extrapulmonary sarcoid. This more commonly 
results in hypercalciuria than hypercalcemia. 
Lymphomas can produce hypercalcemia via the 
same mechanism. The source of calcitriol with 
lymphomas may be from macrophages adjacent 
to the tumor and not the malignant cells them- 
selves. Lymphomas may also cause hypercalcemia 
via cytokine-induced activation of osteoclasts and 
osteolysis. 

Increased bone calcium resorption is the most 
common pathophysiologic mechanism leading to 
hypercalcemia. This plays a primary role in the 
hypercalcemia of hyperparathyroidism, malig- 
nancy, hyperthyroidism, immobilization, and 
Paget's disease. The two most common causes of 
hypercalcemia are primary hyperparathyroidism 
and malignancy. 

Primary hyperparathyroidism occurs in as many 
as 1 per 10,000 people in the general population. 
The pathologic lesion in 80-90% is a solitary ade- 
noma. Of the remaining, as many as 10-20% have 
diffuse hyperplasia and some of these have the 
inherited familial syndrome multiple endocrine 
neoplasia (MEN). MEN type I is associated with 



148 



Chapter 10 



Disorders of Serum Calcium 



pituitary adenomas and islet cell tumors. It has an 
estimated prevalence of 1 per 50,000. Primary 
hyperparathyroidism is the initial manifestation 
occurring in general by age 40-50. The mutation 
resides in the menin gene. Menin is a tumor sup- 
pressor expressed in the nucleus that binds to JunD. 
Menin mutations occur in approximately 15% of 
sporadic adenomas. MEN type II is associated with 
medullary carcinoma of the thyroid and pheochro- 
mocytoma. It is subdivided into MEN Ha that is asso- 
ciated with parathyroid hyperplasia and type lib 
that is not. MEN type II is caused by mutations in 
the RET protooncogene that is a tyrosine kinase. 
In developing tissues including neural crest, 
kidney, and ureter RET is a receptor for growth and 
differentiation. Multiple adenomas can occur 
and parathyroid carcinoma is very rare (<1%). 

Hypercalcemia in hyperparathyroidism is the 
combined result of increased bone calcium resorp- 
tion, increased calcium absorption from intestine, 
and increased calcium reabsorption in kidney. In 
primary hyperparathyroidism hypercalcemia is 
mild (less than 11.0 mg/dL), and often identified on 
routine laboratory testing in the asymptomatic 
patient. Patients present most commonly between 
the ages of 40 and 60 and women are affected two 
to three times more often than men. The majority of 
patients are postmenopausal women. 

Secondary hyperparathyroidism may cause 
hypercalcemia in two clinical settings. In the renal 
transplant patient although renal function improves, 
PTH concentration is still elevated as a result of 
increased parathyroid gland mass. Hypercalcemia 
generally does not persist more than a year. In the 
patient with end-stage renal disease and second- 
ary hyperparathyroidism, hypercalcemia can 
occur with calcium and/or vitamin D supplemen- 
tation. This occurs primarily in patients with low 
turnover bone disease (adynamic bone disease). 

Malignancy results in hypercalcemia from pro- 
duction of parathyroid hormone-related peptide 
(PTHrP), local bone resorption in areas of metas- 
tasis (cytokine mediated), or calcitriol production 
(lymphomas). Breast cancer, squamous cell lung 
cancer, multiple myeloma, and renal cell carcinoma 
are the most common malignancies associated 



with hypercalcemia. Hypercalcemia secondary to 
PTHrP is known as humoral hypercalcemia of 
malignancy (HHM). A large variety of tumors can 
produce PTHrP. A partial list includes squamous 
cell cancers of the head, neck and lung, breast 
cancer, pancreatic cancer, transitional cell carci- 
nomas, and germ cell tumors. The first 13 amino 
acids of PTHrP are highly homologous to PTH, 
and as a result PTHrP binds to the PTH receptor 
and has similar biologic activity to PTH. PTHrP 
may be the fetal PTH. PTH is not secreted by the 
parathyroid gland in utero and does not cross the 
placenta. Humoral hypercalcemia of malignancy 
typically presents with severe hypercalcemia 
(serum calcium concentration >14 mg/dL). At the 
time of initial presentation the cancer is usually 
easily identified. An assay for PTHrP is commer- 
cially available. PTHrP is immunologically distinct 
from PTH and as a result is not detected by PTH 
assays. In patients with HHM PTH concentration 
will be low. Humor hypercalcemia of malignancy 
carries a poor prognosis with a median survival 
of only 3 months. Hypercalcemia from primary 
hyperparathyroidism and malignancy can be seen 
in the same patient. Patients with malignancy 
were reported to have an increased incidence of 
primary hyperparathyroidism. 

Osteolytic metastases produce a variety of 
cytokines resulting in calcium release from bone. 
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) 
stimulate the differentiation of osteoclast precur- 
sors into osteoclasts. IL-6 stimulates osteoclast 
production. 

Approximately one-third of patients with mul- 
tiple myeloma will develop hypercalcemia. 
Multiple myeloma presents with anemia, hyper- 
calcemia, and localized osteolytic lesions. Release 
of calcium from bone results from cytokine 
release (IL-6, IL-1, TNF-/?, MIP-1 alpha and MIP-1 
beta). Myeloma cells also disturb the ratio of 
osteoprotegerin and its ligand NF-kappa B ligand 
(RANKL), which play a critical role in bone 
remodeling and the regulation of osteoclast to 
osteoblast activity. By decreasing expression and 
increasing degradation of osteoprotegerin and 
increasing RANKL expression in their local 



Chapter 10 



Disorders of Serum Calcium 



149 



environment myeloma cells tip the balance in 
favor of bone resorption. Lytic bone lesions are 
characterized by increased osteoclast resorption 
without new bone formation. This is in contradis- 
tinction to bone metastases with breast and 
prostate cancer where areas of lysis are sur- 
rounded by new bone formation. As a result 
radionuclide bone scans will show uptake at sites 
of metastasis and not at sites of bone involvement 
with multiple myeloma. 

Increased bone turnover and mild hypercal- 
cemia occur in 5-10% of patients with hyperthy- 
roidism. Hyperthyroid patients may also have an 
increased incidence of parathyroid adenomas. 
Immobilization and Paget's disease can cause 
hypercalcemia; however, this is more common in 
children. Hypercalciuria is the more common 
abnormality in adults. 

Lithium administration may cause mild hyper- 
calcemia that results from interference with cal- 
cium sensing by the calcium-sensing receptor. 
The calcium-sensing receptor also binds lithium, 
which acts as an antagonist. Hypercalcemia is 
generally mild, clinically insignificant, and resolves 
with discontinuation of the drug. In some cases it 
persists and may be associated with clinical signs 
and symptoms. Pheochromocytoma, primary 
adrenal insufficiency, and the inherited disorder 
familial hypocalciuric hypercalcemia (FHH) are 
additional rare causes of hypercalcemia. Pheochro- 
mocytoma may produce hypercalcemia via its 
association with MEN 2a or by the production of 
PTHrP. Catecholamines are also known to 
increase bone resorption. Familial hypocalciuric 
hypercalcemia is inherited in an autosomal domi- 
nant fashion. The mutation occurs in the calcium- 
sensing receptor and results in a receptor that has 
a decreased affinity for calcium. As a result ele- 
vated calcium concentrations are required to sup- 
press PTH. It presents with mild hypercalcemia at 
a young age, decreased urinary calcium excretion, 
and a high normal or slightly elevated PTH con- 
centration. Notably signs or symptoms of hyper- 
calcemia are often absent. Familial hypocalciuric 
hypercalcemia is important because it can be 
misdiagnosed as primary hyperparathyroidism 



and result in unnecessary parathyroid surgery. 
Patients with FHH often do not have clinical 
sequelae of excessive PTH activity such as hyper- 
parathyroid bone disease or mental status 
changes. The presence of hypercalcemia in family 
members, a lack of previously normal serum cal- 
cium measurements, and low urinary calcium 
suggest familial hypocalciuric hypercalcemia. 
Some authors advocate using the fractional excre- 
tion (FE) of calcium to distinguish FHH from pri- 
mary hyperparathyroidism with values below 1% 
suggestive of FHH. This is not recommended, 
however, given that 25% of patients with primary 
hyperparathyroidism have a fractional excretion 
of calcium below 1%. 

Increased renal calcium reabsorption contributes 
to the hypercalcemia of primary hyperparathy- 
roidism and malignancy. Thiazide diuretics cause 
hypercalcemia due to increased distal tubular cal- 
cium reabsorption. Most reported cases, however, 
have also had associated parathyroid adenomas. 



Key Points 

Etiology of Hypercalcemia 



1. Hypercalcemia results from increased GI 
calcium absorption, increased bone release 
of calcium, and/or decreased renal calcium 
excretion. 

2. Of the three pathophysiologic mechanisms 
increased bone resorption is most common 
and important. 

3. Hypercalcemia from increased GI calcium 
absorption rarely occurs in the absence of 
decreased renal function. 

4. The most common causes of increased bone 
calcium release are primary hyperparathy- 
roidism and malignancy. 



Signs and Symptoms 

As is the case for many electrolyte disorders the 
severity and rate of rise of the serum calcium 



150 



Chapter 10 



Disorders of Serum Calcium 



concentration determine the extent of clinical 
signs and symptoms. Patients with primary hyper- 
parathyroidism present with mild asymptomatic 
hypercalcemia incidentally discovered on routine 
laboratory examination. 

Severe hypercalcemia is associated with promi- 
nent neurologic and GI symptoms. Central nervous 
system symptoms range from confusion to stupor 
and coma. Seizures can occur as a result of severe 
vasoconstriction and transient high intensity signals 
have been documented by magnetic resonance 
imaging (MRI) that resolve with return of serum 
calcium concentration to the normal range. Focal 
neurologic symptoms mimicking a transient ischemic 
attack although rare were described. Gastrointestinal 
symptoms are related primarily to decreased 
gastrointestinal motility that results in nausea, vomit- 
ing, constipation, and obstipation. Hypercalcemia- 
induced pancreatitis can cause epigastric pain. As will 
be discussed, hypercalcemia decreases expression of 
renal water channels resulting in polyuria that leads to 
ECF volume depletion, decreased renal blood flow, 
and decreased renal function. Hypercalcemia predis- 
poses to digitalis toxicity. 



Key Points 

Signs and Symptoms of Hypercalcemia 



Hypercalcemia presents with a wide range 

of neurologic and GI symptoms. 

Acute renal failure secondary to prerenal 

azotemia is commonly associated with 

hypercalcemia. 



Diagnosis 

Primary hyperparathyroidism and malignancy are 
by far the most frequent causes of hypercalcemia 
making up more than 90% of all cases. Initial eval- 
uation of the hypercalcemic patient includes a care- 
ful history and physical examination. Of patients 
with primary hyperparathyroidism about 20% have 
signs and symptoms of disease such as kidney 



stones, neuromuscular weakness, decreased ability 
to concentrate, depression, or bone disease. One 
should inquire carefully about use of calcium sup- 
plements, antacids, and vitamin preparations. A 
recent chest radiograph is essential to exclude lung 
cancers and granulomatous diseases. In patients 
with primary hyperparathyroidism skeletal ra- 
diographs are rarely positive in the present era. 
Bone densitometry, however, is commonly abnor- 
mal. Since primary hyperparathyroidism involves 
cortical more than cancellous bone, bone density is 
reduced to the greatest degree in the distal radius. 
Areas where cancellous bone predominates such 
as the spine and hip show less of a decrease. 

Initial laboratory studies include serum elec- 
trolytes, BUN, creatinine, phosphorus, serum and 
urine protein electrophoresis, and a 24-hour urine 
collection for calcium and creatinine. A ratio of 
serum chloride to serum phosphorus concentra- 
tions of greater than 33:1 is suggestive of primary 
hyperparathyroidism. This results from decreased 
proximal tubular phosphate reabsorption induced 
by PTH. Laboratory hallmarks of milk-alkali syn- 
drome are a low serum chloride, high serum 
bicarbonate, and elevated serum BUN and creati- 
nine concentrations. A monoclonal gammopathy 
on serum or urine protein electrophoresis sug- 
gests multiple myeloma. If the diagnosis of multi- 
ple myeloma is suspected on clinical grounds, it is 
important to perform immunofixation elec- 
trophoresis (IFE) on both blood and a 24-hour 
urine sample in order to exclude the diagnosis. In 
primary hyperparathyroidism and HHM serum 
phosphorus concentration is often low. In hyper- 
calcemia resulting from milk-alkali syndrome, thi- 
azide diuretics, and FHH 24-hour urinary calcium 
excretion will be low. 

Primary hyperparathyroidism is generally the 
cause in asymptomatic outpatients with a serum cal- 
cium concentration below 11 mg/dL. Malignancy is 
the most common cause in symptomatic patients 
with serum calcium concentration above 14 mg/dL. 
Factors favoring the diagnosis of primary hyper- 
parathyroidism include a prolonged history, devel- 
opment in a postmenopausal woman, a normal 
physical examination, and evidence of MEN. 



Chapter 10 



Disorders of Serum Calcium 



151 



After initial evaluation, an intact PTH concen- 
tration is obtained. Primary hyperparathyroidism 
is the most common cause of an elevated PTH. 
PTH concentration is generally 1.5-2.0 times the 
upper limit of normal. Some patients may have 
mildly elevated serum calcium concentration with 
a PTH concentration that is in the upper range of 
normal (inappropriately elevated). Others may 
have a serum calcium concentration in the upper 
quartile of the normal range and a slightly elevated 
PTH concentration. Both of these subgroups of 
patients were demonstrated to have parathyroid 
adenomas. An elevated PTH concentration may 
also be seen rarely with lithium and FHH. If the 
patient is on lithium and it can be safely discontin- 
ued PTH concentration should be remeasured in 
1-3 months. In all other etiologies of hypercal- 
cemia, PTH is suppressed. PTHrP is immunologi- 
cally distinct from PTH and specific assays are 
commercially available. C-terminal fragment 
PTHrP assays may be increased in pregnancy and 
in patients with kidney disease. 

If malignancy is not obvious and PTH concen- 
tration is suppressed, one needs to rule out vitamin 
D intoxication or granulomatous diseases by meas- 
uring calcidiol and calcitriol concentrations. 
Ingestion of vitamin D or calcidiol will result in an 
increased calcidiol concentration and often mild to 
moderately elevated calcitriol concentration. 
Elevated calcitriol concentrations are observed 
with ingestion of calcitriol and in those diseases 
where stimulation of 1-a-hydroxylase occurs 
including granulomatous diseases, lymphoma, and 
primary hyperparathyroidism. If hyperthyroidism 
is suspected, thyroid function tests are obtained. 



Key Points 

Diagnosis of Hypercalcemia 



1. Primary hyperparathyroidism and malig- 
nancy comprise 90% of all cases of hyper- 
calcemia. 

2. Primary hyperparathyroidism is most often 
secondary to a parathyroid adenoma. 



Hypercalcemia is mild, asymptomatic, and 
detected on routine laboratory testing. 

3. Hypercalcemia of malignancy is severe, 
symptomatic, and carries a poor prognosis. 
It is commonly causeci by production of 
PTHrP, a peptide similar but not identical to 
PTH. 

4. After a careful history, physical, and initial 
laboratory evaluation patients are further 
characterized based on PTH and PTHrP 
concentrations. 



Treatment 

Treatment of hypercalcemia will depend on the 
degree of elevation of serum calcium concentra- 
tion and is directed at increasing renal excretion, 
blocking bone resorption, and reducing intestinal 
absorption. 

The first step to enhance renal calcium excre- 
tion is expansion of the ECF volume; subse- 
quently, loop diuretics are added with the goal of 
maintaining urine flow rate at 200-250 mL/hour. 
The hypercalcemic patient is invariably volume 
contracted. Hypercalcemia causes arteriolar vaso- 
constriction and reduces renal blood flow. 
Calcium acts directly in the thick ascending limb 
of Henle to decrease sodium reabsorption and 
reduce the driving force for calcium reabsorption. 
Hypercalcemia also antagonizes the effects of 
antidiuretic hormone in collecting duct. The sub- 
sequent volume contraction that results increases 
proximal sodium and calcium reabsorption and 
further increases serum calcium concentration. 
With chronic kidney disease higher doses of 
loop diuretics are needed. If glomerular filtration 
rate (GFR) is low and hypercalcemia severe 
(>17 mg/dL), hemodialysis may be indicated. 
Hemodialysis is also helpful in patients with neu- 
rologic impairment or in those with concomitant 
congestive heart failure. Volume expansion and 
loop diuretics alone may be sufficient in the 
patient with mild-to-moderate hypercalcemia 
(<12.5 mg/dL). 



152 



Chapter 10 



Disorders of Serum Calcium 



When hypercalcemia is moderate or severe 
bone calcium resorption must be inhibited. In the 
short term, calcitonin is used because of its rapid 
onset ("within a few hours). The usual dose is 
4 IU/kg subcutaneously every 12 hours. It not only 
inhibits bone resorption but also increases cal- 
cium excretion by the kidney. Its effect, however, 
is not large and serum calcium concentration is 
reduced by only 1-2 mg/dL. Another downside is 
tachyphylaxis that develops with repeated use. 
Therefore, another agent that decreases bone 
resorption in addition to calcitonin should be 
used. 

Bisphosphonates are the drug of choice to 
inhibit bone resorption. Their effects are additive 
to calcitonin. Bisphosphonates are concentrated 
in bone where they interfere with osteoclast for- 
mation, recruitment, activation, and function. 
Bisphosphonates have a long duration of action 
(weeks) but their disadvantage is that they have a 
slow onset (48-72 hours). Pamidronate is cur- 
rently the most commonly used bisphosphonate 
to treat hypercalcemia. Sixty or ninety mg is given 
intravenously over 4 hours. The dose varies 
depending on the degree of hypercalcemia (60 mg 
when calcium concentration <13-5 mg/dL, 90 mg 
when calcium concentration >13.5 mg/dL). Serum 
calcium concentration slowly falls over days. A 
single dose lasts 7-14 days. In general serum cal- 
cium concentration will normalize within 7 days. 
Pamidronate use is not recommended in those 
with severe decreases in GFR. Renal toxicities of 
bisphosphonates include focal sclerosis with 
pamidronate and acute renal failure with zolen- 
dronate and pamidronate. 

Mithramycin cannot be used in patients with 
severe liver, kidney, or bone marrow disease. Its 
onset of action is 12 hours with a peak effect at 
48 hours. Due to its severe side-effect profile (hepa- 
totoxicity, proteinuria, thrombocytopenia, and GI 
upset) mithramycin is rarely used. The dose is 
25 |-tg/kg intravenously over 4 hours daily for 
3-4 days. In one study hepatotoxicity was noted in 
26% of patients, nausea and vomiting in 23%, as 
well as bleeding tendencies due to abnormalities in 
several coagulation factors and platelet dysfunction. 



Gallium nitrate also inhibits bone resorption. 
Gallium accumulates in metabolically active 
regions of bone. It reduces bone resorption by 
inhibiting the H + ATPase in the ruffled membrane 
of osteoclasts and blocking osteoclast acid secre- 
tion. It has been used to treat hypercalcemia of 
malignancy. One hundred to two hundred mg/m 2 
is given as a continuous infusion for 5 consecutive 
days. Gallium nitrate is contraindicated if the 
serum creatinine concentration is above 2.5 mg/dL. 
It is rarely used. 

Agents that decrease intestinal calcium absorp- 
tion are generally reserved for outpatients with 
mild hypercalcemia. Corticosteroids were used 
successfully in patients with vitamin D overdose, 
granulomatous diseases, and some cancers (lym- 
phomas and multiple myeloma). Ketoconazole 
and hydroxychloroquine were also employed. 
Ketoconazole reduces calcitriol concentration 
by approximately 75% via inhibition of 1-a- 
hydroxylase. Hydroxychloroquine was used in 
patients "with hypercalcemia and sarcoidosis and 
"works via a similar mechanism. Oral phosphorus 
can be tried, but is contraindicated in patients with 
an elevated serum phosphorus concentration or 
renal dysfunction. Oral phosphorus is often poorly 
tolerated (diarrhea) and reduces serum calcium 
concentration only slightly (1 mg/dL). 

Finally, whether to surgically remove a solitary 
parathyroid adenoma remains controversial. 
Suggested surgical criteria include serum calcium 
concentration more than 1 mg/dL above the 
upper limit of normal, an episode of acute symp- 
tomatic hypercalcemia, overt bone disease, corti- 
cal bone mineral density more than 2 standard 
deviations below age, sex, and race adjusted 
means, reduced renal function (more than 30%), a 
history of nephrolithiasis or nephrocalcinosis, uri- 
nary calcium excretion that exceeds 400 mg/day, 
or young age (<50 years). At least half of affected 
patients will meet these criteria. In approximately 
75% of patients who do not elect surgery, average 
serum calcium and PTH concentrations generally 
do not change. In the remaining 25%, however, 
signs and symptoms worsen with increasing 
hypercalcemia, hypercalciuria, and decreasing 



Chapter 10 



Disorders of Serum Calcium 



153 



bone mineral density. Patients below the age of 
50 and those with nephrolithiasis are at higher risk 
of progression. If surgery is not performed it is 
recommended that serum calcium concentration 
be monitored every 6 months and serum creati- 
nine concentration and bone mineral density 
measured yearly. 

As minimally invasive parathyroid surgery 
becomes more accepted these criteria will be 
broadened. With minimally invasive surgery ade- 
nomas are first localized with a sestamibi scan 
and/or ultrasound preoperatively and parathy- 
roidectomy is performed under local anesthesia. 
PTH assays are performed in the operating room. 
Given PTH's short half-life (4 minutes), after the 
adenoma is removed PTH concentration is mea- 
sured within minutes to verify that surgery was 
successful. If PTH concentration does not decline, 
the patient is placed under general anesthesia and 
more extensive neck exploration is performed 
looking for a second adenoma. Up to 5% of patients 
may have a previously undetected second ade- 
noma. In patients whose surgery is successful the 
rate of kidney stone formation declines. Over the 
next several years bone density often increases in 
hip and back but not in the distal third of the 
radius. Patients treated medically "with bisphos- 
phonates can have some increase in vertebral 
bone density but serum PTH concentrations 
remain elevated. Calcium-sensing receptor ago- 
nists can normalize serum calcium concentration 
but in studies of up to 3 years duration bone den- 
sity does not increase. 



Key Points 



Treatment of Hypercalcemia 



Initial therapy of hypercalcemia is directed 
at ECF volume expansion. 
After ECF volume is expanded a loop 
diuretic is added to increase renal calcium 
excretion. 

If hypercalcemia is moderate-to-severe addi- 
tional measures are required. Drugs that 



reduce calcium release from bone are 
added. The drug of choice in the short term 
is calcitonin and in the long term is the bis- 
phosphonate pamicironate. 
In special circumstances mithramycin, gal- 
lium nitrate, or hemodialysis may be 
required. 




Pathophysiologic Mechanisms 

Hypocalcemia results from decreased intestinal 
calcium absorption or decreased bone resorp- 
tion. Since there is a large reservoir of calcium in 
bone, sustained hypocalcemia can only occur if 
there is an abnormality of PTH or calcitriol effect 
in bone. 

Total serum calcium is comprised of three 
components: an ionized or free fraction; calcium 
complexed with anions; and bound to proteins. 
True hypocalcemia results only when the ion- 
ized calcium fraction is decreased (about half of 
total serum calcium concentration). Normal 
range for ionized calcium concentration is 
4.2-5.0 mg/dL or 1.05-1.25 mmol/L. The first 
step in evaluation of a low total serum calcium 
concentration is to attempt to determine "whether 
the ionized fraction is reduced. One way to 
address this question is to compare the total 
serum calcium concentration to the serum albu- 
min concentration. As a general rule of thumb 
for every 1 g/dL decrease in serum albumin con- 
centration from its normal value (4 g/dL), one 
can expect a 0.8 mg/dL decrement in total serum 
calcium concentration. For every 1 g/dL fall in 
serum albumin concentration, 0.8 mg/dL must 
be added to the total serum calcium concentra- 
tion to correct it for the degree of hypoalbu- 
minemia. Prediction of ionized calcium from 



154 



Chapter 10 



Disorders of Serum Calcium 



albumin-corrected total calcium concentration 
should be done with caution. This correction may 
be unreliable in certain patient populations such 
as the critically ill trauma patient. 

Calcium binding to albumin is also affected by 
pH. As pH decreases, ionized calcium will increase 
and vice versa. This effect is fairly minor and ion- 
ized serum calcium concentration will only 
increase 0.2 mg/dL for each 0.1 decrease in pH. If 
clinical suspicion of true hypocalcemia is high 
then ionized calcium concentration should be 
measured directly. 

True hypocalcemia is the result of either 
decreased PTH secretion or vitamin D concentra- 
tion or end-organ resistance. Less commonly, 
hypocalcemia results from either extravascular cal- 
cium deposition or intravascular calcium binding. 
Extravascular deposition occurs with pancreatitis, 
"hungry bone syndrome" postparathyroidectomy, 
or tumor lysis syndrome. Intravascular calcium 
binding was reported with foscarnet use (pyro- 
phosphate analogue) and after massive transfusion 
(citrate) usually in the presence of hepatic or renal 
failure. The most common etiologies of true 
hypocalcemia grouped by their pathophysiologic 
mechanisms are illustrated in Table 10.2. 



Key Points 

Pathophysiologic Mechanisms of Hypocalcemia 



Table 10.2 



Etiologies of Hypocalcemia 



1. True hypocalcemia results from decreased 
GI calcium absorption, decreased bone 
resorption or, less commonly, acute shift of 
calcium out of ECF or calcium binding 
within the intravascular space. 

2. Given the large reservoir of calcium in bone, 
sustained hypocalcemia cannot occur with- 
out an abnormality of PTH or calcitriol 
action in bone. 

3. When interpreting total serum calcium con- 
centration one needs to take into account 
the serum albumin concentration and sys- 
temic pH. 



Decreased PTH action or effect 

Hypomagnesemia 
Decreased PTH secretion 

Postsurgical 

Polyglandular autoimmune syndrome (type I) 

Familial hypocalcemia 

Infiltrative disorders 
End-organ resistance to PTH 

Pseudohypoparathyroidism (type I and II) 
Defects in vitamin D metabolism 
Nutritional 
Malabsorption 
Drugs 

Liver disease 
Renal disease 

Vitamin D-dependent rickets 
Shift of calcium out of the ECF 
Acute pancreatitis 
Hungry bone syndrome 
Tumor lysis syndrome 
Miscellaneous 
Osteoblastic metastases 
Toxic shock syndrome 
Sepsis 
Pseudohypocalcemia 



Abbreviations: PTH, parathyroid hormone; ECF, extracellular fluid. 



Etiology 

Hypoparathyroidism is caused by several acquired 
and inherited disorders resulting from decreased 
PTH synthesis or release, or resistance to PTH 
action. Polyglandular autoimmune syndrome type I 
is the most common cause of idiopathic hypo- 
parathyroidism. Chronic mucocutaneous can- 
didiasis and primary adrenal insufficiency are also 
part of the spectrum of this disease. Mucocutaneous 
candidiasis presents in early childhood and 
involves skin and mucous membranes without 
systemic spread. This is subsequently followed 



Chapter 10 



Disorders of Serum Calcium 



155 



by hypoparathyroidism after several years. Adrenal 
insufficiency generally develops last with an onset 
in adolescence. Up to half of these patients have 
antibodies directed against the calcium-sensing 
receptor. Mutations in the AIRE gene (autoimmune 
regulator), which is a transcription factor, cause 
the disease. Affected patients are at risk for devel- 
oping other autoimmune disorders including per- 
nicious anemia, vitiligo, hypothyroidism, hepatitis, 
and type I diabetes mellitus. 

Familial hypocalcemia is the result of autoso- 
mal dominant activating mutations in the calcium- 
sensing receptor resulting in a receptor that is 
more sensitive to ECF ionized calcium concen- 
tration. Two patients were described with 
autoantibodies that activate the calcium-sensing 
receptor. One patient had Graves's disease and 
the other Addison's disease. In a cell culture 
system these antibodies bound the receptor, acti- 
vated second messenger systems, and sup- 
pressed PTH secretion. In patients "with end-stage 
renal disease that undergo parathyroidectomy for 
secondary or tertiary hyperparathyroidism, rem- 
ineralization of bone (hungry bone syndrome) 
may result in acute hypocalcemia. With surgical 
removal of a parathyroid adenoma, transient 
hypocalcemia may result due to suppression 
of normal gland function by the adenoma. 
Hypocalcemia can occur after thyroid surgery 
and may be either transient (11.9%) or permanent 
(0.9%). Patients undergoing central lymph node 
dissection for thyroid cancer are at high risk. 
Hypocalcemia or hypophosphatemia that per- 
sists for 1 week despite calcium replacement are 
risk factors for permanent hypoparathyroidism. 
Infiltrative disorders (hemochromatosis and 
Wilson's disease) and infection with HIV can 
cause hypoparathyroidism. 

The most common etiology of decreased PTH 
secretion and/or effect is severe Hypomagne- 
semia. Hypomagnesemia decreases PTH secre- 
tion, as well as results in end-organ resistance to 
PTH. End-organ resistance begins to occur at 
serum magnesium concentration <1.0 mg/dL. 
More severe hypomagnesemia (serum magnesium 



concentration <0.5 mg/dL) is required to decrease 
PTH secretion. Patients with hypocalcemia sec- 
ondary to hypomagnesemia will not respond to 
calcium or vitamin D replacement until the mag- 
nesium deficit is replaced. It often takes several 
days after magnesium is corrected for serum cal- 
cium concentration to return to normal. 

Rare genetic disorders can cause PTH end- 
organ resistance (pseudohypoparathyroidism 
types I and II). Pseudohypoparathyroidism is sub- 
divided based on whether nephrogenous cyclic 
AMP (cAMP) increases in response to PTH admin- 
istration (Ellsworth-Howard test). In type II there 
is a normal response and in type I there is a 
decreased response. In type I the mutation arises 
in the Gsocl protein of the adenylate cyclase com- 
plex. Parathyroid hormone binds to its receptor 
but cannot activate adenylate cyclase. The defect 
in type II is due to resistance to the intracellular 
effects of cyclic AMP and the mutation has yet to 
be identified. Some patients with type II disease 
will respond to theophylline. 

Disorders of vitamin D metabolism are impor- 
tant causes of hypocalcemia. A wide variety of dis- 
orders can interfere with this complex pathway 
including decreased vitamin D intake, GI malab- 
sorption, drugs, liver disease, renal disease, and 
vitamin D-dependent rickets. Despite the fact that 
milk is supplemented with vitamin D in the United 
States one study of noninstitutionalized adults 
showed that 9% had low 25(OH) vitamin D^ con- 
centration. Patients who are poorly nourished 
with little sunlight exposure, as well as the institu- 
tionalized elderly, are at particular risk. Post- 
menopausal women and adolescents are also at 
increased risk. Vitamin D deficiency may result 
from GI malabsorption given that vitamin D is a 
fat-soluble vitamin. Anticonvulsant drugs induce 
the cytochrome P450 system and increase metab- 
olism of vitamin D. It is likely, however, that anti- 
convulsants cause hypocalcemia via a variety of 
other mechanisms as well, including direct inhi- 
bition of bone resorption, impaired GI calcium 
absorption, and resistance to PTH. Vitamin D 
deficiency results from severe parenchymal liver 



156 



Chapter 10 



Disorders of Serum Calcium 



disease since one of the steps involves hydroxy- 
lation in the liver. Chronic kidney disease impairs 
1-a-hydroxylation, the final step in the formation 
of calcitriol. Vitamin D-dependent rickets exists 
in two forms. Type I is caused by impaired 1-a- 
hydroxylation of calcidiol to calcitriol. Since end- 
organ response is intact type I patients respond 
to calcitriol. Type II disease is caused by inacti- 
vating mutations in the vitamin D receptor and 
results in end-organ resistance to calcitriol. Serum 
calcitriol concentration is elevated in these 
patients and they respond poorly to supplemental 
calcitriol. 

Other causes of hypocalcemia include tumor 
lysis syndrome, hyperphosphatemia, acute pancre- 
atitis, and sepsis. Ionized hypocalcemia is common 
in patients in the intensive care unit (ICU) occur- 
ring in up to one-third to two-thirds and many of 
these are septic. Hypocalcemia is an independent 
predictor of increased mortality in the ICU. The 
mechanism of hypocalcemia in sepsis is unknown. 
Postulated mechanisms include a decrease in PTH 
concentration, decreased calcitriol concentration, 
and peripheral resistance to PTH action. 

Pseudohypocalcemia was reported after mag- 
netic resonance angiography. Gadolinium, used 
as a contrast agent in the procedure, interferes 
with some assays used to measure serum calcium 
concentration. The effect is short lived but can 
result in very low spurious calcium determinations 
(decreases of 3 mg/dL or more). The patients, as 
expected, exhibit no symptoms. 



Key Points 

Etiology of Hypocalcemia 



1. Hypoparathyroidism results from decreased 
synthesis, release, or peripheral tissue resis- 
tance to PTH. 

2. The most common cause of idiopathic 
hypoparathyroidism is polyglandular 
autoimmune syndrome type I. It manifests 
with hypoparathyroidism, adrenal insuffi- 
ciency, and mucocutaneous candidiasis. 



3. Severe hypomagnesemia is the most 
common cause of hypoparathyroidism. 

4. Disorders of vitamin D metabolism such as 
nutritional deficiency, liver disease, anticon- 
vulsant use, and chronic kidney disease are 
important causes of hypocalcemia. 



Signs and Symptoms 

The degree of hypocalcemia and rate of decline 
of the serum calcium concentration determine 
whether hypocalcemic symptoms occur. The 
point at which symptoms occur depends on mul- 
tiple factors including pH, and whether other 
electrolyte abnormalities are present (hypo- 
magnesemia and hypokalemia). Symptoms 
are primarily those of enhanced neuromuscular 
activation. Circumoral and distal extremity 
paresthesias are common complaints, as is car- 
popedal spasm. Altered mental status, irritability, 
and seizures may also occur. Hypotension, 
bradycardia, and laryngospasm may be present 
on physical examination. One should test for the 
presence of Chvostek's and Trousseau's sign. 
Chvostek's sign is brought out by gently tapping 
just below the zygomatic arch over the facial 
nerve with the mouth slightly open. A positive 
sign, which is a facial twitch, is occasionally 
observed in normal patients. To test for 
Trousseau's sign a blood pressure cuff is inflated 
to 20 mmHg above systolic pressure for 3 minutes. 
A positive sign is flexion of the wrist, metacar- 
pophalyngeal joints, and thumb with hyperex- 
tension of the fingers. 



Key Points 

Signs and Symptoms of Hypocalcemia 



1 . Signs and symptoms depend on the degree 
and rate of decline of serum calcium con- 
centration. 



Chapter 10 



Disorders of Serum Calcium 



157 



4. 



The serum calcium concentration at which 
symptoms develop varies depending on the 
presence or absence of other associated 
electrolyte or acid-base disturbances. 
Symptoms of neuromuscular excitability 
predominate. 

On physical examination one should look 
for the presence of Chvostek's and 
Trousseau's signs. 



Diagnosis 

An algorithm for the differential diagnosis of 
hypocalcemia is shown in Figure 10.4. Common 
causes are hypomagnesemia (most common), 
chronic kidney disease, and vitamin D deficiency. 
When total serum calcium concentration is low one 
first evaluates the serum albumin concentration and, 
if necessary, measures ionized serum calcium con- 
centration. After the presence of true hypocalcemia 



Figure 10.' 



I Decreased total serum calcium concentration! 

I 



Adjust for serum albumin or measure ionized calcium 



Normal 
no action 



Low 
True hypocalcemia 

, I , 

|Serum magnesium| 

J 



Normal 



|Serum phosphorus! 



High 
|PTH| 

/ \ 

High Low 



Low 

Determine cause 
Replace magnesium 



Low 



Calcidiol, calcitriol 



Tumor lysis syndrome Hypoparathyroidism Calcidiol 

Pseudohypoparathyroidism low 

Renal failure Nutritional 

Malabsorption 
Drugs 



Calcidiol normal Calcitriol 

Calcitriol low high 

Type I vitamin D Type II vitamin D 
dependent rickets dependent rickets 
Renal failure 



Evaluation of the hypocalcemic patient. After adjusting for serum albumin concentration one evaluates serum 
magnesium concentration. Patients are further subdivided based on serum phosphorus, PTH, and calcidiol and 
calcitriol concentrations. (With permission from Schrier, R.W. (ed.). Manual of Nephrology. Lippincott Williams 
& Wilkins, Philadelphia, PA, 2000.) 



158 



Chapter 10 



Disorders of Serum Calcium 



is established, blood is sent for serum BUN, creati- 
nine, magnesium, and phosphorus concentrations. 

Serum magnesium concentration is evaluated 
next. As stated previously, the most common 
cause of hypocalcemia is hypomagnesemia. 
Hypocalcemia will not correct before magnesium 
losses are replenished. 

One then examines serum phosphorus con- 
centrations. If kidney function is normal hyper- 
phosphatemia suggests hypopara-thyroidism or 
pseudohypoparathyroidism. These disorders can 
easily be differentiated by measuring PTH con- 
centration. PTH concentration is low in primary 
hypoparathyroidism due to gland failure, whereas 
with end-organ resistance as in pseudohy- 
poparathyroidism PTH concentration will be 
elevated. Pseudohypoparathyroidism is further 
subdivided by infusing PTH and subsequently 
measuring urinary phosphate and cAMP concen- 
trations. 

Disorders of vitamin D metabolism are charac- 
terized by hypophosphatemia. Hypocalcemia stim- 
ulates the parathyroid gland to secrete PTH that 
results in renal phosphate wasting. To determine 
the defect in vitamin D metabolism serum calcidiol 
and calcitriol concentrations are measured. If, on 
the other hand, the kidney is responding appro- 
priately to phosphate depletion the FE will be 
below 1%. If the FE of phosphate is high, then serum 
calcidiol and calcitriol concentrations are meas- 
ured. Calcidiol levels are low with malabsorption, 
liver disease, phenobarbital, nutritional deficiency, 
and nephrotic syndrome. Calcitriol levels are low 
with chronic kidney disease and increased in type II 
vitamin D-dependent rickets. 



Key Points 

Diagnosis of Hypocalcemia 



1 . The most common causes of hypocalcemia 
are magnesium deficiency, chronic kidney 
disease, and vitamin D deficiency. 

2. If total serum calcium concentration is 
decreased one evaluates the serum albumin 



concentration to attempt to estimate 
whether ionized calcium concentration is 
ciecreased. 

3. Hypomagnesemia is the most common 
cause of hypocalcemia. 

4. If hypomagnesemia is not present serum 
phosphorus concentration and renal phos- 
phate excretion are examined. 

5. Hyperphosphatemia in the absence of 
chronic kidney disease suggests decreased 
PTH concentration or effect. 

6. Decreased serum phosphorus concentration 
is indicative of a defect in vitamin D 
metabolism. 



Treatment 

Treatment will vary depending on the degree 
and cause of hypocalcemia. In life-threatening 
circumstances such as with seizures, tetany, 
hypotension, or cardiac arrhythmias, intra- 
venous calcium at a rate of 100-300 mg over 
10-15 minutes is administered. In general, intra- 
venous calcium should be used initially in the 
symptomatic patient or the patient with severe 
hypocalcemia (total calcium corrected for albu- 
min <7.5 mg/dL). Hypocalcemia that is mild in 
an outpatient setting is corrected with oral cal- 
cium supplementation. A vitamin D preparation 
may need to be added if the response to oral cal- 
cium is insufficient. 

If life-threatening symptoms are not present 
the administration of 15 mg/kg of elemental cal- 
cium over 4—6 hours can be expected to increase 
total serum calcium concentration by 2-3 mg/dL. 
A variety of intravenous preparations can be used 
including 10% calcium gluconate — 10 mL ampules 
(94 mg of elemental calcium), (2) 10% calcium 
gluceptate — 5 mL ampule (90 mg elemental cal- 
cium), and (3) calcium chloride — 10 mL ampule 
(272 mg elemental calcium). After the first ampule 
is administered generally over several minutes, an 
infusion is begun at 0.5-1.0 mg/kg/hour. The 
infusion rate is subsequently adjusted based on 



Chapter 10 



Disorders of Serum Calcium 



159 



serial serum calcium determinations. Magnesium 
deficits must first be corrected or treatment will be 
ineffective. In the patient who also has metabolic 
acidosis, hypocalcemia should be corrected first. 
Correction of acidosis before hypocalcemia will 
result in a further decrease in ionized calcium con- 
centration and exacerbate symptoms. 

Patients with hypoparathyroidism are often 
treated with vitamin D supplements since admin- 
istration of calcium alone is often ineffective. 
Serum calcium concentration should be main- 
tained at a level where the patient is symptom 
free. This is generally at or just below the lower 
limit of normal. An elemental calcium dose of 
1-3 g/day is usually required. Several oral prepa- 
rations can be used and are shown in Table 10.3. 
Supplements should be taken between meals to 
ensure optimal absorption. Calcium citrate is 
more bioavailable than calcium carbonate espe- 
cially in patients with increased gastric pH. If 
higher doses of elemental calcium are required, a 
vitamin D preparation should be added. In the 
presence of severe hyperphosphatemia it is advis- 
able to delay calcium supplementation until 
serum phosphorus concentration is below 6 mg/dL. 
This may not always be possible and clinical judg- 
ment must be used in the severely hypocalcemic 
patient. 

Calcitriol is the most potent vitamin D prepara- 
tion, has a rapid onset of action, a short dura- 
tion of action, but is also the most expensive. A 
dose of 0.5-1.0 |ig/day is often required. As one 
moves from calcidiol to cholecalciferol, and to 



•103 

Oral Calcium Preparations 







Elemental 




Tablet 


Calcium/Tablet 


Preparation 


(mg) 


(mg) 


Calcium carbonate 


500 


200 


Calcium citrate 


950 


200 


Calcium lactate 


650 


85 


Calcium gluconate 


1000 


90 



ergocalciferol, cost decreases and duration of 
action increases. Some of these agents, however, 
may be less efficacious in the presence of renal or 
hepatic disease. 

In hypoparathyroidism distal tubular calcium 
reabsorption is decreased due to a lack of PTH. 
The increased filtered calcium load resulting from 
calcium and vitamin D replacement can lead to 
hypercalciuria, nephrolithiasis, and nephrocalci- 
nosis. Patients with hypoparathyroidism excrete 
more calcium than normal for any given serum 
calcium concentration. If urinary calcium excre- 
tion exceeds 350 mg/day and serum calcium con- 
centration is acceptable, sodium intake should be 
restricted and if this is not effective a thiazide 
diuretic added in order to reduce urinary calcium 
excretion. 

Patients with hypocalcemia postparathyroidec- 
tomy require large doses of supplemental cal- 
cium. In this setting the serum potassium must be 
monitored carefully since for unclear reasons 
these patients are at increased risk of hyper- 
kalemia. Treatment of hypocalcemia in the setting 
of the tumor lysis syndrome is directed at lower- 
ing serum phosphorus concentration. 



Key Points 

Treatment of Hypocalcemia 



Management of the hypocalcemic patient 
depends on its severity and cause. 
Acute symptomatic hypocalcemia is treated 
with intravenous calcium. 
Of the available vitamin D preparations cal- 
citriol is the most potent, has a rapid onset 
of action, a short duration of action, but is 
also the most expensive. 
Serum calcium concentration is maintained 
at the lower limit of normal in patients 
with hypoparathyroidism to minimize 
hypercalciuria. 

If hypercalciuria develops salt restriction or 
thiazide diuretics can be employed. 



160 



Chapter 10 



Disorders of Serum Calcium 



Additional Reading 

Brown, A.J., Dusso, A., Slatopolsky, E. Vitamin D. Am 

J Physiol 277:F157-F175, 1999. 
Bushinsky, D.A. Calcium. Lancet 352:306-311, 1998. 
Fiorino, A.S. Hypercalcemia and alkalosis due to the 

milk-alkali syndrome: a case report and review. Yale 

J Biol Med 69:517-523, 1996. 
Guise, T.A., Mundy, G. Evaluation of hypocalcemia in 

children and adults. / Clin Endocrinol Metab 80: 

1473-1478, 1995. 
Mundy, G.R., Guise, T.A. Hypercalcemia of malignancy. 

AmJMedW3-.134-l45, 1997. 
Potts, J.T. Jr., Fradkin, J.E., Aurbach, J.D., Bilezikian, 

J. P., Raisz, L.G. Proceedings of the NIH consensus 



development conference on diagnosis and manage- 
ment of asymptomatic primary hyperparathyroidism. 
/ Bone Miner Res 6:S1-Sl65, 1991. 

Rankin, W., Grill, V., Martin, T.J. Parathyroid hormone- 
related protein and hypercalcemia. Cancer 80:S1564- 
S1571, 1997. 

Reber, P.M., Heath III, H.H. Hypocalcemic emergen- 
cies. Med Clin North Am 79:93-106, 1995. 

Vetter, T., Lohse, M.J. Magnesium and the parathyroid. 
Curr Opin Nephrol Hypertens 11:403-410, 2002. 

Zahrani, A. A., Levine, M.A. Primary hyperparathy- 
roidism. Lancet 349:1233-1236, 1997. 



Robert F. Reilly, Jr. 



Disorders of Serum 
Phosphorus 




Recommended Time to Complete: 1 day 



QiA+A+4*t Ql*&4t*s04~1> 



1. Of the regulators of serum phosphorus concentration, which are 
most important? 

2. What is the most common cause of hyperphosphatemia? 

Z. What are the advantages and disadvantages of various phosphate 
binders that are available for the treatment of hyperphosphatemia? 

k- How does one evaluate the hypophosphatemic patient? 

S. How well documented are the clinical consequences of hypophos- 
phatemia? 

i. Does the patient with moderate hypophosphatemia require 
phosphorus replacement? 




Regulation 



Phosphorus circulates in the bloodstream in two 
forms, an organic fraction made up primarily of 
phospholipids and an inorganic fraction. Of these 



two fractions, it is the inorganic fraction, which makes 
up approximately one-third of the total serum phos- 
phorus, that is assayed in the clinical laboratory. The 
normal range in most laboratories is 2.5-4.5 mg/dL 
(0.8-1.45 mmol/L). The majority (75%) of inorganic 
phosphorus is free in solution and exists as either 
divalent (HPOp or monovalent (H 2 POj) phosphate. 
The relative amounts of each ion depend on the 



161 



162 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



systemic pH. At pH 7.4, 80% is in the divalent form. 
Of the remainder, 15% is protein bound. A small 
fraction of inorganic phosphorus is complexed with 
calcium or magnesium. In normal individuals there 
is a diurnal variation in serum phosphorus concen- 
tration. Serum phosphorus concentration is at its 
lowest in the morning, gradually rises during the day, 
and peaks in the evening. The change in serum 
phosphorus concentration may be as much as 
1 mg/dL. Whether this diurnal variation persists in 
disease states characterized by hypophosphatemia 
is not as clear, although diurnal variation was noted 
in patients with primary hyperparathyroidism. 

The largest reservoir of phosphorus in the body 
is in the skeleton (80%). The vast majority of the 
remainder of total body phosphorus is in skeletal 
muscle and viscera with only 1% in extracellular 
fluid (ECF). Of the intracellular pool only a very 
small fraction is inorganic and can be used for 
synthesis of high-energy phosphate-containing 
molecules (adenosine triphosphate [ATP]). Phos- 
phorus homeostasis is summarized in Figure 11.1. 

Figure 11.1 



1,000 mg 
32.25 mmol 



650 mg 
21 mmol 



ECF 
700 mg 



250 mg 

8 mmol 



22.5 mmol 
5,850 mg * I 6,500 mg 
189 mmol I 210 mmol 




350 mg 
1 1.3 mmol 



600,000 mg 
19,355 mmol 



650 mg 
21 mmol 



Phosphorus homeostasis. Daily phosphorus fluxes between 
ECF, intestine, kidney, and bone are shown. In the steady 
state net intestinal absorption and renal excretion are equal. 
The majority of phosphorus in the body is in bone. (With 
permission from Schrier, R.W. (ed.). Manual of Nephrology. 
Lippincott Williams & Wilkins, Philadelphia, PA, 2000.) 



On average approximately 800-1400 mg of 
phosphorus is ingested daily. Of this total 
640-1120 mg is absorbed primarily in duodenum 
and jejunum. The majority of phosphorus absorp- 
tion in the intestine is passive but there is a small 
active component regulated by vitamin D. 

Parathyroid hormone (PTH) and calcitriol are 
important regulators of phosphorus homeostasis 
via their actions in bone, intestine, and kidney. 
Recently, a newly described molecule fibroblast 
growth factor-23 (FGF-23) was described that also 
may play a role in phosphorus homeostasis and 
will be discussed more fully below. Excretion of 
phosphate by the kidney, however, is the prime 
regulator of serum phosphorus concentration. 
The majority of phosphate is reabsorbed in the 
proximal tubule (80%). Phosphorus enters this 
cell via the sodium-phosphate cotransporter, which 
is regulated directly by PTH and serum phospho- 
rus concentration. The kidney is capable of reduc- 
ing phosphate excretion to very low levels in 
states of phosphorus depletion. Exit pathways for 
phosphate transport across the basolateral mem- 
brane of the proximal tubular cell are not well 
defined. 

Three types of sodium-phosphate cotransporters 
are expressed in the kidney (Npt-I, -II, and -III). 
Npt-II is further subdivided into three isoforms a, 
b, and c. Properties of Npt transporter isoforms 
are illustrated in Table 11.1, Phosphorus concen- 
tration and PTH regulate Npt-IIa. Npt-IIa is elec- 
trogenic and transports three sodium ions for each 
HPOp and is expressed in the proximal tubule 
of the kidney. Both PTH and exposure to high 
phosphorus concentration result in endocytic 
retrieval of Npt-IIa from the brush border mem- 
brane to small endocytic vesicles. These vesicles 
are shuttled to lysosomes by a microtubule- 
mediated process and degraded. There is little to 
no recycling back to the proximal tubular cell 
membrane once transporters are endocytosed. 
New transporters must then be resynthesized and 
routed to the apical membrane via a subapical 
compartment. Acute regulation involves changes 
in endocytic rates. Endocytosis occurs between 
microvilli at intermicrovillar clefts and involves 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



163 



Table 11.1 



Sodium-Phosphate Cotransporter Isoforms 





Phosphate 


Cellular 


Transport 


Other Transport 


ISOFORMS 


Transported (%) 


Localization 


Mode 


Functions 


Npt-I 


15 


Apical 


Electrogenic 


CI channel, organic anions 


Npt-II 


84 


Apical 






a 






Electrogenic 




b 






Electrogenic 




c 






Electroneutral 




Npt-III 


0.5 


Basolateral 


Electrogenic 





clathrin. Megalin may also play a role. It is medi- 
ated by a variety of protein kinases. This process 
is summarized in Figure 11.2. 

Npt-IIb is expressed in the brush border of 
enterocytes. It lacks the dibasic amino acid motif 
(RK) at the C-terminus of the protein that is critical 



for endocytosis and, therefore, is not regulated in 
the short term by PTH, as is Npt-IIa. The primary 
up regulators of Npt-IIb are a low phosphorus diet 
and calcitriol. Npt-IIb expression is also stimu- 
lated by estrogens and inhibited by glucocorti- 
coids and epidermal growth factor. 



re 11.2 



PTH receptor 



PTH receptor^ 




Synthesis Lysosome 



Luminal 
membrane 



Basolateral 
membrane 



Cellular model of proximal tubular phosphate transport. Sodium-phosphate 
cotransporters (Npt-IIa) are distributed along the luminal membrane 
(dark circles). In response to PTH, transporters localize to the intermi- 
crovillar region where they are endocytosed and degraded in lysosomes. 
This appears to be a unidirectional process. New transporters must be 
resynthesized and routed to the apical membrane via a subapical com- 
partment (SAC). PTH binds to receptors in both the luminal and basolat- 
eral membrane. Parathyroid hormone receptor-mediated signaling 
pathways (protein kinase A — PKA and protein kinase C — PKC) differ at 
the basolateral and luminal membranes. 



164 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



In bone, the end result of PTH action is release of 
phosphorus into the ECF. In small intestine, PTH acts 
indirectly via its stimulation of 1 a-hydroxylase to 
produce calcitriol. Calcitriol in turn stimulates phos- 
phorus absorption in the small intestine where the 
majority of phosphorus is reabsorbed. Importantly, 
in the large intestine there is a component of unreg- 
ulated secretion (100-200 mg/day) that can increase 
with diarrhea and contribute to the pathogenesis of 
hypophosphatemia. In the kidney, PTH increases 
phosphate excretion via its actions in proximal 
tubule. The end result of PTH action is to maintain 
serum calcium concentration without a concomitant 
increase in serum phosphorus concentration. 

Calcitriol on the other hand ensures that calcium 
and phosphorus are present in sufficient concen- 
tration for bone formation and it acts in concert 
with PTH to protect against hypocalcemia and 
hypophosphatemia. This is aided by the fact that 
PTH and hypophosphatemia are the main stimula- 
tors of la-hydroxylase and calcitriol production in 
proximal tubule. In the end, however, the main 
determinant of serum phosphorus concentration is 
the ability of the renal proximal tubule to excrete 
the dietary phosphorus load and conserve phos- 
phorus in the presence of hypophosphatemia. 



Key Points 

Regulation of Serum Phosphorus Concentration 



1 . Serum phosphorus consists of an organic 
and inorganic fraction; of these only the 
inorganic fraction is assayed in the clinical 
laboratory. 

2. PTH and calcitriol regulate serum phospho- 
rus concentration via effects in bone, intes- 
tine, and kidney. 

3. PTH has both direct and indirect effects on 
phosphorus homeostasis. Directly, it 
increases bone resorption and reduces reab- 
sorption of phosphate in the proximal 
tubule. It acts indirectly in the intestine via 
stimulation of 1 Of-hydroxylase with a 
resultant increase in calcitriol production. 



4. Calcitriol enhances phosphorus transport in 
the intestine and potentiates PTH effects in 
bone, which act to increase calcium and 
phosphorus entry into blood. 

5. The main determinant of serum phosphorus 
concentration is the ability of the proximal 
tubule to excrete the dietary phosphorus 
load and to conserve phosphorus in the 
presence of hypophosphatemia. 




Hyperphosphatemia 



Etiology 



Hyperphosphatemia most commonly results from 
decreased renal phosphate excretion. This occurs 
from either a decrease in the filtered load of phos- 
phate due to decreased glomerular filtration rate 
(GFR) as with acute renal failure or chronic 
kidney disease (CKD) or increased proximal tubu- 
lar phosphate reabsorption. An acute phosphorus 
load from either exogenous or endogenous 
sources can also cause hyperphosphatemia. 
Chronic kidney disease is the cause in greater than 
90% of cases. Etiologies of hyperphosphatemia 
grouped by pathophysiologic categories are 
shown in Table 11.2. 

As GFR declines below 60 mL/minute/1.73 m 2 
renal phosphorus excretion increases. Once GFR 
falls below 30 mL/minute/1.73 m 2 , however, phos- 
phate reabsorption is maximally inhibited and 
renal excretion cannot increase further. At this 
point, dietary intake will exceed renal excretion 
and serum phosphorus concentration must increase. 
A new steady state is established at a higher serum 
phosphorus concentration. Approximately 15% of 
patients with a GFR of 15-30 mL/minute/1.73 m 2 
and 50% of those with a GFR <15 mL/minute/1.73 m 2 
have a serum phosphorus concentration 
>4.5 mg/dL. 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



165 



11.2 



Etiologies of Hyperphosphatemia 



Decreased renal excretion 

Decreased glomerular filtration rate 

Acute renal failure 

Chronic kidney disease 
Increased renal phosphorus reabsorption 

Hypoparathyroidism 

Acromegaly 

Thyrotoxicosis 

Drugs — bisphosphonates 

Tumoral calcinosis 
Acute phosphorus addition to extracellular 

fluid 
Endogenous 

Tumor lysis syndrome 

Rhabdomyolysis 

Severe hemolysis 
Exogenous 

Vitamin D intoxication 

Sodium phosphate-containing bowel 
preparation solutions 

High-dose liposomal amphotericin B 

Improperly purified fresh frozen plasma 
Pseudohyperphosphatemia 



Increased renal phosphate reabsorption is an 
uncommon pathophysiologic mechanism for the 
development of hyperphosphatemia. It occurs in 
hypoparathyroidism as a result of decreased PTH 
concentration. In acromegaly insulin-like growth 
factor stimulates phosphate transport. Bisphos- 
phonates directly increase renal phosphate 
reabsorption but this effect is usually offset by 
secondary hyperparathyroidism that results from 
decreases in serum calcium concentration. Tumoral 
calcinosis is an autosomal recessive disease asso- 
ciated with hyperphosphatemia and soft tissue 
calcium deposition. The mutated gene GALNT3 
encodes a glycosyltransferase that is involved in 
O-linked glycosylation. The mechanism whereby 
this mutation increases renal phosphate reabsorp- 
tion remains unclear. 



Serum phosphorus concentration also increases 
as a result of an acute large phosphorus load. 
Phosphorus can be released from an endogenous 
source (within cells), as in tumor lysis syndrome, 
hemolysis, or rhabdomyolysis. Exogenous sources 
of phosphorus reported to cause hyperphos- 
phatemia include phosphorus-containing laxatives 
and enemas, high-dose liposomal amphotericin B 
(contains phosphatidylcholine and phosphatidy- 
lserine), and solvent detergent-treated fresh 
frozen plasma (contained improper amounts of 
dihydrogen phosphate used as a buffer in the 
purification process). Oral sodium phosphate 
solution is commonly used as a bowel prepara- 
tion agent for colonoscopy. It can be given in a 
small volume (45 mL 18 and 6 hours before the 
procedure) and is less expensive than polyethyl- 
ene glycol-based solutions. The 90 mL contains 
43.2 g of monobasic sodium phosphate and 16.2 g 
of dibasic sodium phosphate. A variety of rare 
renal complications occur with its use. Fatal 
hyperphosphatemia was reported in a renal trans- 
plant patient, serum phosphorus concentration 
17.8 mg/dL, who received a single oral dose of 
90 mL and suffered a cardiorespiratory arrest 6 hours 
later. The patient presented with nausea, vomit- 
ing, abdominal pain, and rectal bleeding. Autopsy 
showed ischemic colitis. Four other deaths were 
reported. Two of these four patients had end- 
stage renal disease and therefore, an impaired 
ability to excrete a phosphorus load. A group of 
five patients was reported with acute renal failure 
(mean serum creatinine concentration 4.9 mg/dL) 
secondary to acute nephrocalcinosis after oral 
sodium phosphate bowel cleansing. Their mean 
age was 69.2 years and mean serum creatinine 
concentration was 0.9 mg/dL before administra- 
tion of the bowel preparation. All had calcium 
phosphate precipitation in distal tubules and col- 
lecting ducts and severe tubular damage. Four 
were prescribed angiotensin converting enzyme 
inhibitors or angiotensin receptor blockers and 
two were taking diuretics. At 6 weeks renal func- 
tion was unchanged in four of the five patients. 
Another study showed that the rise in serum phos- 
phorus concentration that occurs after ingestion 



166 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



of oral sodium phosphate was directly correlated 
with patient age. When given to normal volun- 
teers ages 21 — 41 with normal renal function, oral 
phosphasoda caused a rise in serum phosphorus 
concentration to 7.6 mg/dL and a fall in serum cal- 
cium concentration to 8.4 mg/dL. There were no 
adverse clinical effects of these changes. As many 
as 37% of patients with a creatinine clearance 
greater than 70 mL/minute have an increase in 
serum phosphorus concentration to greater than 
8.0 mg/dL. Taken together these studies indicate 
that oral sodium phosphate solution should be 
used with caution in those above age 55, those 
with decreased gastrointestinal (GI) motility, 
patients with decreased glomerular filtration rates, 
and in the presence of volume depletion. 

Tumor lysis syndrome is seen classically with the 
treatment of Burkitt's lymphoma or acute lym- 
phoblastic leukemia. It is characterized by hyper- 
phosphatemia, hypocalcemia, hyperuricemia, and 
hyperkalemia following release of intracellular con- 
tents of dying malignant cells. Acute renal failure is 
a common consequence. Hyperphosphatemia 
classically occurs about 24—48 hours after onset of 
chemotherapy. Malignant lymphoid cells are 
reported to contain up to four times as much 
phosphorus as normal lymphocytes. Precipitation 
of calcium phosphate in the nephron can result in 
acute nephrocalcinosis and acute renal failure. 

Prevention of acute urate nephropathy is 
directed at reducing uric acid formation or con- 
verting it to a more soluble compound to facilitate 
its renal excretion. Purines are metabolized to 
hypoxanthine and xanthine. Xanthine is then 
converted to uric acid by xanthine oxidase, which 
can be inhibited by allopurinol. Allopurinol has a 
half-life of 0.5-2.0 hours. It is metabolized to oxy- 
purinol that also inhibits xanthine oxidase which 
is renally excreted with a half-life of 18-30 hours. 
Allopurinol must be used with caution in patients 
with decreased GFR. Uric acid can be converted 
to the more soluble sodium urate by increasing 
urinary pH to greater than 6.5 with administration 
of sodium bicarbonate. This must be done with 
caution because calcium phosphate precipita- 
tion increases at urinary pH greater than 6.5. 



Higher primates do not express urate oxidase that 
converts uric acid to the more soluble allantoin. 
Recombinant urate oxidase (rasburicase) was 
recently approved by the FDA. It cannot be used 
in patients with glucose-6-phosphate dehydroge- 
nase deficiency since hydrogen peroxide gen- 
erated during allantoin formation may cause 
hemolysis. Tumor lysis syndrome can occur in 
patients with solid tumors when there is a 
decrease in glomerular filtration rate or tumor 
burden is large. An increased lactate dehydroge- 
nase (LDH) concentration (>1500 IU), hyper- 
uricemia, large tumor burden, and high tumor 
sensitivity to treatment are predictive of the devel- 
opment of tumor lysis syndrome. 



Key Points 

Etiology of Hyperphosphatemia 



1. Hyperphosphatemia results from decreased 
renal phosphate excretion or an acute phos- 
phorus load from either exogenous or 
endogenous sources. 

2. Acute renal failure or CKD is the cause in 
the vast majority of cases. 

3. As GFR declines below 60 mL/minute/1.73 m 2 
renal phosphate excretion increases. 

4. Once GFR falls below 30 mL/minute/1.73 m 2 
phosphate reabsorption is maximally inhib- 
ited and renal phosphate excretion cannot 
increase further. 

5. Fifteen percent of patients with a GFR of 
15-30 mL/minute/1.73 m 2 and 50% of those 
with a GFR <15 mL/minute/1.73 m 2 have a 
serum phosphorus concentration >4.5 mg/dL. 



Signs and Symptoms 

Signs and symptoms of hyperphosphatemia are 
primarily the result of hypocalcemia. The most 
common explanation offered for hypocalcemia is 
that the calcium-phosphorus product exceeds a 
certain level and calcium deposits in soft tissues 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



167 



and serum calcium concentration falls. A calcium- 
phosphate product of >72 mgVdL 2 is commonly 
believed to result in this so-called "metastatic" cal- 
cification. It is difficult, however, to find the origi- 
nal studies and data on which this belief is based. 

Short-term intravenous infusion of phosphorus is 
known to depress serum calcium concentration. No 
evidence of increased soft tissue calcification was 
documented in these studies. In addition, the 
hypothesis that hypocalcemia results from soft tissue 
deposition is inconsistent with the observation that 
serum calcium concentration continues to decline 
for up to 5 days after short-term phosphorus infu- 
sion is discontinued and long beyond the time 
period when serum phosphorus concentration 
normalizes. Short-term infusions of phosphorus 
increase bone deposition of calcium and reduce 
bone resorption. Hypocalcemia can also result from 
decreased calcitriol concentration as a result of sup- 
pression of 1 a-hydroxylase by increased serum 
phosphorus. These effects may be more important 
than physicochemical precipitation. 

In patients with end-stage renal disease and 
high serum phosphorus concentration, it is being 
increasingly demonstrated that vascular calcifica- 
tion is a highly regulated process and that smooth 
muscle cells in the blood vessel wall are capable 
of transforming to an "osteoblast-like" phenotype 
and expressing what were previously believed to 
be osteoblast-specific genes. This suggests that 
hyperphosphatemia plays a direct role in vascular 
calcification and increased cardiovascular mor- 
bidity and mortality that may result. 



Key Points 

Signs and Symptoms of Hyperphosphatemia 



1 . Symptoms of an acute rise of serum phos- 
phorus concentration are related to 
hypocalcemia. 

2. Hypocalcemia may be the result of precipita- 
tion of calcium phosphate in tissues and/or 
the acute effects of hyperphosphatemia on 
bone deposition and release of calcium. 



Diagnosis 

Clinically unexplained persistent hyperphos- 
phatemia raises the suspicion of pseudohyperphos- 
phatemia, the most common cause of which is 
paraproteinemia secondary to multiple myeloma. 
No consistent relationship of immunoglobulin type 
or subclass was identified. This is a method- 
dependent artifact and paraprotein interference 
may be a general problem in some automated 
assays. The assay must be rerun with sulfosaly- 
cylic acid deproteinized serum in order to elimi- 
nate the artifact. Otherwise, the cause is generally 
acute renal failure or CKD. An algorithm for the 
differential diagnosis of hyperphosphatemia is 
shown in Figure 11.3. 



Key Points 



Diagnosis of Hyperphosphatemia 



1. Paraproteins may result in a false elevation 
of serum phosphorus concentration. 

2. Acute renal failure and CKD remain the most 
common causes of hyperphosphatemia. 



Treatment 

The cornerstone of management of the hyper- 
phosphatemic patient with CKD is reduction of 
intestinal phosphorus absorption. Early in CKD 
hyperphosphatemia can be controlled "with 
dietary phosphorus restriction. Dietary phospho- 
rus absorption is linear over a wide range of 
intakes, 4-30 mg/kg/day. Therefore, absorption 
will depend on the amount of phosphorus in the 
diet and its bioavailability. The majority of dietary 
phosphorus is contained in three food groups: 

(1) milk and related dairy products such as cheese; 

(2) meat, poultry, and fish; and (3) grains. Processed 
foods may contain large amounts of phosphorus 
and in one study an additional 1154 mg/day of 
phosphorus was ingested secondary to phosphorus- 
containing additives in fast food with no change 



168 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



Figure 11.3 











Increased serum phosphorus 




I 






BUN and creatinine 






Normal 




High 
Chronic kidney disease 
Acute renal failure 


Acute phosphorus 


load 


Increased renal reabsorption 




Exogenous 


Endogenous 


Hypoparathyroidism 




Vitamin D intoxication 


Tumor lysis syndrome 


Acromegaly 




Sodium phosphate 


Hemolysis 


Bisphosphonates 




containing bowel 


Rhabdomyolysis 


Tumoral calcinosis 




preparatons 








High dose liposomal 








amphotericin B 









Evaluation of the hyperphosphatemic patient. Serum concentrations of blood urea nitrogen (BUN) and creatinine are eval- 
uated first. Renal failure is the most common cause of hyperphosphatemia. If renal function is normal an acute phospho- 
rus load or increased renal phosphate reabsorption are likely responsible. 



in dietary protein intake. Phosphorus contained 
in plants is largely in the form of phytate and 
humans do not express the intestinal enzyme phy- 
tase that is necessary to degrade phytate and 
release phosphorus. Phosphorus in meats and 
dairy products is well absorbed. The inorganic 
salts of phosphorus contained in processed foods 
are virtually completely absorbed and patients 
with hyperphosphatemia should avoid these 
foods including hot dogs, cheese spreads, colas, 
processed meats, and instant puddings. Dietary 
estimates of phosphorus ingestion commonly 
underestimate phosphorus intake. 

As CKD worsens phosphate binders must be 
added. The optimal choice of a phosphate binder 
remains controversial. The ideal binder should 
efficiently bind phosphate, have minimal effects 
on comorbid conditions, have a favorable side 
effect profile, and be low in cost. Unfortunately, 



none of the currently available phosphate binders 
fulfill all of these criteria. Calcium-containing 
binders are low in cost but may contribute to net 
positive calcium balance and accelerate calcium 
deposition in vasculature. Aluminum-containing 
phosphate binders can be employed in the short 
term but should be avoided chronically in CKD 
patients because of aluminum toxicity (osteoma- 
lacia and dementia). Sevelamer hydrochloride, a 
synthetic calcium-free polymer, has a favorable 
side effect profile but is costly. In selecting 
between a calcium-containing binder and seve- 
lamer hydrochloride one must balance the higher 
cost of sevelamer hydrochloride against potential 
benefits of decreased vascular calcification. In 
the hyperphosphatemic patient with coexistent 
hypocalcemia it is preferable to first lower the 
serum phosphorus concentration below 6 mg/dL, 
if possible, before treating the hypocalcemia. 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



169 



Key Points 

Treatment of Hyperphosphatemia 



Table 11.3 



;ies of Hypophosphatemia 



1 . Early in CKD dietary phosphorus restriction 
alone can normalize serum phosphorus 
concentration. 

2. As GFR continues to fall phosphate binders 
must be added. 

3. The choice of the optimal phosphate binder 
remains controversial. 




Hypophosphatemia 



Etiology 

Hypophosphatemia results from one or a combi- 
nation of three basic pathophysiologic processes: 
redistribution of ECF phosphorus into intracellu- 
lar fluid (ICF); decreased intestinal phosphorus 
absorption; or increased renal phosphorus excre- 
tion. The differential diagnosis of hypophos- 
phatemia based on pathophysiologic process is 
shown in Table 11.3. 

The two most common causes of a phosphorus 
shift into cells are respiratory alkalosis and the 
"refeeding syndrome." The rise in intracellular pH 
that occurs with respiratory alkalosis stimulates 
phosphofructokinase, the rate-limiting step in gly- 
colysis and phosphorus is incorporated into ATP. 
Severe hypophosphatemia with phosphorus con- 
centrations less than 0.5-1.0 mg/dL is common. In 
1 1 normal volunteers hyperventilation to a PaC0 2 
of 13-20 mmHg caused a fall in serum phos- 
phorus concentration within 90 minutes from a 
mean of 3-1 mg/dL to 0.8 mg/dL. At the same time 
phosphate excretion in urine dropped to near 
zero. Hypophosphatemia "was reported with a rise 
in pH even within the normal range in ventilated 
chronic obstructive pulmonary disease (COPD) 
patients. In concert with the pH rise that occurs 



Decreased net GI absorption 

Decreased dietary intake 

Phosphate-binding agents 

Alcoholism 

Shift into intracellular fluid 

Respiratory alkalosis 

Refeeding 

Diabetic ketoacidosis 

Hungry bone syndrome 

Sepsis 

Increased renal excretion 

Primary hyperparathyroidism 

Secondary hyperparathyroidism from vitamin D 

deficiency 
X-linked hypophophatemic rickets 
Autosomal dominant hypophosphatemic rickets 
Oncogenic osteomalacia 
Fanconi's syndrome 
Osmotic diuresis 
Partial hepatectomy 
Pseudohypophosphatemia 



after intubation, serum phosphorus concentration 
falls over the span of several hours. 

With refeeding, the time of onset of hypophos- 
phatemia depends on the degree of malnutrition, 
caloric load, and amount of phosphorus in the for- 
mulation. In undernourished patients it develops 
in 2-5 days. It was reported with enteral as well as 
parenteral refeeding. The fall is more marked in 
patients with liver disease. In adolescents with 
anorexia nervosa the decline in serum phospho- 
rus concentration was directly proportional to the 
percent loss of ideal body weight. Serum phos- 
phorus concentration generally does not decline 
below 0.5 mg/dL with glucose infusion alone. 
Carbohydrate repletion and insulin release enhance 
intracellular uptake of phosphorus, glucose, and 
potassium. The combination of total body phos- 
phorus depletion from decreased intake and 
increased cellular uptake during refeeding leads 



170 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



to profound hypophosphatemia. Phosphorus also 
moves into cells with treatment of diabetic ketoaci- 
dosis, and in the "hungry bone syndrome" that 
occurs after subtotal parathyroidectomy for 
secondary hyperparathyroidism in patients 
with end-stage renal disease. Renal phosphate 
loss from osmotic diuresis also contributes to the 
hypophosphatemia of DKA. In "hungry bone syn- 
drome" serum calcium and phosphorus concen- 
tration often fall abruptly in the immediate 
postoperative period. From a clinical standpoint 
hypocalcemia is the more important management 
issue. Catecholamines and cytokines may also 
cause a phosphorus shift into cells and this may 
be the mechanism whereby sepsis results in 
hypophosphatemia. 

Decreased GI absorption alone is an uncom- 
mon cause of hypophosphatemia since dietary 
phosphorus intake invariably exceeds GI losses 
and the kidney is extraordinarily effective at con- 
serving phosphorus. Decreased dietary intake 
must be combined with phosphate binder use or 
increased GI losses as with diarrhea. In Banter's 
original description of diet-induced hypophos- 
phatemia 75-100 days of a low phosphorus diet 
and phosphate-binding antacids were required 
before symptoms developed. The primary symp- 
tom was musculoskeletal weakness that resolved 
with phosphorus replacement. Steatorrhea and 
malabsorption can result in calcitriol deficiency, 
secondary hyperparathyroidism, and increased 
renal excretion of phosphate. 

Increased renal phosphate excretion is seen in 
primary hyperparathyroidism, as well as secondary 
hyperparathyroidism from disorders of vitamin D 
metabolism. In primary hyperparathyroidism the 
serum phosphorus concentration is rarely below 
1.5 mg/dL. Although PTH increases renal phos- 
phate excretion, this is partially offset by PTH action 
to increase calcitriol that in turn increases GI phos- 
phoms absorption. On the other hand, secondary 
hyperparathyroidism from calcitriol deficiency may 
be associated with severe hypophosphatemia if the 
patient has normal renal function. 

Three rare diseases associated with isolated 
renal phosphate wasting deserve further discus- 
sion because their pathogenic mechanism was 



recently elucidated. These include X-linked hypo- 
phosphatemia (XLH), autosomal dominant hypo- 
phosphatemic rickets (ADHR), and oncogenic 
hypophosphatemic osteomalacia. XLH is an X- 
linked dominant disorder with a prevalence of 
1:20,000. It is manifested by growth retardation, 
rickets, hypophosphatemia, renal phosphate 
wasting, and a low serum calcitriol concentration. 
XLH is caused by mutations in the PHEX (phos- 
phate regulating gene with homology to endopep- 
tidases) gene. PHEX is a member of the M13 family 
of metalloproteinases. The gene is expressed in 
bones, teeth, and the parathyroid gland but not in 
the kidney. In bone, PHEX is expressed in the cell 
membrane of osteoblasts and plays a role in 
osteoblast mineralization. The mutated protein is 
not expressed in the cell membrane and is 
degraded in endoplasmic reticulum. How a defect 
in a membrane protein expressed in osteoblasts 
results in renal phosphate wasting is unclear. 
PHEX may play a role in the activation or inactiva- 
tion of peptide factors involved in skeletal mineral- 
ization, renal phosphate transport, and vitamin D 
metabolism. 

Subsequently, the genetic defect responsible for 
autosomal dominant hypophophatemic rickets 
(ADHR) was identified. ADHR has a similar pheno- 
type to XLH but is inherited in an autosomal domi- 
nant fashion with variable penetrance. Mutations 
in a novel fibroblast growth factor, FGF-23, cause 
ADHR. FGF-23, a 251-amino acid protein, is secreted 
and inactivated at a cleavage site into N- and C- 
terminal fragments. Mutations in ADHR occur at 
the proteolytic site and prevent cleavage. 

Oncogenic hypophosphatemic osteomalacia 
(OHO) is caused by overproduction of FGF-23 by 
mesenchymal tumors. The tumor is often difficult 
to localize. Overproduction of FGF-23 results in 
hypophosphatemia, renal phosphate wasting, sup- 
pression of la- hydroxylase, and osteomalacia. 
Tumor resection is curative. Immunohistochemical 
staining of these tumors shows an overabundance 
of FGF-23. 

FGF-23 can be detected in the circulation of 
healthy individuals suggesting it plays a role in 
normal phosphorus homeostasis. When adminis- 
tered to animals FGF-23 causes hypophosphatemia, 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



171 



increased renal phosphate excretion, suppression 
of l,25(OH) 2 vitamin D 3 , and osteomalacia. 
Biologic activity of FGF-23 is limited to the full- 
length molecule and it is degraded by protease 
cleavage. In ADHR missense mutations in FGF-23 
occur at the cleavage site and prevent its proteo- 
lysis. The enzyme responsible for FGF-23 cleavage 
is unknown. One report suggested that it was 
cleaved by PHEX but this was not confirmed in 
subsequent studies. 

XLH is the result of inactivating mutations of 
PHEX. PHEX belongs to a family of zinc-dependent 
proteases that cleave small peptides. The substrate 
of PHEX is unknown. Some authors have postu- 
lated that FGF-23 is the substrate of PHEX; how- 
ever, its large size (251 amino acids) makes this 
unlikely. More recent studies indicate that FGF-23 
is likely cleaved by subtilisin-like proprotein con- 
vertases. It is more likely that other small molecular 
weight intermediates link PHEX and FGF-23. Renal 
phosphate wasting also occurs in the immediate 
postoperative period after partial hepatectomy. 
The mechanism is unclear. Serum FGF-23 concen- 
trations in these patients are normal. 

FGF-23 when injected into experimental 
animals reduces calcitriol concentration within 
3 hours. This occurs as a result of decreased cal- 
citriol synthesis (decreased expression of \a- 
hydroxylase) and increased degradation (increased 
expression of 24-hydroxylase). Serum phosphorus 
concentration and Npt-IIa fall after 9-13 hours. 
This effect occurs in parathyroidectomized ani- 
mals indicating that it is PTH-independent. It is 
likely that only a part of the phosphaturic effect of 
FGF-23 is related to decreased calcitriol concen- 
tration. Injection of calcitriol into mice results in 
an increase in FGF-23 concentration and FGF-23 
knockout mice have high serum calcitriol concen- 
trations. Taken together these studies indicate that 
FGF-23 plays a central role in feedback regulation 
of calcitriol concentration. 

Fanconi's syndrome is characterized by renal 
phosphate wasting, glycosuria in the face of a 
normal serum glucose, and aminoaciduria. A vari- 
ety of inherited diseases are associated with 
Fanconi's syndrome including cystinosis, Wilson's 
disease, hereditary fructose intolerance, and 



Lowe's syndrome. Acquired causes include mul- 
tiple myeloma, renal transplantation, and drugs. 
Implicated drugs include ifosfamide, streptozocin, 
tetracyclines, valproic acid, ddl, cidofovir, adefovir, 
tenofovir, and ranitidine. 

Tenofovir is being increasingly reported as a 
cause of Fanconi's syndrome in human immunod- 
eficiency virus (HIV)-positive patients. Tenofovir 
is an acyclic nucleoside phosphorate that is 
excreted by glomerular filtration and tubular 
secretion. It enters the proximal tubular cell 
across the basolateral membrane on the human 
organic anion transporter 1 (hOATl) and exits 
into urine on the multidrug resistance-associated 
protein 2 (Mrp-2). Since ritonavir inhibits Mrp-2, 
its use with tenofovir could result in increased 
toxicity. Renal injury occurs from weeks to 
months after starting treatment. In addition to 
Fanconi's syndrome, decreases in creatinine 
clearance and nephrogenic diabetes insipidus 
(DI) were also reported. The Chinese herb 
Boui-ougi-tou, used for treatment of obesity, 
also causes Fanconi's syndrome. Dent's disease is 
caused by a mutation in the chloride channel 
CLCN-5. It results in hypophosphatemia and renal 
phosphate wasting associated with low molecular 
weight proteinuria, hypercalciuria, nephrolithiasis, 
nephrocalcinosis, and chronic kidney disease. A 
urinalysis for glycosuria should be performed when 
the diagnosis of Fanconi's syndrome is being con- 
sidered. The diagnosis is established by measuring 
serum and urinary amino acids and glucose and cal- 
culating the fractional excretion of each. 



Key Points 

Etiology of Hypophosphatemia 



The most common pathophysiologic 
processes that reduce serum phosphorus 
concentration are decreased GI absorption, 
shifts of phosphorus from ECF into ICF and 
increased renal excretion. 
Intracellular phosphorus shifts are the most 
common cause of hypophosphatemia in 
hospitalized patients. 



172 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



3. Decreased GI absorption alone is a rare 
cause of hypophosphatemia. 

4. The most common causes of increased renal 
phosphorus excretion are primary and sec- 
ondary hyperparathyroidism. 

5. In primary hyperparathyroidism serum 
phosphorus concentration is rarely below 
1.5 mg/dL. 

6. Secondaiy hyperparathyroidism due to 
calcitriol deficiency may cause severe 
hypophosphatemia. 



Signs and Symptoms 

Hypophosphatemia causes a variety of signs and 
symptoms. Their severity varies with the degree of 
severity of hypophosphatemia. With the excep- 
tion of two studies there is little evidence that 
moderate hypophosphatemia (serum phosphorus 
concentration between 1.0 and 2.5 mg/dL) results 
in any clinically significant morbidity. Moderate 
hypophosphatemia does not impair myocardial 
contractility. It increases insulin resistance but the 
clinical significance of this is unclear. Correction 
of moderate hypophosphatemia did improve 
diaphragmatic function in patients with acute res- 
piratory failure. Eight intubated patients were 
given a short-term infusion of phosphorus (10 mmol 
[310 mg] over 4 hours). Mean serum phosphorus 
concentration increased from 1.72 to 4.16 mg/dL. 
Transdiaphragmatic pressure increased in all 
patients. One can question the clinical relevance 
of this finding given the small number of patients 
and lack of clinically important end points. In 
the second study a group of 16 patients were 
evaluated in the early stages of sepsis. Ten of the 
16 patients had significant atrial and ventricular 
arrhythmias. Those patients with arrhythmias had 
a significantly lower serum phosphorus concentra- 
tion, 2.8 mg/dL, than those that did not, 3.19 mg/dL. 
There was no increase in mortality in the 
hypophosphatemic patients. 

On the other hand, severe hypophosphatemia 
(serum phosphorus concentration <1.0 mg/dL) is 
associated with morbidity. Failure to wean from 



mechanical ventilation without correction of severe 
hypophosphatemia was demonstrated. In one study 
severe hypophosphatemia increased the length of 
time patients spent on a ventilator (10.5 versus 
7.1 days) and in the hospital (12.1 versus 8.2 days). 
This was also shown after cardiac surgery where 
patients with severe hypophosphatemia required 
more time on the ventilator (2.1 versus 1.1 days), a 
longer hospital stay (7.8 versus 5.6 days), and car- 
dioactive drugs for a longer period of time. 

Although hypophosphatemia causes a leftward 
shift in the oxygen dissociation curve, the clinical 
significance of this is unclear. Severe hypophos- 
phatemia produces reversible myocardial dys- 
function and an impaired response to pressors. 
Correction of severe hypophosphatemia increases 
myocardial contractility by 20%. The effect of short- 
term correction is variable between patients with 
some showing minimal to no response and others 
showing larger responses. Severe hypophos- 
phatemia rarely, if ever, results in clinical congestive 
heart failure. A variety of neuromuscular symptoms 
were noted including paresthesias, tremor, and 
muscle weakness. Hematologic disturbances 
include increases in red cell fragility that lead to 
hemolysis. Hemolytic anemia was reported in two 
patients with serum phosphorus concentrations 
of 0.1 and 0.2 mg/dL, respectively. Red cell ATP 
was reduced to very low levels. In vitro studies in 
humans show that a serum phosphorus concen- 
tration less than 0.5 mg/dL decreased chemo- 
taxis, phagocytosis, and bacterial killing by white 
cells. Whether this could predispose to infection 
is unknown. Severe hypophosphatemia causes 
rhabdomyolysis in dogs only if there is a preexist- 
ing subclinical myopathy. There are very few 
reports of rhabdomyolysis in man. 



Key Points 

Signs and Symptoms of Hypophosphatemia 



1 . Correction of moderate hypophosphatemia 
improves diaphragmatic function in patients 
with acute respiratory failure. The clinical 
importance of this is unclear. 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



173 



Moderate hypophosphatemia does not 
impair myocardial contractility. 
Severe hypophosphatemia impairs the abil- 
ity to wean patients from mechanical venti- 
lation and prolongs hospital stay. 
Myocardial contractility is decreased in severe 
hypophosphatemia; however, this rarely, if 
ever, results in clinical congestive heart failure. 
Very severe hypophosphatemia increases 
red cell fragility that can lead to hemolysis. 
Severe hypophosphatemia causes rhab- 
domyolysis in dogs only if there is a preex- 
isting subclinical myopathy. There are very 
few reports of rhabdomyolysis in humans. 



Diagnosis 

A summary of the diagnostic approach to the patient 
with hypophosphatemia is illustrated in Figure 11.4. 
One can use the fractional excretion (FE) of phos- 
phorus, the 24-hour urinary phosphorus excretion, 
or the calculated renal threshold phosphate concen- 
tration (TmPO/GFR) to distinguish among patho- 
physiologic mechanisms of hypophosphatemia. The 
FE of phosphorus is calculated using the formula: 

UpXS& xlOO 



U rr xS p 



Urine and serum creatinine (Cr) and phosphorus 
(P) concentrations are all expressed in mg/dL. 



Figure 11.4 



Decreased serum phosphorus 



FE phosphorus, 24-hour urine phosphorus or TmP0 4 /GFR 



Low 
Decreased Gl absorption 
Shift from ECF to ICF 



High 
Increased renal excretion 




Normal or high 



Low 

Secondary 

hyperparathyroidism 



Aminoaciduria, Glycosuria 



/ 



Calcidiol, Calcitriol 



Present 
Generalized proximal 
tubular dysfunction 
Fanconi's syndrome 
Dent's disease 



Absent 



Primary hyperparathyroidism 

X-linked hypophosphatemia 

Autosomal dominant hypophosphatemia rickets 

Oncogenic hypophosphatemic osteomalacia 



Evaluation of the hypophosphatemic patient. The first step in the evaluation of the hypophos- 
phatemic patient is the evaluation of renal phosphorus excretion. Decreased renal phosphorus 
excretion suggests a gastrointestinal cause or a shift in phosphate from ECF to ICF. Increased 
renal phosphorus excretion is further subdivided based on serum calcium concentration. 
Abbreviations: FE, fractional excretion; TmP04/GFR, renal tubular maximum reabsorptive 
capacity for phosphate (expressed as a function of the glomerular filtrate rate) 



174 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



A FE of phosphorus below 5% or a 24-urine phos- 
phorus less than 100 mg/day indicates that the 
kidney is responding properly to decreased intes- 
tinal absorption or the shift of phosphorus into 
cells. If renal phosphorus wasting is the patho- 
physiologic reason for hypophosphatemia, then 
the FE of phosphorus exceeds 5% and the 24-hour 
urine phosphorus excretion is greater than 100 
mg. Primary and secondary hyperparathyroidism 
are the most common causes of renal phosphate 
wasting. 

In the patient with increased renal phosphorus 
excretion one next evaluates the serum cal- 
cium concentration. In secondary hyperparathy- 
roidism serum calcium concentration is low 
provided that renal function is intact. If second- 
ary hyperparathyroidism from vitamin D defi- 
ciency is suspected, calcidiol and calcitriol con- 
centrations will help identify the defect. In the 
patient with a normal or elevated serum cal- 
cium concentration one subdivides patients based 
on whether they have isolated renal phosphate 
wasting or a generalized proximal tubular disor- 
der. Of the isolated phosphate wasting disorders 
primary hyperparathyroidism is by far the most 
common. It is associated with high serum calcium 
concentration and a low serum phosphorus con- 
centration. The diagnosis is established by mea- 
suring PTH concentration. Three rare disorders 
make up the remainder of patients in this cate- 
gory. These include X-linked hypophosphatemia, 
autosomal dominant hypophosphatemic rick- 
ets, and oncogenic hypophosphatemic osteo- 
malacia. 

The generalized proximal tubular disorders are 
much less common and include Fanconi's syn- 
drome and Dent's disease. If severe hypophos- 
phatemia is noted and the patient is either 
asymptomatic or serum phosphorus concentra- 
tion remains low despite repletion then one 
should consider the possibility of pseudohypo- 
phosphatemia. As is the case with pseudohyper- 
phosphatemia paraproteins can also result in a 
spuriously low serum phosphorus concentration. 
This artifact is avoided if deproteinized serum is 
analyzed. 



Key Points 

Diagnosis of Hypophosphatemia 



1 . The first step in evaluation of the hypophos- 
phatemic patient is examination of renal 
phosphorus excretion with a FE, a 24-hour 
urine, or renal threshold phosphate concen- 
tration. This separates patients with renal 
phosphate wasting from those with 
decreased intake and intracellular shifting 
of phosphorus. 

2. The most common cause of hypophos- 
phatemia from intracellular shifts of phos- 
phorus in hospitalized patients is respiratory 
alkalosis. 

3. If increased renal phosphate excretion is 
detected one next examines the serum cal- 
cium concentration. 

4. Secondary hyperparathyroidism is the most 
common cause of renal phosphate wasting 
associated with hypocalcemia. 

5. If serum calcium is normal or elevated, 
primary hyperparathyroidism is the most 
common cause. 



Treatment 

There is little evidence that treatment of moderate 
hypophosphatemia (serum phosphorus concen- 
tration 1.0-2.5 mg/dL) is necessary except per- 
haps in the patient being mechanically ventilated. 
Severe hypophosphatemia (<1 mg/dL) or symp- 
toms are indications for treatment. One must keep 
in mind that serum phosphorus concentration 
may not be a reliable indicator of total body phos- 
phorus stores since the majority of phosphorus is 
contained within cells. Hypophosphatemia is 
commonly associated with other electrolyte dis- 
turbances (hypokalemia and hypomagnesemia). 
One must cautiously replete phosphorus in 
patients who have impaired ability to excrete 
phosphorus loads (those with decreased GFR). 
Most hypophosphatemic patients can be corrected 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



175 



11.4 



Phosphate Preparations 



Preparation 


Contents 


Phosphorus 


Sodium 


Potassium 


K-phos-neutral 


Dibasic Na phosphate 
Monobasic Na phosphate 
Monobasic K phosphate 


250 mg/tab 


13 meq/tab 


1.1 meq/tab 


K-phos original 


Monobasic K phosphate 


114 mg/tab 


— 


3.7 meq/tab 


Fleets phospho-soda 


Monobasic Na phosphate 
Dibasic Na phosphate 


129 mg/mL 


4.8 meq/mL 




Neutra-phos-K 


Monobasic K phosphate 
Dibasic K phosphate 


250 mg/cap 


— 


13.6 meq/cap 


Neutra-phos 


Monobasic and dibasic Na 
and K phosphates 


250 mg/cap 


7.1 meq/cap 


6.8 meq/cap 


IV Na phosphate 


Monobasic Na phosphate 


93 mg/mL 


4.0 meq/mL 


— 


IV K phosphate 


Monobasic K phosphate 


93 mg/mL 


— 


4.4 meq/mL 



with up to 1 g of supplemental phosphorus per 
day orally. Several forms of oral and intravenous 
phosphorus replacement therapy are listed in 
Table 11.4. Oral repletion is most commonly lim- 
ited by the development of diarrhea. 

Intravenous phosphorus administration may 
be complicated by hypocalcemia and hyperphos- 
phatemia and is only justified in those with severe 
symptomatic phosphorus depletion. Sodium phos- 
phate should be employed except in patients that 
require concomitant potassium supplementation. 
During intravenous replacement blood chemistries 
including serum phosphorus, calcium, magnesium, 
and potassium concentrations should be moni- 
tored closely. Once serum phosphorus concentra- 
tion has risen above 1 mg/dL, an oral preparation 
is begun and intravenous phosphorus is discon- 
tinued. In the severely malnourished patient, such 
as an adolescent "with anorexia nervosa, refeeding 
must be accomplished slowly. Serum phosphorus 
concentration should be monitored closely and 
the patient placed on telemetry, since sudden 
death and ventricular arrhythmias were reported 
with refeeding. 



Key Points 



Treatment of Hypophosphatemia 



Treatment of moderate hypophosphatemia 
should be considered in the ventilated 
patient. 

Severe hypophosphatemia (<1 mg/dL) 
or symptoms are indications for 
treatment. 

The safest mode of therapy is oral. 
Intravenous phosphorus replacement carries 
the risk of hypocalcemia and is only war- 
ranted in patients with severe symptomatic 
phosphorus depletion. 



Additional Reading 

Brooks, M.J., Melnik, G. The refeeding syndrome: an 
approach to understanding its complications and 
preventing its occurrence. Pharmacotherapy 15: 
713-726, 1995. 



176 



Chapter 1 1 ♦ Disorders of Serum Phosphorus 



Bugg, N.C., Jones, J.A. Hypophosphatemia. Anaesthesia 

53:895-902, 1998. 
Crook, M. Phosphate: an abnormal anion? BrJHosp 

Med 52:200-203, 1994. 
DiMeglio, L.A., Econs, M.J. Hypophosphatemic rickets. 

Rev EndocrMetab Disord 2:165-173, 2001. 
Econs, M.J., Francis, F. Positional cloning of the PEX 

gene: new insights into the pathophysiology of 

x-linked hypophosphatemic rickets. Am J Physiol 

273:F489-F498, 1997. 
Kalemkerian, G.P., Darwish, B., Varterasian, ML. 

Tumor lysis syndrome in small cell carcinoma and 

other solid tumors. Am J Med 103:363-367, 1997. 



Lotz, M., Zisman, E., Bartter, F. Evidence for a phos- 
phate depletion syndrome in man. N Engl J Med 
278:409^15, 1968. 

Murer, H, Tenenhouse, H.S. Disorders of renal tubular 
phosphate transport. J Am Soc Nephrol 14:240-247, 
2003. 

Nelson, A.E., Robinson, B.G., Mason, R.S. Oncogenic 
osteomalacia: is there a new phosphate regulating 
hormone? Clin Endocrinol 47:635-642, 1997. 

Sabbagh, Y., Tenenhouse H.S. Novel phosphate-regu- 
lating genes in the pathogenesis of renal phosphate 
wasting disorders. Pflugers Arch- Eur J Physiol 
444:317-326, 2002. 



Robert F. Reilly, Jr. 



Disorders of Serum 
Magnesium 




Recommended Time to Complete: 1 day 



QiA+A+4*t Ql*&4fco4~1> 



1. How is extracellular fluid (ECF) magnesium concentration 
regulated? 

2. What role does the thick ascending limb of Henle play in this process? 
1. Which are the most important causes of hypomagnesemia? 

k. Why is hypomagnesemia associated with both hypocalcemia and 

hypokalemia? 
S. How does one approach the patient with hypomagnesemia? 
i. What are the most common causes of hypermagnesemia? 
7- Why are patients with chronic kidney disease (CKD) , gastrointestinal 

(GI) disorders, and the elderly at increased risk for hypermagnesemia? 




Regulation 



Magnesium is the fourth most abundant cation in 
the body and second most abundant within cells. 



It plays a key role in a variety of cellular processes. 
Magnesium is an important cofactor for ATPases 
and thereby, in the maintenance of intracellular 
electrolyte composition. Ion channels involved in 
nerve conduction and cardiac contractility are 
regulated by magnesium. Over 300 enzymatic sys- 
tems depend on magnesium for optimal function 



177 



178 



Chapter 12 



Disorders of Serum Magnesium 



including those involved in protein synthesis and 
deoxyribonucleic acid (DNA) replication. Magne- 
sium deficiency is implicated in the pathogenesis of 
hypertension, type II diabetes mellitus, athero- 
sclerosis, and asthma. 

Normal serum magnesium concentration is 
between 1.4 and 2.1 mg/dL (0.6-0.86 mmol/L). Only 
1% of the 21-28 g of magnesium in the body is con- 
tained within the ECR Of the remainder, 67% is in 
bone and 20% in muscle. The distribution of magne- 
sium within the body is shown in Figure 12.1. In 
bone the majority of magnesium is complexed in 
hydroxyapatite crystals. Approximately 30% of 
magnesium in bone is exchangeable with the ECF 
compartment. The rate of exchange is unclear. 
Magnesium within muscle and red cells is largely 
complexed to intracellular ligands and has limited 
ability to move from intracellular fluid (ICF) to ECF 
in conditions of total body magnesium depletion. 

Magnesium is regulated by both the GI tract and 
the kidney, with kidney playing the more important 



role. The average North American diet contains 
approximately 200-350 mg of magnesium. The 
average daily requirement in men is 220-400 mg 
and in women is 180-340 mg. The North American 
diet is only marginally adequate with respect to 
magnesium. The majority is complexed to chloro- 
phyll in green leafy vegetables. Seafoods, nuts, 
meats, and grains are high in magnesium. 

Magnesium absorption is inversely proportional 
to intake. Under normal circumstances 30^40% is 
absorbed. This can vary from a low of 25% with 
large magnesium intakes to a high of 80% with 
dietary magnesium restriction. The majority of 
magnesium absorption occurs in the small intestine 
via both a paracellular and transcellular pathway. 
Magnesium absorption is affected by water absorp- 
tion and prolonged diarrheal states result in signif- 
icant intestinal magnesium losses. Secretions from 
the upper GI tract are relatively low in magnesium 
(1 mg/dL) while those from the colon are relatively 
high in magnesium (18 mg/dL). 



Figure 12.1 



300 
12.3 

1 


mmol 


120 mg 
4.9 mmol 




H 


Extracellular 

fluid 

(280 mg) 

11.5 mmol 





180 mg 
7.4 mmol 





14,500 mg 
597 mmol 



120 mg 
4.9 mmol 



Magnesium homeostasis. Daily magnesium fluxes between ECF, intes- 
tine, kidney, and bone are shown. In the steady state net intestinal absorp- 
tion and renal excretion of magnesium are equal. 



Chapter 12 



Disorders of Serum Magnesium 



179 



Figure 12.2 



Lumen 

Na 

K 

2CI 



Blood 



K+ ( ) ' 
-r ^ r * » 



f* - \ — *3Na 

_i 2- Ok - * 



NKCC2 




CP 



3Na + 
2K + 



Na + -K + ATPase 
*- CLC-K b 



- Ca 2+ , Mg 2+ 
Ca 2+ , Mg 2+ sensing receptor 



Mg 2+ - 



Paracellin-1 



Na' 



ZV ^ - r* » 



NKCC2 



cr 




MNa + -K + ATPase 
-*■ CLC-K h 



■ Ca 2+ , Mg 2+ 



Ca 2+ , Mg 2+ sensing receptor 



Thick ascending limb magnesium transport model. Five transporters expressed in the 
thick ascending limb of Henle are associated with a Bartter's-like syndrome: type I — 
sodium-potassium-chloride cotransporter; NKCC2; type II — the ROMK potassium 
channel; type III — CIC-Kb, the basolateral chloride channel; type IV — barttin, a 
P subunit required for the trafficking of CLC-K (both CIC-Ka and CIC-Kb) channels 
to the plasma membrane; and type V — severe gain-of-function mutations in the 
calcium-sensing receptor. 



The primary regulator of ECF magnesium con- 
centration is the kidney. Renal reabsorption of 
magnesium varies widely to maintain homeostasis. 
Reabsorption is reduced to near zero in the pres- 
ence of hypermagnesemia or CKD. With magne- 
sium depletion secondary to GI causes the fractional 
excretion of magnesium can be reduced to 0.5%. 

Only 30% of magnesium is bound to albumin. 
The remainder is freely filtered across the glomeru- 
lus. Twenty percent of magnesium is reabsorbed in 
the proximal tubule in adults. Extracellular fluid 
volume status affects magnesium reabsorption in 
this segment. Volume contraction increases and 
volume expansion decreases magnesium reabsorp- 
tion. The bulk of magnesium reabsorption occurs in 
the thick ascending limb of Henle (60-70%). 



Magnesium is reabsorbed paracellularly with the 
lumen-positive voltage acting as driving force 
(Figure 12.2). The voltage is generated by potas- 
sium exit across the apical membrane through 
the ROMK channel. Potassium recycling is essen- 
tial for Na + -K + -2C1" function given that the luminal 
concentration of potassium is much lower than 
that of sodium or chloride. Magnesium moves 
across the tight junction through a specific chan- 
nel, paracellin-1, that transports magnesium and 
calcium. 

Although a variety of peptide hormones increase 
magnesium reabsorption including parathyroid 
hormone (PTH), calcitonin, glucagon, and antidi- 
uretic hormone, magnesium concentration at 
the basolateral surface of the thick ascending 



180 



Chapter 12 



Disorders of Serum Magnesium 



limb is the major determinant of magnesium reab- 
sorption. In hypermagnesemic states magnesium 
reabsorption approaches zero and in hypomag- 
nesemia the loop reabsorbs virtually all of the 
filtered magnesium reaching it. This effect is pre- 
sumably mediated via the calcium magnesium- 
sensing receptor expressed along the thick 
ascending limb basolateral surface. The receptor 
senses elevated calcium and magnesium concen- 
tration and transduces this signal to the apical 
membrane resulting in an inhibition of sodium 
entry via the Na + -K + -2Cl" cotransporter and potas- 
sium recycling via ROMK. This dissipates the 
lumen-positive voltage and decreases the driving 
force for magnesium reabsorption. 

Approximately 5—10% of magnesium is reab- 
sorbed in distal convoluted tubule (Figure 12.3). 
Magnesium transport here is active and transcellular. 



Figure 12.3 



Lumen 



Na + 

cr 



& 



CH 




Blood 

3Na + 
2K + 



Na + -K + ATPase 



m 



•*■ 3Na + 
— 2K + 



Na + -K + ATPase 



Distal convoluted tubule magnesium transport model. 
Transporters expressed in distal tubule that are associated with 
renal magnesium wasting include the thiazide-sensitivc Na + -Cr 
cotransporter (Gitelman's syndrome), the ysubunit of the Na + - 
K + ATPase (isolated dominant hypomagnesemia), and TRMP6 
a magnesium channel (primary intestinal hypomagnesemia). 



Magnesium enters the cell passively through a 
channel and exits actively via an unknown mecha- 
nism. Despite differences in transport mechanisms 
compared to thick ascending limb, PTH, calcitonin, 
glucagon, antidiuretic hormone, and hypomagne- 
semia increase magnesium reabsorption in this 
segment. Amiloride increases magnesium reab- 
sorption in distal nephron and is used therapeuti- 
cally to reduce renal magnesium loss. Thiazide 
diuretics, on the other hand, cause mild magnesium 
wasting. Distal magnesium loss is partially offset by 
increased proximal reabsorption due to mild ECF 
volume contraction. The collecting duct plays a 
very limited role in magnesium reabsorption. 



Key Points 

Magnesium Regulation 



6. 



Magnesium plays a key role in a variety of 
cellular process. 

Magnesium is regulated by both the GI tract 
and the kidney, with the kidney playing the 
more important role. 
Twenty percent of magnesium is reab- 
sorbed in the proximal tubule in adults. 
Volume contraction increases and volume 
expansion decreases proximal magnesium 
reabsorption. 

The majority of magnesium reabsorption 
occurs in the cortical thick ascending limb. 
Magnesium is reabsorbed passively across 
the paracellular space with the lumen- 
positive voltage acting as the driving force. 
It is the concentration of magnesium at the 
basolateral membrane of the cortical thick 
ascending limb that is the major determinant 
of magnesium reabsorption. 
Approximately 5-10% of magnesium is 
reabsorbed in the distal convoluted tubule. 
Magnesium transport here is active and trans- 
cellular. Amiloride increases magnesium 
reabsorption in the distal nephron and can 
be used therapeutically to reduce renal 
magnesium loss. Thiazide diuretics cause 
mild magnesium wasting. 



Chapter 12 



Disorders of Serum Magnesium 




Hypomagnesemia 



Etiology 



Hypomagnesemia is caused by decreased oral 
intake, increased GI losses, increased renal excre- 
tion, and shifts of magnesium from ECF to ICF. GI 
and renal losses are the most common causes of 
hypomagnesemia . 

Magnesium depletion was first appreciated in 
animals in 1932 with the report of locoism in 
cattle. Locoism or "grass staggers" closely resem- 
bles magnesium depletion in humans and occurs 
within 1-2 weeks after grazing on early spring 
grass that is high in ammonium. The ammonium 
complexes magnesium and phosphate-forming 
insoluble struvite in the intestinal lumen prevent- 
ing magnesium absorption. Cattle develop signs 
and symptoms of neuromuscular excitability, hypo- 
magnesemia, hypocalcemia, and hypokalemia. In 
I960, Vallee, Wacker, and Ulmer first reported 
magnesium deficiency in man. They described 
five patients "with carpopedal spasm, Chvostek's 
and Trousseau's signs, and seizures. 

GI causes of hypomagnesemia include decreased 
intake, malabsorption, diarrheal states, and pri- 
mary intestinal hypomagnesemia. Clinically sig- 
nificant magnesium depletion from decreased 
oral intake alone is rare due to the ubiquitous 
nature of magnesium in foods and the kidney's 
ability to conserve magnesium. Hypomagnesemia 
was described in a number of patients with mal- 
absorption. Serum magnesium concentration in 
these patients tends to correlate with the degree 
of steatorrhea. Presumably intestinal free fatty 
acids bind to magnesium forming insoluble soaps. 
Magnesium malabsorption is improved with a 
low-fat diet. Magnesium depletion can occur in 
any severe diarrheal state. Fecal magnesium 
increases as stool water increases and colonic 
secretions are high in magnesium. 

Primary intestinal hypomagnesemia is an auto- 
somal recessive disorder characterized by hypo- 
magnesemia and hypocalcemia. Patients present 



181 



in the first 6 months of life with symptoms of neu- 
romuscular excitability including seizures second- 
ary to hypomagnesemia and hypocalcemia. The 
hypocalcemia is resistant to therapy with calcium 
or vitamin D analogues. Passive intestinal magne- 
sium transport is normal and large doses of oral 
magnesium reverse the hypomagnesemia and 
hypocalcemia. Mutations in the TRMP6 gene cause 
this disorder. TRMP6 is a member of the transient 
receptor potential (TRP) channel family and is 
expressed in the intestine and distal nephron. 
TRMP6 is likely the pathway whereby magnesium 
crosses the apical membrane of epithelial cells in 
intestine and distal nephron. Renal magnesium 
wasting was described in these patients consistent 
with TRMP6 expression in the kidney. 

Renal losses of magnesium are due to primary 
defects in renal tubular reabsorption or secondary 
to a variety of systemic and local factors to which 
the kidney is responding normally. Primary renal 
defects are more likely to cause severe hypomag- 
nesemia than secondary defects. Drug- or toxin- 
induced injury is the most common cause of 
primary renal magnesium wasting. Offending drugs 
include aminoglycosides, cis-platinum, ampho- 
tericin B, pentamidine, cyclosporin, and tacrolimus. 
With cz's-platinum hypomagnesemia may persist 
for years after the drug is discontinued. Cyclosporin- 
induced hypomagnesemia is often associated 
with normal or elevated serum potassium and 
resolves rapidly after discontinuation of the drug. 
Hypomagnesemia may occur up to 2 weeks after 
a course of pentamidine. Hypomagnesemia was 
reported after tubular damage resulting from 
acute tubular necrosis, urinary tract obstruction, 
and delayed renal allograft function. This may 
result from increased flow in the loop of Henle 
that decreases magnesium reabsorption in this 
segment. 

A variety of uncommon inherited renal magne- 
sium wasting diseases are described. They are 
subdivided based on whether the genetic defect is 
in a protein expressed in the loop of Henle or in 
distal convoluted tubule. 

Inherited diseases affecting magnesium 
reabsorption in the loop of Henle include 
familial hypomagnesemia with hypercalciuria and 



182 



Chapter 12 



Disorders of Serum Magnesium 



nephrocalcinosis (FHHNC), autosomal dominant 
hypocalcemia (ADH), and Banter's syndrome. In 
FHHNC the paracellular channel through which 
magnesium moves is mutated, while in ADH and 
Bartter's syndrome the driving force stimulating 
passive magnesium transport (lumen-positive 
voltage) is dissipated. 

FHHNC is characterized by renal magnesium 
and calcium wasting. It presents in early child- 
hood with recurrent urinary tract infections, 
nephrolithiasis, and a urinary concentrating defect. 
The associated hypercalciuria, incomplete distal 
renal tubular acidosis, and hypocitraturia result in 
nephrocalcinosis and a progressive decrease in 
glomerular filtration rate. One-third develop end- 
stage renal disease by early adolescence. Mutations 
in paracellin-1 cause FHHNC. Paracellin-1 is 
expressed in the tight junction of the thick ascend- 
ing limb of Henle. It likely functions as a paracel- 
lular calcium- and magnesium-selective channel. 

Approximately 50% of patients with ADH have 
associated hypomagnesemia. ADH results from 
an activating mutation in the calcium magnesium- 
sensing receptor. Activating mutations shift the set 
point of the receptor and increase its affinity for 
calcium and magnesium. This signal is transduced 
to the apical membrane resulting in an inhibition 
of apical sodium entry and potassium exit. The 
resulting reduction in lumen-positive transepithe- 
lial voltage reduces the driving force for magne- 
sium and calcium reabsorption in the loop of 
Henle. 

Bartter's syndrome is caused by a variety of 
genetic defects in the thick ascending limb of the 
loop of Henle that present with renal salt wasting, 
hypokalemic metabolic alkalosis, and increased 
renin and aldosterone concentrations. Mutations 
in five ion transport proteins were described. All 
play a key role in transcellular sodium transport 
and generation of the lumen-positive voltage that 
is the driving force for magnesium and calcium 
transport. These include the Na + -K + -2Ch cotrans- 
porter (NKCC2); the apical membrane potassium 
channel (ROMK); the basolateral membrane chlo- 
ride channel (ClC-Kb); barttin, the /J subunit of the 
basolateral membrane chloride channel; and 



severe gain of function mutations of the calcium- 
sensing receptor. The phenotype varies depend- 
ing on the gene mutated. Mutations in NKCC2 and 
ROMK are associated with severe salt wasting, 
neonatal presentation, and nephrocalcinosis. 
For unclear reasons hypomagnesemia is not 
common. Mutations in ClC-Kb present during 
adolescence and 50% have hypomagnesemia. 
Mutations in barttin are associated with sen- 
sorineural deafness and hypomagnesemia was not 
reported. 

Genetic disorders resulting in magnesium 
wasting in the distal tubule include isolated dom- 
inant hypomagnesemia (IDH) and Gitelman's 
syndrome. IDH is an autosomal dominant disor- 
der associated with hypocalciuria and chrondro- 
calcinosis. It is due to a defect in the FXYD2 gene 
that encodes the y subunit of the basolateral Na + -K + 
ATPase in distal convoluted tubule. Mutations 
result in subunit retention in the Golgi complex. 
How a mutation in this subunit results in isolated 
renal magnesium wasting and increased calcium 
reabsorption is unclear. Gitelman's syndrome 
results from loss of function mutations in the 
thiazide-sensitive sodium chloride cotransporter 
(NCCT). Mutant NCCT is trapped in the Golgi and 
not trafficked to the apical membrane. Patients 
present in adolescence with symptoms of hypo- 
magnesemia and almost always have associated 
hypocalciuria. Gitelman's syndrome results in 
more profound hypomagnesemia than is seen 
with chronic thiazide therapy. The reason for this 
is unclear. 

A variety of systemic and local factors affect 
magnesium reabsorption in the proximal tubule, 
thick ascending limb of Henle, and distal convo- 
luted tubule resulting in secondary renal magne- 
sium wasting. In the proximal tubule magnesium 
reabsorption is decreased by volume expansion as 
might occur after saline infusion and osmotic diure- 
sis. In the loop of Henle magnesium reabsorption 
is inhibited by furosemide. This effect is mild due 
to an associated increase in proximal reabsorption. 
Hypercalcemia also results in magnesium wasting. 
Calcium binds to the calcium magnesium-sensing 
receptor in the basolateral membrane of the loop 



Chapter 12 



Disorders of Serum Magnesium 



183 



of Henle decreasing the lumen-positive voltage 
that drives paracellular magnesium transport. 
Thiazide diuretics act in distal convoluted tubule to 
inhibit magnesium transport. 

Shifts of magnesium from the ECF to the ICF 
can occur as with calcium. These are uncommon 
causes of hypomagnesemia and can result after 
parathyroidectomy, refeeding, and in patients 
with hyperthyroidism. Hypomagnesemia devel- 
ops in patients with burns due to magnesium 
losses through skin. Magnesium loss is propor- 
tional to the skin area burned. 



Key Points 

Etiology of Hypomagnesemia 



1 . GI and renal losses are the most common 
causes of hypomagnesemia. 

2. GI causes of hypomagnesemia include 
decreased oral intake, malabsorption, diar- 
rheal states, and primary intestinal hypo- 
magnesemia. 

3. Clinically significant magnesium depletion 
from decreased oral intake alone is uncom- 
mon due to the ubiquitous nature of magne- 
sium in foods. 

4. Renal magnesium losses are due to primary 
defects in renal tubular reabsorption or sec- 
ondary to systemic and local factors that the 
kidney is responding to normally. 

5. Primary renal defects cause severe hypo- 
magnesemia more often than secondary 
defects. Drug- and toxin-induced injuries 
are the most common causes of primary 
renal magnesium wasting. 

6. Common secondary renal causes of hypo- 
magnesemia include volume expansion, 
osmotic diuresis, furosemide, hypercal- 
cemia, and thiazide diuretics. 

7. A variety of inherited renal magnesium 
wasting diseases were described and can be 
subdivided based on whether the genetic 
defect is in the loop of Henle or in distal 
convoluted tubule. 



Signs and Symptoms 

It is difficult to attribute specific symptoms to 
hypomagnesemia due to its common association 
with metabolic alkalosis, hypocalcemia, and 
hypokalemia. Symptoms commonly attributed to 
hypomagnesemia involve the neuromuscular and 
cardiovascular systems. Increased neuromuscular 
excitability manifests as weakness, tetany, positive 
Chvostek's and Trousseau's signs, and seizures. 
A decreased concentration of either magnesium 
or calcium can lower the threshold for nerve 
stimulation. 

Magnesium effects a variety of ion channels in 
the heart. Specifically, it regulates potassium chan- 
nels that open in the absence of magnesium. It is a 
critical cofactor for the Na + -K + ATPase and hypo- 
magnesemia decreases pump activity. As a result, 
intracellular potassium decreases with hypomag- 
nesemia and depolarizes the cardiac myocyte 
resting membrane potential. The threshold for 
generation of an action potential is reduced and 
the potential for arrhythmias increased. Hypo- 
magnesemia is associated with a variety of atrial 
and ventricular arrhythmias. Decreased intracellular 
potassium also decreases the speed of potassium 
efflux resulting in a prolonged repolarization time. 
Hypomagnesemia aggravates digitalis toxicity 
since both decrease the activity of the Na + -K + 
ATPase. Magnesium depletion produces acute 
changes in the electrocardiogram such as peaked 
T waves and widening of the QRS complex. In 
severe magnesium depletion the T wave dimin- 
ishes in amplitude, the QRS widens further, and the 
PR interval becomes prolonged. These effects are 
also seen with hypokalemia and may be secondary 
to changes in serum potassium concentration. 

Hypokalemia is frequently associated with 
hypomagnesemia. There are at least two possible 
explanations for this. Magnesium is an inhibitor of 
ROMK, the apical membrane potassium secretory 
channel in the loop of Henle and distal nephron. A 
decrease in intracellular magnesium releases the 
inhibitory effect and increases potassium secretion. 
The second is that renal magnesium and potassium 
losses are unrelated but both occur in patients with 



184 



Chapter 12 



Disorders of Serum Magnesium 



specific diseases such as alcoholism, diabetic 
ketoacidosis, osmotic diuresis, and diuretic use. 

Severe magnesium depletion alters calcium 
homeostasis and results in hypocalcemia. Chronic 
hypomagnesemia suppresses PTH release from the 
parathyroid gland and this effect is rapidly reversed 
by intravenous magnesium infusion. This suggests 
that magnesium's effect is more likely due to inhi- 
bition of PTH release rather than on PTH synthesis. 
Balance studies show that the hypocalcemia is not 
associated with a net negative calcium balance 
indicating that it results from alterations in inter- 
nal homeostatic mechanisms. Hypomagnesemia- 
induced hypocalcemia may result from skeletal 
resistance to the effects of PTH. In vitro studies 
show that magnesium depletion interferes with 
PTH-stimulated cyclic adenosine monophosphate 
(cAMP) generation. End-organ resistance occurs at 
serum magnesium concentrations <1.0 mg/dL. 
Serum magnesium concentrations <0.5 mg/dL are 
required to decrease PTH secretion. 



Diagnosis 

The two major sources of magnesium loss are GI 
tract and kidney (Table 12.1). The most common GI 
causes are malabsorption and diarrheal states. A 
careful history and physical examination should 
reveal the presence of these disorders. Hypomag- 
nesemia from decreased oral intake alone and pri- 
mary intestinal hypomagnesemia are rare. 

Renal magnesium wasting is caused by primary 
defects in renal tubular reabsorption or secondary 
to systemic and local factors that the kidney is 
responding to normally. Drug- or toxin-induced 
injury is the most common cause of primary renal 
magnesium wasting. A careful drug exposure his- 
tory is obtained for aminoglycosides, c»-platinum, 
amphotericin B, pentamidine, and cyclosporin. A 
variety of rare inherited renal magnesium wasting 
diseases should be considered. 

Systemic and local factors can affect mag- 
nesium reabsorption in proximal tubule, thick 



Key Points 

Signs and Symptoms of Hypomagnesemia 



Table 12.1 

Etiologies of Hypomagnesemia 



1 . Specific symptoms are difficult to attribute 
to hypomagnesemia due to its common 
association with metabolic alkalosis, 
hypocalcemia, and hypokalemia. 

2. Hypomagnesemia results in increased neu- 
romuscular excitability manifested by 
tetany, positive Chvostek's and Trousseau's 
signs, and seizures. 

3. Hypomagnesemia is associated with a vari- 
ety of atrial and ventricular arrhythmias. 

4. Magnesium depletion produces acute 
changes in the electrocardiogram due to its 
effects on a variety of ion channels in heart. 

5. Hypokalemia is frequently associated with 
hypomagnesemia . 

6. Severe magnesium depletion suppresses 
PTH release from the parathyroid gland and 
causes skeletal resistance to PTH resulting in 
hypocalcemia. 



Increased gastrointestinal losses 

Decreased oral intake 

Malabsorption 

Diarrhea 

Primary intestinal hypomagnesemia 

Increased renal losses 

Primary 

Drugs 

Toxins 

Miscellaneous tubular injury 

Genetic disorders 
Secondary 

Osmotic diuresis, saline infusion 

Diuretics 

Hypercalcemia 
Shifts from the extracellular to the intracel- 
lular space 
Hungry bone syndrome 
Refeeding syndrome 
Hyperthyroidism 



Chapter 12 



Disorders of Serum Magnesium 



185 



ascending limb of Henle, and distal tubule. Osmotic 
diuresis reduces proximal tubular reabsorption of 
magnesium. Loop diuretics such as furosemide 
cause mild renal magnesium wasting due to an 
associated increase in proximal tubular magne- 
sium reabsorption secondary to volume contrac- 
tion. Hypercalcemia results in renal magnesium 
wasting. Thiazide diuretics act in distal convo- 
luted tubule to block magnesium transport. As 
with loop diuretics, their effect is mild due to 
enhanced proximal tubular magnesium reabsorp- 
tion from ECF volume contraction. 

Shifts of magnesium from ECF to ICF are uncom- 
mon causes of hypomagnesemia but should be 
looked for after parathyroidectomy, refeeding, 
and in patients with hyperthyroidism. 

An algorithm for the evaluation of the hypo- 
magnesemic patient is illustrated in Figure 12.4. If 
the diagnosis is not readily apparent from the 



history, either a 24-hour urine for magnesium or a 
spot urine for calculation of the fractional excre- 
tion of magnesium is obtained. The fractional 
excretion of magnesium is calculated from the 
equation below: 



FE 



Mg 



u Mg x s c 



(0.7xS Mg )xU Cl 



The serum magnesium concentration is multi- 
plied by 0.7 since only 70% of magnesium is freely 
filtered across the glomerulus. 

When magnesium losses are extrarenal the 
kidney will conserve magnesium. The 24-hour 
urinary magnesium excretion is less than 30 mg 
and the fractional excretion of magnesium less 
than 4%. If renal magnesium wasting is the cause 
of hypomagnesemia renal magnesium excretion is 
increased. The 24-hour urinary magnesium excre- 
tion is greater than 30 mg and the fractional 



Figure 12. 4 




Shift from ECF to ICF 

Hungry bone syndrome 
Refeeding syndrome 
Hyperthyroidism 



Increased Gl losses 

Decreased oral intake 

Malabsorption 

Diarrhea 



High (>30 mg/day, >4%) 
Increased renal losses 

Primary 
Drugs 
Toxins 

Miscellaneous tubular injury 
Genetic disorders 

Secondary 
Osmotic diuresis 
Diuretics 
Hypercalcemia 



Evaluation of the hypomagnesemic patient. The first step in the evaluation of the hypomagnesemic patient is the evaluation 
of renal magnesium excretion. Decreased renal magnesium excretion suggests a gastrointestinal cause or a shift in magnesium 
from the ECF to the ICF. Increased renal magnesium excretion may be primary or secondary. Abbreviations: FE, fractional 
excretion: ECF, extracellular fluid; ICF, intracellular fluid; GI, gastrointestinal. 



186 



Chapter 12 



Disorders of Serum Magnesium 



excretion of magnesium greater than 4%. In a 
study of 74 patients with Hypomagnesemia the 
mean fractional excretion of magnesium in 
patients with renal magnesium wasting was 15% 
(range 4-48%). 

Serum magnesium concentration may not 
accurately reflect total body magnesium stores. In 
patients with unexplained hypocalcemia, hypo- 
kalemia, or symptoms of neuromuscular exci- 
tability, the possibility of normomagnesemic 
magnesium depletion should be considered. In 
this setting, especially in patients at high risk for 
magnesium depletion, a therapeutic trial of magne- 
sium replacement may be warranted. Magnesium 
replacement carries little risk provided renal func- 
tion is normal. Some authors advocate perform- 
ing a magnesium-loading test. A magnesium load 
is administered (2.4 mg/kg over 4 hours) and its 
renal excretion monitored over the next 24 hours. 
If less than 80% of the load is excreted this is con- 
sidered evidence of total body magnesium deple- 
tion. Unfortunately, the test is of limited use. It is 
often positive in the setting of diarrhea, malnutri- 
tion, and diuretic use even in the absence of 
symptoms and may be falsely negative with renal 
magnesium wasting. 



Key Points 

Diagnosis of Hypomagnesemia 



1 . A careful history and physical examination 
often reveals the cause of hypomagnesemia. 

2. The most common cause of primary renal 
magnesium wasting is drug- or toxin- 
induced injury. 

3. If the diagnosis is not apparent from the his- 
tory, a 24-hour urine for magnesium or a 
fractional excretion of magnesium is 
obtained. 

4. The possibility of normomagnesemic hypo- 
magnesemia should be considered in 
patients with unexplained hypocalcemia, 
hypokalemia, and symptoms of neuromus- 
cular excitability. 



Treatment 

The route of magnesium repletion varies depend- 
ing on the severity of associated symptoms. The 
acutely symptomatic patient with seizures, tetany, 
or ventricular arrhythmias thought to be related to 
hypomagnesemia should be administered magne- 
sium intravenously. In the life-threatening setting 
4 ml (2 ampules) of a 50% solution of magnesium 
sulfate diluted in 100 mL of normal saline (200 mg) 
can be administered over 10 minutes. This is fol- 
lowed by 600 mg of magnesium given over the 
next 12-24 hours. The goal is to increase the 
serum magnesium concentration above 1.0 mg/dL. 
Magnesium is administered cautiously in patients 
with impaired renal function and serum concen- 
tration monitored frequently. In the setting of 
CKD the dose is reduced by 50-75%. Since renal 
magnesium excretion is regulated by the concen- 
tration sensed at the basolateral surface of the 
thick ascending limb of Henle, an acute infusion 
results in an abrupt increase in serum concentra- 
tion and often a dramatic increase in renal mag- 
nesium excretion. For this reason much of 
intravenously administered magnesium is quickly 
excreted by the kidney. 

In the absence of a life-threatening condition 
magnesium is administered orally. Oral administra- 
tion is more efficient because it results in less of an 
acute rise in serum magnesium concentration. 
Some of the more common oral magnesium prepa- 
rations are shown in Table 12.2. Slow release prepa- 
rations of magnesium chloride and magnesium 
lactate are preferable since they cause less diarrhea. 
Diarrhea is the major side effect of magnesium reple- 
tion that limits therapy. A range of 300-1200 mg/day 
in divided doses is generally required. Attempts are 
also made to correct the underlying condition. 
Drugs that result in renal magnesium wasting 
should be minimized. Amiloride increases magne- 
sium reabsorption in the distal convoluted tubule 
and collecting duct and may reduce renal magne- 
sium wasting or decrease the dose of magnesium 
replacement if diarrhea becomes problematic. 
Amiloride is not used in patients with impaired 
renal function because of the risk of hyperkalemia. 



Chapter 12 



Disorders of Serum Magnesium 



187 



12.2 



Oral Magnesium Preparations 



Preparation 


Molecular Weight 


Formula 


MG MG/GM 


MEQ MG/GM 


Mg carbonate 


84 


MgCO, 


289 


24 


Mg chloride 


203.3 


MgCl 2 ■ 6H 2 


119 


10 


Mg gluconate 


414.6 


(CH 2 OH(CHOH) 4 COO) 2 Mg 


58 


5 


Mg lactate 


202.4 


Mg(C 3 H 5 3 ) 2 


120 


10 


Mg oxide 


40.32 


MgO 


602 


50 


Mg sulfate 


246.5 


MgS0 4 -7H 2 


98 


8 



Certain cardiovascular conditions deserve spe- 
cial comment. Hypomagnesemia was implicated 
in ventricular and atrial arrhythmias in patients 
with cardiac disease. Patients with mild hypomag- 
nesemia in the setting of an acute myocardial 
infarction (MI) have a two-to threefold increased 
incidence of ventricular arrhythmias in the first 
24 hours. This relationship persists for as long as 
2-3 weeks after an MI. Magnesium should be 
maintained in the normal range in this setting. 

The American Heart Association Guidelines for 
Cardiopulmonary Resuscitation recommend the 
use of intravenous magnesium for the treatment 
of torsade de pointes and refractory ventricular 
fibrillation. Torsade de pointes is a ventricular 
arrhythmia often precipitated by drugs that pro- 
long the QT interval. The exact mechanism of 
action of magnesium is unknown. Magnesium 
does not shorten the QT interval and its effect may 
be mediated via the inhibition of sodium channels. 

Hypomagnesemia is common after cardiopul- 
monary bypass and may result in an increased 
incidence of atrial and ventricular arrhythmias. 
Studies on prophylactic magnesium repletion in 
this setting are conflicting "with some showing a 
reduction in the incidence of atrial fibrillation 
postcardiac surgery and others no effect. 

Studies of magnesium administration in the 
setting of ischemic heart disease show conflicting 
results. In animal models magnesium limits 
ischemia reperfusion injury if given prior to 



reperfusion. Two large clinical trials examined 
this issue in the setting of acute MI in humans. In 
LIMIT-2 a randomized, placebo-controlled, double- 
blind study in 2316 patients with acute MI, mag- 
nesium was given prior to the onset of thrombol- 
ysis. There was a 24% reduction in relative risk of 
mortality in the first month in the treatment group. 
ISIS-4, however, showed no benefit from magne- 
sium in the setting of acute MI. In this study mag- 
nesium was not given until after thrombolysis and 
an average of 8 hours after the onset of chest pain. 
Animal models show that the benefit is lost if mag- 
nesium is administered after reperfusion. 

Epidemiologic studies revealed an association 
between hypomagnesemia and atherosclerotic 
cardiovascular disease. The Atherosclerosis Risk 
in Communities Study (ARIC) followed a cohort 
of 15,792 subjects over a 4— 7-year period. The rel- 
ative risk of coronary heart disease in men and 
"women increased as serum magnesium concen- 
tration decreased. This finding "was statistically 
significant only in "women. Men and women that 
developed coronary heart disease during the 
study had a lower serum magnesium concentra- 
tion. Other studies showed that as the magnesium 
concentration of drinking water increased the inci- 
dence of ischemic heart disease decreased. 
Magnesium deficiency in animal models promotes 
atherosclerosis. Hypomagnesemia activates macro- 
phages, stimulates the peroxidation of lipopro- 
teins, and increases circulating concentrations of 



188 



Chapter 12 



Disorders of Serum Magnesium 



proinflammatory cytokines. Magnesium repletion 
is associated with improvement in lipid profile, a 
decrease in insulin resistance, reduction of free 
radical generation, and inhibition of platelet reac- 
tivity. All of these factors play a role in the athero- 
sclerotic process. 



Key Points 



Table 12.3 

Etiologies of Hypermagnesemia 



Treatment of Hypomagnesemia 



The route of magnesium repletion varies 
depending on the severity of associated 
symptoms. The treatment goal is to increase 
the serum concentration above 1.0 mg/dL. 
Magnesium is administered cautiously in 
patients with impaired renal function and 
serum concentration monitored frequently. 
Magnesium is administered orally in the 
absence of a life-threatening condition. 
Amiloride may reduce renal magnesium 
wasting but should not be used in patients 
with impaired renal function. 
Magnesium should be maintained in the 
normal range in the setting of ischemic heart 
disease. 

Hypomagnesemia is associated with an 
increased risk of a variety of cardiovascular 
conditions including atrial and ventricular 
arrhythmias, torsade de pointes, and athero- 
sclerotic cardiovascular disease. 




Hypermagnesemia 



Etiology 

The kidney is capable of excreting virtually the 
entire filtered load of magnesium in the presence 
of an increased serum magnesium concentration 



Intravenous magnesium load in the 
absence of chronic kidney disease 

Treatment of preterm labor 
Treatment of eclampsia 
Oral magnesium load in the presence of 
chronic kidney disease 

Laxatives 
Antacids 
Epsom slats 
Miscellaneous 

Salt water drowning 



or a decrease in the glomerular filtration rate. For 
this reason hypermagnesemia is relatively uncom- 
mon. Some of the more common etiologies are 
shown in Table 12.3. It most often occurs with 
magnesium administration in the setting of a 
severe decrease in glomerular filtration rate. It was 
recently reported with magnesium-containing 
cathartics in patients with renal failure, intra- 
venous magnesium for postpartum eclampsia in 
patients with renal failure, and in patients using 
Epsom salts (magnesium sulfate) as a mouthwash. 

The most common cause of hypermagnesemia 
is CKD. As glomerular filtration rate falls the frac- 
tional excretion of magnesium increases. This 
allows magnesium balance to be maintained until 
the glomerular filtration rate falls well below 
30 mL/minute. Mild hypermagnesemia resulting 
from decreased renal excretion of magnesium can 
occur with lithium intoxication and familial 
hypocalciuric hypercalcemia. This is due to the 
interaction of lithium with the basolateral calcium 
magnesium-sensing receptor in the thick ascend- 
ing limb of Henle. Antagonism of this receptor 
causes enhanced magnesium reabsorption. 

Intravenous administration of magnesium can 
result in hypermagnesemia even in the absence of 
CKD. The typical setting is obstetrical with magne- 
sium infused for the management of preterm labor 



Chapter 12 



Disorders of Serum Magnesium 



189 



or eclampsia. Typical protocols often result in 
serum magnesium concentrations of 4-8 mg/dL. 
Hypermagnesemia due to oral magnesium inges- 
tion occurs most commonly in the setting of CKD. 
Cathartics, antacids, and Epsom salts are frequently 
the source of magnesium. Advanced age, CKD, and 
GI disturbances that enhance magnesium absorp- 
tion such as decreased motility, gastritis, and colitis 
are contributing factors. A rare setting where 
magnesium concentration may be elevated is salt 
water drowning. Seawater is high in magnesium 
(14 mg/dL) with the Dead Sea having the highest 
recorded concentration (394 mg/dL). 



blockage resulting in fixed and dilated pupils that 
mimics brainstem herniation was reported. 
Smooth muscle can be affected resulting in ileus 
and urinary retention. 

In cardiac tissue, magnesium blocks calcium 
and potassium channels required for repolariza- 
tion. At serum magnesium concentrations above 
7 mg/dL hypotension and ECG changes such as 
PR prolongation, QRS widening and QT prolon- 
gation are noted. At magnesium concentrations 
greater than 10 mg/dL ventricular fibrillation, 
complete heart block, and cardiac arrest occur. 



Key Points 

Etiology of Hypermagnesemia 



Key Points 

Signs and Symptoms of Hypermagnesemia 



In the presence of an increased serum mag- 
nesium concentration or a decrease in the 
glomerular filtration rate the kidney is capa- 
ble of excreting virtually the entire filtered 
load of magnesium. 

Hypermagnesemia most commonly occurs 
with magnesium administration in patients 
with severe decreases in glomerular filtra- 
tion rate. 

Hypermagnesemia with oral magnesium 
ingestion occurs most commonly in the 
setting of CKD. 



Signs and Symptoms 

Hypermagnesemia can result in significant neuro- 
muscular and cardiac toxicity. Magnesium blocks 
the synaptic transmission of nerve impulses. 
Initially this results in lethargy and drowsiness. As 
magnesium concentration increases deep tendon 
reflexes are diminished (4—8 mg/dL). Deep tendon 
reflexes are lost and mental status decreases at 
serum magnesium concentrations of 8-12 mg/dL. 
If the magnesium rises further (>12 mg/dL) flaccid 
paralysis and apnea may ensue. Parasympathetic 



At magnesium concentrations between 
4 and 8 mg/dL deep tendon reflexes are 
diminished. Deep tendon reflexes are lost 
and mental status decreases at serum mag- 
nesium concentrations of 8-12 mg/dL. At 
serum magnesium concentrations greater 
than 12 mg/dL flaccid paralysis and apnea 
may ensue. 

Magnesium blocks calcium and potassium 
channels required for repolarization in the 
heart. 

Hypotension and ECG changes such as PR 
prolongation, QRS widening, and QT pro- 
longation are noted at serum magnesium 
concentrations above 7 mg/dL. 
Fatal complications such as ventricular fibril- 
lation, complete heart block, and cardiac 
arrest were reported at magnesium concen- 
trations greater than 10 mg/dL. 



Diagnosis 

Hypermagnesemia is often iatrogenic. A careful 
medication history is essential to determine the 
source of the magnesium, whether intravenous, 
as in the treatment of obstetrical disorders, or oral. 



190 



Chapter 12 



Disorders of Serum Magnesium 



Laxatives, antacids, and Epsom salts are the most 
common oral sources of magnesium. High doses 
of intravenous magnesium may result in hyper- 
magnesemia in the absence of kidney disease. 
Hypermagnesemia from increased gastroin- 
testinal absorption of magnesium often requires 
some degree of renal impairment. The elderly are 
at increased risk, often because the degree of 
decrease in glomerular filtration rate is not ade- 
quately appreciated based on the serum creati- 
nine concentration. For example, an 85-year-old 
Caucasian female weighing 50 kg with a serum 
creatinine of 1.5 mg/dL may have a creatinine 
clearance as low as 20 ml/minute. The elderly 
often have decreased intestinal motility that fur- 
ther increases intestinal magnesium absorption. 



Key Points 

Diagnosis of Hypermagnesemia 



1. Hypermagnesemia is commonly iatrogenic. 

2. Hypermagnesemia from intravenous infu- 
sion of magnesium can occur in the absence 
of kidney disease. 

3. Some degree of renal impairment is often 
present in patients developing hypermagne- 
semia from increased GI absorption of mag- 
nesium. 

4. The elderly are at increased risk. 



Treatment 

Since the majority of cases of hypermagnesemia 
are iatrogenic, caution should be exercised in the 
use of magnesium salts especially in patients with 
CKD, those with GI disorders that may increase 
magnesium absorption, and in the elderly. 
Patients with CKD should be cautioned to avoid 
magnesium-containing antacids and laxatives. If 
the patient has hypotension or respiratory depres- 
sion calcium (100-200 mg of elemental calcium 
over 5-10 minutes) is administered intravenously. 
The source of magnesium should be stopped. 



Renal magnesium excretion is increased "with a 
normal saline infusion and/or furosemide admin- 
istration. In the patient with severe CKD or end- 
stage renal disease dialysis is often required. 
Hemodialysis is the modality of choice if the 
patient's hemodynamics can tolerate it, since it 
removes more magnesium than continuous veno- 
venous hemofiltration or peritoneal dialysis. 



Key Points 



Treatment of Hypermagnesemia 



Caution should be exercised in the use of 
magnesium salts in high-risk patients. 
Intravenous calcium can be used if the 
patient has significant hypotension or respi- 
ratory depression. 

The source of magnesium should be 
stopped. If renal function is normal, saline 
infusion and/or furosemide administration 
are employed if the rate of renal magnesium 
excretion needs to be increased. 
In severe hypermagnesemia hemodialysis is 
often required in those with significant CKD 
or end-stage renal disease. 



Additional Reading 

Agus, Z.S. Hypomagnesemia. / Am Soc Nephrol 
10:1616-1622, 1999. 

Agus, M.S, Agus, Z.S. Cardiovascular actions of magne- 
sium. Crit Care Clin 17:175-186, 2001. 

Al-Ghamdi, S.M., Cameron, B.C., Sutton, R.A. Magnesium 
deficiency: pathophysiologic and clinical overview. 
Am J Kidney Dis 24:737-752, 1994. 

Cole, D.E., Quamme, GA. Inherited disorders of renal 
magnesium handling. J Am Soc Nephrol 11:1937- 
1947, 2000. 

Elisaf, M, Panteli, K., Theodorou, J., Siamopoulos, K.C. 
Fractional excretion of magnesium in normal sub- 
jects and in patients with hypomagnesemia. Magnes 
Res 10:315-320, 1997. 

Fiser, R.T., Torres, A. Jr., Butch, A.W., Valentine, J.L. 
Ionized magnesium concentrations in critically ill 
children. Crit Care Med 26:2048-2052, 1998. 



Chapter 12 



Disorders of Serum Magnesium 



191 



Konrad, M., Weber, S. Recent advances in molecular 
genetics of hereditary magnesium-losing disorders. 
J Am Soc Nephrol 14:249-260, 2003. 

Simon, D.B., Lu, Y., Choate, K.A., Velazquez, H., Al- 
Sabban, E., Praga, M., Casari, G., Bettinelli, A., 
Colussi, G., Rodriguez-Soriano, J., McCredie, D., 
Milford, D., Sanjad, S., Lifton, RP. Paracellin-1, a 



renal tight junction protein required for paracellular 
Mg 2+ resorption. Science 285:103-106, 1999. 

Topf, J.M, Murray P.T. Hypomagnesemia and hypermag- 
nesemia. Rev EndocrMetab Disord 4:195-206, 2003. 

Weisinger, JR., Bellorin-Font, E. Magnesium and phos- 
phorus. Lancet 352:391-396, 1998. 



Robert F. Reilly, Jr. 



Nephrolithiasis 




Recommended Time to Complete: 2 days 



Qi*uiih*C Q4+I4fc04~t> 



1. Why do stones form in the urinary tract? 

2. How does one evaluate the patient with renal colic and what is the 
likelihood that a stone will pass spontaneously? 

1. What are the important risk factors for the formation of calcium- 
containing stones? 

ty. Is there an optimal approach to the patient with a single calcium- 
containing stone? 

5. How does one evaluate and treat the patient with multiple recurrent 
calcium-containing stones? 

6. Which risk factors are most important for the formation of uric acid 
stones? 

7- What role does bacterial infection play in struvite stones? 
$. Why is medical therapy difficult in patients with cystine stones? 
e l. Which prescription and over-the-counter drugs form stones in the 
urinary tract? 



192 



Chapter 13 ♦ Nephrolithiasis 




Introduction 



Kidney stones are a common problem facing 
nephrologists, urologists, and general internists in 
the United States with an annual incidence of 
10-20 per 10,000. The frequency of stone forma- 
tion varies with sex and race. Men are affected 
3—4 times more often than women and Caucasians 
more frequently than African Americans or 
Asians. By age 70 as many as 20% of all Caucasian 
men and 7% of all Caucasian women will have 
formed a kidney stone. The peak incidence for 
the initial episode of renal colic occurs early in life 
between the ages 20 and 35. In women there is a 
second peak at age 55. Nephrolithiasis is a major 
cause of morbidity due to pain (renal colic), renal 
parenchymal damage from obstruction of the 
urinary tract, and infection. 

Calcium-containing stones make up approxi- 
mately 80% of all stones in the United States and 
contain calcium oxalate either alone or in combi- 
nation with calcium phosphate. The remainder 
are composed of uric acid or struvite. Cystine 
stones are rare in adults. In more arid climates, 
such as the Middle East, uric acid stones are more 
common than calcium-containing stones. Studies 
based on samples received by stone analysis lab- 
oratories suggest that 10-20% of all stones are 
made up of struvite but this is due to an overrep- 
resentation of stones from surgical specimens. 

A kidney stone is an organized mass of crystals 
that grows on the surface of a renal papilla. They 
result whenever the excretory burden of a poorly 
soluble salt exceeds the volume of urine available 
to dissolve it. Supersaturation of urine with 
respect to a stone-forming salt is necessary but 
not sufficient for stone formation. Interestingly, in 
normal patients urine is often supersaturated with 
respect to calcium oxalate, calcium phosphate, 
and uric acid yet stone formation does not occur. 
Other factors such as heterogeneous nucleation 
and inhibitors of crystallization play an important 
role in the pathogenesis of stone formation. 



193 



Heterogeneous nucleation refers to the principle 
that crystallization requires less energy when a 
surface is present on which it can grow, as 
opposed to in the absence of a surface (homoge- 
neous nucleation). Normal urine contains several 
inorganic and organic inhibitors of crystallization. 
Citrate, magnesium, and pyrophosphate are the 
most important of these. 

A recent study of 19 stone formers shed addi- 
tional light on the pathophysiology of kidney stone 
formation. Surprisingly, the initial site of crystal for- 
mation was on the basolateral surface of the thin 
limb of the loop of Henle in 15 patients with idio- 
pathic hypercalciuria. Stones consisted of a core of 
calcium phosphate surrounded by a shell of cal- 
cium oxalate. The crystal nidus eroded through the 
surface of the renal papilla into the renal pelvis. 
Why calcium phosphate precipitates in this region 
of the nephron remains unclear. Another four 
patients formed stones after intestinal bypass sur- 
gery. In this subgroup calcium phosphate crystals 
initially attached to the luminal membrane of inner 
medullary collecting duct (IMCD) cells. The 
deposit acted as a nidus for further calcium oxalate 
precipitation resulting in luminal occlusion and 
stone growth out into the renal pelvis. Further stud- 
ies are needed to examine those factors important 
for calcium salt precipitation in the renal medulla 
and crystal attachment in the IMCD. 



Key Points 

Kidney Stones 



1 . Nephrolithiasis is a common clinical prob- 
lem whose frequency varies with sex and 
race. 

2. Calcium oxalate stones are the most 
common stone in the United States. 

3. Supersaturation is required but not sufficient 
for stone formation. 

4. Other factors such as heterogeneous nucle- 
ation and inhibitors play an important role 
in the pathogenesis of stone formation. 




The Patient with Renal Colic 



Stones form on the surface of a renal papilla and 
if they remain there do not produce symptoms. If 
the stone dislodges it can impact anywhere 
between the ureteropelvic and ureterovesicular 
junction resulting in renal colic. Renal colic pre- 
sents as severe flank pain that begins suddenly, 
peaks within 30 minutes, and remains constant 
and unbearable. It requires narcotics for relief 
and is associated with nausea and vomiting. The 
pattern of pain radiation may provide a clue as to 
where in the urinary tract the stone is lodged. 
Pain radiating around the flank and into the 
groin is common for a stone trapped at the 
ureteropelvic junction. Signs of bladder irritation 
such as dysuria, frequency, and urgency are 
associated with stones lodged at the ureterovesic- 
ular junction (the narrowest portion of the 
ureter). Pain may radiate to the testicles or vulva. 
Struvite stones are often incidentally discovered 
on plain abdominal radiograph since they are 
generally too large to move into the ureter. The 
abdominal, rectal, and pelvic examination are 
directed at ruling out other potential etiologies 
of abdominal pain. Physical examination is 
remarkable for costovertebral angle tenderness 
and muscle spasm. 

A complete blood count, serum chemistries, 
and urinalysis are required to evaluate patients. 
The white blood cell (WBC) count may be 
mildly elevated due to the stress of the acute 
event. A WBC count greater than 15,000 cells/mm 3 
suggests either another intraabdominal cause 
for the pain or pyelonephritis behind an 
obstructing calculus. An elevation of the serum 
blood urea nitrogen (BUN) and creatinine 
concentrations is not common and if present is 
usually secondary to prerenal azotemia from 
volume depletion. Obstruction of a solitary func- 
tioning kidney, as is the case after a renal trans- 
plant, will result in acute renal failure. Any patient 



Chapter 13 ♦ Nephrolithiasis 

with abdominal pain should have a careful 
urinalysis performed. Approximately 90% of 
patients with renal colic will have microscopic 
hematuria. 

If nephrolithiasis is suspected after the initial 
evaluation, one must next establish a definitive 
diagnosis. A radiograph of the abdomen can identify 
radio-opaque stones larger than or equal to 2 mm 
in size (calcium oxalate and phosphate, struvite, 
and cystine stones). Radiolucent stones (uric acid) 
and stones that overlie the bony pelvis are often 
missed. Unfortunately, two-thirds of kidney stones 
trapped in the ureter will overlie the bony pelvis. 
As a result, an abdominal radiograph is most valu- 
able to rule out other intraabdominal processes. It 
is not sensitive enough to exclude nephrolithiasis 
with certainty. An ultrasound examination readily 
identifies stones in the renal pelvis, but is much 
less accurate for detecting ureteral stones. The 
intravenous pyelogram (IVP) was formerly the 
gold standard for the diagnosis of renal colic. It 
identifies the site of the obstruction, although the 
stone itself may not be visualized. Structural or 
anatomic abnormalities and renal or ureteral com- 
plications can be detected. Major disadvantages 
of the IVP include the need for intravenous con- 
trast and the prolonged waiting time required to 
adequately visualize the collecting system in the 
presence of obstruction. As a result, spiral com- 
puterized tomography (CT) is the test of choice in 
the majority of emergency departments. Spiral CT 
is highly sensitive, rapid, and does not require 
contrast. It may also identify the site of obstruc- 
tion. An example of a kidney stone detected on 
spiral CT scanning is shown in Figure 13.1. If the 
patient does not have a stone the spiral CT may 
also identify other causes of abdominal pain such 
as appendicitis and ischemic bowel. 

After a stone is identified in the ureter by spiral 
CT, subsequent management involves an assess- 
ment of the likelihood of spontaneous passage, 
the degree of pain present, and whether there is 
suspected urinary tract infection (UTI). The prob- 
ability of spontaneous passage is related to the 
stone size and its location in the ureter at the time 



Chapter 13 ♦ 
Figure 13. 1 



195 




Spiral CT scan of a kidney stone. Shown by the arrow is a 
kidney stone impacted in the ureter. 



of initial presentation (Table 13.1). In general, the 
smaller the stone and the more distal in the ureter 
it is located, the higher the likelihood of sponta- 
neous passage. The patient with pain that cannot 
be managed with oral medication or with evi- 
dence of pyelonephritis requires hospital admis- 
sion for parenteral analgesics and/or antibiotics. 
Stones unlikely to pass spontaneously require fur- 
ther urologic intervention. 



Key Points 

The Patient with Renal Colic 



The radiation pattern of renal colic may pro- 
vide a clue as to where in the ureter the 
stone is lodged. 

A WBC count greater than 15,000 cells/mm 3 
is indicative of either another intraabciominal 
cause for pain or pyelonephritis behind an 
obstructing calculus. 

Microscopic hematuria is present in 90% of 
patients. 

Spiral CT is the diagnostic test of choice in 
the patient with suspected renal colic. 
The size of the stone and its location in the 
ureter at the time of initial presentation 
determine its likelihood of spontaneous 
passage. 




Risk Factors for 
Calcium-Containing Stones 



Table 13.1 

Likelihood of Spontaneous Kidney Stone Passage 



Size 

>6 mm— 0-25% 
4-6 mm— 20-60% 
<4 mm— 50-90% 
Location 
Upper ureter 

>6 mm — <1% 
<4 mm— 40-80% 
Lower ureter 

<4 mm— 70-95% 



Calcium-containing stones make up the majority of 
stones in the United States and are generally com- 
posed of a mixture of calcium oxalate and calcium 
phosphate. In mixed stones calcium oxalate pre- 
dominates, and pure calcium oxalate stones are 
more common than pure calcium phosphate stones. 
Calcium phosphate precipitates in alkaline urine, 
whereas calcium oxalate precipitation does not vary 
with pH. Since urine is acidic in most patients on a 
standard Western diet, calcium oxalate stones are 
more common. Hypercalciuria, hypocitraturia, 
hyperuricosuria, hyperoxaluria, low urine volume, 
and medullary sponge kidney are the major risk fac- 
tors for calcium-containing stone formation. Patients 
may form calcium-containing stones with a single or 
any combination of risk factors. Some patients form 



196 



Chapter 13 ♦ Nephrolithiasis 



Table 13.2 

Abnormal Values for Calcium Oxalate Stone Risk Factors 



Substance 




mg/24 hours 




Male 




Female 


Calcium 


>200 




>200 


Uric acid 


>800 




>750 


Oxalate 


>45 




>45 


Citrate 


<320 




<320 



calcium-containing stones with no risk factors indi- 
cating that our knowledge of the stone-forming 
process is incomplete. The upper limits of normal in 
a 24-hour urine for some of these risk factors in men 
and women are shown in Table 13.2. 

Hypercalciuria is present in as many as two- 
thirds of patients with calcium-containing stones. It 
results from an increased filtered load, decreased 
proximal tubular reabsorption, or decreased distal 
tubular reabsorption. Proximal tubular calcium 
reabsorption is similar to sodium. Whenever 
proximal sodium reabsorption is decreased there 
is a parallel decrease in proximal calcium reab- 
sorption and vice versa. Distal nephron calcium 
reabsorption is stimulated by parathyroid hor- 
mone (PTH) and diuretics (thiazides and amilo- 
ride) and inhibited by acidosis and phosphate 
depletion. 

The most common cause of hypercalciuria 
(90%) is idiopathic. In three families the absorp- 
tive hypercalciuria phenotype was localized to a 
region of chromosome 1 (Iq23.3-q24). Although 
the precise mechanism is unknown these patients 
have increased l,25(OH) 2 vitamin D 3 (calcitriol) 
concentration, low PTH concentration, and 
reduced bone mineral density. Three potential 
pathophysiologic mechanisms were proposed: 
increased intestinal calcium absorption; enhanced 
bone demineralization; and decreased renal cal- 
cium or phosphorus reabsorption. Patients with 
idiopathic hypercalciuria can be subdivided on 
the basis of a fast and calcium load study into 



absorptive hypercalciuria types I, II, and III and 
renal leak hypercalciuria. This is based on the 
assumption that if the physiologic mechanism is 
identified this information will guide specific ther- 
apy. In practice, however, this is often unnecessary. 
Randomized controlled trials of pharmacologic 
intervention did not subdivide patients in this 
fashion. 

Other important causes of hypercalciuria include 
primary hyperparathyroidism, renal tubular acido- 
sis (RTA), sarcoidosis, immobilization, Paget's dis- 
ease, hyperthyroidism, milk-alkali syndrome, and 
vitamin D intoxication. Filtered calcium load is 
increased in primary hyperparathyroidism due to 
bone calcium release and increased intestinal cal- 
cium absorption mediated by calcitriol. In the 
subset of patients with hypercalciuria increased 
filtered load overcomes distal PTH action to 
increase calcium excretion. In RTA, an increased 
filtered calcium load results from bone calcium 
release in response to buffering of systemic 
acidosis. Acidosis also directly inhibits distal 
tubular calcium reabsorption. In sarcoidosis 
macrophages produce calcitriol via activation of 
la hydroxylase leading to increased intestinal 
calcium absorption with a resultant increase in fil- 
tered load. Immobilization, Paget's disease, and 
hyperthyroidism result in calcium release from 
bone and increase the filtered load. 

Citrate is an important inhibitor of calcium 
oxalate precipitation in urine. It complexes cal- 
cium in the tubular lumen and as a result there is 
less calcium available to associate with oxalate. 
Citrate also deposits on the surface of calcium 
oxalate crystals and prevents them from growing 
and aggregating. This latter effect may be more 
important. It was estimated that the transit time of 
a crystal through the nephron is 2-3 minutes. This 
is too short a period for growth of a single crystal 
to occlude the tubular lumen or form a stone; 
however, crystal aggregation is a much more 
rapid process and may play a role in either the 
occlusion of the tubular lumen or stone growth 
on the surface of the renal papilla. Chronic meta- 
bolic acidosis as occurs with chronic diarrhea 
or distal RTA and an acid-loading diet high in 



Chapter 13 ♦ Nephrolithiasis 



197 



protein enhance proximal tubular citrate reab- 
sorption and reduce urinary citrate concentration. 
Hypokalemia also causes hypocitraturia. Sodium- 
citrate cotransporter expression in the apical 
membrane of proximal tubule is upregulated with 
hypokalemia. 

Hyperuricosuria is an important risk factor for 
calcium-containing stone formation. Uric acid 
and monosodium urate decrease calcium oxalate 
and calcium phosphate solubility by several 
mechanisms. They act as a nidus on which cal- 
cium salts can precipitate. As discussed above 
less energy is required to form a crystal on a sur- 
face (heterogeneous nucleation). Uric acid can 
bind to macromolecular inhibitors and decrease 
their activity. 

Oxalate in urine is derived from two sources. 
The majority comes from endogenous production 
in liver. The remainder (10-40%) is derived from 
dietary oxalate and ascorbic acid. The most 
common causes of hyperoxaluria include enteric 
hyperoxaluria from inflammatory bowel disease, 
small bowel resection, or jejuno-ileal bypass; 
dietary excess; and the very uncommon inherited 
disorder primary hyperoxaluria. In enteric hyper- 
oxaluria, intestinal hyperabsorption of oxalate 
occurs via two mechanisms. Free fatty acids bind 
calcium and decrease the amount available to 
complex oxalate increasing free oxalate, which 
can then be absorbed. In addition, bile salts and 
fatty acids increase colonic oxalate permeability. 
Intestinal fluid losses also decrease urine volume, 
and bicarbonate and potassium losses can lead to 
hypocitraturia. 

Low urine volume is a very common risk factor 
for calcium-containing stone formation. The risk 
of stone formation in the United States is largest in 
areas where temperature is highest and humidity 
lowest (the stone belt of the Southeast and 
Southwest). 

Studies show that 3-12% of patients with calcium- 
containing stones have medullary sponge kidney. 
One should have a high index of suspicion for 
medullary sponge kidney in women and those 
that do not have any of the previously dis- 
cussed risk factors for calcium-containing 



stone formation. It occurs in 1 in 5000 patients 
and involves men and women with equal fre- 
quency. The medullary and inner papillary col- 
lecting ducts are irregularly enlarged resulting in 
urinary stasis that promotes precipitation and 
attachment of crystals to the tubular epithelium. 
An IVP establishes the diagnosis revealing linear 
papillary striations or collections of contrast 
media in dilated collecting ducts. Patients present 
in the fourth or fifth decade with kidney stones or 
recurrent urinary tract infection that may be asso- 
ciated with a distal RTA. 

Nanobacteria were isolated in all 30 calcium- 
containing stones in one report. Nanobacteria 
grow in protein- and lipid-free environments. 
They can nucleate carbonate apatite on their 
surface at physiologic pH. A subsequent study, 
however, failed to detect nanobacteria in 10 calcium- 
containing stones. A recent study called into ques- 
tion the existence of nanobacteria. The develop- 
ment of biomineralization that had been attributed 
to nanobacteria could not be inhibited by sodium 
azide (a potent inhibitor of mitochondrial respira- 
tion). Amplification of nanobacterial DNA from 
stone samples appears to have resulted from 
contamination with DNA from other bacterial 
species. In addition, biomineralization was shown 
to reoccur in diluted samples by self-propagation 
of microcrystalline apatite. The role of these bac- 
teria in calcium-containing stone formation is 
unclear at present. 



Key Points 

Risk Factors for Calcium-Containing Stones 



1 . Important risk factors for calcium-containing 
stone formation are hypercalciuria, hypoci- 
traturia, hyperuricosuria, hyperoxaluria, low 
urine volume, and medullary sponge kidney. 

2. Hypercalciuria is most commonly idio- 
pathic but other important causes are 
primary hyperparathyroidism, RTA, and 
sarcoidosis. 



198 



Chapter 13 ♦ Nephrolithiasis 



Calcium phosphate stones suggest the diag- 
nosis of RTA or primary hyperparathy- 
roidism. 

Citrate is the most important inhibitor of cal- 
cium oxalate precipitation in urine. 
Uric acid and monosodium urate act as a 
nidus for the precipitation of calcium 
oxalate by a variety of mechanisms. 
Anatomic abnormalities of the urinary tract 
should be suspected when patients in low- 
risk groups (women) form stones. 




The Patient with a Single 
Calcium-Containing Stone 



The assessment of the patient with an initial 
calcium-containing stone includes a careful history 
and physical examination evaluating for a family 
history of stone disease, skeletal disease, inflam- 
matory bowel disease, and urinary tract infec- 
tion. Environmental risk factors such as fluid 
intake, urine volume, immobilization, diet, med- 
ications, and vitamin ingestion are examined. 
Initial laboratory studies include blood chemistries, 
urinalysis, and either an abdominal radiograph 
or a spiral CT to assess stone burden. Stone 
analysis is always performed if the patient saved 
the stone. One study showed that in 15% of 
cases analyses of 24-hour urines would not have 
correctly predicted the chemical composition of 
the stone. Stone analysis is inexpensive, estab- 
lishes a specific diagnosis, and can help direct 
therapy. 

Most authors recommend that the patient with 
a single isolated stone and no associated systemic 
disease be managed with nonspecific forms of 
treatment including increased fluid intake and a 
normal calcium diet. Increasing fluid intake is the 
cheapest way to reduce urinary supersaturation. 



In a prospective randomized trial of 199 first-time 
stone formers followed for a 5-year period, the 
risk of recurrent stone formation was reduced 
55% by increasing urine volume to greater than 
2 L/day with water intake. If the patient will not 
drink water, lemonade is a sensible, but unproven, 
alternative. Lemon juice is low in oxalate and high 
in citrate. One should keep in mind that the likeli- 
hood of future stone formation is high, approxi- 
mately 50% in the subsequent 5-8 years. In 
high-risk subgroups (Caucasian males), patients 
with significant morbidity from the initial event 
(nephrectomy), or patients with a solitary func- 
tioning kidney, a more aggressive approach may 
be warranted (see the section on the patient with 
multiple or recurrent calcium-containing stones). 

In the past, patients with calcium-containing 
stones were advised to follow a low-calcium diet. 
Recent studies, however, suggest that a low- 
calcium diet may increase the risk of stone forma- 
tion. The postulated mechanism is that ingested 
calcium complexes dietary oxalate and a reduction 
in dietary calcium results in a reciprocal increase in 
intestinal oxalate absorption. This increases urinary 
supersaturation of calcium oxalate. Confounding 
factors may also play a role, however, in that high 
calcium diets are also associated with increased 
ingestion and excretion of phosphorus, magnesium, 
and citrate, as well as increased urine pH and 
volume, factors that also reduce the incidence of 
stone formation. Recently, a randomized prospec- 
tive trial compared patients on a low-calcium diet 
to those on a normal calcium, low-sodium, and 
low-protein diet. The relative risk of stone forma- 
tion was reduced 51% in those consuming a normal 
calcium diet. Based on these findings the safest 
approach is to recommend a normal calcium diet. 

The Atkins diet adversely impacts several risk 
factors for calcium-containing stone formation. In 
one study net acid excretion increased 56 meq/day, 
urinary citrate fell from 763 mg to 449 mg/day, uri- 
nary pH declined from 6.09 to 5.67, and urine cal- 
cium excretion increased from 160 mg to 248 mg/ 
day. High-protein, low-carbohydrate diets are best 
avoided in patients with a history of calcium- 
containing kidney stones. 



Chapter 13 ♦ Nephrolithiasis 



199 



The question of whether supplemental calcium 
increases the risk of nephrolithiasis in women is 
unclear. One report suggested that any use of sup- 
plemental calcium raises the relative risk of stone 
disease 20%. Surprisingly, the risk did not increase 
with increasing dose. The timing of calcium inges- 
tion (with meals or between meals) was not 
addressed. 



Key Points 

Risk Factors for Calcium-Containing Stones 



1 . The majority of first-time calcium-containing 
stone formers can be managed by increas- 
ing fluid intake. 

2. Stone analysis is cheap and may help guide 
future management. 

3. Dietary calcium restriction should be 
avoided. 

4. Supplemental calcium may increase the risk 
of stone formation in some patients. 




The Patient with Multiple 

or Recurrent 
Calcium-Containing Stones 



Complicated calcium-containing stone disease 
is defined as the presence of multiple stones, 
new stone formation, enlargement of existing 
stones, or passage of gravel. This is established 
based on initial evaluation and these patients 
require a full metabolic evaluation. Serum cal- 
cium concentration is measured and if any value 
is above 10 mg/dL a PTH concentration must be 
obtained. Blood chemistries are evaluated for 
the presence of RTA. At least two 24-hour urine 
collections are obtained on the patient's usual 



diet for calcium, citrate, uric acid, oxalate, sodium, 
creatinine, and pH. Further therapeutic inter- 
vention depends on the results of these collec- 
tions. An IVP may be indicated to evaluate the 
possibility of structural abnormalities predispos- 
ing to stone formation especially if the stone 
disease is unilateral. If a specific disease is iden- 
tified such as primary hyperparathyroidism, sar- 
coidosis, enteric hyperoxaluria, or primary gout, 
it is treated appropriately. 

The patient with complicated disease is man- 
aged with both nonspecific and specific treat- 
ment. Nonspecific therapies such as increased 
fluid intake and a normal calcium diet were dis- 
cussed above. Specific therapies vary depending 
on risk factor assessment derived from 24-hour 
urine testing. Treatment is based on therapies 
shown to be effective in randomized placebo- 
controlled clinical trials with a follow-up period of 
at least 1 year, the results of which are shown in 
Table 13.3. This is critical because of the "stone 
clinic effect." After a patient develops a sympto- 
matic kidney stone, the next several months are 
often characterized by a period of decreased risk 
for new stone formation (stone clinic effect). At 
least two factors play a role in this process: regres- 
sion to the mean and increased adherence to non- 
specific treatments (increased fluid intake). 
Pharmacologic agents that reduced the risk of 
stone formation in randomized placebo-controlled 
trials are thiazides, allopurinol, potassium citrate, 
and potassium magnesium citrate. 

Hypercalciuria is the most common abnormality 
and is treated with thiazide diuretics. Clinical trials 
showing benefit used hydrochlorothiazide 25 mg 
bid, chlorthalidone 50 mg daily, or indapamide 
2.5 mg daily. Thiazides directly increase distal tubu- 
lar calcium reabsorption and indirectly increase 
calcium reabsorption in the proximal tubule by 
inducing mild volume contraction. For thiazides to 
be maximally effective, one must maintain volume 
contraction and avoid hypokalemia. They usually 
decrease urine calcium excretion by 50%. If inef- 
fective, the usual reason is a high sodium intake. 
Proximal reabsorption of sodium and calcium is 
decreased and urinary calcium excretion increased 



200 



Chapter 13 ♦ Nephrolithiasis 



Table 133 

Randomized Placebo-Controlled Trials 



Treatment 


Dose 


Patient Group 


Water 


Urine volume >2L 


Unselected 


HCTZ 


25 mg bid 


Unselected 


Chlorthalidone 


50 mg qd 


Unselected 


Indapamide 


2.5 mg qd 


Hypercalciuria 


Allopurinol 


300 mg qd 


Hyperuricosuria 


K + citrate 


60 meq qd 


Hypocitraturia 


K+-Mg 2+ citrate 


40 meq qd 


Unselected 



Abbreviations: HCTZ, hydrochlorothiazide; bid, twice a day; qd, once a day. 



with volume expansion. A 24-hour urine for 
sodium will detect the patient with increased 
sodium intake. Amiloride acts in a more distal site, 
collecting duct, than thiazides and is added if 
needed. Three randomized controlled trials in 
recurrent stone formers showed a reduced risk for 
new stone formation with thiazides. Although 
patients in these trials had calcium-containing 
stones, the majority were not hypercalciuric, sug- 
gesting that thiazides have effects in addition to 
decreasing urine calcium or that reduction of urine 
calcium decreases the risk of recurrent stone for- 
mation even in the absence of hypercalciuria. 

Sodium cellulose phosphate and orthophos- 
phate were used in patients who cannot tolerate 
thiazides, however, these therapies are often 
poorly tolerated as well. Slow-release neutral 
phosphate may be better tolerated from a gas- 
trointestinal standpoint. A randomized controlled 
trial of potassium acid phosphate showed no 
effect compared to placebo. 

Potassium citrate or potassium magnesium cit- 
rate were employed in patients with and without 
hypocitraturia. Each reduced the relative risk of 
stone formation in placebo-controlled trials. In 
patients taking thiazides potassium magnesium 
citrate has the advantage that it replaces diuretic- 
induced potassium and magnesium losses. 
Patients with struvite stones should not receive 
citrate because it may increase stone growth. 



Citrate increases intestinal aluminum absorption 
in chronic kidney disease patients and should be 
avoided. The use of citrate preparations is often 
complicated by diarrhea. Slow release citrate 
(10-20 meq with meals) is generally well toler- 
ated but is relatively expensive. If urinary citrate 
excretion is <150 mg/day 60 meq is given in 
divided doses with meals. A total of 30 meq/day is 
given if urinary citrate excretion is >150 mg/day. 

Hyperuricosuria is best treated with allopurinol. 
It is unclear whether alkalinization is of benefit since 
heterogeneous nucleation can be caused by sodium 
urate, as well as uric acid. Citrate administration 
might reduce the precipitation of calcium oxalate on 
the surface of uric acid crystals but this is unproven. 

The degree of hyperoxaluria often provides a 
clue as to its etiology. Dietary hyperoxaluria is gen- 
erally mild with urinary oxalate excretion between 
40 and 60 mg/24 hours and is managed with a low- 
oxalate diet. Enteric hyperoxaluria is more severe 
with urinary oxalate excretion between 60 and 
100 mg/24 hours. Initially, it is treated with a 
low-fat, low-oxalate diet. Calcium carbonate 
and/or cholestyramine can be added if this is 
unsuccessful. Primary hyperoxaluria is a rare auto- 
somal recessive disorder and urinary oxalate excre- 
tion is often in excess of 100 mg/24 hours. It is the 
result of one of two enzyme defects in glyoxalate 
metabolism that leads to enhanced conversion of 
glyoxalate to oxalate. Type I disease is the result of 



Chapter 13 ♦ Nephrolithiasis 



201 



a defect in hepatic peroxisomal alanine:glyoxalate 
aminotransferase. Pyridoxine is a cofactor of this 
enzyme. Type II disease is due to a defect in cytoso- 
lic gly oxalate reductase/n-glycerate dehydrogenase. 
Treatment of primary hyperoxaluria is difficult. 
Pyridoxine supplementation and maintenance of a 
high urine output can be tried. The disease often 
recurs in the transplanted kidney. Combined liver- 
kidney transplant may be the best treatment option 
for children with progressive type I disease. 

If metabolic evaluation fails to detect risk factors 
for calcium-containing stone formation an IVP is 
performed to rule out medullary sponge kidney. 
One also needs to consider whether a trial of citrate 
alone or citrate plus hydrochlorothiazide is war- 
ranted. Both agents are relatively inexpensive and 
have limited toxicity. In addition, a significant 
percentage of patients in randomized placebo- 
controlled trials of thiazides and citrate had no 
detectable risk factors for stone formation. There is 
good reason to suspect, therefore, that these thera- 
pies would be effective in this subgroup of patients. 

If thiazides, allopurinol, or citrate are pre- 
scribed, it is important to repeat the 24-hour urine 
in 6-8 weeks to examine the effect of pharmaco- 
logic intervention on urinary supersaturation of 
calcium oxalate, calcium phosphate, and uric 
acid. Several commercial laboratories provide this 
service. Computer programs (EQUIL) and algo- 
rithms are also capable of calculating supersatura- 
tion from a 24-hour urine collection. 

This approach directed at specific and nonspe- 
cific risk factor reduction for calcium-containing 
stone disease decreases the frequency of recur- 
rent stone formation, and reduces the number of 
cystoscopies, surgeries, and hospitalization. 



Key Points 

The Patient with Multiple or Recurrent 
Calcium-Containing Stones 



stones, enlargement of old stones, or the 
passage of gravel. This subgroup of patients 
requires complete metabolic evaluation. 

2. Therapy is based on an analysis of risk fac- 
tors for calcium-containing stones. 

3. Treatment is guided by results of random- 
ized placebo-controlled trials. 

4. Urinary supersaturation of calcium oxalate, 
calcium phosphate, and uric acid is moni- 
tored with treatment. 




1. Complicated calcium-containing stone dis- 
ease is present if the patient has multiple 
stones, evidence of the formation of new 



Uric acid stones represent 5-10% of stone disease 
in the United States. Their highest incidence is 
reported in the Middle East, where as many as 75% 
of stones contain uric acid. This is secondary in part 
to the arid climate and reduced urinary volume. 
Unlike other mammals, humans do not express uri- 
case that degrades uric acid into the much more 
soluble allantoin. Therefore, uric acid is the major 
metabolic end product of purine metabolism. 
Stones made up of uric acid are by far the most fre- 
quent radiolucent stone. 

Uric acid has low solubility at acidic pH. It is a 
"weak organic acid "with two dissociable protons. 
Only the dissociation of the first proton, which 
occurs at a pK^ of 5.5, is of clinical relevance. At a 
pH of less than 5.5 it remains as an undissociated 
acid (uric acid), which is much less soluble than 
the salt (sodium urate). As pH increases, it disso- 
ciates into the more soluble salt, sodium urate. At 
pH 4.5 only 80 mg/L of uric acid is soluble, whereas 
at pH 6.5 1000 mg/L of sodium urate is dissolved. 
Because of the dramatic increase in solubility as 
urinary pH increases, uric acid stones remain the 
only kidney stones that can be completely dis- 
solved with medical therapy alone. Patients with 
uric acid stones exhibit a lower urinary pH and 
ammonium ion excretion than normals. As many 



202 



Chapter 13 ♦ Nephrolithiasis 



as 75% have a defect in renal ammoniagenesis in 
response to an acid load. Urinary buffers other 
than ammonia are titrated more fully with a result- 
ant urine pH approximating 4.5. Patients with 
defects in ammoniagenesis, such as the elderly 
and those with polycystic kidney disease, are at 
increased risk for uric acid stones. There is also a 
high incidence of uric acid stones in patients with 
type II diabetes mellitus (34%). It has been sug- 
gested that a renal manifestation of insulin resist- 
ance may be reduced urinary ammonium 
excretion and decreased urine pH. Given the cur- 
rent epidemic of obesity and diabetes mellitus in 
the United States population uric acid stones may 
increase in frequency in the future. 

The second most important risk factor for uric 
acid stone formation is decreased urine volume. 
Hyperuricosuria is the third and least important 
risk factor and is seen in less than 25% of 
patients with recurrent uric acid stones. The 
importance of urinary pH compared to uric acid 
excretion is illustrated by the fact that a three- 
fold increase in uric acid excretion from 500 to 
1500 mg would not overcome the effect of a pH 
change from 5.0 to 6.0 that increases uric acid 
solubility sixfold. 

Another determinant of uric acid solubility is 
the cations present in urine. Uric acid solubility is 
decreased by higher sodium concentration, and 
increased by higher potassium concentration. 
This may explain calcium phosphate stone for- 
mation that can occur during sodium alkali ther- 
apy but not with potassium alkali therapy. The 
sodium load increases urinary calcium excretion 
and reduces uric acid solubility while potassium 
does not. 

Uric acid stones are more likely to pass sponta- 
neously than calcium oxalate or phosphate 
stones, because of their smooth contour. 
Although a definitive diagnosis is established by 
stone analysis, uric acid stones are suggested by 
the presence of a radiolucent stone, or the pres- 
ence of uric acid crystals in unusually acidic urine. 
Xanthine, hypoxanthine, and 2,8-dihydroxy- 
adenosine stones are radiolucent but are very 
rare. When a radiolucent stone fails to dissolve 



with standard alkali therapy their presence should 
be suspected. 

Etiologies are subdivided based on the three 
major risk factors. Low urine volume is important 
in gastrointestinal disorders such as Crohn's dis- 
ease, ulcerative colitis, diarrhea, and ileostomies, 
as well as with dehydration. Acidic urinary pH 
plays an important role in primary gout and gas- 
trointestinal disorders. Hyperuricosuria is subdi- 
vided based on whether hyperuricemia is present 
(primary gout, enzyme disorders, myeloprolifera- 
tive diseases, hemolytic anemia, and uricosuric 
drugs) or absent (dietary excess). Primary gout is 
an inherited disorder transmitted in an autosomal 
dominant fashion 'with variable penetrance. 
Hyperuricemia, hyperuricosuria, and persistently 
acid urine are its hallmarks. Uric acid stones are 
present in 10-20% of patients. In a sizeable group 
(40%) stones occur before the first attack of gouty 
arthritis. Since urine is always acidic in patients 
with primary gout, the risk of uric acid stones will 
vary directly with serum and urinary uric acid con- 
centration (Tables 13.4 and 13.5). 

As might be expected therapy is directed at 
reversal of the three risk factors. First, urine volume 
is increased to 2 L/day or greater. Next, potassium 
citrate is employed to alkalinize the urine to pH 6.5. 
The starting dose is 10 meq tid with meals and one 
titrates upward to achieve the desired urine 
pH. More than 100 meq/day is rarely required. 

Table 13-4 

Risk of Uric Acid Stones in Patients with Primary Gout 

as a Function of Serum Urate Concentration 



Serum Urate 


With Stones 


(mg/dL) 


(%) 


5.1-7.0 


11 


7.1-9.0 


18 


9.1-11.0 


25 


11.1-13.0 


28 


>13.1 


53 



Adapted with permission from Yu, TE and Gutman AB, Ann Intern 
Med 67:1133-1148, 1967. 



Chapter 13 ♦ Nephrolithiasis 



203 



Table 135 

Risk of Uric Acid Stones in Patients with Primary Gout 
as a Function of Urinary Urate Excretion 



Urinary Urate Excretion 




(mg/24 hours) 


With Stones (%) 


<300 


11 


300-499 


21 


500-699 


21 


700-899 


34 


900-1,099 


38 


>1100 


50 



Adapted with permission from Yu, TE and Gutman AB, Ann Intern 
Med 67:1133-1148, 1967. 



Sodium alkali therapy is less preferable since it 
may cause hypercalciuria. In a study of 12 patients 
with uric acid stones, alkali therapy resulted in 
complete stone dissolution in 1 to 5 months. 
Increases in urine pH above 6.5 are not necessary 
and should be avoided because of the potential 
risk of calcium phosphate precipitation. If early 
morning urine remains acidic acetazolamide 
(250 mg) is added before bedtime. If hyperurico- 
suria is present, one should first attempt to decrease 
purine consumption in the diet. Allopurinol is 
used in patients •whose stones recur despite fluid 
and alkali, patients with difficulty tolerating this 
regimen (diarrhea), or when uric acid excretion is 
greater than 1000 mg/day. If allopurinol is admin- 
istered in patients with massive uric acid overpro- 
duction as in the tumor lysis syndrome, adequate 
hydration must be ensured to avoid precipitation 
of xanthine and hypoxanthine. 



Key Points 

Uric Acid Stones 



1. Uric acid stones make up approximately 
5-10% of kidney stones in the United States. 

2. The three most important risk factors are 
decreased urine pH, decreased urine 



6. 



volume, and increased urinary uric acid 
excretion. 

Of the three risk factors low urine pH is 
most important. 

Due to their uniform round shape uric acid 
stones are more likely to pass sponta- 
neously than calcium-containing stones. 
Uric acid stones are the most common 
radiolucent stone. 

Uric acid stones can be completely dis- 
solved with medical therapy. 




Struvite Stones 



Struvite stones are composed of a combination 
of magnesium ammonium phosphate (struvite — 
MgNH 4 P0 4 • 6H 2 0) and carbonate apatite 
(Ca 10 (PO 4 ) 6 CO 3 ). It is suggested that they com- 
prise 10-15% of all stones, however, this is likely 
an overestimation. These percentages are based 
on reports from chemical stone analyses and sur- 
gical specimens are overrepresented in these 
studies. It is likely that their true prevalence is less 
than 5% of kidney stones. Prior to more recent 
therapeutic urologic advances, they were the 
cause of significant morbidity and mortality. 
Struvite stones are the most common cause of 
staghorn calculi, although any stone may form a 
staghorn. Urine is supersaturated with struvite in 
only one circumstance — infection with urea 
splitting organisms that secrete urease. Urease- 
producing bacterial genuses include Proteus, 
Morganella, Providencia, Pseudomonas, and 
Klebsiella. Escherichia coli and Citrobacter do not 
express urease. 

Women with recurrent UTI, patients with 
spinal cord injury or other forms of neurogenic 
bladder, and those with ileal ureteral diversions 
are at high risk for struvite stone formation. 
Struvite stones can present as fever, hematuria, 



204 



Chapter 13 ♦ Nephrolithiasis 



flank pain, recurrent UTI, and septicemia. They 
grow and fill the renal pelvis as a staghorn calcu- 
lus and are radio-opaque due to the carbonate 
apatite component. Rarely do they pass sponta- 
neously and in many cases they are discovered 
incidentally. Loss of the affected kidney occurs in 
50% of untreated patients. 

For struvite stones to form, it is necessary that 
the urine be alkaline (pH greater than 7.0) and 
supersaturated with ammonium hydroxide. Urea 
is hydrolyzed to ammonia and carbon dioxide 
(Figure 13.2), Ammonia is converted to ammo- 
nium hydroxide. Carbon dioxide hydrates to form 
carbonic acid and then loses protons to form 
bicarbonate and carbonate. Elevated concentra- 
tions of ammonium hydroxide and carbonate at 
alkaline pH never occurs under physiologic con- 
ditions and is seen only with urinary tract infection 
with a urease-producing organism. The stone 
behaves like an infected foreign body. A symbiotic 
relationship develops, whereby bacteria provide 
conditions suitable for stone growth and the stone 
acts as a protected environment for the bacteria. 

The majority of staghorn calculi are composed 
of struvite. Stmvite stones are larger and less radio- 
dense than calcium oxalate stones. The associa- 
tion of a kidney stone and an infected alkaline 
urine is highly suggestive of a struvite stone. 



Definitive diagnosis, however, can only be estab- 
lished by stone analysis. If a UTI is associated with 
an acidic urine and a staghorn calculus, it is likely 
that the two are unrelated. All staghorn calculi 
should be cultured and sent for stone analysis 
after percutaneous nephrolithotomy or extracor- 
poreal shock wave lithotripsy (ESWL) treatment. 
Stone culture is important since urine cultures are 
not always representative of the organism(s) pres- 
ent in the stone. Proteus mirabilis is the most 
common urease-producing organism isolated. If 
the culture is negative, one should consider the 
possibility of infection with Ureaplasma ure- 
alyticum. Some patients have stones that contain 
a mixture of struvite and calcium oxalate. A meta- 
bolic evaluation should be performed since these 
patients often have an underlying metabolic 
abnormality and are at higher risk for stone 
recurrence. 

Open surgical removal is no longer the treat- 
ment of choice for staghorn struvite calculi given 
the high recurrence rate (27% after 6 years), how- 
ever, and the persistence of UTI (41%). A combi- 
nation of percutaneous nephrolithotomy and 
ESWL is currently the treatment of choice and is 
associated with improved outcomes compared 
with surgery. Total elimination of the stone is 
difficult. Small particles containing bacteria that 



Figure 13.2 



NH 
NH, 



2\ 



p = O + H 2 UreaSe > 2NH 3 + C0 2 



pK = 9.03 



NhLOH 



pK = 6.3 pK = 10.1 
C0 2 + H 2 ► H 2 C0 3 - HC0 3 " - C0 3 = 



Pathophysiology of struvite stone formation. Struvite does not form 
under physiologic conditions. Urease converts urea to ammonia and 
carbon dioxide. Ammonia hydrates to form ammonium hydroxide. 
The resultant high pH converts bicarbonate to carbonate. The combi- 
nation of high pH, ammonium hydroxide, and carbonate provide the 
conditions for formation of magnesium ammonium phosphate and 
carbonate apatite (struvite). 



Chapter 13 ♦ Nephrolithiasis 



205 



can act as a nidus for further stone growth are 
difficult to remove. Culture-specific antimicrobial 
agents are employed as prophylaxis against recur- 
rent infection after complete stone removal. If a 
struvite stone is not completely removed, recur- 
rent UTIs and stone growth will occur. Most 
patients with residual fragments progress despite 
treatment with antibiotics. Reducing the bacterial 
population often slows stone growth but stone res- 
olution with antibiotics alone is unlikely. Urease 
inhibitors (acetohydroxamic acid) can decrease 
urinary supersaturation of struvite, reduce stone 
growth, and can result in dissolution of stones. 
Acetohydroxamic acid is associated with severe 
toxicities, however, including hemolytic anemia, 
thrombophlebitis, and nonspecific neurologic 
symptoms (disorientation, tremor, and headache). 
The half-life is prolonged in patients with chronic 
kidney disease (normal: 3-10 hours; chronic 
kidney disease: 15-24 hours). Acetohydroxamic 
acid should not be used if the serum creatinine 
concentration is greater than 2.0-2.5 nig/dL or the 
glomerular filtration rate less than 40 ml/minute. It 
is teratogenic and also should not be administered 
in patients taking iron supplements. 



Key Points 

Struvite Stones 



1 . Struvite stones are the most common cause 
of staghorn calculi. 

2. Women with recurrent UTIs make up the 
majority of patients and struvite stones. 

3. Struvite stones form only when urine is 
infected with urease-producing bacteria. 

4. The stone should always be sent for culture 
since urine cultures may not be representa- 
tive of the organisms in the stone. 

5. The combination of percutaneous 
nephrolithotomy and ESWL has replaced 
open nephrolithotomy as the treatment of 
choice. 

6. In order to cure the patient the stone must 
be completely removed. 



7. Stone growth is suppressed by antimicrobial 
therapy but a cure is unlikely without uro- 
logic inteivention. 




Cystine Stones 



Cystinuria is secondary to an inherited defect 
(autosomal recessive) in proximal tubular and 
intestinal reabsorption of dibasic amino acids 
(cysteine, ornithine, lysine, and arginine). As a 
consequence increased amounts of these amino 
acids are excreted by the kidney. Clinical disease 
results from the poor solubility of cystine (dimer 
of cyteine) in water. Stones are radiodense due to 
the sulfhydryl group of cysteine. Cystine stones 
are less radiodense on radiography than calcium 
or struvite stones and typically have a homoge- 
neous structure without striation. They are rare in 
adults, but make up as many as 5-8% of stones 
in children. The prevalence of cystinuria is 
approximately 1 per 7000 in the United States. 
Stones consisting entirely of cystine occur only 
in homozygotes. Normal adults excrete less than 
20 mg of cystine per gram of creatinine per day. 
Most patients form their first stone before age 20. 
Men are generally more severely affected than 
women. Patients present with bilateral large 
staghorn calculi and elevated serum BUN and 
creatinine concentrations. Hexagonal cystine 
crystals are often seen in first morning void urine. 
Calcium oxalate and calcium phosphate stones 
can be seen in heterozygotes with cystine acting 
as a nidus. 

Urinary supersaturation occurs at cystine con- 
centrations greater than 250 mg/L. In order to pre- 
vent cystine stones urinary concentration should be 
maintained below 200 mg/L. Given that the pA" a of 
cysteine is 6.5 its solubility will gradually increase as 
pH increases from 6.5 to 7.5. Homozygotes excrete 



206 



Chapter 13 ♦ Nephrolithiasis 



an average of 800-1000 mg/day, therefore, 4 L of 
urine must be produced daily to maintain cystine 
solubility. Cystine crystals when seen in first 
morning void urine are diagnostic of cystinuria, 
but this is an uncommon observation. Acidifying 
urine to pH 4 with acetic acid and storage 
overnight may bring out crystals in dilute or alka- 
line urine. The sodium-nitroprusside test, which 
can detect cystine at a concentration of 75 mg/L, 
is a commonly employed screening test. 
Nitroprusside complexes with sulfide groups and 
the test may be falsely positive in those taking 
sulfur-containing drugs. A positive screening test 
should be followed by 24-hour urine cystine 
quantitation. Homozygotes excrete greater than 
250 mg/g of creatinine. 

The hallmark of treatment is water, water, and 
more water. The amount is based on the patient's 
cystine excretion. In order to reduce urinary cys- 
tine concentration below 250 mg/L a urine output 
of 4 L/day is often necessary. This requires 
approximately two 8 oz glasses of water every 
4 hours. The patient should also drink two large 
glasses of water when awakening to void during 
the night. This is a difficult regimen to comply 
with and water alone is often ineffective when uri- 
nary cystine excretion exceeds 500 mg/day. 
Alkalinization is a secondary measure used in 
those who do not respond to water alone. Since 
the dissociation constant of cysteine is 6.5, a uri- 
nary pH of 7.5 must be achieved in order for 90% 
of cystine to be in the ionized form. The risk of 
calcium phosphate stone formation is increased at 
this pH. Potassium citrate is preferable to sodium 
citrate or bicarbonate since extracellular fluid 
volume expansion that occurs with sodium salts 
will increase urinary cystine excretion. 

n-penicillamine, alpha-mercaptopropionyl- 
glycine, or captopril is used if water and alkali are 
ineffective. These drugs are thiols that bind to cys- 
teine and form compounds that are more soluble 
in aqueous solution than cystine. The D-penicil- 
lamine-cysteine complex is 50 times more soluble 
than cystine and the captopril-cysteine complex is 
200 times more soluble. Alpha-mercaptopropionyl- 
glycine is better tolerated than D-penicillamine. 



n-Penicillamine binds pyridoxine and pyridoxine 
(50 mg/day) should be administered to prevent 
deficiency. Zinc supplements help prevent the 
anosmia and loss of taste that can occur with d- 
penicillamine. Captopril, although it has fewer 
side effects, may be less efficacious in decreasing 
urinary cystine concentration. 



Key Points 



Cystine Stones 



1 . Cystinuria is secondary to an autosomal 
recessive defect in proximal tubular and 
jejunal reabsorption of dibasic amino acids. 

2. The amino acid cysteine dimerizes to form 
cystine that has limited solubility in water 
(250 mg/L). 

3. Homozygotes excrete upward of 1000 mg of 
cystine daily. 

4. Water is the hallmark of treatment but is 
often of limited use in patients who excrete 
more than 500 mg of cystine. 

5. Ancillary measures include alkalinization 
of the urine with potassium citrate, and 
agents that form dimers with cysteine 
including alpha-mercaptopropionyl- 
glycine, n-penicillamine, and captopril. 




A variety of prescription drugs precipitate in urine 
including sulfonamides, triamterene, acyclovir, 
and the antiretroviral agent indinavir. Of the sulfa 
drugs sulfadiazine is more likely to precipitate 
than sulfamethoxazole. This occurs most com- 
monly after several days of high-dose therapy 
for Toxoplasmosis gondii or Pneumocystis carinii 
infection and often presents as acute renal failure. 



Chapter 13 ♦ Nephrolithiasis 



207 



The risk is increased with hypoalbuminemia. 
Treatment involves discontinuation of the drug, 
alkalinization of the urine to pH >7.15, and main- 
tenance of high urine flow rate. 

Triamterene is a weak base that can precipitate 
and form stones in the urinary tract. Triamterene 
and parahydroxytriamterene sulfate are the major 
stone constituents. In one series 22% of reported 
stones contained only triamterene, 14% had >90% 
triamterene, and 42% had <20% triamterene 
mixed with calcium oxalate and uric acid. The 
annual incidence was estimated at 1 in 1500 
patients among those prescribed the drug. Most 
patients were taking 75 mg for several years but 
some were taking only 37.5 mg for 3-6 months. 
Triamterene should be avoided in patients with a 
previous history of calcium oxalate or uric acid 
stones. There are rare case reports of crystal- 
induced acute renal failure. 

Acyclovir use can result in crystal-induced 
acute renal failure, especially if the drug is infused 
rapidly intravenously or the dose is not adjusted 
for renal dysfunction. The incidence is reduced 
by slow infusion over 1-2 hours with vigorous 
prehydration. There are rare case reports of acute 
renal failure with oral therapy in those who were 
dehydrated or received too high a dose. 

Indinavir has limited solubility at physiologic 
pH and 15-20% of the drug is excreted unchanged 
in urine. Microscopic hematuria occurs in up to 
20% of patients. Nephrolithiasis develops in 3%, 
and 5% will experience either dysuria or flank 
pain that resolves when the drug is discontinued. 
Recently, it has been increasingly recognized that 
indinavir can cause an insidious increase in serum 
BUN and creatinine concentrations associated 
with pyuria. Nelfmavir may also crystallize in the 
urine and cause stones. 

As many as 1 in 2000 stones are composed pri- 
marily of ephedrine. This results from abuse of over- 
the-counter cold formulations or the ingestion of 
Ma-huang. Ma-huang is rich in ephedrine, 
norephedrine, pseudoephedrine, and norpseu- 
doephedrine. Ephedrine was recently removed from 
the market in the United States. Guaifenesin and its 



metabolites have been detected in kidney stones. 
Topiramate is an antiepileptic medication that 
inhibits carbonic anhydrase and causes both type I 
and type II RTA. Calcium phosphate and calcium 
oxalate stones were reported with its use. 



Key Points 



Drug-Related Stones 



A variety of prescriptions and over-the- 
counter drugs can precipitate in urine and 
form stones. 

A careful medication histoiy should be a 
part of the evaluation of all patients with 
nephrolithiasis. 



Additional Reading 

Asplin, J.R. Uric acid stones. Semin Nephrol 16:412-424, 

1996. 
Coe, F.L., Favus, M.J., Pak, C.Y.C., Parks, J.H., 

Preminger, G.M. (eds.), Kidney Stones: Medical and 

Surgical Management. Lippincott-Raven, Philadelphia, 

PA, 1996. 
Cohen, T.D., Preminger, G.M. Struvite calculi. Semin 

Nephrol 16:425-434, 1996. 
Low, R.K., Stoller, M.L. Uric acid-related nephrolithiasis. 

Urol Clin North Am 24:135-148, 1997. 
Moe, O.W., Abate, N., Sakhaee, K. Pathophysiology of 

uric acid nephrolithiasis. Encrinol Metab Clin North 

Am 31:895-914, 2002. 
Pak, CYC. Medical prevention of renal stone disease. 

Nephron 81:S60-S65, 1999. 
Parks, J.H., Coe, F.L. Pathogenesis and treatment of cal- 
cium stones. Semin Nephrol 16:398-411, 1996. 
Rodman, J. S. Struvite stones. Nephron 81-.S50-S59, 1999. 
Rutchik, S.D., Resnick, M.I. Cystine calculi: diagnosis 

and management. Urol Clin North Am 24:163-171, 

1997. 
Sakhaee, K. Pathogenesis and medical management of 

cystinuria. Semin Nephrol 16:435—447, 1996. 
Wang, L.P., Wong, H.Y., Griffith, D.P. Treatment options 

in struvite stones. Urol Clin North Am 24:149-162, 

1997. 



Mark A. Perazella 



Urinalysis 




Recommended Time to Complete: 1 day 



Q *U^U*%Z Qyjti^OA^ 



1. What information does the urinalysis provide about patients with 
kidney disease? 

2. What are the various components of the urinalysis? 
I. Does the dipstick detect all urine proteins? 

k. Is the dipstick test for blood specific for red blood cells? 

S. Does red blood cell morphology help differentiate the site of kidney 
bleeding? 

i. What information does the presence of cellular casts in the urine 
sediment provide? 

7- Is the presence of uric acid or calcium oxalate crystals always 
indicative of a renal disease? 

9- What factors contribute to the formation of crystals in urine? 

e l. Is the random spot urine protein: creatinine ratio an accurate esti- 
mate of daily protein excretion? 
10. Do patterns of urinary findings help differentiate various types of 
kidney disease? 



208 



Chapter 14 ♦ Urinaly: 



sis 




Introduction 



Kidney disease, whether acute or chronic, may 
present with systemic features of renal injury 
(hypertension, edema, uremia), renal limited 
manifestations (flank or loin pain, gross hema- 
turia), or asymptomatically with only abnormal- 
ities in blood testing or urinalysis. Kidney 
disease is fully assessed with complete history 
and physical examination, directed blood test- 
ing, and examination of the urinary sediment. 
Although the urinary sediment evaluation does 
not measure level of renal function or shed light 
on severity of kidney disease, it is extremely 
important in providing insight into the cause of 
kidney disease. Thus, in addition to urinalysis, 
the clinical examination, estimates of glomeru- 
lar filtration rate (GFR), radiologic testing, and 
renal biopsy are used in combination to assess 
the patient with kidney disease. This chapter 
reviews the components of the urinalysis, as well 
as their interpretation in patients with kidney 
disease. 




Urinalysis: Role in Kidney 
Disease 



Examination of urine in patients with kidney dis- 
ease provides invaluable information. It is one of 
the major noninvasive diagnostic tools available 
to the clinician. The urinalysis is comprised of sev- 
eral components. These include the appearance 
of the urine, various parameters measured on 
dipstick and spot collections, and examination 
of the urine under the microscope. As will be 



209 



discussed later, urine microscopy is essential to 
complete the urinalysis and assess kidney disease. 
The full urinalysis can provide insight into the 
cause of kidney injury/disease, some of the func- 
tional consequences of renal injury, and the 
course of kidney disease following various inter- 
ventions. For example, in a patient suffering from 
acute glomerulonephritis, the urine sediment can 
provide information about activity of the inflam- 
matory process. It will not always predict, however, 
eventual renal outcomes. Thus, normalization of 
the urine sediment may represent either resolu- 
tion with full recovery of kidney function or heal- 
ing of the inflammatory process with residual 
glomerulosclerosis and nephron loss (chronic 
kidney disease). In this circumstance, other test- 
ing is required to accurately predict the status of 
kidney disease. 

Despite some of the limitations of urinalysis, it 
should be performed in all patients with kidney 
disease or suspected kidney problems. The urine 
specimen is examined within an hour of voiding 
to provide optimal information and eliminate 
false-positive or negative results. A midstream 
specimen is adequate in men. In women, the 
external genitalia should be cleaned prior to 
voiding to avoid contamination of the urine with 
vaginal secretions. Following collection, dipstick 
testing is performed and the sample centrifuged 
at 3000 rpm for 3-5 minutes. Urine color and 
appearance are noted both before and after cen- 
trifugation, as this "will provide clues to potential 
causes of the underlying kidney process. The dip- 
stick measures pH, specific gravity, protein (albu- 
min), heme, glucose, leukocyte esterase, bile, and 
nitrite. The centrifuged specimen is decanted to 
remove the supernatant and placed in a separate 
tube. This allows examination of the sediment. A 
small amount of sediment is placed on a glass 
slide. A cover slip is applied and both stained and 
unstained sediment are examined at various 
powers under the microscope. These aspects of 
urinalysis are discussed in more detail throughout 
the chapter. 



210 



Chapter 14 ♦ Urinary; 



sis 



Key Points 

Urinalysis: Role in Kidney Disease 



Table 14.1 



Abnormalities in the urinalysis may signal 
kidney disease in the otherwise asympto- 
matic patient. 

Findings on the urinalysis provide insight 
into the cause of acute or chronic kidney 
disease. 

The evaluation of patients with suspected or 
known kidney disease should include his- 
tory, physical examination, directed blood 
testing, and radiologic studies, as well as 
complete examination of the urine. 




Urinalysis: Components 



Appearance 

Initial examination of urine consists of assess- 
ment of urine color and appearance. Normal 
urine is typically clear and light yellow in color. It 
tends to be lighter when more dilute (large water 
intake or polyuric states) and darker when more 
concentrated (overnight water restriction, prere- 
nal disease states). The urine may appear cloudy 
due to infection (white cells, bacteria, proteina- 
ceous material) or crystalluria (uric acid or calcium- 
containing crystals). The urine can look white 
from the presence of pyuria or calcium phos- 
phate crystals; green from drugs such as methyl- 
ene blue, amitriptyline, or propofol; or black due 
to certain malignancies or ochronosis. Table 14.1 
lists some of the substances that can alter urine 
color. While these urinary colors are unusual, var- 
ious shades of red or brown are more common. 
Intermittent excretion of red to brown urine 
occurs in a variety of clinical settings. Assessment 
of red/brown urine should proceed through the 
following steps: 



Substances That May Change the Color of Urine 



Substance 



Color 



Bilirubin 

Nitrofurantoin 

Chloroquine 

Sulfasalazine 

Serotonin 

Riboflavin 

Phosphate crystals 

(precipitated) 
Severe pyuria 
Chyle 

Phenazopyridine 
Heme pigments 
Hematuria 
Phenothiazines 
Senna, rhubarb, cascara, aloe 
Phenytoin 
Porphyrins 
Phenolphthalein 
Beets 
Melanin 

Homogentisic acid 
Phenol 

Porphobilinogen 
Methyldopa 
Quinine 
Metronidazole 
Ochronosis 
Certain malignancies 
Amitriptyline 
Methylene blue 
Biliverdin 
Propofol 
Pseudomonas infection 



Yellow-amber 



White 



Red-brown 



Brown-black 



Blue-green 



Centrifuge the urine and examine the sediment 

and supernatant. 

Red/brown sediment supports hematuria or 

acute tubular necrosis (with muddy brown 

casts). 



Chapter 14 ♦ Urinaly: 



sis 



211 



3. Red/brown supernatant should be examined 
further with dipstick testing for the presence of 
heme. 

4. Heme negative supernatant may be due to 
beeturia (beet ingestion in certain hosts), 
porphyria, or therapy with phenazopyridine 
(bladder analgesic). 

5. Heme positive supernatant may result from 
either hemoglobinuria or myoglobinuria. 
These are distinguished by examination of the 
plasma that will be red with hemoglobinuria 
and clear with myoglobinuria. 



Dipstick Examination of Urine 

Urine dipstick allows rapid examination of the 
urine for several abnormalities. They include spe- 
cific gravity, pH, protein, blood/heme, glucose, 
leukocyte esterase, nitrite, and bile. Each of these 
components of the dipstick, as well as their appli- 
cation to the evaluation of kidney disease will be 
discussed. 



Specific Gravity 



The kidney can vary urine osmolality to appropri- 
ately maintain plasma osmolality within a very 
narrow range. Thus, the osmolality of urine varies 
markedly based on the status of the patient's 
intravascular volume. To assess whether the 
kidney's response is appropriate or abnormal for 
the patient's volume status, measures of concen- 
trating ability are employed. Specific gravity is 
one such available test. Importantly, the specific 
gravity and other measures of urine concentrating 
ability are assessed in correlation with the 
patient's clinical state. The specific gravity is 
defined as the weight of a solution compared with 
that of an equal volume of water. As such, it is a 
reasonable reflection of concentrating ability. It is 
most useful in the diagnosis of patients with dis- 
orders of water homeostasis (hyponatremia, 
hypernatremia) and states of polyuria. It can vary 



significantly, however, with measured urine 
osmolality under certain clinical situations. For 
example, the presence of large molecules in the 
urine such as glucose and radiocontrast media can 
produce large changes in specific gravity, while 
having minimal effects on osmolality. These 
potential confounders must be accounted for 
when interpreting the specific gravity. 



UrinarypH 

Urine pH reflects the degree of acidification of 
urine; hence it is a measure of the urine hydrogen 
ion concentration. Urine pH normally ranges from 
4.5 to 8.0 based on the prevailing systemic acid- 
base balance. Examination of urine pH is most 
useful in the workup of a metabolic acidosis. The 
appropriate response to metabolic acidosis is an 
increase in renal acid (buffered hydrogen ion) 
excretion, with a reduction in urine pH to below 
5.5. Urine pH above 5.5 in the setting of metabolic 
acidosis may signal kidney disease, such as one of 
the forms of renal tubular acidosis (RTA). Changes 
in urine pH in response to various provocative 
tests can help distinguish which type of RTA 
exists. A urine pH less than 5.5 can also suggest 
risk for crystal and stone formation from uric acid, 
as "well as medications such as sulfadiazine and 
methotrexate. Alkaline pH (>7.0) can provide 
clues to various clinical disorders such as urinary 
infection with urease-producing organisms {Proteus 
mirabilis) and risk for crystal and stone formation 
from calcium phosphate and certain drugs (indi- 
navir). Management of these clinical disorders is 
assessed by measuring urine pH following the 
appropriate intervention. 



Urine Protein 

The urine dipstick measures albumin. It does 
not identify other proteins that may be found in 
the urine such as immunoglobulins and their 
light chains, or proteins secreted by tubular 
cells. Although the dipstick test is highly specific 



212 



Chapter 14 ♦ Urinary; 



sis 



for albumin, it is insensitive in the detection of 
urinary albumin levels that are less than 
300-500 mg/day. This is an important point as 
this makes the dipstick an unreliable test in the 
detection of microalbuminuria in certain patient 
populations. For example, microalbuminuria is 
an important early manifestation of diabetic 
nephropathy, one that would prompt changes 
in disease management. Waiting for dipstick 
positive proteinuria allows significant amounts 
of structural damage to occur prior to aggres- 
sively managing kidney disease. Similarly, 
microalbuminuria is associated with cardiovas- 
cular disease in nondiabetic patients and its 
detection would likely alter management in 
these patients. In addition to the insensitivity of 
the dipstick protein measurement, the semi- 
quantitative values (trace, 1+, 2+, 3+, 4+) obtained 
are only rough guides to actual amounts of pro- 
teinuria. Furthermore, these values should be 
interpreted cautiously recognizing that urine 
concentration, pH, and substances such as iodi- 
nated radiocontrast can influence the dipstick 
reading. For example, dilute urine can underes- 
timate the degree of proteinuria "while both 
concentrated urine and alkaline urine can over- 
estimate proteinuria. Finally, radiocontrast can 
cause a false-positive dipstick reading for pro- 
teinuria. Therefore, the urine should not be 
tested for at least 24 hours following radiocon- 
trast administration. Other tests to measure pro- 
teinuria are discussed later. 



Urine Blood/Heme 

Dipstick testing of urine for blood/heme is sensi- 
tive in detecting both red blood cells and heme 
pigment (hemoglobin or myoglobin) in urine. As 
few as one to two red blood cells per high-power 
field register positive on dipstick, making this test 
at least as sensitive as urine sediment examina- 
tion. False-positive results (heme pigments) for 
hematuria can, however, occur. In contrast, false- 
negative tests are unusual and a dipstick negative 
for heme reliably excludes hematuria. Importantly, 



the dipstick test for heme is never a substitute for 
a thorough urine sediment examination. All 
patients with hematuria on dipstick should have 
their urine spun down and the sediment exam- 
ined closely for any abnormalities, especially evi- 
dence of glomerular disease (dysmorphic red 
blood cells, red blood cell casts) or nephrolithia- 
sis (monomorphic red blood cells, crystals). 



Urine Glucose 

Dipstick testing for glucose is a relatively insen- 
sitive measure of hyperglycemia and is not 
recommended for screening of patients for dia- 
betes mellitus. Significant glycosuria does not 
occur until the mean plasma glucose concentra- 
tion is approximately 180 mg/dL. Additionally, it 
depends on urine volume. Also, glucose detected 
semiquantitatively on urine dipstick may reflect a 
kidney abnormality rather than hyperglycemia. 
Certain disease states may alter the ability of the 
kidney to reabsorb filtered glucose in the proxi- 
mal tubule despite normal plasma glucose con- 
centration. This renal glycosuria can manifest 
as an isolated proximal tubular defect. More 
commonly, it can develop in association with 
other defects in proximal tubular reabsorption 
including hypophosphatemia (phosphaturia), 
hypouricemia (uricosuria), renal tubular acidosis 
(bicarbonaturia), and aminoaciduria. This con- 
stellation of proximal tubular dysfunction is 
termed Fanconi's syndrome. This syndrome is 
hereditary or acquired through diseases (multiple 
myeloma) or drugs (toxins) that primarily injure 
proximal tubular cells in kidney. Drugs such as 
adefovir, cidofovir and tenofovir cause Fanconi's 
syndrome. 



Urine Leukocyte Esterase 

Positive dipstick testing for leukocyte esterase 
represents the presence of white blood cells in 
urine (pyuria). While the presence of urinary 
white blood cells most often reflects infection 



Chapter 14 ♦ Urinaly: 



sis 



213 



of the urinary tract, it can also be indicative of 
diseases associated with sterile pyuria. Included 
are tubulointerstitial nephritis from various 
causes, crystalluria and nephrolithiasis, and 
renal mycobacterial infection. As with hema- 
turia, a thorough examination of the urine sedi- 
ment should be performed in patients with 
pyuria. 



Urine Nitrite 

The urine nitrite test is most valuable when used 
in conjunction with leukocyte esterase to assess a 
patient for the presence of urinary tract infection. 
Certain bacteria (Enterobactericeae) convert uri- 
nary nitrate to nitrite (Figure 14.1). Thus, the com- 
bination of leukocyte esterase and nitrite positive 
tests on dipstick strongly suggests infection with 
this family of bacteria. 



Figure 14.1 



INGREDIENTS: 

■ p-Arsanilic acid 

■ N-(l-Naphthyl) ethylenediamine dihydrochloride 
• Acid buffer 



Urinary 
nitrate 



Bacteria 



Nitrite + p-Arsanilic acid 



Urinary 
* nitrite 

Diazonium compound 



Diazonium compound + N-(l-Naphthyl) Ethylenediamine -*■ 
Diazonium complex (pink color) 



Laboratory components of the nitrite test used to identify bac- 
teria in the urine. The conversion of nitrate to nitrite results in 
the production of a pink-colored diazonium complex. 



Urine Bile 

Bile present on urine dipstick reflects the filtra- 
tion of serum bilirubin. Normal bile pigment 
metabolism is shown in Figure 14.2. The finding 



Figure 14.2 



Hemoglobin 



Reticuloendothelial system 



i 



Free bilirubin 



Conjugated bilirubin and urobilinogen excreted in bile 




Free bilirubin converted to 
conjugated bilirubin in the liver 



Urobilinogen 
reabsorbed 



'\ f HITS \ j Bilirubin converted to 



Urobilinogen excreted 
in urine 



w 



yy 



n 



urobilinogen in intestine 



Pathway of normal bile pigment metabolism. Free bilirubin is converted in the liver and 
intestine to urobilinogen that is subsequently excreted in the urine. 



214 



Chapter 14 ♦ Urinary; 



sis 



14.2 



Conditions Associated with Urine Urobilinogen 
and Urine 1 





Urine 


Urine 


Condition 


Bilirubin 


Urobilinogen 


Normal 


- 


+ 


Hepatitis 


+ 


+ 


Hepatotoxins 


+ 


+ 


Biliary obstruction 


+ 


- 


Cirrhosis 


+ 


+ 



for other defects in proximal tubular func- 
tion and, if present, evaluation for the cause 
of Fanconi's syndrome. 
Urinary tract infection is likely in patients 
with urine dipstick positive for both leuko- 
cyte esterase and nitrite. Isolated positive 
leukocyte esterase with a negative urine 
culture result should promote evaluation 
for causes of sterile pyuria such as tubuloin- 
terstitial nephritis. 



of bile pigment is common in patients with vari- 
ous forms of liver disease with associated hyper- 
bilirubinemia. It does not represent a disturbance 
in kidney function although liver disease may 
be associated with renal failure (hepatorenal 
syndrome). Testing for urine bilirubin and uro- 
bilinogen separates obstructive jaundice from 
other forms of liver disease. In this situation, 
complete biliary obstruction has positive urine 
bilirubin with negative urobilinogen, while other 
forms of liver disease are positive for both sub- 
stances (Table 14.2). 



Key Points 




Urinalysis: Components 



Dipstick examination of the urine provides 
useful information about patients with various 
forms of kidney disease. 
A red or brown appearance of urine is 
appropriately evaluated with dipstick testing 
and urine sediment examination. 
Dipstick proteinuria identifies urinary albu- 
min excretion greater than 300-500 mg/day 
but does not measure nonalbumin proteins. 
Glycosuria in patients with normal plasma 
glucose concentration suggests a proximal 
tubular disturbance in glucose reabsorption. 
This finding should stimulate investigation 



Urine Sediment Examination 



Microscopy of the urine sediment is a very important 
aspect of the evaluation of patients with known or 
suspected kidney disease. It is important to also 
recognize that normal subjects without kidney dis- 
ease may also have minor amounts of abnormal ele- 
ments (red blood cells, white blood cells, casts, and 
crystals) in the urine. For example, a patient without 
kidney disease may have zero to four white blood 
cells or zero to two red blood cells in one high- 
power field and one cast, often hyaline in 10-20 
low-powered fields. Additionally, a few crystals 
made up of uric acid, calcium oxalate, or calcium 
phosphate may occasionally be observed. A greater 
number of these elements in the urine is, however, 
very suggestive of either systemic or renal-related 
disease states. Various elements found in urine on 
sediment examination are described below. 



Cellular Elements 

The most common cell types observed in urine are 
red blood cells, white blood cells, and epithelial 
cells. The urine can also contain cells from the 
bladder, and when contaminated during collec- 
tion, vaginal squamous cells can be noted. Less 
commonly, tumor cells from the uroepithelium 



Chapter 14 ♦ Urinaly: 



sis 



215 



(bladder and ureteral epithelium), lymphoma, or 
leukemic cells that have infiltrated the renal 
parenchyma, and "decoy cells" associated with 
BK-polyoma virus-induced changes in renal tubu- 
lar cells or uroepithelial cells are identified in 
urine sediment. The various cellular elements 
present in urine are reviewed. 



Red Blood Cells 

The presence of red blood cells in urine, either 
microscopic or visible grossly, is called hematuria. 
Hematuria can be transient and benign, or alterna- 
tively, signal a disease of the kidneys or urogeni- 
tal tract. Microscopic hematuria is defined as two 
or more red blood cells per high-power field in a 
spun urine sediment. Red cell morphology is 
useful to help localize the source of injury or dis- 
ease within the kidneys or elsewhere in the uri- 
nary system. Monomorphic red cells, which 
appear round and uniform like those seen on a 
peripheral blood smear, typically suggest extrarenal 
bleeding (Figure 14.3). In contrast, dysmorphic 
red cells often indicate a renal lesion, in particular 
a glomerular process. The morphology of dys- 
morphic red cells is characterized by blebbing, 
budding, and partial loss of the cellular mem- 
brane. Acanthocytes are one form of dysmorphic 
red cell that have a ring form with vesicle-shaped 
protrusions. This process results in altered red cell 
size (smaller) and shape. Monomorphic and dys- 
morphic red cells may be difficult to distinguish 
on routine urine microscopy. Phase contrast 
microscopy and scanning electron microscopy of 
urine more accurately identify red cell morphol- 
ogy but are not routinely available in most clinical 
settings. Persistent hematuria most often signals 
nephrolithiasis, glomerular pathology, or malig- 
nancy of the kidneys or urinary tract. 



White Blood Cells 

White blood cells in urine, known as pyuria, are 
larger than red blood cells and have a granular 



Figure 14.3 




f 

O . 

o 



& 



o C 



8 l3W$P% & 




Monomorphic red blood cells in the urine sediment. The 
red cells are the smaller uniform cells without nuclei. 
(With permission from Graff, L. (ed), A Handbook of 
Routine Urinalysis. J.B. Lippincott, Philadelphia, PA, 
1983.) 



cytoplasm. Neutrophils are the most common 
white blood cells in urine. They have multilobed 
nuclei, and often signal infection of the urinary 
tract or kidney (Figure 14.4). Eosinophils with 
their bilobed nuclei, may also be observed in 
urine on Wright's stain or Hansel's stain, which 
stains the granules bright red. Once thought to 
indicate the presence of acute interstitial nephri- 
tis, urinary eosinophils are seen with various renal 
processes including cholesterol emboli, glomeru- 
lonephritis, urinary tract infection, and prostatitis. 
Lymphocytes may also be visualized in urine. 
These cells are observed in urine sediment when 
lymphocytes, which are present in the renal inter- 
stitium, are shed into the urine. Examples are 
chronic tubulointerstitial diseases such as sar- 
coidosis and uveitis-tubulointerstitial nephritis 
syndrome. The nucleus of a lymphocyte is circu- 
lar and uniform and not divided into lobes. 



216 
Figure 14.4 



Chapter 14 ♦ Urinary; 



sis 




White blood cells in the urine sediment. White cells have a 
multilobed nucleus and a granular cytoplasm. (With permis- 
sion from Graff, L. (ed.), A Handbook of Routine Urinalysis. 
J.B. Lippincott, Philadelphia, PA, 1983.) 



Epithelial Cells 

While epithelial cells can be shed into urine from 
any part of the genitourinary system, only renal 
tubular epithelial cells have clinical relevance. In 
general, renal tubular epithelial cells are several 
times larger than white blood cells; however, their 
size varies greatly (Figure 14.5). Also, their nuclei 
are round and located centrally in the cytoplasm. 
It is often difficult to distinguish these cells from 
uroepithelial cells from the lower urinary tract, 
making the presence of renal tubular epithelial 
cell casts diagnostically important. Renal tubular 
epithelial cells and casts are essentially diagnostic 
of either ischemic or nephrotoxic acute tubular 
necrosis, but occasionally are seen with glomeru- 
lar disease. Lipid-filled tubular epithelial cells and 
free fat droplets (Maltese cross-appearance when 
polarized) are present in the urine sediment of 
patients with high-grade proteinuria. 



Malignant Cells 

Close scrutiny of urine can sometimes discover 
cancer present in the kidneys or genitourinary tract. 



Figure 14.5 






% 











Renal tubular epithelial cells in the urine sediment. 
Renal tubular epithelial cells have a central uniform 
nucleus and are larger than white blood cells. (With 
permission from Graff, L. (ed.), A Handbook of Routine 
Urinalysis. J.B. Lippincott, Philadelphia, PA, 1983) 



Atypical lymphocytes or lymphoid cells observed 
in the urine sediment can represent lymphoma of 
the kidneys or bladder. Similarly, leukemic cells 
may be present in urine, signaling leukemic infil- 
tration of the kidneys, or genitourinary tract. 
Tumor cells of uroepithelial origin are noted in 
the urine sediment when ureteral or bladder 
cancer is present. 



Decoy Cells 



Examination of the urine sediment in renal trans- 
plant patients treated with tacrolimus or myco- 
phenylate mofetil can confirm the presence of 
BK-polyoma virus infection if "decoy cells" are 
demonstrated. These cells are renal tubular 
epithelial cells and other uroepithelial cells that 



Chapter 14 ♦ Urinaly: 



sis 



217 



manifest changes associated with viral infection. 
These cells are best visualized employing Papan- 
icolaou-stained urine sediment or phase contrast 
microscopy of unstained urine sediment. Several 
cellular findings characterize "decoy cells." They 
include: (1) ground glass nucleus; (2) chromatin 
margination; (3) course granules (chromatin pat- 
terns); (4) nuclear body inclusions with a periph- 
eral halo; and (5) cytoplasmic vacuoles. Virus 
particles are seen when scanning electron 
microscopy is used. 



Other Cellular Elements 



6. 



7. 



nephritis, nephrolithiasis, and renal 

mycobacterial infection. 

Tubular epithelial cells are commonly seen 

when acute tubular necrosis from ischemia 

or nephrotoxins is present. 

Rarely, malignant cells are observed in the 

urine sediment. Examples include renal and 

bladder lymphoma and uroepithelial tumors 

of the ureters and bladder. 

"Decoy cells" represent epithelial cells 

infected with BK-polyoma virus in renal 

transplant patients. 



Bacteria are quite commonly seen in urine sedi- 
ment during infection of the urinary tract. Rarely, 
other infectious organisms are seen in the urine 
sediment. Included are Candida albicans, Cocci- 
diodes immitis, Mycobacterium tuberculosis, 
Cryptococcus neoformans, Curvularia species, 
and Schistosoma haematobium. These organisms 
are often found associated with white blood cells, 
red blood cells, abnormal epithelial cells, and 
cellular casts. 



Key Points 



Urine Sediment Examination 



Examination of the urine sediment is crucial 
to provide insight into the cause of kidney 
disease. 

Cellular elements present in the urine sedi- 
ment include red blood cells, white blood 
cells, epithelial cells, tumor cells, decoy 
cells, and various infectious agents. 
Red blood cell morphology can distinguish 
glomerular bleeding (dysmorphic cells with 
blebbing) from nonglomerular bleeding 
(monomorphic cells). 
White blood cells in urine are indicative of 
urinary infection or processes associated 
with sterile pyuria such as interstitial 




Urine Casts 



Casts observed in urine are formed within renal 
tubular lumens and, therefore, conform to the 
shape of these lumens. They are typically cylindri- 
cal with regular margins, but can be fractured 
during the process of spinning and placing the sed- 
iment on the glass slide. All casts have an organic 
matrix that is composed primarily of Tamm-Horsfall 
mucoprotein that is synthesized and released at the 
thick ascending limb of the loop of Henle. Various 
urinary casts are observed in urine, some in normal 
subjects. Often, the presence of casts in urine repre- 
sents significant kidney disease, suggesting an 
intrarenal origin. The diverse casts that can be 
viewed in the urine sediment are reviewed below. 



Hyaline Casts 

These slightly refractile casts (Figure 14.6) are not 
associated with any particular disease. Hyaline 
casts may occur in a frequency as high as 5-10 per 
high-power field. They are found in small vol- 
umes of concentrated urine and following diuretic 
therapy. 



218 
Figure 14.6 



Chapter 14 ♦ Urinary; 



sis 




Hyaline cast in the urine sediment. Hyaline casts are acellular 
and are seen in normal urinary sediment. (With permission 
from Graff, L. (ed.), A Handbook of Routine Urinalysis. J.B. 
Lippincott, Philadelphia, PA, 1983.) 



Red Blood Cell Casts 

The demonstration or even one red blood cell cast 
is significant for glomerulonephritis or vasculitis. 
These casts are difficult to find and require thor- 
ough evaluation or the entire sediment on the 
microscope slide. Red blood cell casts are often 
found with free dysmorphic red cells (Figure 14.7). 



Figure 14. 7 




Red blood cell cast in the urine sediment. Red cell casts 
are the hallmark of glomerulonephritis. (With permis- 
sion from Graff, L. (ed.), A Handbook of Routine 
Urinalysis. J.B. Lippincott, Philadelphia, PA, 1983.) 




White blood cell cast in the urine sediment. White cell casts 
are often seen in diseases of the tubulointerstitium. (With 
permission from Graff, L. (ed.), A Handbook of Routine 
Urinalysis. J.B. Lippincott, Philadelphia, PA, 1983) 



These casts typically contain red cells within a 
hyaline or granular cast; although sometimes the 
cast can be tightly packed with red blood cells. 



White Blood Cell Casts 

Casts containing white blood cells (Figure 14.8) 
are found most commonly in the urine sediment 
ol' patients with acute pyelonephritis or tubuloin- 
terstitial disease. Occasionally, these casts are also 
present with other inflammatory diseases ot" the 
kidney such as glomerular disorders, vasculitis, 
and cholesterol emboli. Like red cell casts, white 
blood cell casts are often found with free white 
cells such as neutrophils with pyelonephritis and 
eosinophils with acute interstitial nephritis. 



Epithelial Cell Casts 

Injury to the tubular epithelium with the devel- 
opment or necrosis causes shedding or cells into 
the lumen. This is the proximate cause or renal 
tubular epithelial cell casts in urine sediment. The 
casts contain tubular epithelial cells or varying 
sizes and shapes admixed with granular material. 
Free renal tubular epithelial cells are also present 



Chapter 14 ♦ Urinaly: 



sis 



219 



in the sediment. While desquamation of these 
cells is most indicative of tubular injury and 
necrosis, they are also observed with glomeru- 
lonephritis and vasculitis. 



waxy casts suggests advanced kidney disease. 
Once again, the company these casts keep pro- 
vides useful diagnostic information. 



Granular Casts 

Casts containing granular debris (Figure 14.9) rep- 
resent degenerating cells of various origins. While 
most often seen with acute tubular necrosis from 
degenerating tubular epithelial cells, they can also 
be degraded red blood cells or white blood cells. 
Thus, it is important to assess these casts along 
with other urinalysis findings (protein, other cell 
types present in urine, and their morphology), as 
well as the pertinent clinical data. 



Casts 



As granular casts continue to degenerate, they 
form waxy casts. Since this is a relatively slow 
process, the presence of significant numbers of 



Figure 14.9 



r * "* 

J 


k 






■ 








■ > 








<6 








■■ M 


E 




^ 




i 




» 


i 









Granular cast in the urine sediment. Granular casts are com- 
posed of degenerating cells and reflect tubular injury. They 
are often seen in acute tubular necrosis. (With permission 
from Graff, L. (ed.), A Handbook of Routine Urinalysis. J.B. 
Lippincott, Philadelphia, PA, 1983.) 



Broad Casts 

As their name implies, broad casts are wider than 
other casts and are thought to form in large 
(dilated) tubules of nephrons with sluggish urine 
flow. They often are granular or waxy, and like 
■waxy casts are indicative of advanced kidney 
disease. 



Fatty Casts 

Tubular epithelial cells filled with lipid droplets 
are known as oval fat bodies (Figure 14.10). Those 
contained in a cast matrix constitute fatty casts. 
These casts are found in patients with significant 
levels of proteinuria and lipiduria, and are observed 



Figure 14.10 




Lipid-filled tubular epithelial cells (oval fat body) in 
the urine sediment. Oval fat bodies are seen with 
nephrotic syndrome (With permission from Graff, L. 
(ed.), A Handbook of Routine Urinalysis. J.B. 
Lippincott, Philadelphia, PA, 1983.) 



220 



Chapter 14 ♦ Urinary; 



sis 



in the nephrotic syndrome. The droplets are com- 
posed of cholesterol and cholesterol esters, both 
of which can be seen free in the urine. 



with both white and red blood cells. The different 
crystals seen in urine are reviewed. 



Key Points 

Urine Casts 



Urinary casts are formed in the tubular 
space, and as such are cylindrical in shape 
and composed of an organic matrix consist- 
ing of Tamm-Horsfall protein. At times, 
various cellular elements are contained in 
the casts. 

Red blooci cell casts are indicative of 
glomerulonephritis or vasculitis; even one 
cast is very significant. 
White blood cell casts are seen in the set- 
ting of acute pyelonephritis or interstitial 
nephritis. 

Renal tubular epithelial cell casts, along 
with granular casts and free epithelial cells 
are commonly seen with acute tubular 
necrosis. 

Fatty casts develop in urine in diseases asso- 
ciated with high-grade proteinuria 
(nephrotic range). They are refractile casts 
containing tubular epithelial cells filled with 
cholesterol and cholesterol esters. 




Urine Crystals 



The formation of crystals in urine depends on a 
variety of factors. The most important factors 
include the degree of supersaturation of con- 
stituent molecules, urine pH, and the presence or 
absence of inhibitors of crystallization. These 
crystals may form in normal subjects, as well as in 
patients with known disorders associated with 
crystalluria. Not uncommonly, crystals are admixed 



Uric Acid Crystals 

Acid urine favors the conversion of relatively solu- 
ble urate salts into insoluble uric acid. As a result 
of this milieu, uric acid crystals and amorphous 
urates form in urine and cause either asympto- 
matic crystalluria, renal failure from crystal-induced 
tubular obstruction, or nephrolithiasis. In parti- 
cular, tumor lysis syndrome can cause severe uric 
acid crystalluria and acute renal failure. Low urine 
volumes also contribute to the formation of uric 
acid crystals and stone formation. These crystals 
are pleomorphic and can be rhombic or rosette 
shaped (Figure 14.11). They can be easily identi- 
fied under polarized light. 



Calcium Oxalate Crystals 

The formation of calcium oxalate crystals is inde- 
pendent of urine pH. Excess urinary oxalate, as 



Figure 14.11 




Uric acid crystals in the urine sediment. Uric acid crystals can 
be rhomboid or needle-shaped and may be a normal finding 
in an acidic urine. (With permission from Graff, L. (ed.), A 
Handbook of Routine Urinalysis. J.B. Lippincott, Philadelphia, 
PA, 1983.) 



Chapter 14 ♦ Urinalysis 



221 



Figure 14. 12 



Figure 14.13 




Calcium oxalate crystals in the urine sediment. 
Calcium oxalate may crystalize in a monohydrate or 
dihydrate form. The dihydrate form is shown in this 
figure. (With permission from Graff, L. (ed.), A 
Handbook of Routine Urinalysis. J.B. Lippincott, 
Philadelphia, PA, 1983.) 



seen with ethylene glycol ingestion and short 
bowel syndrome, is associated with calcium 
oxalate crystal excretion and nephrolithiasis. Also, 
hypocitraturia is an important contributor to the 
formation of calcium oxalate crystals. These crystals 
are envelope-shaped if calcium oxalate dihydrate 
(Figure 14.12) or dumbbell or needle-shaped if 
calcium oxalate monohydrate. 



Calcium Phosphate Crystals 

In contrast to calcium oxalate crystals, an alkaline 
pH increases the formation of calcium phosphate 
crystals. Hypercalciuria also contributes impor- 
tantly to calcium phosphate crystalluria. These 
crystals are seen in patients with renal tubular aci- 
dosis and can cause cloudy white urine, hema- 
turia, and kidney stones. 



Cystine Crystals 

Cystine crystals are observed in urine of patients 
with the hereditary disorder known as cystinuria. 
The crystals tend to precipitate when their 




Cystine crystals in the urine sediment. Cystine crystals are 
hexagon shaped and are the hallmark of cystinuria. (With 
permission from Graff, L. (ed.), A Handbook of Routine 
Urinalysis. J.B. Lippincott, Philadelphia, PA, 1983) 



concentration exceeds 250 mg/L of urine. Acid 
urine also increases crystallization. The crystals 
are hexagonal; their presence in urine is diagnostic 
of cystinuria (Figure 14.13). 



Magnesium Ammonium Phosphate Crystals 

Struvite or "infection stones" are made up of two 
constituents — magnesium ammonium phosphate 
and calcium carbonate-apatite. Normal urine is 
never supersaturated with ammonium phosphate, 
however, infection with certain bacteria increase 
the ammonia concentration (and hence the pH) 
through urease production. The alkaline pH 
(>7.0) decreases the solubility of phosphate and 
contributes to both crystal and stone formation. 
Struvite crystals appear as coffin lid covers in the 
urine sediment (Figure 14.14). 



Drug-Associated Crystals 

A number of medications can cause crystal forma- 
tion in urine. Most occur due to supersaturation of 
a low volume urine with the culprit drug, while 
others develop due to drug insolubility in either 
alkaline or acid urine pH. Acyclovir crystals, noted 
as needle-shaped crystals that polarize, occur when 
the drug is rapidly infused in volume-depleted 



Chapter 14 ♦ 



sis 



mre 14.14 



■ 






>, 






'•■'** 


-*■■, 






\ 






\ 






\^ 




* 






v 


• 











Triple phosphate crystals in the urine sediment. 
Triple phosphate crystals are shaped like a 
coffin lid and are only seen in urine infected 
with urease-producing bacteria. (With permis- 
sion from Graff, L. (ed.), A Handbook of Routine 
Urinalysis. J.B. Lippincott, Philadelphia, PA, 
1983.) 



patients. Excess drug dose for the level of renal 
function also contributes to crystalluria. This can 
result in acute renal failure. Urine pH is unimpor- 
tant in the development of acyclovir crystals. 
Alkaline urine pH contributes importantly to the 
formation of crystalluria with drugs such as 
methotrexate, sulfadiazine, and triamterene. 
Volume depletion "with low urinary flow rates also 
enhances crystalluria with these drugs. All of 
these medications are associated with acute renal 
failure, while both sulfadiazine and triamterene 
also cause renal stone formation. Indinavir, a pro- 
tease inhibitor, is also associated with crystalluria. 
Both volume depletion and alkaline urine 
enhance crystallization and nephrolithiasis from 
indinavir. Approximately 20% of patients are 
unable to take indinavir due to symptomatic crys- 
talluria or stone formation. Other therapeutic 
agents associated with urinary crystals include 
pyridium, amoxacillin, ampicillin, aspirin, xylitol, 



foscarnet, cephalexin, ciprofloxacin, primidone, 
piridoxylate, and vitamin C. 



Key Points 



Urine Crystals 



A variety of crystals can be viewed in urine. 
Some can occur in normal subjects, as well 
as patients with defined disease states. 
Urinary crystals can be asymptomatic, cause 
hematuria or renal failure, or form kidney 
stones. 

Uric acid crystals form in acid urine. Patients 
may develop acute renal failure and 
nephrolithiasis from uric acid crystalluria. 
Calcium oxalate crystals can be envelope- 
shaped, dumbbell-shaped, or needle-like 
when viewed in the urine sediment. High 
urine oxalate and hypocitraturia are common 
causes of the formation of these crystals. 
Cystine crystals signal the hereditary disease 
cystinuria. Crystal formation occurs with 
excessive cystine concentration in the urine 
(>250 mg/L), as well as a urine pH <7.0. 
Medication-induced crystals develop from 
insoluble drug characteristics, low urine 
flow rates, and either acid or alkaline pH 
(depending on the drug). They can be asso- 
ciated with asymptomatic crystalluria, hema- 
turia and pyuria, renal failure, and kidney 
stone formation. 




Tests of Urinary Protein Excretion 



In addition to the aforementioned dipstick tests of 
urine, other important tests are required in the 
evaluation of patients with proteinuria and kidney 
disease. Perhaps one of the most important uri- 
nary markers of disease progression is urinary 
protein excretion. While the dipstick protein 



Chapter 14 ♦ Urinaly: 



sis 



223 



measurement is a specific test, it provides only a 
rough guide to the actual degree of proteinuria. 
Protein detection on dipstick should stimulate 
more accurate assessment of proteinuria. High-risk 
populations like diabetics should have screening 
with more sensitive measures of albuminuria. The 
following section will discuss tests that should be 
employed to more fully evaluate patients with 
known or suspected kidney disease. 



Sulfosalicylic Acid Test 

The sulfosalicylic acid (SSA) test, in contrast to the 
dipstick, detects all proteins in urine. The SSA 
gained its major usage in the assessment of elderly 
patients with renal failure, a benign urine sediment, 
and negative or trace protein on dipstick who were 
suspected of having myeloma kidney. A strikingly 
positive SSA test in such a patient is consistent with 
the presence of nonalbumin proteins, such as 
immunoglobulin light chains in urine. The SSA is 
performed by mixing one part urine supernatant 
with three parts (3%) sulfosalicylic acid. The result- 
ant turbidity is graded as follows with approximate 
protein concentrations in the parentheses: 

= no turbidity (0 mg/dL) 

trace = slight turbidity (1-10 mg/dL) 

1+ = turbidity through which print can be read 

(15 mg to 30 mg/dL) 

2+ = white cloud without precipitate (40 mg to 

100 mg/dL) 

3+ = white cloud with fine precipitate (150 mg to 

350 mg/dL) 

4+ = flocculent precipitate (>500 mg/dL) 

The rapid availability and accuracy of the random 
spot urine protein: creatinine ratio has, however, lim- 
ited the use of the SSA test in clinical medicine. 



Spot Protein: Creatinine Ratio 

Several studies confirmed the accuracy of the 
random spot measurement of protein and creati- 
nine in estimating 24-hour urine protein excretion. 
The protein:creatinine ratio correlates closely with 



the 24-hour measurement of protein in g/1.73 m 2 
of body surface area. The units of measure for the 
urine protein and creatinine are required to be 
identical to allow the calculation of the ratio. The 
following case illustrates the use of spot urinary 
protein and creatinine in the estimation of daily 
protein excretion. 

A 41-year-old patient with diabetic nephropathy 
is on therapy with an ACE-inhibitor (lisinopril 
40 mg/day). An angiotensin receptor blocker 
(losartan 100 mg/day) is added in an attempt to 
reduce proteinuria. Prior to losartan, daily urinary 
protein excretion was 2.1 g. A random spot urine is 
sent for protein and creatinine concentration to 
monitor response to the addition of losartan after 8 
weeks of therapy. Urine protein concentration is 
110 mg/dL and creatinine concentration is 90 mg/dL 
(110 mg/dL/90 mg/dL = 1.2); thus the ratio is 1.2. 
This is equivalent to a urinary protein excretion of 
1.2 g/day. 

Daily protein excretion above 150 mg/day, 
when documented on more than one measure- 
ment, is considered abnormal and the patient 
should undergo a thorough investigation to diag- 
nose and treat the underlying kidney disease. The 
Work Group of the Kidney Disease Outcome 
Quality Initiative (K-DOQI) of the National Kidney 
Foundation recommends use of the random spot 
protein:creatinine ratio to evaluate and monitor 
proteinuria in patients at risk for or with known 
kidney disease. 

Like the spot protein:creatinine ratio, the random 
spot albumin:creatinine ratio is invaluable in the 
diagnosis of microalbuminuria and for monitoring 
the status of microalbuminuria in patients with dia- 
betes mellitus. This test accurately estimates urine 
albumin excretion. Albumin concentrations in the 
30-300 mg/day range are considered diagnostic of 
microalbuminuria. Microalbuminuria is confirmed 
with more than a single urine sample since several 
factors can increase urinary albumin excretion. 



24-Hour Urine Collection 

The 24-hour urine collection for protein and cre- 
atinine is considered the gold standard measure of 



Chapter 14 ♦ Urinary; 



sis 



urine protein excretion. It is more accurate than 
the random spot urine protein estimation and 
allows simultaneous calculation of creatinine 
clearance. In addition, it detects changes in urine 
creatinine excretion from vigorous exercise, high 
meat or vegetarian diet, creatine supplementa- 
tion, and medications that effect creatinine pro- 
duction. All of these can confound the urine 
creatinine excretion and render the spot measure- 
ment less accurate. Finally, the 24-hour urine col- 
lection provides relevant information regarding 
nutrient and fluid intake by measuring urine 
volume, urea, sodium, and potassium. The bene- 
fits of this test are, however, compromised by its 
cumbersome nature in the ambulatory setting. 
Many patients are unwilling to perform these col- 
lections on a regular basis, making the random 
spot protein: creatinine ratio invaluable in moni- 
toring proteinuria. 

In patients •with diseases associated with the 
production of monoclonal proteins (immunoglob- 
ulins or light chains) and those considered as 
potentially having these disorders, collection of 
24-hour urine is required. Such diseases include 
multiple myeloma, primary amyloidosis, some 
lymphomas, and diseases associated with mono- 
clonal light or heavy chain production. This urine 
collection will allow the measurement of both pro- 
tein electrophoresis and Immunoelectrophoresis, 
detecting the presence of monoclonal proteins. 
The 24-hour urine collection is also useful in the 
evaluation and treatment of patients with certain 
forms of hypertension (primary aldosteronism 
and pheochromocytoma) and nephrolithiasis. 



Key Points 

Tests of Urinary Protein Excretion 



The SSA test, 'which measures all urinary 
proteins, is useful to evaluate patients with 
negative dipstick protein measurement who 
are suspected of having a disorder associ- 
ated with monoclonal immunoglobulin pro- 
duction. 



The random spot protein: creatinine ratio 
accurately estimates 24-hour urine protein 
excretion and is recommended as the test of 
choice to monitor patients with proteinuric 
kidney disease. 

The 24-hour urine collection for protein 
and creatinine is the most precise measure 
of proteinuria and provides insight into 
renal function from the creatinine clearance 
calculation. 




As with any test in clinical medicine, urinalysis is 
most useful diagnostically when different compo- 
nents of the test are combined to allow patterns of 
urinary findings to associate with different kidney 
diseases. Often times, the combination of urinary 
findings will suggest only one or two renal disor- 
ders. Below are examples to illustrate the point. 
Table 14.3 also demonstrates the use of urinalysis 
and urine sediment examination in the detection 
of various kidney disease states. 



Isolated Hematuria with Monomorphic 
Red Blood Cells 

The differential diagnosis of this combination of 
findings is limited to crystalluria, nephrolithiasis, 
or malignancy of the genitourinary system. Rarely, 
glomerular disorders such as IgA nephropathy or 
thin basement membrane disease may present 
in this way. Patients with these glomerulo- 
pathies often have, however, dysmorphic red 
blood cells and red blood cell casts in the urine 
sediment. 



Chapter 14 ♦ Urinaly: 



sis 



225 



14.3 



Urinalysis and Microscopic Examination of the Urine Sediment 



Test 


Prerenal 


Vasculitis 


GN 


ATN 


AIN 


Postrenal 


Specific gravity 


High 


Normal/high 


Normal/high 


Isosmotic 


Isosmotic 


Isosmotic 




>1.020 


1.010-1.020 


1.010-1.020 


1.010 


1.010 


1.010 


Blood (dip) 


Negative 


Positive 


Positive 


± 


± 


Negative 


Protein (dip) 


Negative 


Positive 


Positive 


Negative 


± 


Negative 


Sediment 


Negative, 


RBC casts, 


RBC casts, 


Granular 


WBC casts, 


Negative, 


examination 


hyaline 


dysmorphic 


dysmorphic 


casts, RTEs 


eosinophils 


sometimes 




casts 


RBCs 


RBCs 






WBCs/RBCs 



Abbreviations: GN, glomerulonephritis; ATN, acute tubular necrosis; AIN, acute interstitial nephritis; RBC, red blood cells; WBC, white blood cells 
RTE, renal tubular epithelial cells. 



Hematuria with Dysmorphic Red Blood 
Cells, Red Blood Cell Casts, 
and Proteinuria 

Patients with this constellation of findings are 
likely to have a glomerular disease or renal vas- 
culitis. As discussed in chapter 17, this presenta- 
tion is termed nephritic syndrome and strongly 
suggests glomerulonephritis. Importantly, the 
absence of these findings does not exclude 
glomerulonephritis. A kidney biopsy may be indi- 
cated in this situation. 



Hematuria with Dysmorphic Red Blood Cells 
and Pyuria with White Blood Cells 

This combination of urinary findings is seen with 
various kidney processes. Included are glomeru- 
lar disease, tubulointerstitial nephritis, vasculitis, 
urinary obstruction, crystalluria (typically the 
offending crystal is also present), cholesterol 
embolization, and renal infarction. All these dis- 
ease states can injure the kidney and cause an 
inflammatory lesion within the renal paren- 
chyma. 



Free Tubular Epithelial Cells, Epithelial Cell 
Casts, and Granular Casts 

The patient with acute renal failure and this com- 
bination of urinary findings is likely to suffer from 
acute tubular necrosis induced by either an 
ischemic event or administration of a nephro- 
toxin, or both. The injured tubular cells are 
sloughed into the tubular lumen and form a cast 
in combination with Tamm-Horsfall matrix pro- 
tein. Marked hyperbilirubinemia can also cause 
this urinary sediment; usually the serum bilirubin 
concentration "will exceed 10 mg/dL and the dip- 
stick is strongly positive for bile. The cells and 
casts are also stained with bile. 



Free White Blood Cells, White Blood Cell 
Casts, Granular Casts, and Mild Proteinuria 

These urinary findings are seen in patients with 
tubulointerstitial disease. They include pyelonephri- 
tis, drug-induced tubulointerstitial nephritis, and 
systemic diseases such as sarcoidosis. Rarely, an 
acute glomerulonephritis or other inflammatory 
renal disease may have this sediment. Evidence of 



226 



Chapter 14 ♦ Urinary; 



sis 



glomerular disease is, however, also usually 
present (heme positive dipstick, dysmorphic red 
blood cells) in these disease processes. 



Bland Urine Sediment and High-Grade 
(4+) Proteinuria 

This combination of findings on urinalysis sug- 
gests the patient has a glomerular lesion associ- 
ated with the nephrotic syndrome. A bland urine 
sediment, defined as the absence of cells or casts, 
suggests a noninflammatory glomerular lesion. 
Lipiduria with Maltese crosses and fatty casts may 
also be present in the urine sediment. Some of the 
glomerular lesions that cause nephrotic syndrome 
include membranous glomerulonephritis, focal 
glomerulosclerosis, minimal change disease, mem- 
branoproliferative glomerulonephritis, mesangial 
proliferative glomerulonephritis, amyloidosis, 
and diabetic nephropathy. 



Additional Reading 

Bradley, M., Schulmann, G.B. Examination of the urine. 
In: Bernarci, J.H. (ed.), Clinical Diagnosis and 
Management by Laboratory Methods . W.B. Saunders, 
Philadelphia, PA, 1984, pp. 38CM58. 

Faber, M.D., Kupin, W.L., Krishna, G.G., Narins, R.G. 
The differential diagnosis of acute renal failure. In: 
Acute Renal Failure, 3rd ed., 1993, pp. 133-192. 



Fairley, K.F., Birch, D.F Hematuria: a simple method 

for identifying glomerular bleeding. Kidney Int 

21:105-108, 1982. 
Fogazzi, G.B., Garigali, G. The clinical art and science 

of urine microscopy. Curr Opin Nephrol Hypertens 

12:625-632, 2003. 
Haber, M.H., Corwin, H.L. Urinalysis. Clin Lab Med 

8:415-621, 1988. 
Kurtzmann, N.A., Rogers, P.W. A Handbook of 

Urinalysis and Urinary Sediment. Charles C. Thomas, 

Springfield, IL, 1974. 
National Kidney Foundation (NKF) Kidney Disease 

Outcome Quality Initiative (K/DOQI) Advisory 

Board. K/DOQI clinical practice guidelines for 

chronic kidney disease: evaluation. Classification 

and stratification. Kidney Disease Outcome Quality 

Initiative. Am J Kidney Dis 39(Suppl. 2):S1-S246, 

2002. 
Perazella, M.A. Crystal-induced acute renal failure. Am 

J Med 106:459-465, 1999. 
Pollock, C, Pei-Ling, L, Gyory, A.Z., Grigg, R., Gallery, 

E.D., Caterson, R., Ibels, L., Mahony, J., Waugh, D. 

Dysmorphism of urinary red blood cells value in 

diagnosis. Kidney Lnt 36:1045-1049, 1989. 
Schwab, S.J., Christensen, R.L., Dougherty, K, Klahr, S. 

Quantitation of proteinuria by the use of protein-to- 

creatinine ratios in single urine samples. Arch Intern 

Med 147:943-944, 1987. 
Wesson, M.L., Schrier, R.W. Diagnosis and treatment of 

acute tubular necrosis. Ann Lntern Med 137:744- 

752, 2002. 
Wilmer, W.A., Rovin, BH., Hebert, C.J., Rao, S.V., 

Kumor, K, Hebert, L.A. Management of glomerular 

proteinuria: a commentary. / Am Soc Nephrol 

14:3217-3232, 2003. 



Mark A. Perazella 



Acute Renal Failure 




Recommended Time to Complete: 1 day 



QiA*jUi*6 Ql*£4tlc4«4 



1. What is acute renal failure (ARF)? 

2. What tests are currently used to diagnose ARF? 

1. What is the best measure of glomerular filtration rate (GFR)? 

fy. In what clinical situations are blood urea nitrogen (BUN) and serum 

creatinine concentrations poor reflections of GFR? 
S. Is community-acquired ARF more common than hospital-acquired 

ARF? 
i. What is a simple yet useful classification system for ARF? 
7. What are the principal causes of ARF in each category? 
?. What are the clinical tools available to diagnose the etiology of ARF? 
e l. What are the clinical and biochemical consequences of ARF? 
10. What are the best available preventive measures and treatments 

of ARF in the various categories? 




Introduction 



ARF is broadly defined as a rapid deterioration in 
kidney function as manifested by a reduction in 



GFR. It is comprised of a variety of syndromes that 
are characterized by renal dysfunction that occurs 
over hours to days. Acute renal failure can occur 
in the patient with previously normal kidney func- 
tion or superimposed upon chronic kidney dis- 
ease. The loss of renal function results in the 
accumulation of nitrogenous wastes within body 



227 



fluids that would otherwise be excreted by the kid- 
neys. The most commonly employed markers of 
ARF are serum creatinine and BUN concentrations, 
both which rise in this setting. ARF may also cause 
disturbances in salt and water balance, potassium 
and phosphorus retention, acid-base homeostasis, 
and endocrine abnormalities. Descriptive terms in 
the setting of ARF include the following: 

1 . Azotemia. A buildup of nitrogenous wastes in 
blood. 

2. Uremia. A constellation of symptoms and 
signs of multiple organ dysfunction caused by 
retention of "uremic toxins" in the setting of 
renal failure. 

Urine output is highly variable in the setting of 
ARF. It is often oliguric (<400 mL/day), but may be 
nonoliguric with urine volumes actually exceeding 
3 L/day (polyuric). In certain clinical states, urine 
output "will be less than 100 mL/day, defined as 
oligoanuric or anuric (no urine output). Therefore, 
it is important to recognize that the presence of 
urine output does not exclude the possibility of 
ARF. In general, the level of renal impairment in 
ARF includes a spectrum ranging from mild and 
rapidly reversible to very severe with a prolonged 
course and often a poor outcome. As will be dis- 
cussed later, the etiology of ARF, as well as the pop- 
ulation of patients it occurs in will determine the 
ultimate clinical course of ARF. 



Key Points 

Acute Renal Failure 




1. Acute renal failure is denned as an abrupt 
reduction in GFR. 

2. Accumulation of nitrogenous wastes, dis- 
turbed electrolyte and acid-base balance, and 
abnormal volume status may result from ARF. 

3. Acute renal failure may be polyuric, non- 
oliguric, oliguric, or anuric based on mea- 
sured levels of urine output for the 24-hour 
period. 



Chapter 15 ♦ Acute Renal Failure 



Measures of Renal Function 



Although serum creatinine concentration is the 
most commonly employed clinical laboratory 
measure of renal function, it actually is a poor 
reflection of true GFR in many patients. This 
problem exists because changes in serum creati- 
nine concentration do not precisely correlate 
with changes in GFR. The concentration of 
serum creatinine is influenced by a number of 
factors. 

1. In the setting of kidney disease, creatinine is 
cleared from the body by the kidney through 
both glomerular filtration and tubular secretion. 

2. Certain drugs compete with tubular secretion 
of creatinine (trimethoprim, cimetidine) and 
may increase serum creatinine concentration 
in the absence of any change in GFR. 

3. The reported serum creatinine concentration 
can be falsely elevated by interference with the 
laboratory technique used to measure creati- 
nine (certain cephalosporins, endogenous 
chromophores). 

4. The gender and muscle mass of the patient 
influence the serum creatinine concentration 
and can mask changes in GFR. This results 
because muscle is the primary source of cre- 
atine, which is nonenzymatically converted 
to creatinine. Female gender and severe 
muscle wasting will reduce the production of 
creatine and limit the rise in serum creatinine 
concentration that would normally accom- 
pany a reduction in GFR. 

The relationship between BUN and GFR is even 
more confounded. First, renal handling of urea 
includes glomerular filtration, as well as tubular 
secretion and reabsorption. Thus, any disease state 
associated with reduced tubular flow rates will 
increase urea reabsorption in the kidney and 
increase serum BUN concentration. Second, multi- 
ple factors increase serum BUN concentration in 
the absence of changes in GFR. They include 



Chapter 15 



Acute Renal Failure 



229 



protein loading (total parenteral nutrition, high pro- 
tein supplements), hypercatabolic states (infection, 
steroids), gastrointestinal (GI) bleeding (reabsorbed 
blood converted to urea), and tetracycline antibi- 
otics (increase urea generation). Alternatively, 
serum BUN concentration may remain very low 
despite significant renal dysfunction in states such 
as cirrhosis (reduced urea generation), poor protein 
intake, and protein malnutrition, all which are asso- 
ciated with decreased urea generation. 

In spite of the problems associated with serum 
creatinine and BUN concentrations as accurate 
estimates of GFR, they are the most commonly 
employed laboratory tests to identify ARF. 
Clinicians use these less than optimal markers of 
renal function because they are readily available, 
are familiar to all physicians, and there are no good 
alternative tests. Better measures of GFR, such as 
technetium-labeled iothalamate, are not practical 
in the acute clinical situation and not widely avail- 
able. Inulin clearance, the gold standard measure 
of GFR, is strictly a research tool. Estimates of GFR 
or creatinine clearance, such as those based on the 
MDRD formulas and Cockcroft-Gault formula, 
were only tested in patients with stable chronic 
kidney disease and would probably be inaccurate 
in the setting of ARF with a rapidly changing GFR. 
To complicate the diagnosis of ARF further, there 
is no consensus on a universal definition of ARF. 
Several studies of this entity employ widely vary- 
ing definitions. For example, an absolute change 
in serum creatinine concentration (increase by 
0.5-1.0 mg/dL) is used by some investigators. 
Also, a relative increase in serum creatinine con- 
centration (increase of 25-100%) is employed by 
others. At times, both definitions of ARF are used. 
The time interval of increase in serum creatinine 
concentration to define ARF also varies from study 
to study, ranging from 24 to 72 hours. Other serum 
(cystatin C) and urinary markers (kidney injury 
molecule-1) of renal function are being investi- 
gated, but at this time appear no better and are 
not widely available. Thus, the clinician assesses 
the patient with suspected ARF using all of the 
clinical tools currently available while recogniz- 
ing their limitations. 



Key Points 

Measures of Renal Function 



1. Serum creatinine and BUN concentrations are 
the most common tests used to identify ARF. 

2. An abrupt increase in serum creatinine con- 
centration usually reflects a decline in GFR 
and signals the development of ARF. 

3. Unfortunately, the two commonly used lab- 
oratory tests suffer from a number of limita- 
tions that reduce their accuracy in the 
estimation of GFR. 

4. Factors besides GFR that influence serum 
creatinine concentration include gender, 
muscle mass, and certain drugs. 

5. In addition to the level of underlying renal 
function, serum BUN concentration is influ- 
enced by the urea avidity of the kidney 
(slow urine flow rates), presence of gastroin- 
testinal bleeding, protein intake, catabolic 
states, protein malnutrition, and cirrhosis. 




Acute renal failure is a frequent problem in hospi- 
talized patients, whereas it is less common in the 
community setting. Clearly, the actual incidence 
and outcomes of ARF are dependent on the defi- 
nition used, as well as the patient population eval- 
uated. A few studies were published to evaluate 
the incidence and etiology of community-acquired 
renal failure, as well as ARF that develops in hos- 
pitalized patients. 

In a study designed to examine community- 
acquired ARF, renal failure was defined as an 
increase in serum creatinine concentration of 
0.5 mg/dL in patients with a baseline <2.0 mg/dL, 
a rise of 1.0 mg/dL in patients with a baseline 



230 



Chapter 15 



Acute Renal Failure 



between 2.0 and 4.9 mg/dL, or a rise of 1.5 mg/dL 
in patients with a baseline >5.0 mg/dL. The inci- 
dence of ARF on admission to the hospital was 
0.9%. Approximately half of the patients had ARF 
superimposed on chronic kidney disease. Prerenal 
azotemia accounted for 70% of the cases, while 
obstructive uropathy caused 17%. Intrinsic renal 
failure from various etiologies resulted in only 
11% of the ARF cases. Overall mortality was 15% 
in patients with ARF. Mortality was highest in 
patients with intrinsic renal failure (55%) and 
lowest in patients with prerenal azotemia (7%). 
As will be seen in the discussion of hospital- 
acquired ARF, the mortality of community- 
acquired ARF is much less compared with that 
seen in the hospital. 

Two studies evaluated the incidence of ARF in 
the hospital. It is worth noting that the incidence 
of hospital-acquired ARF is higher than community- 
acquired ARF. In a study performed in 1979, the 
incidence of ARF was 4.9% of all hospital admis- 
sions when a definition of ARF similar to the one 
employed above was used. Once again, prerenal 
azotemia was the most common cause of ARF 
(42%), whereas postoperative ARF resulted in 
18%, radiocontrast material in 12%, and aminogly- 
cosides in 7% of episodes. Overall mortality asso- 
ciated with ARF was 29% and mortality was 
highest in patients with a serum creatinine con- 
centration >3.0 mg/dL (64% versus 3.8% in 
patients with serum creatinine concentration 
<2.0 mg/dL). As noted, this study represents 
trends in ARF that occurred in the late 1970s. In 
1996, the same group of investigators performed 
a similar study to determine if the incidence of and 
mortality associated with hospital-acquired ARF 
changed. They postulated that the population of 
patients studied in this time period were older, 
possessed higher comorbidities, and received 
more nephrotoxic medications, placing them at 
higher risk for ARF. When compared with the 
study 20 years earlier, the incidence of hospital- 
acquired ARF increased slightly to 7.2%. Once 
again, prerenal azotemia remained the most 
common cause of ARF (39%). This was followed 
by nephrotoxic drugs (aminoglycosides and non- 
steroidal anti-inflammatory drugs [NSAIDs]) 



causing 16%, radiocontrast material causing 11%, 
and postoperative renal impairment causing 9% of 
the episodes of ARF. Chronic kidney disease was 
a common underlying risk factor for ARF as com- 
pared with patients with previously normal 
kidney function. Remarkably, the overall mor- 
tality was 19.4%, lower than the mortality noted 
20 years prior. This may reflect improved support- 
ive care and advances in several lifesaving tech- 
nologies. Mortality, however, remained high in 
patients with serious illnesses, such as sepsis 
(76%), when ARF developed. As seen previously, 
the correlation between severity of ARF and mor- 
tality was again observed. 

The mortality associated with hospitalized ARF 
depends on the severity of illness and burden of 
organ system dysfunction. For example, whether 
quantifying disease severity by number of failed 
organ systems or Acute Physiology and Chronic 
Health Evaluation (APACHE) II or III score, the 
mortality increases as the severity of patient ill- 
ness increases. As the number of organs failed 
increased from to 4, the mortality associated 
with ARF increased from less than 40% to above 
90%. Similarly, the mortality associated with ARF 
progressively increased from less than 10% with 
an APACHE III score <50, to 52% with a score of 
51-70, to 58% with a score of 71-90, to 86% with 
a score of 91-110, and to 100% with a score >110. 
As one might suspect when examining these data, 
the mortality associated with ARF that develops in 
the medical or surgical intensive care unit is 
extremely high. 



Key Points 



Epidemiology of Acute Renal Failure 



1 . The incidence of ARF varies depending on 
whether it occurs in the hospital (5-7%) or 
community setting (0.9%). 

2. Prerenal azotemia is the most common cause 
of ARF in patients with either community- or 
hospital-acquired ARF. 



Chapter 15 



Acute Renal Failure 



231 



Obstructive uropathy is the second leading 
cause of ARF in community-acquired renal 
failure, whereas drug nephrotoxicity and 
postoperative renal failure are the next most 
common causes in hospitalized patients. 
The overall mortality associated with ARF is 
higher with hospital-acquired ARF (19-29%) 
than community-acquired ARF (15%). 
The mortality associated with ARF increases 
as the severity of patient illness increases 
(up to 100%). 




Classification of Acute Renal 
Failure 



Table 15.1 provides a list of the etiologies of acute 
renal failure classified as prerenal, intrinsic renal, 
or postrenal. Figure 15.1 is a schematic representa- 
tion of the various causes of ARF. A logical 
approach to ARF is achieved by broadly classifying 
the clinical causes into the following categories: 

1. Prerenal azotemia. A decrease in GFR that 
occurs as a consequence of reduced renal 
blood (plasma) flow and/or reduced renal per- 
fusion pressure. 



Table 15.1 

Etiologies of Acute Renal Failure 



Prerenal 

"True" volume depletion 
Extrarenal losses 

Nausea/vomiting 

Diarrhea, external fistulae 
Renal losses 

Overdiuresis 



Renal salt wasting 

Diabetes insipidus 
"Effective" volume depletion 

Sepsis 

Cardiomyopathy 

Cirrhosis/hepatic insufficiency 

Nephrotic syndrome 
Structural renal artery/arteriolar disease 

Renal artery stenosis, arteriolo- 
nephrosclerosis 
Altered intrarenal hemodynamics 

NSAIDs, calcineurin inhibitors, ACE 
inhibitors, ARBs 
Intrarenal 
Vascular disease 

Arterial, arteriolar, venous 
Glomerular disease 

Acute glomerulonephritis (immune complex, 
vasculitis, anti-GBM) 

Thrombotic microangiopathy (TTP/HUS) 

Monoclonal immunoglobulin deposition 
disease 
Acute tubular necrosis 

Nephrotoxic 

Ischemic 

Pigment-related 

Crystal-associated nephropathy 

Osmotic nephropathy 
Acute interstitial nephritis 

Medication-induced 

Infection (viral, fungal, bacterial) 

Systemic diseases 
Postrenal 
Pelvic/ureteral obstruction 

Retroperitoneal disease 

Nephrolithiasis 

Fungus balls, blood clots 
Bladder obstruction 

Structural (stones, benign prostatic hyper- 
plasia, blood clots) 

Functional (neuropathic, drugs) 
Urethral obstruction 



Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; ACE, 
angiotensin-converting enzyme; ARB, angiotensin receptor blocker; 
GBM, glomerular basement membrane; TTP, thrombotic thrombocy- 
topenic purpura; HUS, hemolytic uremic syndrome 



Chapter 15 



Acute Renal Failure 



2. Intrinsic renal azotemia. A decrease in GFR 
due to direct parenchymal injury in the kidney, 
often subdivided by the various anatomical 
compartments involved (vascular, glomerular, 
interstitial, tubular). 

3. Postrenal azotemia. A decrease in GFR due 
to an obstruction to urine flow anywhere 
from the pelvis and calyces to the urethra. 



Prerenal Azotemia 

Acute renal failure is classified as prerenal 
azotemia when a patient exhibits rising serum 
BUN and creatinine concentrations due to inade- 
quate blood flow to the kidneys. To provide a 
framework to understand the concept of prerenal 
azotemia, the following description of renal 



blood flow is provided. The kidneys receive up 
to 25% of the cardiac output, which results in 
more than a liter of renal blood flow per minute. 
This high rate is necessary to not only maintain 
GFR, but also to preserve renal oxygen delivery 
(to sustain ion transport and other energy 
requiring processes). Thus, normal kidney func- 
tion is dependent on adequate perfusion. It is 
intuitive that a significant reduction in renal per- 
fusion may be sufficient to diminish filtration pres- 
sure and lower GFR. Broad examples of prerenal 
azotemia include the following causes of renal cir- 
culatory insufficiency: 

1, Renal circulatory insufficiency from "true" 
intravascular volume depletion, 

a. Hypovolemia from hemorrhage, renal 

losses (diuretics), gastrointestinal losses 



Figure 15- 1 



Direct tubular cell 
toxicity & necrosis 
Acute tubular 



Intratubular crystal 

deposition 

Crystal nephropathy 




\ f ■»*» Allergic 



Allergic reaction in the 
interstitium 
Allergic Interstitial 
nephritis 



Obstruction from stones 
Postrenal azotemia 



H 



Etiologies of acute renal failure. Common causes of acute renal failure are noted in this schematic representation. 



Chapter 15 



Acute Renal Failure 



233 



(vomiting, diarrhea), third spacing, and 
severe sweating. 

2. Renal circulatory insufficiency from "effective" 
intravascular volume depletion. 

a. Impaired cardiac function from cardiomy- 
opathy, hypertensive heart disease, valvular 
heart disease, pericardial disease, and severe 
pulmonary hypertension. 

b. Impaired liver function from acute hepatic 
failure and severe cirrhosis with hepatore- 
nal physiology. 

c. Impaired systemic vascular tone (inappro- 
priate vasodilatation) due to sepsis, medica- 
tions, and autonomic failure. 

3. Renal circulatory insufficiency due to renal 
artery disease. 

a. Main renal artery disease (renal artery 
stenosis). 

b. Small renal vessel narrowing (hypertensive 
arteriolonephrosclerosis) . 

4. Renal circulatory insufficiency due to altered 
intrarenal hemodynamics. 

a. Afferent arteriolar vasoconstriction (NSAIDs, 
calcineurin inhibitors, and hypercalcemia). 

b. Efferent arteriolar vasodilatation (angiotensin- 
converting enzyme [ACE] inhibitors, angi- 
otensin receptor blockers [ARBs]). 

Both "true" and "effective" intravascular volume 
depletion activate several neurohormonal vasocon- 
strictor systems as mechanisms to protect circulatory 
stability. These include catecholamines from the 
sympathetic nervous system, endothelin from the 
vasculature, angiotensin II (All) from the renin 
angiotensin system (RAS), and vasopressin from the 
neurohypophysis. All these substances raise blood 
pressure through arterial and venous constriction. 
They also possess, however, the ability to constrict 
the afferent arteriole and reduce GFR, especially 
when systemic blood pressure is inadequate to 
maintain renal perfusion pressure. Structural lesions 
in the renal arterial and arteriolar tree can also 
reduce perfusion and promote prerenal azotemia. 
In response to these hemodynamic challenges, renal 
adaptive responses are stimulated to counterbalance 
diminished renal perfusion, whether due to 



functional or structural causes. Myogenic influences 
and the production of vasodilator substances consti- 
tute these adaptive processes. The myogenic reflex 
is activated by low distending pressures sensed in 
the renal baroreceptors, thereby causing afferent 
arteriolar vasodilatation. Prostaglandins (PGE 2 , 
PGI 2 ), nitric oxide, and products from the 
kallikrein-kinin system modify the effects of above- 
noted vasoconstrictors on the afferent arteriole. 

Hepatorenal syndrome (HRS) is a classic exam- 
ple of "effective" intravascular volume depletion 
as a cause of prerenal azotemia. It is characterized 
clinically by low blood pressure, oliguria and pro- 
gressive renal failure in patients with advanced 
liver disease. Urine findings consistent with HRS 
include a urine Na + concentration <10meq/L, 
urine osmolality at least 100 mOsm greater than 
plasma osmolality, and an unremarkable urine 
sediment. HRS requires careful evaluation of 
volume status to help distinguish it from prerenal 
azotemia from "true" intravascular volume deple- 
tion. A trial of intravascular volume expansion 
and/or measurement of central filling pressure are 
required to differentiate HRS from prerenal 
azotemia. HRS is a diagnosis of exclusion that car- 
ries a poor prognosis. Orthotopic liver transplant 
is the best treatment while the transjugular intra- 
hepatic portosystemic shunt (TIPS) procedure is 
beneficial in some patients. Medications such as 
midodrine, octreotide and vasopressin analogues 
(terlipressin, and ornipressin) when used in con- 
junction with intravenous albumin may provide 
some benefit. 

Disturbance of the balance between afferent 
vasodilatation and efferent vasoconstriction can 
disrupt intrarenal hemodynamics and precipitate 
ARF. Medications such as NSAIDs and selective 
cyclooxygenase-2 (COX-2) inhibitors act to cause 
prerenal azotemia through inhibition of vasodila- 
tory prostaglandins in patients who require 
prostaglandin effects to maintain renal perfusion. 
Despite its vasoconstrictor properties, All actually 
acutely preserves glomerular filtration pressure 
and GFR in states of reduced renal perfusion by 
constricting the efferent arteriole. This effect in 
part explains the reduction in GFR that occurs 



234 



Chapter 15 



Acute Renal Failure 



when an ACE inhibitor or an ARB is administered 
to a patient who is dependent on All to constrict 
the efferent arteriole. 

In general, prompt correction of the underly- 
ing hemodynamic insult causing the reduction in 
renal perfusion will result in rapid correction of 
renal blood flow and GFR. This ultimately pre- 
vents structural kidney damage in the form of 
ischemic renal tubular necrosis and preserves 
tubular function. Recognizing that renal tubular 
function remains intact is important. In prerenal 
azotemia, the tubules will reabsorb sodium avidly 
and maximally concentrate the urine. This protec- 
tive mechanism preserves intravascular volume, 
sometimes appropriately as with "true" volume 
depletion and at other times inappropriately "with 
congestive heart failure. This tubular effect on 
renal sodium and water reabsorption is useful to 
identify prerenal azotemia as a cause or contributor 
to ARF. The urine sodium concentration is usually 
less than 20 meq/L and the urine osmolarity is 
very high (greater than plasma). The ratio of the 
clearance of sodium to creatinine concentrations 
(fractional excretion of sodium or FENa) is calcu- 
lated as follows: 



FENa = — — — x 100 (expressed in percent) 

(S Na /U Cr ) 



The FENa is generally useful to separate prerenal 
azotemia from other causes of ARF. A FENa less 
than 1% supports a diagnosis of prerenal azotemia 
and a FENa greater than 2% suggests other causes 
of ARF. The fractional excretion of urea (FEUrea) 
is employed to separate prerenal azotemia from 
acute tubular necrosis (ATN) in patients who have 
received diuretics. It is calculated from the formula 



FEUrea = - — ^^ — x 100 (expressed in percent) 



ARF due to other causes (>2%). Its formula is RFI = 
U Na x (P Cr /U Cr ) x 100. The urinalysis is unrevealing 
and the urine sediment is typically bland without 
cells, protein, or casts in prerenal azotemia. 

As will be discussed later, prolonged prerenal 
azotemia can sometimes result in ATN from 
ischemic-induced injury. Ischemic ATN will 
change the clinical picture of ARF. The course of 
ARF will likely be protracted as compared with 
prerenal azotemia. In addition, injured renal 
tubules will no longer have the capacity to reab- 
sorb sodium and water, resulting in a FENa >2% 
and a urine osmolality fixed around 300 mOsm. 
This entity will be more fully discussed in the 
intrinsic renal azotemia section. 



Key Points 

Prerenal Azotemia 



1 . Prerenal azotemia occurs when renal blood 
flow is reciuced and causes a reduction in 
GFR and associated ARF. 

2. Prerenal azotemia is broadly classified on 
the basis of intravascular volume depletion 
(true versus effective), the presence 

of structural lesions in the renal arterial/ 
arteriolar system, and altered intrarenal 
hemodynamics. 

3. The urine sodium and osmolality, the FENa, 
and the RFI are useful to help distinguish 
prerenal azotemia from other causes of 
ARF. The FENa and the RFI are both less 
than 1% with prerenal azotemia. 

4. Rapid identification and prompt correction 
of the prerenal disturbance often improves 
kidney function quickly. 



(S L - ra xU Cr ) 



A FEUrea greater than 50% suggests ATN, whereas 
a level less than 35% supports prerenal azotemia. 
The renal failure index (RFI) is another equation 
used to separate prerenal azotemia (<1%) from 



Intrinsic Renal Azotemia 

Acute renal failure that arises from a process that 
damages one of the compartments of the renal 



Chapter 15 



Acute Renal Failure 



235 



parenchyma is called intrinsic renal azotemia. For 
ease of organization and simplicity, the renal 
compartments are divided into the following 
anatomic sites of injury: 

1. Vasculature 

a. Artery (thrombosis superimposed on 
stenotic renal arterial lesion, thromboem- 
bolism with renal artery occlusion, renal 
artery dissection, large and medium vessel 
vasculitis) 

b. Arteriole (atheroemboli, vasculitis, sclero- 
derma kidney, fibrinoid necrosis from malig- 
nant hypertension, septic emboli) 

c. Venous (renal vein thrombosis) 

2. Glomerulus 

a. Acute proliferative glomerulonephritis 
(immune complex, vasculitis, antiglomerular 
basement membrane antibody) 

b. Thrombotic microangiopathy (hemolytic 
uremic syndrome [HUS]/thrombotic throm- 
bocytopenic purpura [TTP]) 

c. Monoclonal immunoglobulin deposition dis- 
ease (light/heavy chain, amyloid, fibrillary/ 
immunotactoid) 

3. Tubules 

a. Acute tubular necrosis (ischemic, nephro- 
toxic) 

b. Pigment nephropathy (hemoglobin, myo- 
globin) 

c. Crystal deposition (medications, uric 
acid) 

d. Osmotic nephropathy (sucrose, intravenous 
immune globulin [IVIG], hydroxyethyl- 
starch, dextran, mannitol) 

e. Cast nephropathy (multiple myeloma) 

4. Interstitium 

a. Allergic interstitial nephritis (drugs) 

b. Infection-induced interstitial nephritis (viral, 
bacterial, tuberculosis, rickettsial) 

c. Systemic diseases associated with interstitial 
nephritis (sarcoid, systemic lupus erythe- 
matosus [SLE], Sjogren's syndrome) 

d. Malignant interstitial infiltration 

e. Idiopathic interstitial nephritis 



Vasculature 

Disease of the blood vessels leading to the kid- 
neys (large- and medium-sized arteries), within 
the renal parenchyma (small arteries and arteri- 
oles), and draining the kidneys (veins) may 
cause ARF. Large vessel arterial disease that 
causes ARF consists of the following: (1) throm- 
bosis superimposed on high-grade renal artery 
stenosis (unilateral in a single functioning 
kidney or bilateral disease), (2) significant throm- 
boembolism from the heart or an aortic 
aneurysm causing occlusion of the renal arteries, 
or (3) dissection of the renal arteries from 
trauma or a collagen vascular disorder. Patients 
with these renal disorders often present with 
flank or abdominal pain, fever, hematuria if urine 
is still formed, and oligoanuria or anuria. 
Laboratory testing reveals elevations in serum 
and urine lactate dehydrogenase (LDH) concen- 
tration, urinalysis dipstick positive for blood, and 
many red blood cells present in the urine sedi- 
ment. If discovered early enough, treatment of 
thrombosis and thromboembolism is administra- 
tion of thrombolytic agents to dissolve clot and 
restore renal blood flow. Long-term anticoagula- 
tion may be required to prevent further renal 
embolization from the heart. Surgical repair of 
an aortic aneurysm may be indicated, while per- 
cutaneous angioplasty with or without stent 
placement is a relatively noninvasive procedure 
to correct significant renal artery stenosis. In cer- 
tain centers, surgical revascularization of the 
kidney may be more appropriate. A renal artery 
dissection clearly is an indication for surgical 
repair. Vasculitis may affect the large renal blood 
vessels in Takayasu's arteritis and Giant Cell 
arteritis. More commonly, the small arterial vessels 
and arterioles are injured by vasculitis as dis- 
cussed below. 

Embolization of atheromatous material to the 
interlobar, arcuate, and interlobular arteries in the 
kidneys induces ischemic injury in downstream 
tissue while also eliciting a giant cell reaction in 
the interstitium surrounding the occluded vessel 



236 



Chapter 15 



Acute Renal Failure 



Figure 15-2 



F *«.iw-..'iV ..- :•- .:i;<SV}I 




Atheroembolic renal disease. Clefts of atheromatous material 
occlude the vessel lumen and cause acute renal failure in the 
setting of cholesterol emboli. 



(Figure 15.2). Debris from ulcerated plaques in the 
aorta and renal arteries are composed primarily 
of cholesterol crystals. Embolization of the crys- 
tals occurs most commonly from invasive proce- 
dures (percutaneous arterial interventions and 
vascular surgery) that disrupt the fibrous cap on 
the ulcerated plaque; however, thrombolytic ther- 
apy and therapeutic anticoagulation can also pre- 
cipitate embolization. Rarely, this process occurs 
spontaneously in patients with significant burden 
of renal artery or aortic plaque. The clinical mani- 
festations of atheroembolic disease include abrupt 
onset of severe hypertension, acute or subacute 
renal failure, livedo reticularis, digital/limb ischemia, 
abdominal pain (pancreatitis or bowel ischemia), 
GI bleeding, muscle pain, central nervous system 
(CNS) symptoms (focal neurologic deficits, confu- 
sion, amaurosis fugax), and retinal ischemic 
symptoms. The presenting symptoms depend on 
the extent and distribution of the cholesterol 
embolization. Peripheral eosinophilia, hypocom- 
plementemia, elevated sedimentation rate, and 
eosinophiluria variably accompany the syn- 
drome, while urinary findings range from bland 
to varying levels of cylinduria and proteinuria 



(occasionally nephrotic proteinuria). Diagnosis of 
this syndrome can be confused by intravenous 
contrast administration at the time of the invasive 
procedure. The time course of contrast nephropa- 
thy, however, is different from cholesterol emboli. 
Contrast-associated renal failure develops within 
48 hours, peaks within approximately a "week, 
and then recovers over the next several days. In 
contrast, cholesterol emboli-induced renal failure 
follows a more delayed onset and protracted 
course of renal failure with infrequent recovery, 
development of chronic kidney disease, and 
sometimes progression to end-stage renal disease. 
In addition to the clinical and laboratory findings 
noted, cholesterol embolization syndrome is diag- 
nosed with biopsy of involved organs including 
kidney and skin. Treatment is based primarily on 
prevention by avoiding the factors known to pre- 
cipitate atheroembolization, especially in patients 
with severe vascular disease. Supportive care with 
blood pressure control, amputation of necrotic 
limbs, aggressive nutrition, avoidance of antico- 
agulation (reduce risk for further embolization), 
and dialytic support for severe renal failure 
improves the dismal prognosis associated 
with this syndrome. Steroids have been used to 
treat the inflammatory lesion that accompanies 
renal atheroembolism. A small number of 
reports describe benefit with steroids, as well as 
iloprost. 

Macroscopic polyarteritis nodosa (PAN) 
causes arterial injury in medium and small ves- 
sels. It is typically idiopathic or may be associated 
with hepatitis B antigenemia. This type of PAN 
presents "with severe hypertension and renal 
failure. Diagnosis is confirmed by renal arteri- 
ogram demonstrating beading in the arterial tree 
of the kidney. Disease can also occur in other 
arterial beds, causing symptoms attributable to 
disease specific to the affected organ. 
Scleroderma is a systemic disorder characterized 
by narrowing of the arteries from the deposition 
of mucinous material. Multiple organs may be 
involved including the lungs, heart, GI tract, and 
skin. Scleroderma renal crisis manifests as ARF 



Chapter 15 



Acute Renal Failure 



237 



and severe hypertension in a patient with a flaring 
of their disease. ACE inhibitors are an effective 
therapy to control blood pressure and improve 
renal function. Poorly controlled or untreated 
hypertension can cause ARF from severe renal 
injury related to malignant hypertension. 
Fibrinoid necrosis with ischemic injury occurs in 
the kidney. Initial blood pressure control is asso- 
ciated with worsening renal function because the 
autoregulatory capability of the kidney is 
impaired and renal perfusion is solely dependent 
on systemic pressure. Over time, renal function 
improves. 

Renal vein thrombosis is a complication of 
nephrotic syndrome, especially when the under- 
lying glomerular lesion is membranous nephropa- 
thy. Loss of anticoagulant substances in the urine 
(antithrombin 3, plasminogen activator inhibitor) 
and increased production of procoagulants 
(tissue plasminogen activator, fibrinogen) under- 
lies the development of a hypercoagulable state. 
Thrombosis of the renal vein is thought to cause 
ARF through raised intrarenal pressures and 
reduced renal perfusion. Treatment of renal vein 
thrombosis is thrombolysis and anticoagulation, 
as well as remission of the underlying glomerular 
lesion and reduction in proteinuria. 



Key Points 

Vasculature 



1 . Intrinsic renal disease is categorized by 
anatomic compartments that were acutely 
injured. They include the vasculature, 
glomerulus, tubules, and interstitium. 

2. Acute renal failure from large vessel arterial 
disease occurs most commonly from throm- 
bosis of preexisting renal artery stenosis or 
thromboembolism from a cardiac thrombus. 

3. Atheroembolic disease causes systemic 
disease from occlusion of small arteries 
and arterioles, inducing end-organ 



ischemia. Renal atheroemboli is associated 
with ARF, hypertension, and variable 
findings in the urine sediment ranging 
from minor cylinduria to eosinophiluria 
and proteinuria. 

4. Macroscopic PAN presents with severe hyper- 
tension and ARF. Arteriogram of the renal 
arteries reveals a characteristic beading pattern. 

5. Scleroderma renal crisis also presents 
with severe hypertension and ARF. ACE 
inhibitors are the treatment of choice for 
this disease. 

6. Renal vein thrombosis complicates heavy 
proteinuria, especially with membranous 
nephropathy. Acute renal failure likely 
results from reduced renal perfusion. 



Glomerulus 

Glomerular diseases occur through various mech- 
anisms. Acute proliferative glomerulonephritis 
may be classified as immune complex, pauci- 
immune, or anti-glomerular basement membrane 
(GBM)-related disease. This group of diseases is 
characterized by glomerular cell proliferation and 
necrosis, polymorphonuclear cell infiltration, and 
with severe injury, epithelial crescent formation. 
TTP and HUS are two of the more common 
causes of thrombotic microangiopathy. Platelet 
deposition and endothelial injury with thrombo- 
sis of arterioles and glomerular capillaries underlie 
the renal injury associated with thrombotic 
microangiopathies. Glomerular damage can be 
severe with profound ischemia and necrosis 
(Figure 15.3). Treatment is usually plasmaphere- 
sis, plasma exchange, blood pressure control, 
dialysis when required, and avoidance of platelet 
transfusions. 

Deposition of monoclonal immunoglobulin 
light and/or heavy chains may also promote 
glomerular lesions. The type of immunoglobulin, 
as well as the metabolism and packaging of the 



238 

Figure 153 



Chapter 15 



Acute Renal Failure 




Histopatholgy of thrombotic microangiopathy. As seen in this 
glomerulus, capillary loops are occluded with microthrombi 
associated with thrombotic microangiopathy. An occluded 
capillary loop is shown by the arrow. 



immunoglobulin determine which type of 
glomerular lesion develops. Light chain deposi- 
tion disease, heavy chain deposition disease, 
and light/heavy chain deposition disease were 
all described to cause nodular glomerular 
lesions. Similarly, amyloidosis forms glomerular 
nodules. These diseases are separated by 
appearance on electron microscopy. Light and 
heavy chain diseases have granular deposits 
whereas, amyloidosis appears as haphazard fib- 
rils in the 8-12-nm size range. The fibrillary 
glomerulonephritides (fibrillary and immunotac- 
toid) are sometimes associated with mesangial 
expansion or glomerular nodules. They more 
commonly appear as a mesangial proliferative, 
mesangiocapillary, or membranous lesion. At 
times, crescents are also present. They are also 
distinguished from amyloidosis by a larger 
fibril size (fibrillary: 20 nm; immunotactoid: 
30-50 nm) and organized microtubular fibrils 
(immunotactoid only) seen on electron 
microscopy. 

Acute proliferative glomerulonephritis pre- 
sents with hematuria and proteinuria, described 



as a nephritic sediment. Examination of the urine 
sediment under the microscope classically 
reveals dysmorphic red blood cells and red blood 
cell casts. ARF is typically present as are hyper- 
tension and edema formation. The thrombotic 
microangiopathies may also present with a 
nephritic sediment. Acute renal failure may be 
severe, as seen with HUS or may be mild, as 
noted with TTP. A microangiopathic hemolytic 
anemia and thrombocytopenia are key features 
of this disease complex. The immunoglobulin 
deposition diseases more often manifest with 
nephrotic proteinuria and renal failure. On very 
rare occasions, these diseases "will have hema- 
turia. The glomerular diseases will be covered 
more fully in chapter 17. 



Key Points 

Glomerulus 



1. Acute proliferative glomerulonephritis 
may result from an immune complex- 
disease, pauci-immune vasculitis, or anti- 
glomerular basement membrane-related 
disease. 

2. The clinical presentation of this renal lesion 
is hypertension, azotemia, and a nephritic 
urinary sediment. 

3. Other glomerular lesions associated with 
ARF include the thrombotic microan- 
giopathies and monoclonal immunoglobulin 
deposition diseases. 



Tubules 

ATN is the most common form of intrinsic renal 
azotemia (Figure 15.4). It probably accounts for 
greater than 80% of the episodes of intrinsic 
renal disease. It is classically divided into 
ischemic, which makes up 50% of ATN, and 
nephrotoxic ATN, which constitutes the remainder 



Chapter 15 ♦ Acute Renal Failure 



239 



Figure 15.4 




Histopathology of acute tubular necrosis. Acute tubular 
necrosis is characterized by tubular injury with cellular 
blebbing, necrosis, and sloughing of cells into the tubular 
lumen. 



of cases. In many instances, ATN results from 
multiple insults acting together to induce multi- 
factorial renal injury. The end result of either 



ischemic or toxic insult is tubular cell necrosis 
and death. Table 15.2 outlines the important fac- 
tors underlying the pathogenesis of acute tubu- 
lar necrosis. 

Ischemic ATN is an extension of severe and 
uncorrected prerenal azotemia. Prolonged 
renal hypoperfusion causes tubular cell injury, 
which persists even after the underlying hemo- 
dynamic insult resolves. Various etiologies 
precipitate ischemic ATN. Surgical causes include 
intraoperative and postoperative hypotension 
with impaired renal perfusion. This occurs rela- 
tively frequently following cardiac and vascular 
surgical procedures. Obstructive jaundice also 
appears to increase the risk of ischemic ATN. In 
the medical intensive care unit and on the med- 
ical wards, ischemic and multifactorial ATN are 
common. This relates to the severe comorbidities 
these patients manifest. Superimposition of 
sepsis with or without shock, severe intravas- 
cular volume depletion from hemorrhage or 
gastrointestinal/renal fluid losses, or cardio- 
genic shock can induce severe ischemic ATN. 
Employment of vasopressors to restore blood 



Table 15.2 

Pathogenesis of Acute Tubular Necrosis 







Reperfusion Injury 




Intrarenal Hemodynamics 


Tubular Cell Injury 


from Infiltrating 


Role of Growth 


and Vasoconstriction 


and Necrosis 


Leukocytes and T Cells 


Factors in Renal Injury 


Elevated endothelin, 


Disruption of actin 


Recruitment of neu- 


Growth factors partici- 


increased sympathetic 


cytoskeleton with loss 


trophils and adhesion 


pate in regenerative 


discharge, reduced 


of cell polarity 


of cells, release of 


process after ischemic 


nitric oxide, loss of 


Generation of reactive 


ROS, proteases, elas- 


injury 


renal autoregulation 


oxygen species 


tases, other enzymes 


Growth factors may also 


Reduction in cortical and 


Tubular shedding: 


Infiltration of T lympho- 


promote renal injury 


medullary blood flow 


Backleak of nitrate 


cytes — > unknown 


Augmentation of tubulo- 


Ischemic tubular injury 


Cast formation with 


mechanism of injury 


interstitial injury and 


with apoptosis and 


tubular obstruction 


Tubular cell death, inter- 


fibrosis 


cell necrosis 




stitial inflammatory 
infiltrate with fibrosis 





Abbreviations: ROS, reactive oxygen species. 



240 



Chapter 15 



Acute Renal Failure 



pressure further reduces renal perfusion. In some 
cases, ischemic ATN is so profound that cortical 
necrosis (ischemic atrophy of the renal cortex) 
develops. 

Nephrotoxic ATN occurs when either endo- 
genous or exogenous substances injure the 
tubules. Tubular toxicity occurs through 
direct toxic effects of the offending substance, 
changes in intrarenal hemodynamics, or a com- 
bination of these effects. Organic solvents and 
heavy metals (mercury, cadmium, lead) were a 
frequent cause of ATN in the past. Over time, 
many drugs were noted to cause tubular injury 
by multiple mechanisms. Aminoglycoside antibi- 
otics cause proximal tubular injury. These drugs 
are reabsorbed into the cell by pinocytosis. Once 
intracellular, they promote cell injury and 
death, leading to clinical ATN and ARF. It is 
notable that acute tubular necrosis from amino- 
glycosides rarely develops within the first week 
of therapy. The antifungal agent amphotericin 
B destroys cellular membranes through sterol 
interactions. A component of tubular ischemia 
also contributes via acute afferent arteriolar 
constriction. ATN develops in a dose-dependent 
fashion. Newer formulations (liposomal, lipid 
complex) are less nephrotoxic, but can also pre- 
cipitate ARF in high-risk patients. Radiocontrast 
material is a common cause of ARF because it is 
so widely employed with imaging procedures. 
Radiocontrast nephropathy develops in patients 
with underlying risk factors such as kidney dis- 
ease, especially diabetic nephropathy, and 
"true" and "effective" intravascular volume 
depletion. Radiocontrast causes ATN through 
both ischemic tubular injury (prolonged 
decrease in RBF) and direct toxicity (reactive 
oxygen species and osmotic cellular injury). 
Large volumes of contrast clearly increase risk 
while low osmolar and isoosmolar radiocon- 
trast reduce the incidence of dye-induced ARF. 
Drugs such as the antiviral agents cidofovir, 
adefovir, and tenofovir cause ARF through dis- 
ruption of mitochondrial and other cellular 
functions following their uptake from the per- 
itubular blood into the cell via the human 



organic anion transporter-1 on the basolateral 
membrane. 

Pigment nephropathy represents the renal 
tubular effects of overproduction of heme moi- 
eties in plasma that are filtered at the glomerulus 
and excreted in urine. Heme pigment, from either 
hemoglobinuria (massive intravascular hemolysis) 
or myoglobinuria (severe rhabdomyolysis), 
induces tubular injury by promoting the formation 
of reactive oxygen species, as well as by reducing 
renal perfusion through inhibition of nitric oxide 
synthesis. 

Crystal deposition in distal tubular lumens 
causes a well-recognized syndrome of ARF fol- 
lowing massive rises in uric acid and therapy 
with certain medications. Keys to developing 
ARF from crystal deposition are underlying renal 
disease and intravascular volume depletion. 
Uric acid nephropathy with tubular obstruction 
from urate crystals develops in patients suffer- 
ing from tumor lysis syndrome. Sulfadiazine 
promotes intratubular deposition of sulfa crys- 
tals in an acid urine, acyclovir crystal deposition 
occurs with large intravenous doses of the drug, 
while indinavir crystal deposition (Figure 15.5) 



Figure 155 






i> ^ *_'■ 1. m \° m - - ' - * i * * ( . 




Indinavir nephropathy. Indinavir crystal deposition (shown 
by the arrows) noted in the tubule of an HIV-infected 
patient with acute renal failure. (From Reilly R, Tray K, 
Perazella MA: Am. J. Kidney Dis. Vol 38: E23, with 
permission.) 



Chapter 15 



Acute Renal Failure 



241 



develops in the setting of volume contraction 
and urine pH above 5.5. Methotrexate, foscarnet, 
and large doses of intravenous vitamin C also 
promote intratubular crystal deposition. Vitamin 
C, which is metabolized to oxalate, causes dep- 
osition of calcium oxalate crystals within 
tubules. 

Acute renal failure can occur in patients with 
multiple myeloma secondary to either prerenal 
azotemia or cast nephropathy. Hypercalcemia 
causes prerenal azotemia by multiple mecha- 
nisms including: (1) reduction of renal blood 
flow by direct renal vasoconstriction; (2) activa- 
tion of the calcium sensing receptor in the baso- 
lateral membrane of the thick ascending limb 
resulting in inhibition of sodium transport by the 
Na + -K + -2C1" cotransporter; and (3) reduced 
AQP2 expression leading to an acquired nephro- 
genic diabetes insipidus. In cast nephropathy 
monoclonal light chains precipitate in the tubu- 
lar lumen resulting in both obstruction and 
tubular injury. Light chains have variable 
nephrotoxicity that may be related to their ability 
to bind Tamm-Horsfall protein (THP), their abil- 
ity to self-associate, or their isoelectric point (pi). 
A higher pi may promote interaction with nega- 
tively charged THP. Treatment consists of ade- 
quate hydration, management of hypercalcemia, 
chemotherapy to decrease light chain produc- 
tion, and plasmapheresis to remove circulating 
light chains. 

Finally, the interesting and poorly recognized 
entity of osmotic nephrosis can promote ARF 
through the induction of tubular swelling, cell 
disruption, and occlusion of tubular lumens. 
The hyperosmolar nature of substances such as 
sucrose, dextran, mannitol, IVIG (sucrose), and 
hydroxyethylstarch underlies the pathophysiol- 
ogy of this renal lesion. All of these substances 
are freely filtered at the glomerulus where they 
are then reabsorbed by the proximal tubule 
through pinocytosis. Once inside the cell, they 
cannot be metabolized further, thereby promot- 
ing cellular uptake of water driven by the high 
osmolality within the cell. Cells then develop 
severe swelling, disturbing cellular integrity, 



and occluding tubular lumens. Acute renal fail- 
ure results from this abnormal tubular process 
"when patients •with underlying kidney disease 
or other risk factors for ARF (intravascular 
volume depletion, older age) receive these 
hyperosmolar substances. 



Key Points 



Tubules 



1 . Acute tubular necrosis is the most common 
cause of intrinsic renal azotemia. Ischemic 
insults and various nephrotoxins are the 
major causes. 

2. Tubular injury leading to ATN also results 
from endogenous toxins such as heme pig- 
ment. Both massive intravascular hemolysis 
and rhabdomyolysis are associated with 
pigmenturia. 

3. Crystal deposition in distal tubular lumens is 
another cause of ARF. Acute tumor lysis syn- 
drome and certain medications underlie 
crystal nephropathy. 

4. Acute renal failure in multiple myeloma may 
be secondary to hypercalcemia or cast 
nephropathy. 

5. Hyperosmolar substances such as sucrose, 
IVIG, mannitol, dextran, and hydrox- 
yethylstarch induce tubular cell swelling 
and ARF. This entity is called osmotic 
nephropathy. 



iNTERSTTTrUM 

Disease of the renal interstitium can result from 
drugs, certain infectious agents, systemic diseases, 
and infiltrative malignancies. The syndrome of 
acute interstitial nephritis (AIN) is characterized 
by ARF and a myriad of clinical findings. What is 
constant in AIN is the presence of a cellular 
infiltrate (lymphocytes, monocytes, eosinophils, 
plasma cells) and edema (or fibrosis) in the 



Chapter 15 



Acute Renal Failure 



Figure 15.6 




Acute interstitial nephritis. The renal interstitium is infiltrated 
with lymphocytes, plasma cells, and eosinophils in acute 
interstitial nephritis. 



interstitium of the kidney (Figure 15.6). Tubulitis 
or invasion of lymphocytes into the tubular cells 
may also occur. Typically, the glomeruli and vas- 
culature are spared by this process. The clinical 
presentation varies based on the offending agent 
and the host response. For example, beta-lactams 
often cause the classic triad of fever, maculopapular 
skin rash, and eosinophilia. Other clinical findings 
include arthralgias, myalgias, and flank pain. In 
contrast, patients with AIN secondary to NSAIDs 
rarely develop any extrarenal manifestations. 
Aside from ARF, patients receiving NSAIDs do not 
develop a fever, rash, or eosinophilia. Other 
drugs such as the sulfa-containing agents, 
rifampin, phenytoin, allopurinol, H 2 -blockers, 
and fluoroquinolones may or may not cause 
extrarenal manifestations. At times, there might 
be a slight increase in liver transaminases, repre- 
senting an associated drug-induced hepatitis. The 
urinalysis may reveal mild proteinuria, hema- 
turia, and leukocyturia. The urine sediment 
examination may be bland or demonstrate white 
blood cells (sometimes eosinophils), red blood 
cells, and white blood cell casts. The Wright stain 
or Hansel stain may reveal eosinophils in the 
urine, but unfortunately neither of these tests are 



sensitive or specific for AIN. For example, the 
most common cause of eosinophiluria is urinary 
tract infection. In general, renal disease occurs 
2-3 "weeks following drug exposure, however, it 
may occur more quickly in patients previously 
exposed to the inciting agent. Diagnosis is best 
made by renal biopsy. Characteristic findings are 
as described above — a cellular infiltrate and 
either edema or fibrosis in the interstitium. When 
biopsy is not possible, gallium scan of the kid- 
neys may provide help in ruling out the diagnosis, 
as it is a sensitive but not specific test. Treatment 
is most successful "when AIN is identified early, 
allowing withdrawal of the offending agent prior 
to the development of advanced tubulointerstitial 
fibrosis. Therapy with steroids is controversial, 
but may reduce the duration of ARF and perhaps 
improve functional recovery in patients with 
severe renal impairment. There are no convinc- 
ing data, however, to support widespread 
steroid use. 

Infection in the renal interstitium was described 
as a cause of interstitial nephritis prior to the AIN 
reported with the drugs noted above. Infection 
with bacteria such as Staphylococci, Streptococci, 
Mycoplasma, Diptheroids, and Legionella pro- 
motes acute interstitial nephritis. Several viral 
agents including cytomegalovirus, Epstein-Barr 
virus, human immunodeficiency virus (HIV), 
Hantaan virus, parvovirus, and rubeola also cause 
acute interstitial nephritis. Finally, acute interstitial 
nephritis may result from other infectious agents 
such as rickettsia, leptospirosis, and tuberculosis. 

A number of systemic illnesses cause disease in 
the renal interstitium. Sarcoidosis promotes a 
lymphocytic interstitial nephritis, at times associ- 
ated with noncaseating granulomas. This leads to 
renal injury and chronic kidney disease. Steroids 
reduce the severity of interstitial nephritis with sar- 
coidosis. Systemic lupus erythematosis (SLE) is an 
immune complex disease more commonly asso- 
ciated with a proliferative glomerulonephritis. 
An underrecognized histopathologic finding that 
occurs with SLE is acute interstitial nephritis. The 
interstitial inflammatory lesion is due to immune 
complex deposition in the tubulointerstitium. 



Chapter 15 



Acute Renal Failure 



243 



This lesion responds to usual therapy given for 
lupus nephritis. Interstitial nephritis also occurs in 
Sjogren's syndrome. This also appears to be an 
immune complex-mediated disease of the renal 
interstitium. 

Malignant infiltration of the kidney is an 
uncommon cause of clinical renal disease. The 
malignancies most often associated with intersti- 
tial infiltration are the leukemias and lymphomas. 
Leukemic infiltration causes nephromegaly, acute 
renal failure, and sometimes urinary K + wasting 
(due to either tubulointerstitial damage or lysozyme 
production). Renal involvement from lymphoma- 
tous infiltration can be in the form of discrete nod- 
ules or diffuse interstitial infiltration. Lymphoma 
may also cause massive kidney enlargement and 
ARE Successful treatment of the underlying malig- 
nancy typically improves the infiltrative lesion; 
however, irradiation of the kidneys may also pro- 
vide additional benefit. 

A more complete discussion of all of the diseases 
that affect the tubulointerstitium will be undertaken 
in chapter 18. This will include chronic interstitial 
nephritis and tubulointerstitial disease secondary to 
glomerular disease. The pathogenesis of tubuloint- 
erstitial disease will also be examined. 



Key Points 

Interstitium 



1 . Acute interstitial nephritis results from a 
variety of medications. Beta-lactams such as 
the penicillins produce the classic syndrome 
of fever, skin rash, and eosinophilia along 
with ARF more often than other drugs. In 
contrast, NSAIDs lack most of the extrarenal 
manifestations of AIN. 

2. Infectious agents such as bacteria, viruses, 
mycobacteria, rickettsial organisms, and lep- 
tospira cause AIN. 

3. Acute interstitial nephritis is also a conse- 
quence of systemic diseases. Included are 
sarcoidosis, SLE, and Sjogren's syndrome. 



Altered immunity associated with these dis- 
eases promotes interstitial disease in such 
patients. 

Infiltration of the interstitium with malignant 
cells occurs most commonly with the 
leukemias and lymphomas. Massive 
nephromegaly often accompanies ARF, 
while tubular damage may manifest as 
hypokalemia. 



Postrenal Azotemia 

Anatomic obstruction of urine flow anywhere 
along the genitourinary system can result in ARR 
The process causing postrenal azotemia is called 
obstructive uropathy. The radiographic (ultra- 
sound, intravenous or retrograde pyelogram, 
computed tomography [CT] scan) demonstration 
of a dilated urinary collecting system is termed 
hydronephrosis. Abnormal kidney function (ARF, 
tubular defects) that occurs with urinary obstruc- 
tion is called obstructive nephropathy. For ARF to 
develop, obstruction must be bilateral (both 
ureters or below the bladder) or unilateral in a 
single functioning kidney. It is important to rec- 
ognize that obstruction may be complete and 
associated with anuria, or partial (incomplete) 
and associated with urine volumes varying (and 
fluctuating) from low to normal to polyuric levels. 
Either complete or partial obstruction may 
cause ARF; however, obstructive uropathy that is 
complete is typically associated with more 
severe renal failure and clinical manifestations 
(hypertension, intravascular volume overload, 
hyperkalemia, and hyponatremia). 

The pathogenesis of ARF from urinary 
obstruction is briefly discussed in this section. A 
more thorough description will be presented 
in chapter 19. Following acute obstruction, a 
triphasic response occurs in the renal plasma 
flow. An initial and short-lived (2-4 hours) 
increase in plasma flow develops as vasodilatory 
prostaglandins are produced in response to the 



244 



Chapter 15 



Acute Renal Failure 



rise in intratubular pressure. This represents an 
attempt to maintain GFR by overcoming the ele- 
vated intratubular pressure. Blood flow begins to 
decline after 2-5 hours, an effect due to increased 
ureteral and tubular pressure transmitted to the 
renal interstitium. Intratubular pressure also 
returns to normal at 24 hours, after increasing 
acutely with obstruction. A further decline in renal 
plasma flow at 24 hours (30-50% of baseline) 
occurs despite normalization of ureteral and tubu- 
lar pressures. This fall is due to production of 
angiotensin II and thromboxane A 2 , both vaso- 
constrictors. These substances also reduce GFR 
not only by reducing renal plasma flow but by 
inducing mesangial contraction and reducing the 
glomerular ultrafiltration coefficient. Despite all 
these effects, GFR declines progressively but 
never reaches zero. The explanation for main- 
tained GFR is the continued reabsorption of 
sodium and water (urine) along the nephron and 
in lymphatics. 

Obstruction of the urinary system can occur 
anywhere starting at the renal calyces and extend- 
ing to the urethra. A wide variety of disorders 
cause ARF from urinary obstruction. They can be 
classified according to the site or level of obstruc- 
tion (Table 15.3). In general, the most common 
causes of obstructive uropathy in the upper uri- 
nary tract (above the bladder) include stones and 
retroperitoneal disease, whereas in the lower 
tract, prostatic hyperplasia and bladder dysfunc- 
tion most often obstructs urine flow at this level. 
The diagnosis of obstructive uropathy should be 
considered in most patients with ARF since it is 
highly reversible when identified and treated 
early on. History may point to upper tract (history 
of nephrolithiasis or certain cancers, flank pain) 
or lower tract (prostatism, neuropathic bladder). 
Physical examination should include assessment 
of flank tenderness, prostatic enlargement, or 
palpable bladder. Straight catheterization of the 
bladder helps evaluate for lower tract obstruction 
(large residual urine in the bladder). Imaging of the 
kidneys with ultrasound is the most appropriate 
initial test to evaluate the patient with ARF and 



15.3 



Etiologies of Postrenal Azotemia 



Ureterocalyceal obstruction 

Retroperitoneal disease 

Tumor 

Lymph nodes 

Fibrosis 
Papillary necrosis 
Nephrolithiasis 
Fungus balls 
Blood clots 
Strictures 

Infection 

Granulomatous disease 

Prior instrumentation 
Bladder obstruction 
Structural 
Stones 
Blood clots 
Tumor 

Benign prostatic hyperplasia 
Functional 

Cerebrovascular accident 

Diabetes mellitus 

Spinal cord injuries 

Drugs 

Other neuropathic conditions 
Urethral obstruction 
Urethritis 
Urethral stricture 
Blood clots 



possible urinary tract obstruction. In general, the 
sensitivity and specificity of renal ultrasonogra- 
phy for the detection of urinary obstruction 
(hydronephrosis) are high; however, several clin- 
ical situations can reduce its accuracy. Acute 
obstruction (<48 hours) does not allow the uri- 
nary system time to fully dilate, causing a negative 
ultrasound study for hydronephrosis. In patients 
with superimposed severe intravascular volume 
depletion, GFR and urine formation are reduced, 



Chapter 15 



Acute Renal Failure 



245 



limiting dilatation of the urinary system and the 
ability of ultrasound to detect obstruction. 
Retroperitoneal disease involving the kidneys 
and ureters (cancer, fibrosis, and enlarged nodes) 
encases the collecting system and blunts dilata- 
tion. In addition, obese patients and overlying 
bowel gas reduce visualization of the kidneys 
and urinary system, potentially confounding 
ultrasound results. In cases such as these, where 
the ultrasound findings are equivocal or negative 
yet the suspicion for urinary obstruction is high, a 
CT scan may provide more information. CT scan's 
use stems from its ability to detect the etiology of 
obstruction (stones, tumor, enlarged lymph 
nodes) despite the absence of hydronephrosis. 
If these studies are negative but obstruction is 
still considered likely, retrograde pyelogra- 
phy can diagnose many forms of upper tract 
obstruction. 

Adequate treatment of obstructive uropathy 
hinges on early recognition. As time passes with 
obstruction, especially if complete, reversibility of 
renal impairment is compromised. Upper urinary 
tract obstruction is relieved by retrograde ureteral 
stent placement. When severe retroperitoneal dis- 
ease and ureteral or bladder cancer limit ureteral 
stent placement, nephrostomy tube insertion is 
often required. Relief of lower tract obstruction 
with a bladder catheter or suprapubic tube (when 
indicated), like the procedures for upper tract 
obstruction noted above, is the first step in treat- 
ment. Management of electrolyte and fluid balance 
is the next step in patients with obstructive uropa- 
thy. Postobstructive diuresis is a phenomenon that 
occurs most commonly in patients with bilateral, 
complete obstruction. Large urine volumes can 
attend the diuresis that accompanies relief of 
obstruction. The diuresis is, in part, physiologic in 
that excess sodium and water are being excreted. 
Disturbed tubular function, however, may con- 
tribute to the excessive diuresis. Tubular abnor- 
malities in sodium and water reabsorption can 
develop and persist for days (or permanently). 
Also, elevated levels of atrial natriuretic peptide 
may also induce diuresis while urea may cause an 



osmotic diuresis. Judicious fluid repletion is 
required in this circumstance, avoiding both iatro- 
genic contribution of postobstructive diuresis, as 
well as underresuscitation and hypotension. 



Key Points 



Postrenal Azotemia 



1 . Anatomic obstruction of urine flow results in 
an entity called obstructive uropathy. When 
renal defects develop in this situation, it is 
termed obstructive nephropathy. 

2. Obstruction of the urinary system can be 
partial or complete, and either unilateral or 
bilateral. Acute renal failure most often com- 
plicates bilateral, complete obstruction. 

3. Urine output can fluctuate between polyuria 
and oliguria in patients with partial obstruc- 
tion. Bilateral, complete obstruction is char- 
acterized by anuria. 

4. The pathogenesis of obstructive uropathy 
includes a reduction in GFR from both ele- 
vated intratubular pressure (resisting filtration 
pressure) and production of vasoconstrictor 
substances that reduce renal plasma flow. 

5. Obstruction of the urinary system is classi- 
fied as either upper tract (renal pelvis and 
ureters) or lower tract (bladder and urethra) 
according to the site of obstruction. 

6. Diagnosis of obstructive uropathy entails a 
complete history (anuria, prostatism, history 
of bladder, prostate, or cervical cancer) and 
physical examination (suprapubic fullness, 
flank tenderness), as well as imaging with 
renal ultrasound. This imaging test is both 
sensitive and specific, but can be negative 
(no hydronephrosis) in the presence of 
obstruction in a few clinical situations. 

7. Treatment of obstruction focuses on rapid 
identification to preserve renal function. 
Upper tract obstruction is usually managed 
with ureteral stent placement or percuta- 
neous nephrostomy tube insertion. 



246 



Chapter 15 



Acute Renal Failure 



Lower tract disease is managed with a 
bladder catheter or suprapubic tube. 
Postobstructive ciiuresis may develop fol- 
lowing relief of complete, bilateral obstruc- 
tion for several reasons. Excess sodium and 
water are excreted while obstruction- 
related tubular defects may occur and 
cause inappropriate sodium and water 
wasting. Elevated serum BUN concentra- 
tions may also contribute through an 
osmotic diuresis. 




Approach to the Patient 
with Acute Renal Failure 



Evaluation of the patient with ARF should be 
methodical to ensure that potentially reversible 
causes are rapidly diagnosed and treated to pre- 
serve kidney function and limit chronic kidney dis- 
ease. A thorough history to identify causes of and 
risk factors for prerenal azotemia (vomiting, 
diuretics, diarrhea, heart failure, cirrhosis), potential 



nephrotoxic drugs (either prescribed or over-the- 
counter), and risk factors for (prostate disease, 
cervical cancer) or symptoms of urinary obstruc- 
tion (prostatism, overflow incontinence, anuria) 
is required. Physical examination should focus on 
extracellular fluid volume status to allow initial 
classification into one of the broad categories of 
ARF. These include hypotension, an orthostatic 
fall in blood pressure or flat neck veins (volume 
depletion), as well as edema, pulmonary rales, or 
an S3 gallop (cardiac dysfunction). In situations 
where intravascular volume status is uncertain, 
measurement of cardiac filling pressures with a 
Swan-Ganz catheter is useful. Examination for evi- 
dence of systemic disease should also be sought. 
For example, this includes signs of pulmonary 
hemorrhage (vasculitis, Goodpasture's disease), 
skin rash (SLE, atheroemboli, vasculitis, cryoglob- 
ulins, AIN), and joint disease (SLE, rheumatoid 
arthritis) to name a few. 

Laboratory tests are directed by the differential 
diagnosis postulated following a complete his- 
tory and physical examination. Basic tests include 
a complete blood count to assess for anemia 
(microangiopathic or immune-mediated) and 
thrombocytopenia (TTP, HLJS, disseminated 
intravascular coagulation [DIC]). The urinalysis is 
a key component of the ARF work-up. Table 15.4 
outlines the various urine findings in some of the 



Table 15.4 

Urinalysis and Microscopic Examination of the Urine Sediment 



Test 


Prerenal 


Vasculitis 


GN 


ATN 


ATN 


Postrenal 


Specific gravity 


High 


Normal/high 


Normal/high 


Isosmotic 


Isosmotic 


Isosmotic 


Blood (dip) 


Negative 


Positive 


Positive 


+ 


± 


Negative 


Protein (dip) 


Negative 


Positive 


Positive 


Negative 


+ 


Negative 


Sediment 


Negative, 


RBC casts, 


RBC casts, 


Granular 


WBC casts, 


Negative, 


examination 


hyaline 


dysmorphic 


dysmorphic 


casts, RTEs 


eosinophils 


sometimes 




casts 


RBCs 


RBCs 






WBCs/RBCs 



Abbreviations: GN, glomerulonephritis; ATN, acute tubular necrosis; AIN, acute interstitial nephritis; RBC, reel blood cell; WBC, white blood cell; 
RTEs, renal tubular epithelial cells. 



Chapter 15 



Acute Renal Failure 



247 



different causes of ARK It is essential to evaluate 
urine specific gravity, as well as the presence of 
blood (or heme), protein, or leukocyte esterase 
on urinary dipstick. A very high urine specific 
gravity typically suggests a prerenal process 
while isosthenuria (SG = 1.010) indicates intrinsic 
renal disease such as ATN. A bland urine with no 
blood or protein favors a diagnosis of prerenal 
azotemia. Vascular causes of ARF have a variable 
urine specific gravity and sometimes hematuria 
and granular casts. Glomerulonephritis will have 
variable urine specific gravity, blood and protein 
(usually), and red blood cells and red blood cell 
casts. Acute tubular necrosis has isosthenuria, 
variable heme (positive with rhabdomyolysis and 
hemolysis) and protein, renal tubular epithelial 
cells, and pigmented coarsely granular casts. 
The urine in patients with postrenal azotemia is 
typically isosthenuric and bland unless there is 
associated infection (pyuria) or nephrolithiasis 
(hematuria). Urine chemistries sometimes help 
distinguish the type of pathology in the kidney. 
As stated earlier, a low urine sodium and a FENa 
and RFI (both <1%) support prerenal azotemia. 
In contrast, urine sodium greater than 20 meq/L 
and a FENa and RFI both greater than 2% sug- 
gest ATN (Table 15.5). Evidence of systemic dis- 
ease should prompt directed testing using 
anti-nuclear antibodies (ANA-SLE), anti-nuclear 



Table 155 



Urine Chemistries 






Lab Test 


Prerenal 


ATN 


Urine Na + (meq/L) 


<20 


>20 


UOsm (mOsm/kg) 


>500 


<400 


RFI (%) 


<1 


>2 


FENa (%) 


<1 


>2 


FEUrea (%) 


<35 


>50 



Abbreviations: ATN, acute tubular necrosis; Na + , sodium; U, urine; 
Osm, osmolality; RFI, renal failure index; FENa, fractional excretion of 
sodium; FEUrea, fractional excretion of urea. 



cytoplasmic antiboby (ANC A- vasculitis), hepa- 
titis serology, serum cryoglobulins (cryoglobu- 
linemia), complement levels, serum and urine 
Immunoelectrophoresis (monoclonal immuno- 
globulin diseases), and blood cultures (endovas- 
cular infection) 

Diagnostic imaging tests play an important role 
in the evaluation of patients with ARF. The modal- 
ity most often employed is retroperitoneal ultra- 
sonography of the kidneys, ureters, and bladder. 
This test provides information about kidney size 
(large or small) and parenchyma (echogenicity), 
status of the pelvis and urinary collecting system 
(hydronephrosis), and the presence of structural 
abnormalities (stones, masses, and enlarged 
lymph nodes). In the setting of ARF, renal ultra- 
sound's biggest use is in rapidly confirming or 
excluding the presence of hydronephrosis and a 
diagnosis of obstructive uropathy. Doppler inter- 
rogation of the renal arteries provides important 
information about renal blood flow and renal 
artery stenosis; however, this test is highly opera- 
tor dependent. CT scan of the retroperitoneum 
also provides important information about the eti- 
ology of postrenal azotemia when ultrasound is 
negative or inconclusive. Magnetic resonance 
imaging with gadolinium angiography also safely 
provides important information about renal artery 
stenosis/ thrombosis. 

Percutaneous renal biopsy is sometimes 
required to determine the etiology of ARF, as 
well as to direct appropriate therapy. Reasonable 
criteria to support use of renal biopsy are the fol- 
lowing: no obvious cause of ARF (no evidence 
of hypotension, nephrotoxins); prolonged oli- 
guria (>2-3 weeks); assess for multiple myeloma 
in the elderly with unexplained renal failure; 
extrarenal manifestations of systemic disease 
(SLE, vasculitis); and to determine if AIN is pres- 
ent in patients receiving a potentially culprit 
drug. Examination of kidney tissue using light 
microscopy, immunofluorescence staining, and 
electron microscopy will facilitate an accurate 
diagnosis in virtually all cases of ARF. Renal 
biopsy, however, should be employed judiciously 



248 



to avoid complications such as traumatic arteri- 
ovenous malformation within the kidney, severe 
bleeding requiring transfusion, other organ 
injury (liver, spleen, bowel), and kidney loss 
(severe bleeding requiring embolization or 
nephrectomy). 



Chapter 15 



Acute Renal Failure 




Clinical Consequences of Acute 
Renal Failure 



Failure of kidney function precipitates clinical 
problems related to toxin excretion, fluid balance, 
acid/base homeostasis, and electrolyte/mineral 
regulation. Disturbance of the homeostatic renal 
processes result in the following: 



Retention of nitrogen 

wastes 
Retention of sodium 

Retention of water 
Retention of metabolic 

acids 
Retention of potassium 
Retention of phosphate 



azotemia and uremia 

volume overload, 

hypertension 
hyponatremia 
metabolic acidosis 

hyperkalemia 
hyperphosphatemia, 
hypocalcemia 



Clinical manifestations of ART vary based on the 
severity of renal dysfunction. Uremic symptoms 
include anorexia, nausea/vomiting, weakness, dif- 
ficulty mentating, lethargy, and pruritus. Physical 
examination findings supporting uremia include 
asterixis, pericardial friction rub, sensory and/or 
motor neuropathy, and hyper- or hypotension 
depending on the cause of ARF. Other associated 
findings of severe uremia include GI ulcerations, 
bleeding from platelet dysfunction, infection from 
abnormal WBC function, impaired wound healing, 
and malnutrition from the catabolic state. 




Treatment of Acute Renal 
Failure: General Principles 



Therapy of ARF first requires identification of the 
etiology and pathogenesis of the inciting process 
(prerenal, intrarenal, postrenal). Hence, treatment 
is based on diagnosis directed therapy. Also, the 
consequences of ARF need to be identified and 
rapidly managed to avoid serious adverse events 
(hyperkalemia, pericarditis, and acidosis). Prerenal 
azotemia is best treated by optimizing renal 
perfusion. Repletion of intravascular volume 
and correction of heart failure, liver failure, and 
other "effective" causes of reduced intravascular 
volume constitute treatment for this form of ARF. 
Intrarenal azotemia is managed through directed 
therapy for the disturbed kidney compartment 
(vasculature, glomerulus, tubules, interstitium). In 
certain situations, preventive therapy reduces 
renal injury. Examples include volume repletion 
prior to any nephrotoxic or ischemic exposure. 
Fluid therapy (isotonic saline or sodium bicarbon- 
ate), acetylcysteine, and fenoldopam may reduce 
the renal damage associated with radiocontrast 
exposure in high-risk subjects. As discussed pre- 
viously, management of postrenal azotemia man- 
dates rapid identification of the obstruction 
process and early intervention to relieve obstruc- 
tion and preserve renal function. 

Conservative therapy of many of the conse- 
quences of ARF is initially employed. These include 
correction of volume overload/hypertension, 
hyponatremia, hyperkalemia, and acidosis. The 
actual therapies for these clinical situations will be 
covered in other chapters. Conversion of patients 
from oliguric to nonoliguric ARF makes manage- 
ment easier, but probably does not improve mor- 
bidity or mortality. Azotemia and uremia, as well 
as the other consequences previously noted may 
require renal replacement therapy to allow appro- 
priate management when conservative measures 
are unsuccessful. 



Chapter 15 



Acute Renal Failure 



249 



Initiation of acute hemodialysis or continuous 
renal replacement therapies is required in certain 
patients with ARE Continuous therapies, which can 
only be employed in critical care units, include con- 
tinuous venovenous hemofiltration/hemodialysis/ 
hemodianltration (CWH, CWHD, CWHDF) and 
extended daily dialysis (EDD). Emergent indica- 
tions include severe hyperkalemia, uremic end- 
organ damage (pericarditis, seizure), refractory 
metabolic acidosis, and severe volume overload 
(pulmonary edema). Other clinical situations that 
mandate the commencement of renal replacement 
therapy are uremic symptoms such as anorexia, 
nausea/vomiting, somnolence, restless legs, and 
neuropathy. Bleeding from platelet dysfunction 
and extreme hyperphosphatemia are other reasons 
to consider initiation of dialysis. Acute hemodialy- 
sis is the modality most commonly employed to 
treat the consequences of ARF. In patients who are 
critically ill and hemodynamically unstable, contin- 
uous therapies are preferred. The continuous 
modalities allow more precise control of volume, 
uremia, acid-base disturbances, and electrolyte 
disorders with less hemodynamic instability (hypo- 
tension). They also allow aggressive nutritional 
support "without associated volume overload. 
Peritoneal dialysis is another gentle therapy for 
ARF, but it is less commonly used. 



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Nash, K., Hafeez, A., Hou, S. Hospital-acquired renal 

insufficiency. Am J Kidney Dis 39:930-936, 2002. 
Pascual, J., Liano, F, Ortuno, J. The elderly patient with 

acute renal failure. J Am Soc Nephrol 6:144-153, 

1995. 
Perazella, M.A. Acute renal failure in HIV-infected 

patients: a brief review of some common causes. 

AmJMedSci 319:385-391, 2000. 
Perazella, M.A. COX-2 selective inhibitors: analysis of 

the renal effects. Expert Opin Drug Safl:53-64, 2002. 



250 



Chapter 15 



Acute Renal Failure 



Schoolwerth, AC, Sicca, D.A., Ballerman, B.J., Wilcox, 
C.S. Renal complications in angiotensin converting 
enzyme inhibitor therapy. Circulation 104:1985- 
1991, 2001. 

Shokeir, A. A., Shoma, A.M., Mosbah, A., Mansour, O., 
Abol-Ghar, M., Eassa, W., El-Asmy, A. Noncontrast 
computed tomography in obstructive anuria: a 
prospective study. Urology 59:861-864, 2002. 



Thadhani, R., Pascual, M., Bonventre, J.V. Acute renal 
failure. TV Engl J Med 334:1448-1460, 1996. 

Wesson, M.L., Schrier, R.W. Diagnosis and treatment of 
acute tubular necrosis. Ann Intern Med 137:744- 
752, 2002. 



Mark A. Perazella 



Chronic Kidney Disease 




Recommended Time to Complete: 2 days 

1. Why is the rapid growth of the chronic kidney disease (CKD) popu- 
lation a concern? 

2. Why are estimation equations of glomerular filtration rate (GFR) 
used to measure kidney function? 

1. Why is a staging system beneficial to appropriately care for CKD 

patients? 
ty. What are the major mechanisms of progression of kidney disease? 
S. What are the most effective treatments to slow progression of CKD to 

end-stage renal disease (ESRD)? 
d. Is cardiovascular disease (CVD) common in CKD patients? 
7- What are the various categories of risk factors for the development 

of cardiovascular disease in CKD patients? 
9- What are the most common causes of anemia in CKD patients? 
e l. What are the options available to treat anemia in CKD patients? 

10. What metabolic mineral disturbances occur in CKD patients? 

11. What types of bone disease constitute the spectrum of renal osteo- 
dystrophy? 

12. Why is early referral of CKD patients to nephrologists important? 
11. What are the important aspects of preparation of CKD patients for 

initiation of renal replacement therapy (RRT)? 



251 




Introduction 



CKD is a worldwide health problem. Compre- 
hensive data on CKD provided by the Third 
National Health and Nutrition Examination Survey 
(NHANES III) noted, that approximately 800,000 
Americans have CKD as manifested by a serum 
creatinine concentration of 2.0 mg/dL or greater. 
More than 6.2 million are estimated to have a 
serum creatinine concentration of 1.5 mg/dL or 
greater. Data extrapolated from the Framingham 
study suggest that approximately 20 million 
people in the United States are at risk for CKD. 

The rapid growth in both the incidence and 
prevalence of CKD will result in a huge influx of 
patients into the ESRD system. Based on data from 
the United States Renal Data System (USRDS), the 
incidence of ESRD has increased steadily for the 
past 15 years, rising from 142 cases per million pop- 
ulation in 1987 to 308 cases per million population 
in the year 2000. Expansion of the ESRD population 
will have a significant economic impact on the 
already overextended Medicare system. For exam- 
ple, Medicare expenditures for the ESRD program 
in 1996 increased 12.5% over the previous year, 
costing an estimated $10.96 billion. The increase in 
both CKD and ESRD populations may also over- 
whelm the ability of nephrologists and other health 
care providers to fully provide interventions that 
will improve the length and quality of patients' lives. 

Defining and Staging CKD 

Several terms are used to describe the period of 
kidney disease that precedes the institution of renal 
replacement therapy such as pre-ESRD, chronic 
renal insufficiency, chronic renal failure, and 
chronic renal disease. Unfortunately, none of these 
terms is particularly accurate and may be confusing 
to nonnephrology physicians. The term pre-ESRD 
gives the impression that dialysis is an inevitable out- 
come of all kidney diseases. The terms renal insuf- 
ficiency, chronic renal failure, chronic renal 
disease, and pre-ESRD have negative connotations. 



Chapter 1 6 ♦ Chronic Kidney Disease 

These terms also include the word renal, which is 
not easily understood by patients. For these reasons, 
chronic kidney disease is chosen as the defining 
term. 

The definition and classification of CKD are 
based on measurement of GFR, the best overall 
measure of kidney function. Factors that influence 
GFR include structural or functional kidney disease, 
as well as patient age. In general, the annual 
decline of GFR with age is approximately 1 ml/ 
minute/1.73 m 2 of body surface area, beginning 
after the patient reaches approximately 20-30 years 
of age. Although a chronic decline in GFR to a level 
of <60 mL/minute/1.73 m 2 is evidence of CKD, sub- 
stantial kidney damage can exist without a decrease 
in GFR. In this circumstance, kidney damage is 
defined as a structural or functional abnormality of 
the kidney that persists for more than 3 months. 
Manifestations of kidney damage can include patho- 
logic changes or abnormalities revealed by blood, 
imaging, or urine tests. Using this definition, CKD is 
present if the GFR is <60 mL/minute/1.73 m 2 . CKD is 
also present if the GFR is >60 mL/minute/1.73 m 2 if 
other evidence of kidney damage also exists. A clas- 
sification and staging system based on the level of 
GFR is noted in Table 16.1. This staging system pro- 
vides a common language for communication 
between the various health care providers. It allows 
more reliable estimates of the prevalence of earlier 
stages and of populations at increased risk for CKD. 
In addition, evaluation of factors associated with a 
high risk of progression can be recognized. 
Treatments can be more effectively examined and 
the development of adverse outcomes in this popu- 
lation is more easily determined. 



GFR as an Index of Kidney Function 

Serum creatinine concentration is commonly 
employed as an index of kidney function. It is not an 
accurate measure of GFR, however, and it is espe- 
cially inaccurate when the serum creatinine concen- 
tration is between 1 and 2 mg/dL. This is because 
creatinine, unlike inulin, is secreted by the renal 
tubules. As renal function declines, the amount of 
creatinine secreted by the tubules increases and 



Chapter 16 ♦ Chronic Kidney Disease 



253 



Table 16.1 



Staging System and Action Plan for CKD 










GFR 




Stage 


Description 


(mL/minute/1.73 m 2 ) 


Action* 





At increased risk of CKD 


>90 with 
risk factorst 


Screening CKD risk reduction 


1 


Kidney damage with 


>90 


Diagnosis and treatment 




normal or increased GFR^ 




Slow progression of CKD 
Treat comorbidities 
Cardiovascular disease 
risk reduction 


2 


Mild decrease in GFR 


60-89 


Estimate progression 


3 


Moderate decrease in GFR 


30-59 


Evaluate and treat 
complications 


4 


Severe decrease in GFR 


15-29 


Prepare for renal 

replacement therapy 


5 


Kiciney failure 


<15 or dialysis 


Renal replacement 
if uremic 



includes actions from preceding stages. 

tRisk factors: hypertension, dyslipidemia, diabetes mellitus, anemia, systemic lupus erythematosus, and chronic analgesic ingestion 

^Kidney damage as manifested by abnormalities noted on renal pathology, blood, urine, or imaging tests. 

Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate. 

Source: Adapted from Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) Advisory Board. Am J Kidney 

Dis 39(2 Suppl. 2): S1-S246, 2002 with permission. 



raises the amount of creatinine in the urine. This acts 
to falsely increase the creatinine clearance (CrCl), 
resulting in an overestimation of GFR, Serum creati- 
nine concentration is also influenced by body mass, 
muscle mass, diet, drugs, and laboratory analytical 
methods. "Normal" ranges of serum creatinine con- 
centrations quoted by laboratories are misleading 
because they do not take into account the age, race, 
sex, or body size of the individual. 

Inulin clearance is the gold standard test for meas- 
uring GFR. Unfortunately, this test is cumbersome, 
expensive, and not widely available for clinical use. 
Iothalamate ( 125 I-iothalamate) clearance estimates 
GFR and is a reasonably accurate substitute for the 
inulin clearance method. It is also expensive and 
somewhat cumbersome to perform as a routine clin- 
ical test. A 24-hour urine collection for creatinine 
clearance is the accepted alternative measure of GFR 
because it is widely available and is familiar to most 
clinicians. It is often difficult, however, for patients to 
perform correctly and is less accurate than either 



inulin or iothalamate clearance. The adequacy of the 
24-hour urine collection is assessed by calculating 
the urinary creatinine excretion per kg of body 
weight. Males excrete 20-25 mg creatinine/kg and 
females excrete 15-20 mg creatinine/kg in the 
steady state. In addition, this test often overestimates 
GFR in patients with advanced kidney disease. 

To simplify measurement of renal function, 
GFR estimates from prediction equations are often 
used. These formulas take into account serum cre- 
atinine concentration, age, gender, race, and body 
size, and are better estimates of GFR than serum 
creatinine concentration alone. The formulas 
used are sufficiently accurate. The two most 
widely used are the Cockcroft-Gault and the 
Modification of Diet in Renal Disease Study 
(MDRD) equations. The Cockcroft-Gault equation 
noted below estimates creatinine clearance: 



[140 -age (years)] x weight (kg) 
72 x serum [creatinine] (mg/dL) 



x 0.85 for females 



254 



Chapter 1 6 ♦ Chronic Kidney Disease 



Although it provides an adequate estimate of 
GFR, the MDRD equations are more accurate. 
MDRD equation 7 is the preferred formula but it 
requires serum blood urea nitrogen (BUN) and 
albumin concentrations. The MDRD formula is as 
follows: 

170 x [serum creatinine (mg/dL)]~° " 9 
X [age (years)F on6 x [0.762 if female] 
x [1.18 if African American] 
x [BUN (mg/dL)r° 17 ° 
x [albumin (g/dL)] 10 31S 

An abbreviated form of the MDRD equation that 
does not require serum BUN or albumin concen- 
trations was also developed and is as follows: 

186 x [serum creatinine (rngtlL)] - 

x [age (years)r 203 x [0.742 if female] 
x [1.21 if African American] 

The abbreviated form is reasonably accurate. 
The MDRD equation was tested in over 500 
patients with a range of kidney diseases and eth- 
nicities (European Americans and African 
Americans). GFR values were validated in the 
sample group using 12, I-iothalamate as the gold 
standard, however, certain patient groups were 



not well represented in the MDRD study sample. 
Therefore, clearance measurements are still 
required in groups who were underrepresented 
in the MDRD sample to fully validate the formula 
for all patients. These include: patients at extremes 
of age and body size; the severely malnourished 
or obese; patients •with skeletal muscle diseases, 
paraplegia, or quadriplegia; vegetarians; and 
those with rapidly changing kidney function. The 
MDRD equation underestimates GFR in patients 
with relatively normal kidney function. 



Prevalence ofCKD Stages 

Prevalence estimates for each CKD stage were 
obtained by using a reference group comprised of 
patients evaluated in NHANES III. In this sample of 
patients, the MDRD equation was used to estimate 
GFR. In addition to abnormal GFR levels, the pres- 
ence of micro- or macroalbuminuria on spot urine 
specimens was considered sufficient evidence of 
kidney damage. The level of albuminuria, based on 
the ratio of albumin (and protein) to creatinine on 
spot urine samples, was used to estimate the preva- 
lence of the first two stages. The prevalence of each 
GFR category is noted in Table 16.2. 



Table 16.2 



U.S. Prevalence of CKD by Stage 



Stage 


Description 


GFR 

(mL/minute/1.73 m 2 ) 


Prevalence* 


N (1000s) 


Percent 


1 


Kidney damage with 

normal or increased GFRf 


>90 


5900 


3.3 


2 


Mild decrease in GFR 


60-89 


5300 


3.0 


3 


Moderate decrease in GFR 


30-59 


7600 


4.3 


4 


Severe decrease in GFR 


15-29 


400 


0.2 


5 


Kidney failure 


<15 or dialysis 


300 


0.1 



'Prevalence based on population of 177 million adults age >20 years. 

fKidney damage as manifested by abnormalities noted on renal pathology, blood, urine, or imaging tests. 

Abbreviation: GFR 7 glomerular filtration rate. 

Source- Adapted from National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) Advisory Board. 

Am J Kidney Dis 39(2 Suppl. 2):S1-S246, 2002 with permission. 



Chapter 16 ♦ Chronic Kidney Disease 



255 




Approach to CKD Patients 



The approach to the patient involves establishing 
the presence of CKD, determining the stage of dis- 
ease, and enacting an action plan based on the 
stage. The management of CKD patients requires 
a multidisciplinary approach involving primary 
care physicians, nephrologists, endocrinologists, 
cardiologists, vascular surgeons, physician assis- 
tants, nurse practitioners, dietitians, and social 
workers. The goals of this interdisciplinary 
approach are to identify patients either with or at 
increased risk for CKD, to slow the progression of 
CKD to ESRD, to identify and treat comorbid con- 
ditions, to identify and prevent complications of 
CKD, and to prepare patients mentally and physi- 
cally for renal replacement therapy. As seen in 
Table 16.1, the action taken increases from simple 
screening maneuvers and risk reduction to more 
complex disease management. 

Patients with established CKD are assessed for 
comorbid conditions. Medications are adjusted for 
the level of renal function. Blood pressure (BP) 
monitoring is essential to diagnose hypertension 
and facilitate optimal blood pressure control. 
Serum creatinine concentration is measured to 
allow estimation of GFR. Protein- or albumin-to- 
creatinine ratios on spot urine samples and urinal- 
ysis are performed. Finally, imaging of the kidney 
by ultrasound is warranted in most CKD patients. 

The approach is implemented in a step-wise 
fashion and individualized for each patient based 
on the level of kidney function. In a patient with a 
normal GFR (>90 mL/minute/1.73 m 2 ) or a mildly 
impaired GFR (>60 mL/minute/1 .73 m 2 ) the focus 
will be on delaying progression and treating 
comorbid conditions. Progression is best pre- 
dicted by plotting the reciprocal of the serum cre- 
atinine concentration over time. This plot predicts 
a date when the GFR will reach target levels for 
the initiation of renal replacement therapy. In gen- 
eral, the cut-off values are 15 mL/minute/1.73 m 2 
for diabetic patients and 10 mL/minute/1.73 m 2 
for nondiabetic patients. 



Key Points 

Approach to CKD Patients 



1 . The incidence and prevalence of CKD are 
growing rapidly. 

2. Equation estimates of GFR as well as other 
laboratory, pathologic, and radiographic 
abnormalities allow classification and staging 
of CKD. 

3. The most useful equation to estimate GFR is 
the MDRD formula. 

4. Patients with CKD should be staged and 
then evaluated and managed using their 
CKD stage. 

5. Management of CKD patients will focus on 
disease prevention, management of comor- 
bidities, and preparation for renal replace- 
ment therapy. 




Progression of CKD 



Mechanisms of CKD Progression 

The initiating event in the development of kidney 
disease is a pathologic process that produces 
nephron injury and loss of functioning units. 
Following a reduction in the number of function- 
ing nephrons, remaining nephrons experience 
hyperfiltration and glomerular capillary hyperten- 
sion. Although these changes are initially adap- 
tive to maintain GFR, over time they are 
deleterious to renal function because of pressure- 
induced capillary stretch and glomerular injury. 
The damage caused by glomerular hyperfiltration 
is important in the pathophysiology that underlies 
diabetic nephropathy. The hyperfiltering state 
induced by hyperglycemia upregulates local 
expression of the renin-angiotensin-aldosterone 
system (RAAS) and contributes to progressive 
kidney damage. In this instance, stimulation of 



256 



Chapter 1 6 ♦ Chronic Kidney Disease 



the RAAS causes glomerular injury by further 
raising glomerular capillary pressure through 
angiotensin II (All)-driven efferent arteriolar vaso- 
constriction and facilitating pressure and stretch 
injury in the capillaries. Taken together, these 
effects lead to endothelial injury, stimulation of 
profibrotic cytokines by the mesangium, and 
detachment of glomerular epithelial cells. Other 
maladaptive consequences include glomerular 
hypertrophy with elevated capillary wall stress 
and increased ammoniagenesis per remnant 
nephron. This latter effect promotes complement 
activation and enhanced tubulointerstitial disease. 
Another consequence of renal injury and activa- 
tion of the RAAS is proteinuria. Glomerular capillary 
hypertension, caused by hyperfiltration and All 
effect on efferent arterioles, leads to an increase in 
glomerular permeability and excessive protein fil- 
tration. Pore size is altered by All, increasing protein 
leak across the glomerular basement membrane. An 
activated RAAS may also cause proteinuria through 
novel effects on nephrin expression in kidney. 
Nephrin, a transmembrane protein located in the 
slit diaphragm of the glomerular podocyte, is 
thought to play a key role in the function of the 
glomerular filtration barrier. By maintaining slit 
diaphragm integrity, nephrin limits protein loss 
across the glomerular basement membrane. When 
its expression is disrupted, proteinuria and its con- 
sequences may result. Data in rat models of pro- 
teinuric kidney disease suggest an important 
interaction between the RAAS and nephrin in mod- 
ifying glomerular protein permeability. Although 
proteinuria is a marker for renal disease risk, it is 
also likely that excess protein in urine contributes to 
progressive kidney damage. Proteins present in the 
urine are toxic to the tubules, and can result in tubu- 
lar injury, tubulointerstitial inflammation, and scar- 
ring. Tubular damage is due to protein overloading 
of intracellular lysosomes, stimulation of inflamma- 
tory cytokine expression, and extracellular matrix 
protein production. These processes induce renal 
tubulointerstitial fibrosis and glomerular scarring. 
It was clearly demonstrated that a remission or 
reduction in proteinuria is associated with nephro- 
protection. 



While it is known that elevated glomerular cap- 
illary pressure and capillary stretch lead to scar 
formation in the glomerulus, an activated RAAS 
and other inflammatory mediators directly cause 
irreversible damage in the kidney through other 
mechanisms. Proinflammatory and profibrotic 
effects of All and aldosterone underlie the injury 
that develops in the renal parenchyma. Advanced 
glycation end-products also cause renal injury. 
These various mediators promote fibrosis and 
scarring in the kidney through multiple untoward 
effects such as toxic radical formation, enhanced 
cellular proliferation, and collagen deposition in 
the glomerulus and tubulointerstitium. Ultimately, 
glomerulosclerosis and tubulointerstitial fibrosis 
occur and promote chronic kidney disease. 



Risk Factors for Progression ofCKD 

Hypertension and the RAAS 

Hypertension is clearly associated with progres- 
sion of CKD and is the second most common 
cause of ESRD. Importantly, hypertension is pres- 
ent in the majority of CKD patients, making it a key 
risk factor for progression. Most studies, with a few 
exceptions, confirm that hypertension hastens the 
course of CKD to ESRD in both diabetic and non- 
diabetic patients. The MDRD study demonstrated 
that proteinuric patients, when randomized to a 
lower blood pressure, manifested a slower decline 
in GFR. Also, a significant correlation between the 
achieved blood pressure and the rate of decline in 
renal function, especially in patients with greater 
than 1 g/day of proteinuria was noted. The Joint 
National Committee (JNC VII) recommends the 
following blood pressure target goals: 

1. CKD with <1 g/day of proteinuria: 130/85. 

2. CKD with >1 g/day of proteinuria: 125/75 to 
130/80. 

Proteinuria is a powerful risk factor for pro- 
gression of CKD, especially as levels exceed both 
1 and 3 g/day, respectively. Patients with high- 
grade proteinuria and hypertension are at highest 



Chapter 16 ♦ Chronic Kidney Disease 



257 



risk to progress to ESRD. Both experimental and 
clinical data suggest that inhibition of the RAAS is 
very effective in lowering blood pressure, reduc- 
ing proteinuria, and slowing progression of 
kidney disease in both diabetic and nondiabetic 
patients. This is of particular interest since the 
leading cause of ESRD in the United States is dia- 
betic nephropathy. Treatment of disease states 
resulting from or associated with excessive RAAS 
activity is best achieved by therapies that suppress 
All and aldosterone production or inhibit the 
renal effects of these substances (Figure 16.1). 

Inhibition of angiotensin-converting enzyme 
(ACE) activity decreases All and aldosterone 
formation and potentiates the vasodilatory effects 



of the kallikrein-kinin system by increasing 
bradykinin formation (Figure 16.1). The ACE 
inhibitors reduce proteinuria and delay progres- 
sion of kidney disease in both diabetic nephropa- 
thy and other forms of proteinuric kidney disease. 
In a landmark study, the effect of captopril versus 
conventional therapy on the occurrence of multi- 
ple renal endpoints (time to doubling of serum 
creatinine concentration, progression to ESRD, or 
death) was studied in 409 type 1 diabetic patients 
with proteinuria and CKD. A 50% reduction in 
the development of these renal endpoints was 
demonstrated in patients treated with captopril 
compared with conventional therapy, despite little 
difference in blood pressure control. The beneficial 



Figure 16.1 























Angiotensinoger 










-<^\ 


V 


/ Tonin 
/ tPA 


' 


^-O- 


#> 






/ Cathepsin G 


1 




Bradykinin 






■ Angiotensin 1 










\ / Chym 


ase 
iE 

sin G 




*. ^^^^^^ J* 




\ ( CAC 
\. V Cathep 


' 


X s 




Angiotensin II 






















Inactive 
peptides 
















J^_^^ antagonism 










AT 2 




( AT, J 






\^_^x^n. lAldosterone receptor 
<q »^. antagonism 














^^ 






Aldosterone 

























The renin-angiotensin-aldosterone system. Angiotensin II and aldosterone are formed by classical path- 
ways (renin, ACE) and alternate pathways (tonin, tPA, cathepsin G, chymase, CAGE). The pathway is 
interrupted at various levels by ACE inhibitors, AT, receptor antagonists, and aldosterone receptor antag- 
onists. Abbreviations: tPA, tissue plasminogen activator; AT,, angiotensin type 1; AT, angiotensin type 2; 
CAGE, chymostatin-sensitive angiotensin H-generating enzyme; ACE, angiotensin converting enzyme. 



258 



Chapter 1 6 ♦ Chronic Kidney Disease 



effects of RAAS inhibition also extend to nondia- 
betic kidney diseases complicated by proteinuria. 
The ACE Inhibition in Progressive Renal Insuffi- 
ciency (AIPRI) Study compared the ACE-inhibitor 
benazepril with placebo in 583 nondiabetic 
patients with CKD. Benazepril was associated with 
an overall risk reduction of 53% in the develop- 
ment of the primary renal endpoint (doubling of 
serum creatinine concentration and need for dial- 
ysis) as compared with conventional antihyper- 
tensive therapy. In this trial, the absolute benefit 
of ACE inhibition was most marked in patients 
with the highest level of proteinuria. The REIN 
study (stratum 2) confirmed these positive results 
in a similar group of nondiabetic patients. A 52% 
risk reduction in progression to kidney disease 
endpoints 'was seen with ramipril as compared 
with placebo. Renoprotection was most impres- 
sive in patients with greater than 3 g of protein- 
uria. A metaanalysis of data obtained from I860 
nondiabetic patients from 11 randomized clinical 
trials demonstrated significant renal protection 
with ACE inhibitors. ACE-inhibitor therapy was 
associated with a reduction in relative risk for the 
development of ESRD (0.69) and for the doubling 
of serum creatinine concentration (0.70). Thus, 
the benefit of ACE inhibition is most pronounced 
in patients with heavy proteinuria and a reduction 
in proteinuria correlates with slower declines in 
GFR. 

Angiotensin II type 1 receptor blockers (ARBs) 
lower blood pressure, reduce proteinuria, and 
slow progression of kidney disease. Antagonism 
of the AT, receptor (Figure 16.1) and binding of 
All to the AT 2 receptor probably underlies their 
mechanism of action. Recently completed clinical 
trials suggest that ARBs reduce microalbuminuria 
and proteinuria and retard the progression of dia- 
betic chronic kidney disease in a fashion similar 
to the ACE inhibitors. The RENAAL study com- 
pared the ARB losartan with conventional therapy 
in 1513 type 2 diabetics with hypertension and 
nephropathy. A 16% risk reduction was noted in 
predetermined primary composite endpoints 
(time to doubling of serum creatinine concentration, 



progression to ESRD, or death) in the losartan 
group over a mean follow-up of 3.4 years. This 
study demonstrated a 28% risk reduction in pro- 
gression to ESRD and 25% reduction in doubling 
of serum creatinine concentration in patients 
treated •with losartan. An average reduction in the 
level of proteinuria of 35%, despite similar blood 
pressure control between the groups, was also 
noted. Similar findings were described in the 
IDNT study, which employed irbesartan in patients 
with type 2 diabetes mellitus and nephropathy. 
Like ACE inhibitors, interruption of the RAAS with 
ARBs in diabetics is a logical albeit incomplete 
strategy to provide renoprotection. 

Dual blockade of the RAAS with ACE inhibitors 
and angiotensin receptor blockers may provide 
kidney benefit beyond therapy with either drug 
alone. The CALM study combined lisinopril and 
candesartan to treat hypertension and reduce 
microalbuminuria in patients with type 2 diabetes 
mellitus. Over 24 weeks, dual blockade safely 
reduced blood pressure and reduced microalbu- 
minuria (50%) as compared with candesartan 
(24%) and lisinopril (39%) monotherapy. Similarly, 
a randomized double-blind crossover study in 
18 type 2 diabetic patients with proteinuria demon- 
strated positive renal effects with combination ther- 
apy. In patients with IgA nephropathy, the 
combination of losartan and enalapril were addi- 
tive in decreasing urinary protein excretion, 
whereas doubling the dose of either form of 
monotherapy had no effect on proteinuria. Over 
6 months, the combination of lisinopril plus can- 
desartan reduced proteinuria by 70% compared 
to monotherapy with lisinopril (50% reduction) or 
candesartan (48% reduction). The COOPERATE 
study examined the effect of combination therapy 
on progression of renal disease (time to doubling 
of serum creatinine concentration or ESRD) in 
patients with proteinuric kidney disease. In this 
3-year study, patients were randomly assigned to 
trandolapril (3 mg/day), losartan (100 mg/day), or 
a combination of the 2 drugs. Only 11% of patients 
on combination therapy reached the renal end- 
point, whereas 23% of patients in the two 



Chapter 16 ♦ Chronic Kidney Disease 



259 



monotherapy arms did so. Not all studies demon- 
strate that combination therapy is better than 
maximal dose ACE-inhibitor therapy in decreas- 
ing proteinuria. These studies suffer from small 
patient numbers, surrogate markers of renal pro- 
tection (proteinuria), and short-term follow-up. 
Thus, titration of the single agent to maximal dose 
to control blood pressure and proteinuria is rec- 
ommended. If proteinuria remains greater than 
1 g/day, a second agent to further block the RAAS 
should be considered. 

Aldosterone is associated with renal injury 
through both hemodynamic and profibrotic effects. 
Aldosterone antagonism in animals is renoprotec- 
tive when used alone or in combination with ACE 
inhibition. Preliminary human data suggest that 
the combination of an aldosterone receptor antag- 
onist like spironolactone or eplerenone with an 
ACE inhibitor or ARB significantly reduce protein- 
uria. This therapy, however, is associated with 
higher risk of hyperkalemia. 

Finally, it is important to recognize that 
inhibitors of the RAAS can be used safely in most 
patients with mild-to-moderate CKD. The two 
major concerns associated with these drugs are the 
development of hyperkalemia and/or further wors- 
ening of kidney function. In regards to hyper- 
kalemia, careful dose titration, dietary changes, 
avoidance of potassium altering medications 
(NSAIDs, COX-2 selective inhibitors, and potassium 
sparing diuretics), and use of loop diuretics allow 
safe therapy in most patients. Increases in serum 
creatinine concentration should be tolerated as 
long as the concentration rises no higher than 30% 
above baseline and stabilizes within 2 months of 
therapy. Continued increases should promote drug 
discontinuation and a search for volume contrac- 
tion, critical renal artery stenosis, and other poten- 
tially correctable problems. 

Diabetes Mellitus 

As the prevalence of diabetes mellitus grows in 
the United States, patients with this disease con- 
tinue to contribute a significant number of patients 



to the CKD population. In fact, diabetic kidney 
disease is the most common cause of ESRD. Thus, 
it is important to identify and adequately manage 
these patients to reduce progression of their 
underlying kidney disease. As shown in the 
Diabetes Control and Complications Trial (DCCT), 
intensive insulin therapy to establish tight glucose 
control prevented de novo kidney disease 
(microalbuminuria) by 34% and reduced progres- 
sion of established nephropathy (albuminuria) by 
56% in type 1 diabetics. Progression of CKD in 
type 2 diabetics is an even bigger problem as this 
group makes up the majority of patients who 
develop ESRD. Several studies reveal that inten- 
sive insulin therapy to maintain the HbAlc level 
in the 7.0-7.6% range reduces progression of 
kidney disease (albuminuria/proteinuria) as com- 
pared with conventional insulin therapy. Thus, 
patients with diabetic nephropathy should 
achieve tight glucose control, defined by a HbAlc 
concentration of 7.0-7.5%, in addition to BP con- 
trol with RAAS inhibitors. 



Dietary Protein Restriction 

Restriction of dietary protein reduces renal injury in 
the experimental setting by decreasing glomerular 
capillary hypertension and reducing production 
of profibrotic cytokines and growth factors. In 
humans, it is less clear that a low protein diet is 
beneficial. The results of various studies are 
mixed. In the largest study, two levels of protein 
restriction (low and very low) failed to show a dif- 
ference in GFR decline between groups after a 
mean follow-up of 2.2 years. Posthoc analysis 
identified some benefit of protein restriction 
•when examined by achieved level of protein 
intake. Patients with very low protein intake had a 
1.15 mL/minute/year slower decline in GFR. Two 
metaanalyses also suggest a benefit with protein 
restriction. In one, the risk of ESRD or death was 
reduced by 33% while another noted a small 
benefit in GFR change (0.53 mL/minute/year) with 
a low protein diet. Enthusiasm for this approach 
is tempered by the real risk of malnutrition in 



260 



Chapter 1 6 ♦ Chronic Kidney Disease 



CKD patients. Thus, in the highly motivated 
patient, a moderately low protein diet (0.6- 
0.8 g/kg/day) can be employed along with close 
monitoring of nutritional state. 



Serum Lipid Reduction 

Experimental work demonstrates that low density 
lipoprotein (LDL) lipids are toxic to human mesan- 
gial cells, an effect that is reversed by 3-hydroxy-3- 
methylglutaryl-coenzyme A (HMG-CoA) reductase 
inhibitors (statins). Observational studies in humans 
suggest that reducing serum lipid levels is asso- 
ciated with preservation of kidney function. 
Unfortunately, these studies are plagued by small 
patient numbers and, as a result, are underpowered 
to allow any conclusions. To address this problem, 
a metaanalysis of 13 studies revealed a trend toward 
reduction in proteinuria and a small decrease in the 
rate of GFR loss with lipid lowering. Despite the 
absence of conclusive data, it is logical that lipid 
reduction should be employed in CKD patients to 
reduce cardiovascular risks and potentially slow 
progression of kidney disease. 



Smoking Cessation 

Tobacco smoking may injure the kidney through 
various pathways. Hypertension complicates 
smoking, a "well-known factor associated with 
kidney disease. Smoking also increases single 
nephron GFR and may promote progression of 
kidney disease through hyperfiltration and 
glomerular capillary hypertension. Finally, smok- 
ing raises aldosterone levels. As discussed previ- 
ously, aldosterone may enhance kidney disease 
by increasing BP and direct profibrotic effects. In 
humans, smoking similarly injures the kidney and 
increases the risk of developing albuminuria in 
diabetics. Smoking cessation slows progression of 
kidney disease in patients with diabetic nephropa- 
thy and some nondiabetic forms of kidney disease. 
Given the overall negative health consequences 
associated with smoking, patients with CKD 
should be aggressively counseled to quit. 



Key Points 

Progression of CKD 



7. 



Adaptive changes to nephron injury pro- 
mote various effects that ultimately con- 
tribute to progression of CKD. 
Hypertension, hyperfiltration, hyper- 
glycemia, high-grade proteinuria, and over- 
activation of the RAAS cause renal injury 
and progression of kidney disease to ESRD. 
CKD patients with high levels of proteinuria 
are at highest risk to progress to ESRD. 
Therapies that reduce blood pressure to 
appropriate goals, reduce proteinuria, and 
inhibit the RAAS provide the most benefit to 
slow loss of renal function in diabetic and 
nondiabetic patients with proteinuric kidney 
disease. 

ACE inhibitors and ARBs provide renopro- 
tection in CKD patients; combination ther- 
apy with these drugs and aldosterone 
antagonists may provide further kidney pro- 
tection but need further validation. 
Tight glucose control in diabetics reduces 
progression of micro- and macroalbumin- 
uria. 

Dietary protein restriction, serum lipid low- 
ering with statins, and smoking cessation 
may also reduce progression of kidney dis- 
ease in subgroups of patients. 




CVD is the leading cause of death in CKD patients. 
There is an increase in the overall prevalence of 
CVD in these patients. Left ventricular hyper- 
trophy (LVH) and ischemic heart disease (IHD) 
are the most common manifestations of CVD in 



Chapter 16 ♦ Chronic Kidney Disease 



261 



this population. This is not surprising given the 
shared risk factors (hypertension and diabetes 
mellitus) for both disease entities. Analysis of the 
Framingham study demonstrates that moderate 
CKD was associated with twice the prevalence of 
CVD and higher relative risks for both IHD and 
cerebrovascular accident (CVA) compared with 
individuals with normal kidney function. In a 
recent large cross-sectional study of 5888 elderly 
Medicare patients, the odds ratio for the presence 
of CVD was almost 2.5 times higher in CKD patients. 
In the Heart Outcome Prevention Evaluation 
(HOPE) trial, myocardial infarctions were more 
common in the subset of patients with CKD. A 
similar finding was noted in CKD patients com- 
pared with subjects from the general population 
in France. 

The prevalence of left ventricular hypertrophy 
(LVH) approaches 40% in the early stages of CKD, 
higher rates occur in patients with lower GFR 
values. Left ventricular hypertrophy is present in 
nearly three-quarters of CKD patients initiating dia- 
lysis. Indirect evidence suggests that D7H develops 
progressively in these patients over the years 
preceding dialysis initiation. In addition, eccentric 
rather than concentric LVH is found to be twice as 
prevalent, suggesting a prominent role for anemia 
in the genesis of hypertrophied left ventricles in 
CKD patients. In Canada, the prevalence of IHD 
approaches 39-46% in patients with CKD. Coronary 
artery disease is also more severe with advanced 
renal dysfunction. Finally, PVD is prevalent in CKD 
patients, reaching 20% in one study. It is thus well 
established that CVD is prevalent in CKD patients. 

Chronic kidney disease patients with CVD 
have worse outcomes than the general popula- 
tion. In ESRD patients commencing dialysis, the 
presence of LVH is independently associated 
with increased mortality. The risk of death over 
the first year following a myocardial infarction in 
this group is almost twice that of the general pop- 
ulation. Similar findings are seen in CKD patients. 
The presence of mild-to-moderate kidney disease 
is associated with an increased risk of overall car- 
diovascular mortality. A number of studies docu- 
mented a worse outcome after a myocardial 



infarction in CKD patients. This may be due in 
part to undertreatment of these patients with 
state-of-the-art therapies for cardiovascular dis- 
ease. Fear of exacerbating underlying kidney 
function with inhibitors of the renin-angiotensin 
system, contrast material, and aspirin explain this 
therapeutic approach. Risk of bleeding complica- 
tions from thrombolytics employed for acute 
coronary syndromes in CKD patients with dys- 
functional platelets further reduces use of this 
potentially life-saving therapy. There is also an 
increased risk for death after cardiac surgery. In 
the Studies of Left Ventricular Dysfunction 
(SOLVD) trial, kidney disease confers a higher 
risk of death among patients with ventricular dys- 
function. Similarly, a higher risk of death and 
other cardiovascular events in CKD patients were 
noted in the HOPE trial. In summary, CKD 
patients appear to possess a higher risk of death 
from CVD. 

Many factors increase risk for cardiovascu- 
lar disease in CKD patients. The pathogenesis 
of cardiovascular damage in this group is far 
more complex than in the general population. 
Risk factors for CVD include those identified in 
the general population and additional ones 
associated with kidney disease (Table 16. 3). 
Traditional coronary risk factors are highly 
prevalent in CKD patients. Diabetes mellitus is 
the most common cause of kidney disease in the 
United States and is present in more than 35% of 
patients with ESRD. Similarly, hypertension and 
dyslipidemia are rampant. A cross-sectional 
analysis involving patients enrolled in the 
Modification of Diet in Renal Disease trial noted 
that 64% were hypertensive despite therapy and 
more than half had elevated LDL cholesterol con- 
centrations. "CKD-related" risk factors include 
the hemodynamic and metabolic abnormalities 
associated with kidney disease. Risk factors for 
CVD can be divided into "factors modified by 
CKD" such as hypertension, dyslipidemia, and 
hyperhomocysteinemia, and "CKD state-related 
risk factors" including anemia, hyperparathy- 
roidism, malnutrition, and oxidative stress. Risk 
factor reduction is likely to be effective in reducing 



262 



Chapter 1 6 ♦ Chronic Kidney Disease 



Table 16.3 

Cardiovascular Risk Factors in CKD 



Traditional 


Risk Factors 


CKD-Related 


Risk Factors 


Altered by CKD 


Risk Factors 


Hypertension 


Dyslipidemia 


Hemodynamic overload 


Hyperlipidemia 


High lipoprotein (a) 


Anemia 


Diabetes mellitus 


Prothrombotic factors 


Increased oxidant stress 


Tobacco use 


Hyperhomocysteinemia 


Malnutrition 


Physical inactivity 


Hypertension 


Hyperparathyroidism 




Sleep apnea 


Elevated ADMA levels 



Abbreviation: ADMA, asymmetric dimethyl arginine. 



morbidity and mortality due to cardiovascular 
disease in patients with CKD as they are in the 
general population. An approach to risk reduc- 
tion should target both the traditional coronary 
risk factors and specific risk factors related to 
CKD (Table 16.3). 



Traditional Risk Factors 

Hypertension 

Hypertension is a common problem in CKD and 
is associated "with untoward vascular events. 
From a cardiovascular disease perspective, the 
treatment of hypertension in CKD is incom- 
pletely studied. In stages 3-4, antihypertensive 
therapy improves LVH, and a recent study of 
patients with polycystic kidney disease revealed 
better results in reduction of left ventricular 
mass (35% versus 21%) in the group of patients 
whose target BP was 120/80 mmHg versus the 
conventional <l40/90 mmHg. Patients with dia- 
betic nephropathy have a reduction in hospital- 
ization for first heart failure episode with All 
receptor blockade. Large cohort studies reveal a 
protective effect associated with antihyperten- 
sive drug therapy. Exposure to calcium channel 
blockers or beta-blockers was associated with 



decreased cardiovascular death in hemodialysis 
patients. ACE inhibitor effects are inconsistent 
across studies, but they are probably cardio- 
protective and reduce heart failure. Thus, 
hypertension is important in CKD due to its 
impact on both kidney disease progression and 
cardiovascular events. Lower BP targets lead to 
better control of LVH and likely cardiovascular 
outcomes. 

Diabetes Mellitus 

Patients "with diabetes mellitus constitute a large 
portion of the CKD population. This comorbid 
condition increases their risk of cardiovascular 
disease. In patients without significant degrees of 
renal dysfunction, several studies demonstrate the 
importance of markers of diabetic nephropathy on 
cardiovascular outcomes. The WHO Multinational 
Study of Vascular Disease in Diabetes, which 
included both type 1 and type 2 patients, demon- 
strated an almost twofold increase in the stan- 
dardized mortality ratio of diabetic patients who 
had microalbuminuria. The addition of CKD 
increased this ratio to two-to threefold depending 
on sex. It appears that diabetes mellitus is an inde- 
pendent risk factor for the development of de 
novo ischemic heart disease and de novo heart 
failure in both CKD and ESRD patients. 



Chapter 16 ♦ Chronic Kidney Disease 



263 



Smoking 

Smoking aggravates the excessive cardiovascular 
risk in CKD patients. A random sample of new 
ESRD patients in the United States noted that 
smokers had a 22% greater risk of developing 
coronary artery disease. Like hypercholes- 
terolemia and older age, smoking strongly pre- 
dicted the presence of carotid atherosclerosis in 
ESRD patients. Since smoking has a clear associa- 
tion with cardiovascular disease in CKD patients, 
attempts at modifying its use are warranted. There 
are no published studies on the efficacy of differ- 
ent strategies for smoking cessation in patients 
with CKD or ESRD. Despite this, smoking cessa- 
tion is an important preventive intervention. 



should be considered in the highest risk group as 
defined by the National Cholesterol Education 
Program guidelines. LDL cholesterol concentra- 
tions >100 and >130 mg/dL are treatment initia- 
tion thresholds for diet and drug therapy, 
respectively. Target LDL cholesterol concentra- 
tions are <70 mg/dL in CKD patients. Statins are 
the most effective therapy to reduce total and LDL 
cholesterol concentrations. They are associated 
with decreased mortality in ESRD patients. 
Pharmacologic treatment of hypertriglyceridemia 
and of low HDL is not recommended unless LDL is 
also increased. Statins in combination with ezetim- 
ibe may further improve LDL cholesterol concen- 
trations. Fibric acid analogs are the most effective 
in reducing triglycerides in CKD patients. 



Factors Modified by CKD 

Dyslipidemia 

The prevalence of hyperlipidemia in CKD is higher 
than in the general population but varies depend- 
ing on the lipid, target population, course of kidney 
disease, and level of kidney function. Total or LDL 
cholesterol elevations are common in patients with 
CKD and nephrotic syndrome and ESRD patients 
on peritoneal dialysis (PD). Uremic dyslipidemia is 
characterized by increased plasma triglyceride with 
normal total cholesterol concentration. Very low 
density lipoprotein (VLDL) and intermediate den- 
sity lipoprotein (IDL) concentrations are elevated, 
whereas LDL and high density lipoprotein (HDL) 
concentrations are decreased. Increased triglyc- 
eride and decreased HDL cholesterol concentra- 
tions are more severe in individuals with advanced 
CKD. Limited data suggest that lipid abnormalities 
increase cardiovascular disease in CKD patients. 
For example, the incidence of myocardial infarc- 
tions in 147 CKD patients (creatinine clearance of 
20-50 mL/minute/1.73 m 2 ) was approximately 
2.5 times higher than in the general population. 
Patients with myocardial infarctions had lower 
HDL cholesterol concentrations and higher triglyc- 
eride, LDL cholesterol, apolipoprotein B and 
lipoprotein (a) concentrations. Patients with CKD 



Hyperhomocysteinemia 

Hyperhomocysteinemia, an independent risk 
factor for atherosclerosis in the general popula- 
tion, is highly prevalent in CKD patients. It may 
also increase atherosclerosis in this group. 
Approximately 90% of ESRD patients have ele- 
vated plasma homocysteine concentrations, the 
result of impaired homocysteine metabolism. The 
clinical impact of lowering homocysteine con- 
centrations by employing folate, vitamin B6 and 
vitamin B12 supplementation needs to be con- 
firmed, since conventional doses seldom correct 
the abnormal concentrations observed in patients 
with stage 4 or 5 CKD. 



CKD-Related Risk Factors 

Anemia 

Anemia in ESRD dialysis patients is associated 
with adverse cardiovascular outcomes. Under 
uremic conditions, the hemodynamic changes 
associated with anemia are maladaptive, result- 
ing in cardiac hypertrophy and arteriosclerosis. A 
decrease in hemoglobin (Hb) level of 1 g/dL 
incrementally increases the risk of mortality by 
18-25% and of left ventricular hypertrophy by 



264 



Chapter 1 6 ♦ Chronic Kidney Disease 



approximately 50%. Anemia is also a cardiac risk 
factor in CKD patients. As an example, CKD 
patients with a 0.5 g/dL decrease in hemoglobin 
concentration have a 32% increased risk of left 
ventricular growth. Correction of anemia may 
improve cardiovascular outcomes through mul- 
tiple effects. Regression of LVH occurs in CKD 
patients after 12 months of erythropoietin treat- 
ment aimed at normalizing hematocrit (Hct), in 
the absence of better blood pressure control. 
Target hemoglobin is 12 g/dL. This level is safe 
for most CKD patients, provided that a rapid 
increase is avoided and blood pressure is con- 
trolled. 

Hyperparathyroidism 

Disturbances of calcium and phosphate metabo- 
lism may increase cardiovascular disease in CKD 
patients. Elevated serum calcium and phosphate 
concentrations, secondary hyperparathyroidism, 
administration of calcium-containing phosphate- 
binding agents, and vitamin D supplementation 
were implicated as risk factors for increased car- 
diovascular complications, possibly through end- 
organ calcification. Calcifications of the coronary 
arteries, valves, and myocardial tissue, as well as 
diffuse myocardial fibrosis are common pathologic 
findings in uremic hearts. Hyperphosphatemia is 
strongly associated with mortality in ESRD patients. 
The adjusted relative risk of death is greater at 
serum phosphorus concentration >6.5 mg/dL 
and when the calcium-phosphorus product is 
>72 mg 2 /dL 2 . Increased mortality is due to an 
increase in cardiac deaths, suggesting that correc- 
tion of hyperphosphatemia is important to reduce 
cardiac morbidity and mortality, especially in the 
early stages of CKD. Efforts should be made to 
reduce hyperphosphatemia and hyperparathy- 
roidism through strict phosphorus control and 
judicious use of vitamin D derivatives. Non-calcium- 
containing binders may have additional benefits to 
reduce cardiovascular complications. Calcimimetics 
may also play an important role in CVD reduction 
by improving PTH concentration and calcium- 
phosphorus product in CKD patients. 



Key Points 

Risk Factors 



1. CVD is common in CKD patients and is 
associated with increased risk of mortality. 

2. Several risk factors are present in CKD 
patients that increase the prevalence of 
CVD, including traditional factors, factors 
modified by CKD, and factors related to the 
CKD state. 

3. Hypertension and diabetes mellitus are the 
major factors contributing to the large CVD 
burden in CKD. 

4. Anemia increases the development of LVH, 
a prominent risk factor for untoward cardio- 
vascular events. 

5. Calcification of the vasculature from hyper- 
phosphatemia, a high calcium-phosphorus 
product, and perhaps excessive calcium 
intake also contribute to CVD. 




Anemia of CKD 



Anemia is a common and early complication of 
CKD. It is characterized by normochromic nor- 
mocytic red blood cells (RBCs). In 5222 prevalent 
patients with CKD, mild anemia, as defined by Hb 
level <12 g/dL, was found in 47% of the cohort. 
The degree of anemia was most marked in 
patients with the lowest GFRs. Anemia, however, 
can develop in patients with GFR levels as high as 
60 mL/min/1.73 m 2 . Anemia guidelines for CKD 
patients recommend anemia workup and treat- 
ment for all stage 3 or 4 CKD patients. Patients 
with GFRs <60 mlV minute/1. 73 m 2 and Hb <11 g/dL 
(premenopausal females and prepubertal 
patients) and Hb <12 g/dL (adult males and post- 
menopausal females) should be evaluated. 
Hemoglobin is the recommended parameter for 
the evaluation and management of anemia, given 



Chapter 16 ♦ Chronic Kidney Disease 



265 



the wider variations seen in hematocrit values and 
instability of samples. 

Anemia evolves in patients with CKD for a vari- 
ety of reasons. Decreased RBC production, 
decreased RBC survival, and blood loss all con- 
tribute to anemia. The primary cause of anemia in 
patients with CKD is insufficient production of 
erythropoietin by the diseased kidneys. This is 
supported by a state of "relative" erythropoietin 
deficiency in CKD patients, since levels are inap- 
propriately low for the degree of anemia com- 
pared with normal individuals. Finally, an 
improvement in the RBC count is seen almost 
uniformly following therapy with exogenous 
erythropoietin. 

A common secondary cause of anemia is iron 
deficiency. This is defined in CKD as transferrin 
saturation (TSAR <20% or ferritin <100 ng/mL 
according to the NKF-K/DOQI guidelines. 
Blood loss from phlebotomies associated with 
laboratory testing, occult gastrointestinal bleed- 
ing, decreased iron absorption, dietary restric- 
tion, and iron usage by exogenously stimulated 
erythropoiesis all contribute to the development 
and maintenance of iron deficiency. In an 
analysis of data from the NHANES III, 38.3% 
of 3453 anemic subjects with GFRs between 
20 and 60 mL/minute/1.73 m 2 had TSAT values 
below 20%. Thus, all potential causes of iron 
deficiency must be fully evaluated in CKD patients. 
Other secondary causes of anemia in CKD 
include hypothyroidism, severe hyperparathy- 
roidism, acute and chronic inflammatory conditions, 
aluminum toxicity, folate and B 12 deficiencies, 
shortened red blood cell survival, and hemoglo- 
binopathies. 

Evaluation of anemia in CKD patients should 
include the following tests: 

♦ Hb and/or Hct 

♦ RBC indices 

♦ Reticulocyte count 

♦ A test for occult blood in stool 

♦ Iron parameters: serum iron concentration, total 
iron-binding capacity (TTBC), percent transferrin 
saturation, and serum ferritin concentration 



Diagnosis of iron deficiency is not always 
straightforward in CKD patients. Functional iron 
deficiency, which refers to the imbalance between 
iron needed to support erythropoiesis and the 
amount released from storage sites, is often pres- 
ent. A ferritin concentration below 100 ng/mL is 
usually diagnostic of iron deficiency, however, 
the ferritin concentration may be elevated sec- 
ondary to chronic inflammation or infection. Thus 
it is not always a reliable index of iron deficiency 
in CKD patients. TSAT is considered the best 
routinely available test of iron deficiency. A TSAT 
<20% usually indicates functional iron deficiency. 
Other tests such as the proportion of hypochromic 
red blood cells (>10% with mean corpuscular 
hemoglobin <28 g/dL) and reticulocyte hemoglo- 
bin content may improve the diagnosis of func- 
tional iron deficiency in CKD patients. 



Effects of Anemia in CKD Patients 

Anemia plays a major role in the quality of life in 
CKD patients and has pronounced effects on 
patient well-being. It may ultimately determine 
prognosis both prior to and after starting RRT. For 
these reasons, it is imperative that anemia is 
addressed and corrected in CKD patients. The 
relationship between anemia and morbidity and 
mortality in dialysis patients is well established. 
There is a growing body of evidence similarly 
associating anemia and cardiovascular disease in 
CKD patients. The effect of anemia on CVD 
appears to start many years prior to the develop- 
ment of ESRD. 



Role of Anemia in Cardiovascular 
Disease and Mortality 

Evidence supports a link between anemia and 
CVD. Anemia is independently associated with 
the presence of LVH in CKD patients and plays a 
significant role in its evolution. Evidence in 
favor of the connection of anemia and LVH 



266 



Chapter 1 6 ♦ Chronic Kidney Disease 



includes data generated from a cross-sectional 
study of 175 patients with mean creatinine clear- 
ance of 25.5 mL/minute. A decline in hemo- 
globin of 1 g/dL was associated with a 6% 
independent increased risk for LVH. More severe 
LVH is seen with lower hemoglobin levels. 
Anemia may also increase oxidative stress. 
Other factors peculiar to CKD such as the uremic 
milieu, calcification, hypertension, and volume 
overload contribute to the maladaptive cardiac 
response to anemia. Cardiac fibrosis and poten- 
tially irreversible LVH may result from these 
factors. 

Correction of anemia in ESRD patients was 
shown to reduce left ventricular mass index 
(LVMI), improve ejection fraction (EF), and miti- 
gate ischemic changes that develop during car- 
diac stress tests. Similar limited data are available 
in CKD patients, although small numbers of 
patients with severe LVH and advanced kidney 
disease were studied. Prospective studies are 
underway to further elucidate the long-term benefits 
of anemia correction in earlier stages of CKD and 
less severe LVH. These earlier interventions raise 
the interesting role of primary prevention of 
anemia in CKD patients, which may be important 
in modulating the development of irreversible 
cardiac changes. 



Other Benefits of Anemia Correction 

Correction of anemia in CKD patients maintains 
benefits beyond solely improving cardiac status. 
A reduction in mortality during the first 24 months 
after initiating hemodialysis occurs in patients 
treated with erythropoietin in the predialysis 
phase of care. Additional benefits include the 
following: 

1. Improved sense of well-being, quality of life, 
neurocognitive function, and work capacity. 

2. Reduced need for packed red blood cell trans- 
fusion. 

3. Reduced allosensitization pretransplantation. 

4. Reduced hospitalization. 



Effect of Anemia Correction 
on Renal Function 

Worsening of renal function with anemia correction 
by recombinant human erythropoietin (rHuEpo) 
was an initial concern based on data from an animal 
model of kidney disease. Uncontrolled hyperten- 
sion rather than correction of anemia was the prob- 
able cause of worsening kidney function. Studies in 
humans uniformly show no effect of exogenous 
erythropoietin therapy on renal function in CKD 
patients. Of interest, a beneficial effect of anemia 
correction on renal function •was noted. Several 
studies suggest that correction of anemia slows the 
progression of CKD. The potential mechanisms for 
such a desirable benefit may relate to the effect of 
anemia and hypoxia on interstitial fibrosis and the 
anti-apoptotic effect of erythropoietin. Several in 
vitro and in vivo studies support a nephroprotective 
effect of erythropoietin. 



Effect of Anemia Correction on BP Control 

Anemia correction with rHuEpo may increase BP in 
CKD patients. Concerns for severe hypertensive 
crisis and seizures were prominent following initial 
experience with rHuEpo. The increase in BP that 
develops with rHuEpo is due to an increase in 
systemic vascular resistance, as well as direct and 
indirect pressor effects of rHuEpo. These initial con- 
cerns, however, were almost entirely alleviated 
when the rate of Hb correction was slowed to an 
average of 1 g/dL/month. Since hypertension may 
still develop with slower rates of anemia correction, 
BP monitoring should be a standard part of rHuEpo 
therapy. Blood pressure control is easily achieved 
with adjustments in antihypertensive regimens. 



Therapy of Anemia in CKD 

Recombinant human erythropoietin and darbe- 
poetin both successfully correct anemia in 
patients with CKD. Optimal target hemoglobin 



Chapter 16 ♦ Chronic Kidney Disease 



267 



concentrations are unknown but current recom- 
mendations suggest Hb concentrations between 
11 and 12 g/dL (Hct 33 and 36%). In CKD patients 
with heart disease and chronic obstructive lung 
disease, it is medically justifiable to maintain the 
Hb concentration >12 g/dL. Presently, full cor- 
rection of anemia cannot be recommended given 
the absence of scientific evidence supporting 
either beneficial effects or safety. 

Subcutaneous injection is the preferred route of 
rHuEpo administration. Self-administration is 
simple and well tolerated by most patients. Some 
patients experience minor pain at the site of injec- 
tion. Recombinant human erythropoietin is usually 
given on a weekly or twice-weekly basis. More 
frequent dosing may be required at initiation, 
depending on the degree of anemia. After attaining 
target Hb concentration, many patients may be sub- 
sequently maintained on weekly injections. The 
recommended starting dose of rHuEpo is 50- 
100 U/kg/wk. Dosing changes for rHuEpo should 
not be done more frequently than every week, 
while the frequency for darbepoetin should be less. 
Hemoglobin is measured on a weekly basis during 
the initiation phase of therapy and until the target 
Hb concentration is attained. Thereafter, biweekly 
or monthly determinations are usually sufficient. 

Darbepoetin is a newer erythropoietic agent 
with a longer serum half-life than rHuEpo. It differs 
structurally from rHuEpo by virtue of its higher sialic 
acid-containing carbohydrate content, an important 
determinant of the half-life of these molecules. It is 
generally given no more frequently than once a 
week; bi- or triweekly use may be sufficient to cor- 
rect anemia. The starting dose for darbepoetin is 
0.45 M-g/kg. Most patients will require either a dose 
of 25 or 40 |0,g every other week. The safety profile 
of this long-acting erythropoietic agent is similar to 
that of rHuEpo. 

As erythropoiesis is stimulated and the marrow 
produces RBCs, iron stores are rapidly used. Many 
patients will require iron supplementation to 
maintain erythropoietic responsiveness. Oral sup- 
plementation is usually effective but intravenous 
iron preparations may be required. Iron indices 
such as TSAT and ferritin are followed on a regular 



basis to guide iron administration. Suboptimal 
response to rHuEpo therapy may be the result of 
gastrointestinal blood loss and primary hemato- 
logic disorders. These should be fully investigated 
as clinically indicated. 



Key Points 



Anemia of CKD 



1 . Anemia commonly occurs when GFR 
reaches 30-40 mL/minute/1.73 m 2 in CKD 
patients, but may occur earlier. 

2. Decreased red cell production (erythropoi- 
etin deficiency), reduced red cell survival, 
and enhanced blood loss (with iron defi- 
ciency) contribute to the anemia of CKD. 

3. Iron deficiency is the most common cause 
of exogenous erythropoietin resistance in 
CKD patients. 

4. Correction of anemia is associated with 
reductions in adverse cardiovascular disease 
events and hospitalizations, improvements 
in well being and neurocognitive function, 
and reductions in red blood cell transfusions 
and allosensitization pretransplant. 

5. Anemia is corrected in CKD patients with 
either subcutaneous recombinant erythro- 
poietin or darbepoietin. 

6. CKD patients receiving exogenous erythro- 
poietin should have their hemoglobin cor- 
rected approximately 1 g/dL/month until 
target is reached to avoid severe hyperten- 
sion and seizure. 




In CKD patients, the incidence of hyper- 
phosphatemia, hypocalcemia, and secondary 



268 



Chapter 1 6 ♦ Chronic Kidney Disease 



hyperparathyroidism increase as GFR declines. 
Identification and treatment of mineral metabo- 
lism disturbances at an early stage in CKD may 
reduce many of their adverse consequences. 
These metabolic disturbances ultimately lead to a 
group of bone disorders collectively known as 
renal osteodystrophy. 

Serum phosphorus concentration increases as 
GFR declines below 60 mL/minute/1.73 m 2 . 
Approximately 15% of patients with a GFR from 
15 to 30 mL/minute and 50% of those with a GFR 
<15 mL/minute have a serum phosphorus concen- 
tration >4.5 mg/dL. Parathyroid hormone (PTH) 
increases the renal excretion of phosphorus. In 
the short term, this serves to maintain phosphorus 
homeostasis. As GFR falls below 30 mL/minute/ 
1.73 m 2 renal phosphate excretion reaches a max- 
imum. Hyperphosphatemia directly increases 
PTH secretion and stimulates parathyroid cell pro- 
liferation and hyperplasia. Hyperphosphatemia 
also decreases expression of the calcium-sensing 
receptor. The calcium-sensing receptor is expressed 
on parathyroid cells and senses the extracellular 
fluid (ECF) calcium concentration. There is an 
inverse sigmoidal relationship between serum 
calcium and PTH concentrations with a nonsup- 
pressible component of PTH secretion even at 
high serum calcium concentrations. The PTH- 
calcium response curve is shifted to the right in 
CKD patients with secondary hyperparathy- 
roidism. Decreased calcium sensing may be due 
to reduced expression of the calcium-sensing 
receptor in parathyroid gland. 

Concentrations of l,25(OH) 2 vitamin D 3 decline 
early in the course of CKD (GFR < 60 mL/minute/ 
1.73 m 2 ). l,25(OH) 2 vitamin D 3 is a potent suppres- 
sor of PTH gene transcription, and parathyroid 
growth and cell proliferation. The vitamin D recep- 
tor and calcium-sensing receptor in the parathy- 
roid are downregulated in CKD. Calcium-sensing 
receptor expression is also regulated by l,25(OH) 2 
vitamin D 3 . A decrease in calcium-sensing receptor 
expression decreases the responsiveness of the 
parathyroid gland to inhibition by calcium. 

Hypocalcemia occurs late in the course of 
kidney disease, typically after changes in serum 



phosphorus, l,25(OH) 2 vitamin D 3 , and PTH con- 
centrations. Seven percent of patients with a GFR 
of 15-30 mL/minute and 25% of patients with a GFR 
<15 mL/minute are hypocalcemic. This divalent dis- 
order increases PTH concentration by prolonging 
the half-life of the mRNA and exacerbates second- 
ary hyperparathyroidism. 

Secondary hyperparathyroidism is a near uni- 
versal complication of CKD that develops early in 
the course of the disease. PTH concentration 
begins to rise as the GFR falls below 40 mL/minute/ 
1.73 m 2 . PTH production and secretion are regu- 
lated by phosphorus, l,25(OH) 2 vitamin D 3 , and 
calcium. Alterations in these parameters, as noted 
above, increase the development of secondary 
hyperparathyroidism . 



Renal Osteodystrophy 

Renal osteodystrophy is a group of metabolic 
bone disorders that develop as a consequence of 
kidney disease. They include osteitis fibrosa, 
osteomalacia, mixed uremic osteodystrophy, and 
adynamic bone disease. Osteitis fibrosa develops 
as a result of increased PTH concentration, which 
increases osteoblast and osteoclast number and 
activity (high bone turnover). Osteomalacia is due 
to l,25(OH) 2 vitamin D 3 deficiency. It is character- 
ized by low bone turnover with wide unmineral- 
ized osteoid seams and the absence of osteoclasts 
and erosive surfaces. Mixed uremic osteodystro- 
phy has features of both osteitis fibrosa and osteo- 
malacia. Adynamic bone disease is distinguished 
by a reduction in bone formation and resorption 
and is manifested histologically by thin osteoid 
seams with little or no evidence of cellular activ- 
ity. It is associated with peritoneal dialysis, higher 
doses of calcium carbonate as a phosphate 
binder, the presence of diabetes mellitus, 
l,25(OH) 2 vitamin D 3 treatment, and older age. 

In patients with advanced CKD, the spectrum 
of renal osteodystrophy is similar to that observed 
in ESRD patients. Osteitis fibrosa is seen in 
40-56%, osteomalacia in 2-11%, and adynamic 
bone disease in 27-48%. Few patients have 



Chapter 16 ♦ Chronic Kidney Disease 



269 



normal bone histology. In patients with milder 
kidney disease, osteitis fibrosa and mixed uremic 
osteodystrophy are the most common histologic 
lesions found in 40 and 29% of patients, respec- 
tively. Osteomalacia is the least common abnor- 
mality (4.5% of patients). Normal bone histology 
is found in approximately 20% of those with less 
severe kidney disease. Adynamic bone disease is 
noted in only 6% of those with milder CKD. The 
largest study examining 176 CKD patients with 
bone biopsy found osteitis fibrosa in 56%, mixed 
uremic osteodystrophy in 14%, and adynamic 
bone disease in 5%. Normal histology was seen in 
25% and osteomalacia was observed in only one 
patient. Patients with normal histology had a sig- 
nificantly higher GFR than those with an abnor- 
mal bone biopsy. 

PTH is the most common biomarker used for 
the assessment of bone turnover and classifica- 
tion of renal osteodystrophy. Using second gener- 
ation intact PTH assays a PTH concentration 
<65 pg/mL has a sensitivity of 88% and a speci- 
ficity of 91% for adynamic bone disease. A PTH 
concentration >400 pg/mL has a sensitivity of 83% 
and a specificity of 88% for osteitis fibrosa. 
Although bone biopsy is the gold standard, bio- 
markers such as PTH are followed longitudinally 
in patients at high risk to develop renal osteodys- 
trophy and those with bone disease that is likely 
to become more severe as kidney function deteri- 
orates. Target PTH concentrations in advanced 
CKD were proposed (Table 16.4) but are extrapo- 
lated from the ESRD population. Optimal target 
PTH concentrations are not established for 
patients with mild-to-moderate CKD. 

One consequence of renal osteodystrophy in 
ESRD patients is increased risk of hip and verte- 
bral fractures. Those with adynamic bone disease 
appear to be at highest risk. Analysis of the USRDS 
database of Caucasians starting dialysis between 
1989 and 1996 showed the risk of hip fracture in 
women was 13.63 per 1000 patient years and in 
men was 7.45 per 1000 patient years. The relative 
risk for hip fracture in men and women was 4.44 
and 4.40 times higher, respectively, in dialysis 
patients compared to age and sex-matched 



Table 16.4 



Suggested Ranges for PTH in Relation to GFR 



GFR 




PTH 


>50 mL/minute/1.73 


m 2 


Upper limit of normal 


20-50 mL/minute/ 




1.0-1.5 times the upper 


1.73 m 2 




limit of normal 


<20 mL/minute/1.73 


trr 


1.5-2.0 times the upper 
limit of normal 


On dialysis 




2.0-3.0 times the upper 
limit of normal 



Abbreviations: GFR, glomerular filtration rate; PTH, parathyroid 
hormone. 



controls. Although the age-specific relative risk 
was highest in the youngest age groups, the 
added risk of fracture associated with dialysis 
increased steadily with advancing age. Risk fac- 
tors for hip fracture include age, Caucasian race, 
female sex, low body mass index (BMI), periph- 
eral vascular disease, inability to ambulate, low 
albumin, and smoking. Data in CKD patients are 
not available, but their fracture risk is likely higher 
than the general population. 



Treatment of Renal Osteodystrophy 

Treatment of renal osteodystrophy in CKD patients 
includes several targets. Hyperphosphatemia is ini- 
tially controlled with dietary restriction. Ingestion 
of foods high in phosphorus should be minimized. 
As CKD worsens, oral phosphate binders are 
frequently required. The previous goal of therapy 
in ESRD patients was to maintain the calcium- 
phosphorus product below 72 mg 2 /dL 2 and the 
serum phosphorus concentration below 6.5 mg/dL. 
Concentrations above these increase the relative 
risk of mortality in ESRD patients. The serum phos- 
phorus goal 'was recently lowered to <5.5 mg/dL 
and the calcium-phosphorus product to <55 mg 2 / 
dL 2 . Although no studies on this issue exist in CKD, 
the recommended goals are similar. 



270 



Chapter 1 6 ♦ Chronic Kidney Disease 



The use of calcium-containing phosphate 
binders results in net positive calcium balance in 
ESRD patients. This calcium may deposit in the vas- 
culature and contribute to increased morbidity and 
mortality from ischemic coronary disease. Calcium- 
containing binders, although efficient and low in 
cost, may contribute to excess total body calcium 
burden. Sevelamer hydrochloride, a synthetic 
calcium-free polymer has a favorable side effect 
profile but is costly. Aluminum is the most efficient 
binder and is relatively inexpensive, however, it has 
significant long-term toxicity (aluminum-related 
osteomalacia and dementia). Aluminum-containing 
phosphate binders should only be used in the short- 
term management of severe hyperphosphatemia 
(serum phosphorus concentration <8.5 mg/dL). 
Lanthanum carbonate, another noncalcium con- 
taining phosphate binder may also provide safe and 
effective control of hyperphosphatemia and was 
recently FDA approved for clinical practice. 

Since hypocalcemia is a potent stimulator of 
PTH secretion, serum calcium concentration should 
be corrected into the low normal range. This can 
be achieved with oral calcium, however, it should 
be employed cautiously as it may increase risk for 
vascular calcification and the development of 
adynamic bone disease. 

Acidosis is common in CKD patients. This dis- 
turbance increases bone loss, potentiates the 
effect of PTH and decreases l,25(OH) 2 vitamin D 3 
production. Correction slows the progression of 
secondary hyperparathyroidism. A serum bicar- 
bonate concentration goal of >22 meq/L can be 
achieved with 1-4 g of sodium bicarbonate daily 
with close monitoring for hypertension and fluid 
overload. Addition of a loop diuretic often allows 
continued sodium bicarbonate therapy in patients 
with hypertension and edema. 

The optimal PTH concentration in CKD 
patients is not established. If PTH is more than 
two to four times the upper limit of normal, 
hyperphosphatemia and hypocalcemia should be 
corrected. If PTH remains elevated or these con- 
ditions are absent then vitamin D therapy will 
likely be required. Small doses of oral calcitriol 
(0.25-0.50 g/day) stabilize and decrease PTH 



concentration. Decreases are primarily seen in 
patients with a PTH concentration <200 pg/mL. 
Pulse calcitriol oral therapy (2 g/week dosed once 
per week) may be more effective and is associated 
with a lower risk of hypercalcemia. 



Key Points 



Metabolic Mineral Disturbances Associated with CKD 



1. Disturbances in mineral metabolism 
develop early in CKD and include hyper- 
phosphatemia, hypocalcemia, and low vita- 
min D concentration and seconciaiy 
hyperparathyroidism. 

2. Renal osteodystrophy consists of a spectrum 
of bone diseases in CKD patients. They 
include osteitis fibrosa, osteomalacia, ady- 
namic bone disease, and mixed uremic 
osteodystrophy. 

3. Hip and vertebral fractions are a complica- 
tion of renal osteodystrophy in CKD patients. 

4. Although bone biopsy is the gold standard, 
PTH concentration is employed to guide 
management of renal osteodystrophy and 
use of vitamin D. 




Preparation of the CKD Patient 
for Renal Replacement Therapy 



A critical part of CKD care consists of the emo- 
tional and physical preparation of patients for the 
initiation of RRT. Evaluation and management of 
the patient with advanced CKD focuses on prepa- 
ration for RRT. Importantly, improved predialysis 
care reduces the mortality rate for this high-risk 
group. To address this issue, the appropriate 
timing of nephrology referral, ESRD preparatory 
care, critical components of patient education and 



Chapter 16 ♦ Chronic Kidney Disease 



271 



those resources available to patients, and the opti- 
mal time of RRT initiation is reviewed. 



Nephrology Referral of CRD Patients 

The population of patients with CKD is not uni- 
formly monitored in the United States. As a result, 
most CKD patients are not prepared for entry into 
the world of ESRD. Less than half of new ESRD 
patients have permanent vascular access in place 
at the initiation of hemodialysis. Given the well- 
known advantages of permanent vascular access, 
there is room for improvement in the preparatory 
phase of CKD patients. 

A major reason for this problem is late referral 
(1-4 months prior to RRT) of CKD patients to 
nephrologists. Only about half of incident ESRD 
patients are seen by a nephrologist 1 year prior to 
initiation of ESRD care, and 30% are seen less than 
4 months before RRT is begun. Late referral is 
associated with increased morbidity and a graded 
risk reduction for patient mortality is noted with 
early referral (>12 months). Multiple factors cause 
late referral of CKD patients to nephrology spe- 
cialty care teams. Economic barriers (i.e., lack of 
insurance), as well as patient factors that include 
denial, fear, and procrastination. Provider factors, 
such as underappreciation of severity of kidney 
disease, fear of alarming the patient, lack of a 
multidisciplinary care team, and inadequate 
frequency of patient follow-up may contribute. 
Lack of training about both the appropriate timing 
and indications for referral of CKD patients to 
nephrologists also contribute. Finally, poor com- 
munication and feedback from nephrologists fol- 
lowing CKD patients promotes late referral. 

Late referral to the nephrologist is associated 
with diminished patient choice, as well as adverse 
outcomes (Table 16.5). Patients referred late select 
peritoneal dialysis (PD) as a dialysis modality less 
often. It also promotes delayed referral for renal 
transplantation evaluation and eliminates any 
possibility for preemptive renal transplantation. 
Resource usage is significantly higher when refer- 
ral occurs late in the course of CKD, including 



Table 16.5 

Consequences of Late Referral 



Severe metabolic acidosis 
Severe hyperphosphatemia 
Marked anemia 
Hypoalbuminemia 

Severe hypertension and volume overload 
Low prevalence of permanent dialysis access 
Delayed referral for renal transplantation 
Higher initial hospitalization rate 
Higher costs of initiation of dialysis 
Increased 1-year mortality rate 
Decreased patient choice in RRT modality 
selection 



Abbreviation: RRT, renal replacement therapy. 



higher initial hospitalization rates and cost of ini- 
tiation of dialysis. Most importantly, overall 
patient mortality is greater. In contrast, early refer- 
ral permits multidisciplinary predialysis education 
and improves vocational outcomes. It also delays 
progression of CKD, reduces requirements for 
urgent dialysis, and decreases hospital length of 
stay. Importantly, it increases native arteriove- 
nous fistula (AVF) creation (Table 16.6). The NIH 



Table 16.6 



Benefits of Early Referral to Nephrologist 



Improved vocational outcomes 

Delay in need to initiate RRT 

Increased proportion of patients with perma- 
nent vascular access, particularly AVF 

Patient modality selection differences — greater 
peritoneal dialysis usage 

Reduced need for urgent dialysis 

Reduced hospital length of stay and health care 
costs 

Better metabolic parameters at dialysis initiation 

Better patient survival 



Abbreviations: RRT, renal replacement therapy; AVF, arteriovenous fistula. 



272 



Chapter 1 6 ♦ Chronic Kidney Disease 



Consensus Development Conference Panel pub- 
lished a consensus statement recommending 
nephrology referral of all CKD patients with a 
serum creatinine concentration >2 mg/dL in men 
or >1.5 mg/dL in women. The National Kidney 
Foundation (NKF) also recommends early referral 
to the nephrology team. 



Components ofESRD Care Preparation 

A multidisciplinary clinic approach, consisting of 
physicians, social workers, nutritionists, and 
nurse coordinators, enhances the preparation of 
CKD patients for entry into ESRD care and initia- 
tion of RRT. The use of a multidisciplinary pre- 
dialysis program to reduce urgent dialysis was 
studied. The proactive CKD care program 
reduced the number of urgent dialysis starts from 
35 to 13%. It also decreased the number of hospi- 
tal days during the first month of RRT from 13-5 to 
6.5 days and resulted in net dollar savings of 
$4000 per patient. Hence, a multidisciplinary 
team approach to CKD care improved prepared- 
ness for entry into the ESRD system and reduced 
health care resource usage. Education about the 
various dialysis options allows patients to make 
informed choices about the appropriate modality 
of RRT. Since development of ESRD is emotion- 
ally traumatic news for most patients, early 
nephrology referral allows adequate time for the 
dialysis care team to assist in this aspect of CKD 
patient care. 

The nephrologist should discuss modality 
options for RRT including the specifics of 
hemodialysis, peritoneal dialysis, and preemptive 
renal transplantation. If PD is the patient's pre- 
ferred choice of RRT, the patient and/or the family 
can initiate PD training prior to the actual initia- 
tion of dialysis. If hemodialysis is selected, vascu- 
lar access, preferably an AVF, should be placed. 
Patients should be counseled to protect their non- 
dominant arm to protect veins for future AVF cre- 
ation. K/DOQI guidelines strongly encourage 
placement of permanent vascular access when 
serum creatinine concentration is greater than 



4 mg/dL, the creatinine clearance is <25 cc/minute/ 
1.73 m 2 , or the development of ESRD is anticipated 
within 1 year. Preemptive renal transplantation 
requires a significant amount of time for planning 
and completion of medical testing. In some 
instances, the patient may elect not to initiate RRT. 
In this difficult situation, explicit counseling that 
outlines the serious consequences of this choice 
is mandatory and should include one or more 
members of the patient's family. In addition, an 
evaluation for major depression is required. The 
presence of depression precludes informed con- 
sent and requires further intervention by the 
family and judicial system (conservatorship). If 
this decision is ultimately chosen by the patient 
and is supported by the family, then end-of-life 
care should be pursued. 

As renal disease progresses to ESRD, dietary 
modifications are necessary to avoid life-threatening 
volume overload, hyperkalemia, protein and 
caloric malnutrition, exacerbation of metabolic aci- 
dosis, and divalent ion derangements. Consultation 
"with a renal dietician is essential to avoid or reduce 
the development of these complications. Medication 
adjustments by the nephrologist will also reduce 
these complications. Nutritional state should be 
assessed regularly and dietary counseling under- 
taken to optimize protein intake without inducing 
hyperphosphatemia, hyperkalemia, or metabolic 
acidosis. 

To avoid information overload and patient 
confusion, the introduction of small amounts of 
new information at successive visits will reduce 
patient stress and improve understanding of their 
disease process and ultimate ESRD care plan. It is 
helpful for the primary provider to assess the 
patient's understanding of the aforementioned at 
follow-up visits. Reinforcement of correctly under- 
stood information and clarification of erroneous 
aspects of the patient's education are essential since 
cognitive deficits may exist in advanced uremia. 
Early education improves understanding by reduc- 
ing anxiety and fear through preparation, allowing 
for choices, assuring informed consent, encourag- 
ing independence, and promoting a sense of 
patient self-control. 



Chapter 16 ♦ Chronic Kidney Disease 



273 



Initiation ofRRT 

Timely initiation of RRT is the final aspect of ade- 
quate preparation of the CKD patient. Absolute 
indications for dialysis include uremic serositis 
(especially pericarditis), uremic encephalopathy, 
refractory metabolic acidosis, hyperkalemia, or 
uncontrollable volume overload. It is appropriate 
to commence RRT in patients who are in the 
presymptomatic stage, when CrCl is <10 cc/minute/ 
1.73 m 2 in nondiabetics and <15 cc/minute/ 
1.73 m 2 in diabetics. Ultimately, initiation of RRT 
is based on the combination of kidney function as 
assessed by estimated GFR (or CrCl), the presence 
of signs and symptoms of uremia, and patient pref- 
erence. At the time of initiation of RRT, emotional 
and physical preparation of patients is key. This 
approach will allow a smooth transition and more 
stable entry into ESRD care or preemptive trans- 
plantation. 



Key Points 



Preparation of the CKD Patient for Renal Replacement Therapy 



1 . The patient with advanced CKD requires 
emotional and physical preparation for the 
initiation of RRT 

2. Late referral to the nephrology care team is 
associated with increased morbidity and 
mortality in CKD patients. 

3. A multidisciplinary clinic approach (physi- 
cians, social workers, nutritionists, and nurse 
coordinators) enhances the preparation of 
CKD patients for entry into ESRD care. 

4. In patients with advanced CKD, dietary 
modifications are required to avoid life- 
threatening volume overload, hyper- 
kalemia, acidosis, protein and caloric 
malnutrition, and disturbances in mineral 
metabolism. 

5. Initiation of RRT is based primarily on the 
presence of signs of symptoms of uremia, 
and the level of kidney function. 



Additional Reading 

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Astor, B.C., Muntner, P., Levin, A., Eustace, J. A., Coresh, 
J. Association of kidney function with anemia: the 
Third National Health and Nutrition Examination 
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Bakris, G.L., Weir, M.R. Angiotensin-converting enzyme 
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Block, G.A., Port, F.K. Re-evaluation of risks associated 
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in dialysis patients: recommendations for a change 
in management. Am J Kidney Dis 35:1226-1237, 
2000. 

Consensus Development Conference Panel. Morbidity 
and mortality of renal dialysis: an NIH consensus con- 
ference statement. Ann Intern Med 121:62-70, 1994. 

Garg, A.X., Clark, W.F., Haynes, R.B., House, A.A. 
Moderate renal insufficiency and the risk of cardio- 
vascular mortality: results from the NHANES I. 
Kidney Int 61:1486-1494, 2002. 

Golper, T. The impact of pre-ESRD education on dialy- 
sis modality selection. J Am Soc Nephrol 11:A1223, 
2000. 

Healthy People 2010: Chronic Kidney Disease. National 
Institutes of Health, National Institute of Diabetes and 
Digestive and Kidney Diseases, Bethesda, MD, 2000. 

Hsu, C.Y., McCulloch, C.E., Curhan, G.C. Epidemiology 
of anemia associated with chronic renal insuffi- 
ciency among adults in the United States: results 
from the Third National Health and Nutrition 
Examination Survey. J Am Soc Nephrol 13:504—510, 
2001. 

Jafar, T., Schmid, C, Landa, M., Giatras, I., Toto, R., 
Remuzzi, G, Maschio, G, Brenner, B.M., Kamper, 
A., Zucchelli, P., Becker, G, Himmelmann, A., 
Bannister, K, Landais, P., Shahinfar, S., dejong, P.E., 
de Zeeuw, D., Lau, J., Levey, AS. Angiotensin con- 
verting enzyme inhibitors and progression on non- 
diabetic renal disease. Ann Intern Med 135:73-87, 
2001. 

Jungers, P., Massy, Z.A., Khoa, T.N., Fumeron, C, 
Labrunie, M., Lacour, B., Descamps-Latscha, B., 



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Man, N.K. Incidence and risk factors of atheroscle- 
rotic cardiovascular accidents in predialysis chronic 
renal failure patients: a prospective study. Nephrol 
Dial Transplant 12:2597-2602, 1997. 

Kinchen, K.S., Sadler, J., Fink, N, Brookmeyer, R., Klag, 
M.J., Levey, A.S., Powe, N.R. The timing of specialist 
evaluation in chronic kidney disease and mortality. 
AnnlntMed 137:479-486, 2002. 

Levey, A.S., Bosch, J. P., Lewis, J. B., Greene, T., Rogers, 
N, Roth, D. A more accurate method to estimate 
glomerular filtration rate from serum creatinine: a 
new prediction equation. Modification of Diet in 
Renal Disease Study Group. Ann Intern Med 
130:461-470, 1999. 

Levey, A., Eknoyan, G. Cardiovascular disease in 
chronic renal disease. Nephrol Dial Transplant 
14:828-833, 1999. 

Levin, A. Consequences of late referral on patient out- 
comes. Nephrol Dial Transplant 15(Suppl. 3):8-13, 
2000. 

Lewis, E.J., Hunsicker, L.G., Bain, R.P., Rhode, R.D. The 
effect of angiotensin-converting enzyme inhibition 
on diabetic nephropathy. N Engl ] Med 329:1456- 
1462, 1993. 

Llach, E, Velasquez Forero, E Secondary hyperparathy- 
roidism in chronic renal failure: pathogenic and clin- 
ical aspects. Am J Kidney Dis 38(Suppl. 5):S20-S33, 
2001. 

Locatelli, E, Bommer, J., London, G.M. Cardiovascular 
disease determinants in chronic renal failure: clinical 
approach and treatment. Nephrol Dial Transplant 
16:459-468, 2001. 

Mann, J. E, Gerstein, H.C., Pogue, J., Bosch, J., Yusuf, S. 
Renal insufficiency as a predictor of cardiovascular 
outcomes and the impact of ramipril: the HOPE 
randomized trial. Ann Intern Med 134:629-636, 
2001. 



Maschio, G., Alberti, D., Janin, G., Locatelli, F., Mann, 
J.F., Motolese, M., Ponticelli, C, Ritz, E., Zucchelli, 
P. Effect of the angiotensin-converting-enzyme 
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renal insufficiency. The angiotensin-converting 
enzyme inhibition in progressive renal insufficiency 
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National Kidney Foundation (NKF) Kidney Disease 
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K/DOQI clinical practice guidelines for chronic 
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Am J Kidney Dis 39(2 Suppl. 2):S1-S246, 2002. 

Rostand, S.G., Drueke, T.B. Parathyroid hormone, 
vitamin D, and cardiovascular disease in chronic 
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Shlipak, M.G., Heidenreich, P.A., Noguchi, H., Chertow, 
G.M, Browner, W.S, McClellan, M.B. Association of 
renal insufficiency with treatment and outcomes 
after myocardial infarction in elderly patients. Ann 
Intern Med 137:555-562, 2002. 

Silver, J., Kilav, R., Naveh-Many, T. Mechanisms of sec- 
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Suranyi, M.G., Lindberg, J.S., Navarro, J., Elias, C, 
Brenner, R.M., Walker, R. Treatment of anemia with 
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XJKPDS.BMJ 317:713-720, 1998. 



Robert F. Reillyjr. and 
Mark A. Perazella 



Glomerular Diseases 




Recommended Time to Complete: 2 days 



Q<*ljtlt*C QuClt^Oyp^ 



1. What are the clinical presentations of glomerular disease? 

2. Which primary renal diseases present as the nephrotic syndrome? 

3. What are the five clinical stages of diabetic nephropathy? 

k- Can you describe the characteristic findings on urinalysis of the 
patient with nephritis? 

5. How does rapidly progressive glomerulonephritis (RPGN) present 
and what are its most-common causes? 

6. What is the serum anti-neutrophil cytoplasmic antibody test and how 
is it interpreted? 

7- Which glomerular diseases commonly present with isolated 
abnormalities on urinalysis? 




Presentation of Glomerular 
Diseases 



Diseases that adversely affect the structure and func- 
tion of the glomerulus present to the clinician in a 
limited number of ways. Glomemlar diseases can be 
grouped into four clinical syndromes. These include 



the nephrotic syndrome, the nephritic syndrome, 
rapidly progressive glomerulonephritis (a variant of 
the nephritic syndrome), and asymptomatic abnor- 
malities on urinalysis. The differential diagnosis 
varies depending on the clinical syndrome. 

The nephrotic syndrome is manifested by 
severe proteinuria (>30— 3.5 g/173 mVday) and 
hypoalbuminemia. Associated features include to 
a variable degree: edema; hyperlipidemia; and 
lipiduria. Nephrotic syndrome results from an 



275 



276 



Chapter 17 ♦ Glomerular Diseases 



increase in glomerular permeability to macromol- 
ecules. Etiologies are divided into two broad cat- 
egories: primary renal diseases; and secondary 
forms (infection, malignancy, medications, and 
multisystem diseases). The pathogenesis is not 
well understood. Abnormalities of the immune 
system appear to be the predominant mechanism 
in man. Circulating immune complexes may 
deposit in glomeruli, or the antigen may be 
deposited or originate in the glomerular capillary 
wall and immune complexes (antigen-antibody) 
form in situ. Less commonly inherited diseases of 
the podocyte cause congenital nephrotic syn- 
drome. Mutations in genes that produce proteins 
critical to the maintenance of the normal structure 
and function of the podocyte foot processes and 
slit diaphragm result in proteinuria. 

The nephritic syndrome is characterized by the 
presence of hematuria 'with red blood cell casts, 
increased serum blood urea nitrogen (BUN) and 
creatinine concentrations, varying degrees of 
hypertension, and proteinuria. Nephritic syn- 
drome is secondary to an inflammatory disease of 
the glomerulus that is manifested by an increase 
in cellularity on light microscopy. The increased 
cellularity is secondary to proliferation of endo- 
thelial, epithelial, and/or mesangial cells or to 
glomerular infiltration with inflammatory cells. 

RPGN is a variant of the nephritic syndrome. 
The serum BUN and creatinine concentrations 
rise rapidly over days to weeks. The hallmark of 
RPGN on renal biopsy is the cellular or fibrous 
crescent and this disorder is also referred to as 
"crescentic" glomerulonephritis. A crescent is a 
histologic marker of severe injury. It develops 
when a rent or hole forms in either the glomerular 
capillary basement membrane or in the basement 
membrane of Bowman's capsule. When such a 
disruption occurs, macrophages, inflammatory 
mediators, and plasma proteins gain access to 
Bowman's space. A crescent develops from the 
proliferation of macrophages, fibroblasts, and 
parietal glomerular epithelial cells. Crescents are 
often associated with visible areas of necrosis 
within the glomerular capillary. Rapidly progres- 
sive glomerulonephritis is important to recognize 



because irreversible glomerular damage occurs 
quickly in the absence of therapy. 

Asymptomatic abnormalities on urinalysis 
include the discovery of hematuria or proteinuria 
on routine dipstick analysis of urine. This chapter 
is subdivided into four sections based on the clin- 
ical syndromes described above. Individual 
glomerular diseases are discussed further based 
on their most common clinical presentation. 



Key Points 



Presentation of Glomerular Diseases 



1 . Glomerular diseases present as four clinical 
syndromes: nephrotic syndrome; nephritic 
syndrome; RPGN (a variant of the nephritic 
syndrome); and asymptomatic abnormalities 
on urinalysis. 

2. The nephrotic syndrome is manifested by 
severe proteinuria (>30-35 g/1-73 m 2 /day) 
and hypoalbuminemia. 

3. Hematuria with red blood cell casts, 
increased serum BUN and creatinine con- 
centrations, varying degrees of hypertension, 
and proteinuria are present in the nephritic 
syndrome. 

4. Rapidly progressive glomerulonephritis is a 
variant of the nephritic syndrome in which 
the serum BUN and creatinine concentrations 
rise rapidly over days to weeks. The hall- 
mark of RPGN on renal biopsy is the cellular 
or fibrous crescent. 

5. Glomerular disease may also present as 
asymptomatic abnormalities on urinalysis. 




Under normal circumstances only 30-45 mg of 
protein is excreted in urine, about one-third of 



Chapter 17 



Glomerular Diseases 



277 



that total is albumin. The upper limit of normal for 
urinary protein excretion is 150 mg/day and this 
can increase to 300 mg/day with exercise. The 
glomerular capillary acts as a barrier to the filtra- 
tion of serum proteins. This barrier consists of 
three layers: an endothelial cell; the basement 
membrane itself; and an epithelial cell. There is 
both a size barrier [(small proteins are freely fil- 
tered (MW 5000 Da), and large ones are restricted 
(MW 100,000 Da)], as well as a charge barrier (the 
capillary membrane is negatively charged and 
repels negatively charged proteins). Disorders of 
the filtration barrier result in proteinuria and if 
severe enough the nephrotic syndrome. 

The nephrotic syndrome is manifested by 
severe proteinuria (>30-35 g/1.73 m 2 /day) and 
hypoalbuminemia. Peripheral edema, an elevated 
serum cholesterol concentration and lipiduria are 
often present. Edema results from a change in 
Starling's forces across the capillary wall. As serum 
albumin concentration falls plasma oncotic pres- 
sure decreases. There may also be an intrarenal 
defect resulting in increased sodium reabsorption 
as well. Albumin in the tubular lumen increases 
activity of the Na + -H + exchanger in proximal 
tubule resulting in increased sodium reabsorp- 
tion. Edema should first be treated with sodium 
restriction. If this is ineffective then diuretics are 
added. Milder diuretics that block sodium reab- 
sorption in the distal convoluted tubule or col- 
lecting duct (thiazides, triamterene, amiloride, 
spironolactone, and eplerenone) are often used 
before more potent loop diuretics. 

Hypercholesterolemia is thought to result from 
an increase in synthesis of hepatic proteins in 
response to hypoalbuminemia. This is supported 
by animal studies showing that the degree of cho- 
lesterol elevation is inversely related to the fall in 
plasma oncotic pressure. Animal studies also 
show that raising oncotic pressure with albumin 
infusion results in a fall in serum cholesterol con- 
centration toward normal. If serum cholesterol 
concentration is elevated and the patient does not 
have hypoalbuminemia, the increase is probably 
not due to the nephrotic syndrome. There is also 
a decrease in lipoprotein catabolism. Lipoprotein 



lipase is decreased as is lecithin-cholesterol acyl- 
transferase (esterifies cholesterol to high density 
lipoprotein [HDL]). Down regulation of lipoprotein 
lipase and the very low density lipoprotein 
(VLDL) receptor results in elevated triglycerides 
and VLDL. 

A variety of coagulation abnormalities are often 
present in the nephrotic syndrome. Levels of fac- 
tors V, VIII, and fibrinogen are increased while X, 
XI, and XII and antithrombin III are decreased. 
The platelet count tends to be increased, as is 
platelet aggregation. The end result is that patients 
are hypercoagulable, and have an increased inci- 
dence of both arterial and venous thrombi. Renal 
vein thrombosis occurs in 5-35% and is more com- 
monly associated with membranous glomeru- 
lonephritis. The presentation can be acute or 
chronic. Acute renal vein thrombosis is mani- 
fested by flank pain, hematuria, and a decrease in 
glomerular filtration rate (GFR). Chronic renal 
vein thrombosis is often silent and can present as 
a pulmonary embolus. Since antithrombin III con- 
centration is low, these patients may be relatively 
heparin resistant and require more heparin than 
usual to raise the PTT into the therapeutic range. 

The risk of infection with encapsulated organ- 
isms is increased possibly due to the loss of com- 
plement factor B (alternate pathway) and gamma 
globulin in urine. Patients should be immunized 
with pneumococcal vaccine. 



Key Points 

Nephrotic Syndrome 



1 . The glomerular capillary acts as both a 
charge and size barrier to the filtration of 
serum proteins. 

2. The nephrotic syndrome is manifested by 
severe proteinuria (>30-35 g/1.73 mVday) 
and hypoalbuminemia. 

3. Patients with the nephrotic syndrome are 
hypercoagulable and have an increased inci- 
dence of both arterial and venous thrombi. 




Chapter 17 ♦ Glomerular Diseases 



Primary Renal Diseases That 

Present as the Nephrotic 

Syndrome 



Minimal Change Disease 

Minimal change disease also known as nil disease 
or lipoid nephrosis derives its name from the fact 
that the light microscopic (LM) appearance of the 
glomerulus is normal (Figure 17.1). Immunofluor- 
escence (IF) studies are also negative. On elec- 
tron microscopy (EM) podocyte epithelial foot 
processes are fused (Figure 17.2). Some patients 
have mesangial deposits of IgM and C3. Heavy 
deposition of IgM (IgM nephropathy) associated 
with mesangial hypercellularity may carry a worse 
prognosis. This is thought to represent an inter- 
mediate lesion along a path of progression toward 
focal and segmental glomerulosclerosis (see 
below). 

The pathogenesis may be secondary to a defect 
in cell-mediated immunity, since in vitro T-cell 



ire 17.1 




Figure 17.2 




$fi*T 


Vv/ 










.4 »- » . 


.- 



Minimal change disease (light microscopy). The glomerulus 
on light microscopy in minimal change disease is normal. 



Minimal change disease (electron microscopy). Shown by 
the arrow is fusion of the foot processes of podocytes. This is 
the only abnormality seen on the renal biopsy of a patient 
with minimal change disease. 



function abnormalities are described and minimal 
change disease can occur in association with 
Hodgkin's disease, nonsteroidal anti-inflamma- 
tory drugs (NSAIDs) and treatment of malignant 
melanoma with interferon-/?. T-cell cultures derived 
from patients with minimal change disease release 
a vascular permeability factor. Minimal change dis- 
ease may result from the production of a lym- 
phokine that is toxic to the glomerular epithelial 
cell. The toxin reduces the anionic charge barrier 
of the membrane and leads to albuminuria. In 
adults minimal change disease is the cause of 
10-15% of cases of nephrotic syndrome. In children 
it is the most common cause of nephrotic syndrome 
with a peak incidence between ages 2 and 3- It 
accounts for greater than 90% of cases of 
nephrotic syndrome in the pediatric population. 
The urine sediment is generally unremarkable 
although microscopic hematuria may be present 
in 20% of patients. Proteinuria is "selective" con- 
sisting almost entirely of albumin suggesting that 



Chapter 17 



Glomerular Diseases 



279 



the abnormality in glomerular basement mem- 
brane (GBM) is an alteration in the charge barrier. 
Hypertension is generally absent. Minimal change 
disease responds •well to corticosteroids (within 
4 weeks), although relapses are the rule. Relapses 
may be provoked by an upper respiratory infec- 
tion. Patients with frequent relapses or those who 
are steroid-dependent may be treated with 
cyclophosphamide, chlorambucil, cyclosporin, or 
levamisol. Oral cyclosporin carries the risk of 
nephrotoxicity, especially in those treated for 
longer periods of time. The long-term prognosis 
with respect to the maintenance of renal function 
is good. 



Focal Segmental Glomerulosclerosis 
(Focal Sclerosis) 

Focal segmental glomerulosclerosis (FSGS) is 
characterized by sclerosing lesions associated 
with hyaline deposits involving parts (segmental) 
of some glomeruli (focal). The sclerosis results 
from glomerular capillary collapse with an 
increase in mesangial matrix (Figure 17.3). Mild- 
to-moderate mesangial hypercellularity may be 
seen. On EM subendothelial deposits and foot 
process fusion are present in involved glomeruli. 
Capillary collapse and folding and thickening of 
the basement membrane are present in sclerotic 
glomeruli. Immunofluorescence reveals nonspe- 
cific trapping of IgM and C3 in the sclerotic 
mesangium. As the disease progresses tubular 
atrophy, interstitial fibrosis, and global glomerular 
sclerosis occur. Increasing degrees of interstitial 
fibrosis (>20% of biopsy surface area) is associ- 
ated with a poorer prognosis. Juxtamedullary 
nephrons are affected initially. 

The etiology of primary FSGS is unknown but 
humoral factors, glomerular hypertrophy and 
hyperfiltration, and injury to glomerular cells are 
postulated. Inherited forms of FSGS are caused by 
mutations in genes that encode podocyte proteins 
a-actinin 4, podocin, and nephrin. Focal sclerosis 
can also be secondary to vesicoureteral reflux, 
morbid obesity, urinary tract obstruction, analgesic 



Figure 173 




Focal and segmental glomerulosclerosis (FSGS). The left half 
of this glomerulus is sclerotic (arrow) and the right half is 
normal, hence the term segmental in FSGS. In the sclerotic 
region there is glomerular capillary collapse and an increase 
in mesangial matrix. 



nephropathy, chronic renal transplant rejection, 
heroin nephropathy, human immunodeficiency 
virus (HIV) infection, and substantial loss of 
nephron mass. Focal sclerosis is the most common 
primary renal disease resulting in nephrotic syn- 
drome in African Americans. The urinary sediment 
is usually remarkable for hematuria and pyuria, and 
up to 30% of adults may present with asymptomatic 
proteinuria. Blood pressure is generally elevated, 
GFR decreased, and the development of slowly 
progressive renal failure is the usual course. 
Approximately 50-60% of patients reach end-stage 
renal disease (ESRD) within 10 years of initial diag- 
nosis. Patients with nonnephrotic range proteinuria 
have a better prognosis. The clinical course is much 
more rapid in patients with heroin nephropathy or 
HIV infection (renal failure often is present within 
2 years from the time of initial diagnosis). 

HIV-associated nephropathy (HIVAN) is much 
more common in African Americans than 
Caucasians. It generally occurs late in the course 



280 



Chapter 17 ♦ Glomerular Diseases 



of HIV infection in patients with a CD4 count of 
<250 cells/mm 3 . Patients present with nephrotic 
syndrome and elevated serum BUN and creati- 
nine concentrations. The kidneys are enlarged on 
renal ultrasound with increased echogenicity of 
the renal cortex. On LM there is glomerular col- 
lapse, extensive lymphocytic infiltration, and 
cystic dilation of tubules that are filled with pro- 
teinacious material (microcysts). Tubuloreticular 
inclusion bodies are found within glomerular 
and nonglomerular endothelial cells. Immune 
complex-related diseases such as membranopro- 
liferative glomerulonephritis (MPGN), membra- 
nous glomerulonephritis, and IgA nephropathy 
are more common in Caucasians with HIV infec- 
tion and the nephrotic syndrome. HIV viral pro- 
teins induce podocyte injury and apotosis. Studies 
in HIVAN show that the decrease in GFR was 
slowed by highly active antiretroviral therapy 
(HAART), angiotensin-converting enzyme (ACE) 
inhibitors, and prednisone. Prednisone should be 
reserved for those patients at low risk of infection 
since serious infectious complications may arise 
during its use. A collapsing FSGS was recently 
reported as a complication of pamidronate therapy. 
Focal sclerosis is less responsive to cortico- 
steroids. High-dose corticosteroids often must be 
employed for 6-9 months before a response is 
seen. If corticosteroids fail, the second line agent 
of choice is cyclosporin; cyclophosphamide, and 
mycophenolate mofetil (MMF) can also be used. 
Factors associated with a poorer prognosis 
include persistent high-grade proteinuria, extent 
of tubulointerstitial fibrosis and degree of glomeru- 
losclerosis on renal biopsy, and a higher serum 
creatinine concentration. African American race 
and a lack of response to corticosteroids are also 
predictors of poor outcome. As many as 30% of 
patients may develop a recurrence in the trans- 
planted kidney. Those with a rapid progression 
and with high degrees of proteinuria are at 
increased risk of recurrence. Treatment of sec- 
ondary causes of FSGS are directed at the under- 
lying cause such as repair of reflux, weight 
reduction (obesity), control of hyperfiltration 
(nephron loss), and HAART (HIVAN). 



Mesangial Proliferative Glomerulonephritis 

Mesangial proliferative glomerulonephritis gener- 
ally presents with isolated microscopic hematuria 
or proteinuria although nephrotic syndrome is 
also seen. On LM there is an increase in mesangial 
cell number. Mesangial deposits of immunoglobu- 
lin and complement are present on EM. Treatment 
is often supportive focusing on blood pressure 
control and proteinuria reduction with drugs that 
modulate the renin-angiotensin-aldosterone system 
(RAAS) such as ACE inhibitors and angiotensin 
receptor blockers (ARBs). Initial treatment is 
generally with corticosteroids. Nonresponders or 
partial responders often do not respond to 
cyclosporin. Deposition of IgM in the mesangium 
and lack of response to corticosteroids are associ- 
ated with a poor prognosis. 



Membranous Glomerulonephritis 

Membranous glomerulonephritis is character- 
ized by uniform, diffuse thickening of the 
glomerular capillary wall without cellular prolif- 
eration (Figure 17.4). The most characteristic 



Figure 17.- 




Membranous glomerulonephritis (light microscopy). Shown by 
the arrows are the diffusely thickened glomerular capillary loops 
characteristic of this lesion. There is no increase in cellularity. 



Chapter 17 



Glomerular Diseases 



281 



Figure 17.5 



re 17.6 




Membranous glomerulonephritis (electron microscopy). 
Immune deposits in the glomerular basement membrane are 
shown by the arrow. They are found in the subepithelial space. 



Membranous glomerulonephritis (immunofluorescence 
microscopy). The staining pattern is granular and corresponds 
to the punctate accumulation of immune deposits in the 
glomerular basement membrane and mesangium. 



feature is the presence of subepithelial immune 
deposits on electron microscopy (Figure 17.5). 
The electron-dense deposits are formed in situ 
in the glomerular basement membrane. The 
development of glomerular injury is comple- 
ment-dependent and is related to the formation 
of the membrane attack complex (C5b-C9). The 
membrane attack complex induces matrix pro- 
duction, release of oxidants, and podocyte 
injury. Glomerular basement membrane accu- 
mulates between the deposits, which creates the 
appearance of spikes. With time the basement 
membrane extends over the deposits forming 
domes. Immunofluorescence microscopy shows 
a granular pattern (Figure 17.6). In the idio- 
pathic lesion mesangial deposits are usually 
absent. In membranous glomerulonephritis due 
to secondary causes mesangial deposits are 
generally present. Subendothelial deposits, 
tubulointerstitial deposits, the presence of all 
immunoglobulins in deposits, and mesangial or 
endocapillary proliferation are suggestive of a 
secondary cause. Many of these patients have 
evidence of circulating immune complexes. 



Histologic changes associated "with a poor prog- 
nosis include interstitial fibrosis and segmental 
glomerulosclerosis. 

Membranous glomerulonephritis is the most 
common primary renal disease that causes 
nephrotic syndrome in Caucasian adults. Nephrotic 
syndrome is present in 80% of cases. Hyperten- 
sion is usually absent and the urinary sediment 
may show hematuria in approximately half of 
patients. This lesion is also seen in collagen vas- 
cular diseases (systemic lupus erythematosis 
[SLE], mixed connective tissue disease, and 
rheumatoid arthritis), infections (hepatitis B, 
malaria, secondary and congenital syphilis, 
leprosy, schistosomiasis, and filariasis), drugs 
(NSAIDs, gold, penicillamine, mercury, pro- 
benecid, captopril, and bucillamine), neoplasia 
(lung, colon, stomach, breast, cervix, and ovary), 
and miscellaneous disorders (sickle cell dis- 
ease, thyroiditis, and sarcoid). 

Therapy remains controversial due to the high 
spontaneous remission rate. Without treatment 
generally one-third of patients spontaneously 
remit, one-third progress to renal failure, and 



282 



Chapter 17 ♦ Glomerular Diseases 



one-third remain unchanged. Factors associated 
with an increased frequency of progression to 
renal failure include male sex, age >50, high- 
grade persistent proteinuria, hypertension, and 
an elevated serum creatinine concentration. 
Excretion of IgG and «j-microglobulin is a predictor 
of a poor response to therapy, and progression to 
renal failure, as is the extent of tubulointerstitial 
damage on renal biopsy. An initial study sug- 
gested that corticosteroids alone decreased the 
rate of decline in renal function but this was not 
borne out by subsequent trials. The combination 
of alternating monthly courses of either cortico- 
steroids and chlorambucil or corticosteroids and 
oral cyclophosphamide increase the rate of 
remission of nephrotic syndrome and the proba- 
bility of survival without renal failure. The major- 
ity of therapeutic trials were conducted, however, 
in patients with a serum creatinine concentration 
<1.7 mg/dL. Uncontrolled trials were carried out 
in patients with serum creatinine concentrations 
between 2.0 and 30 mg/dL. The combination of 
prednisone and cyclophosphamide lowered 
serum creatinine concentration in the short term. 
It is unclear whether patients with serum creati- 
nine concentrations >3.0 mg/dL benefit from 
therapy. Cyclosporin was used in patients who 
failed steroid therapy. The rate of remission of 
nephrotic range proteinuria is increased but con- 
flicting data exist as to whether one can slow pro- 
gression of disease. Mycophenylate mofetil was 
employed successfully in small numbers of 
patients. 

Because of the high spontaneous remission 
rate some authors recommend treating only 
patients with elevated serum creatinine concen- 
tration, a progressive decline in GFR, symptomatic 
nephrotic syndrome, those at high risk for pro- 
gression, and patients with thromboembolic dis- 
ease. Because of the association with renal vein 
thrombosis and thromboembolic events some 
recommend treating patients with profound 
hypoalbuminemia with anticoagulants. Patients 
who experience a thromboembolic event should 
be anticoagulated as long as they remain 
nephrotic. 



Membranoprotiferative Glomerulonephritis 

MPGN is characterized by diffuse proliferation of 
mesangial cells with the extension of mesangial 
matrix or cytoplasm into the peripheral capillary 
wall, giving rise to a thickened and reduplicated 
appearance. This gives rise to the double contour 
or "tram-track" appearance of the GBM. There is 
mixed mesangial and endothelial cell prolifera- 
tion that results in a lobular distortion of the 
glomerulus (lobular accentuation) (Figure 17.7). 
Membranoproliferative glomerulonephritis is 
divided into several types based on EM. 

Type I MPGN, which is the most common form 
of the disease, is associated with subendothelial 
electron-dense deposits and marked peripheral cap- 
illary interposition of mesangial cell cytoplasm and 
matrix. Immunofluorescence microscopy reveals 
glomerular deposition of immunoglobulin, C3, 
and C4. Patients may present with the nephrotic 
syndrome, nephritic syndrome, an overlap of these 
two syndromes, RPGN, or with asymptomatic 
hematuria and proteinuria. Episodic macroscopic 



Figure 17.7 




Membranoproliferative glomerulonephritis (light microscopy). 
There is an increase in both cellularity (proliferation of endothelial 
and mesangial cells) and mesangial matrix. Open capillary loops 
are difficult to visualize as a result of endothelial proliferation. The 
lobules of the glomerulus are distorted (lobular accentuation). 



Chapter 17 



Glomerular Diseases 



283 



hematuria may also occur. Blood pressure is gener- 
ally increased, GFR reduced, and anemia present 
out of proportion to the degree of azotemia. 
Complement concentrations are low especially in 
type II MPGN. The classical complement pathway is 
activated in type I MPGN resulting in a decrease in 
C4 concentration. Glomerular crescents, hyperten- 
sion, decreased GFR, and heavy proteinuria are 
poor prognostic signs. Infection (shunt nephritis, 
malaria, endocarditis, hepatitis B and C, and HIV), 
B-cell lymphomas, SLE, mixed connective tissue dis- 
ease, sickle cell disease, and alpha-1-antitrypsin 
deficiency are also associated with MPGN type I. 
Infection with hepatitis C is the most common cause. 

Type II MPGN is characterized by intramembra- 
nous electron-dense deposits and is often called 
dense deposit disease. There are dense ribbon-like 
confluent deposits in the basement membranes of 
the glomeruli, tubules, and vasculature. In type II 
MPGN the alternative complement pathway is acti- 
vated decreasing C3 concentration. Peripheral 
catabolism of C3 is increased by a circulating IgG 
known as C3 nephritic factor. This results in an 
increase in C3 degradation products especially C3c. 
C3c has an affinity for the lamina densa of the GBM 
and is deposited there. The depressed complement 
concentrations do not correlate with disease activity. 
These patients are generally resistant to therapy. 

Subendothelial and subepithelial immune 
deposits and marked fragmentation of the GBM 
are found in type III MPGN. It is associated with 
IgA nephropathy and Henoch-Schonlein purpura 
(HSP) and is rarely a result of hepatitis C infection. 
This lesion is not corticosteroid responsive. 



Key Points 

Primary Renal Diseases that Present 
as the Nephrotic Syndrome 



1. Minimal change disease is the most 

common cause of nephrotic syndrome in 
children. Proteinuria is selective and the 
response rate to prednisone is high. 



Focal segmental glomerulosclerosis is char- 
acterized by sclerosis in a portion (segmen- 
tal) of some (focal) glomeruli. It is the most 
common primary renal disease causing 
nephrotic syndrome in African Americans. 
Membranous glomerulonephritis is charac- 
terized by thickened glomerular capillary 
walls, the absence of cellular proliferation, 
and the presence of subepithelial immune 
deposits. Therapy remains controversial due 
to the high spontaneous remission rate. 
Membranoproliferative glomerulonephritis 
may present with the nephrotic syndrome, 
nephritic syndrome, an overlap of these two 
syndromes, or with asymptomatic hematuria 
and proteinuria. Complement concentra- 
tions are low. 




Secondary Renal Diseases 

Commonly Associated with 

Nephrotic Syndrome in Adults 



Diabetes Mellitus 

Diabetic nephropathy is the single most common 
cause of the nephrotic syndrome and ESRD in the 
United States. Type I diabetics with nephropathy 
have a 50-fold increase in mortality compared to 
those without nephropathy. Nephropathy in type I 
diabetes mellitus rarely develops before 10 years 
disease duration, and approximately 40% of type 
I diabetics have proteinuria within 40 years after 
the onset of disease. The annual incidence of dia- 
betic nephropathy peaks just before 20 years of 
disease duration and declines thereafter. Those 
patients who survive 30 years of type I diabetes 
mellitus without developing nephropathy are at 
low risk of doing so in the future. 




Diabetic glomerulosclerosis (light microscopy). Shown by the 
arrow is an area of nodular glomerulosclerosis (Kimmelstiel- 
Wilson's disease). Note also the diffuse increase in mesangial 
matrix throughout the glomerulus (diffuse glomerulosclerosis). 



The glomeruli in patients with diabetic nephrop- 
athy may exhibit a form of nodular glomeruloscle- 
rosis known as Kimmelstiel-Wilson's disease 
(Figure 17.8). The nodules form in the peripheral 
regions of the mesangium and can be single or 
multiple. They may result from accumulation of 
basement membrane or injury from micro- 
aneurysmal dilation of the glomerular capillary. 
Nodular glomerulosclerosis can occur in associa- 
tion with diffuse glomerulosclerosis. Diffuse 
glomerulosclerosis results from widening of the 
mesangial space by an increase in matrix produc- 
tion. Glomerular injury in diabetes mellitus is 
related to the severity and duration of hyper- 
glycemia and may be related to advanced glyca- 
tion end products (AGEs). Elevation of serum 
glucose concentration leads to glycosylation of 
serum and tissue proteins resulting in AGE forma- 
tion that can cross-link with collagen. In animal 
models administration of AGEs induces glomeru- 
lar hypertrophy and stimulates mesangial matrix 
production. Upregulation of TGF-/}, and its recep- 
tor likely play an important role in renal cell 
hypertrophy and stimulation of mesangial matrix 
production. In addition to glomerular changes, 



Chapter 17 ♦ Glomerular Diseases 



there is diffuse accumulation of hyaline material 
in the subendothelial layers of the afferent and 
efferent arterioles. 

The natural history of type I diabetic nephropa- 
thy is divided into five stages: (1) time of initial 
diagnosis; (2) the first decade (characterized by 
renal hypertrophy and hyperfiltration); (3) the 
third stage is manifested by glomerulopathy 
(microalbuminuria) in the absence of clinical 
disease; (4) clinically detectable disease (the 
hallmarks of this stage are dipstick positive pro- 
teinuria, hypertension, and a progressive decline 
in renal function); and (5) ESRD. 

Stage I. At the onset of diabetes mellitus virtu- 
ally all patients experience functional changes 
such as increased kidney size, microalbuminuria 
that reverses with the control of blood glucose 
concentration, and an increased GFR that 
decreases with initiation of insulin therapy in most 
patients. 

Stage II. In stage II GFR may be increased, and 
it is postulated that this finding predicts the later 
development of nephropathy but this remains 
controversial. The pathogenesis of the hyperfiltra- 
tion is unclear but may be due in part to hyper- 
glycemia and activation of the RAAS. At the onset 
of diabetes mellitus the renal biopsy is usually 
normal. Within 1.5-2.5 years GBM thickening 
begins in nearly all patients. No correlation exists 
between GBM thickening and clinical renal func- 
tion. Mesangial expansion begins about 5 years 
after the onset of disease. 

Stage m. Stage III is manifested by microalbu- 
minuria. Microalbuminuria is an albumin excretion 
rate between 30 and 300 mg/day (20 to 200 u.g/min). 
This amount of albumin excretion is below the level 
of sensitivity of a urine dipstick. A mid morning albu- 
min to creatinine ratio greater than 30 mg/g is 
abnormal and correlates well with 24-hour or timed 
urine collections. Several groups reported the pre- 
dictive value of a slightly elevated urinary albumin 
excretion occurring in the first or second decade of 
diabetes mellitus as a harbinger of the later develop- 
ment of clinical diabetic nephropathy. These studies 
used thresholds ranging from 15 to 70 u.g/minute to 
classify patients. Microalbuminuria best predicts 



Chapter 17 



Glomerular Diseases 



285 



diabetic nephropathy when it is progressive over 
time and is associated with hypertension. 

Stage IV. Stage IV is defined by the presence of 
dipstick positive proteinuria and is associated with 
a slow gradual decline in GFR that may result in 
ESRD. Classically the rate of decline of GFR was 
stated to be 1 mL/minute/month, but this number 
is probably now closer to 0.5 mL/minute/month or 
less. The rate of progression can be slowed by anti- 
hypertensive therapy. It may decline further with 
combined treatment with ACE inhibitors and ARBs. 

Stage V. As the GFR continues to decline ESRD 
may develop. Diabetic nephropathy is the most 
common cause of ESRD in the United States. 
Because of associated autonomic neuropathy and 
cardiac disease, diabetics often experience uremic 
symptoms at higher GFRs (15 ml/minute/1.73 m 2 ) 
than nondiabetics. 

Although the five clinical stages of diabetic 
nephropathy are best characterized in patients with 
type I diabetes mellitus, they are similar in patients 
with type II disease with the following exceptions. 
The ability to date the time of onset of type II dia- 
betes mellitus is more difficult than in patients with 
type I disease. Therefore, one needs to be more 
flexible in interpreting the first decade. It may be 
shorter than 10 years. In virtually 100% of patients 
with type I diabetes mellitus and diabetic nephropa- 
thy, retinopathy is present, while retinopathy is 
present in two-thirds of those with type II disease 
and diabetic nephropathy. Therefore, the absence 
of retinopathy in a patient with type II diabetes mel- 
litus should not dissuade one from the diagnosis in 
the appropriate clinical setting. On the other hand, 
the absence of retinopathy in a patient with type I 
disease would argue strongly against diabetes mel- 
litus as a potential cause of renal disease. 

The urinalysis in diabetic nephropathy is gen- 
erally remarkable for proteinuria with little in the 
way of cellular elements present. On occasion 
microscopic hematuria is seen. This should prompt 
a workup for other causes of hematuria such as 
transitional cell carcinoma in the patient greater 
than age 40 (cystoscopy). The most common 
cause of microscopic hematuria in the patient 
with diabetic nephropathy is, however, diabetic 



nephropathy. Macroscopic hematuria or the pres- 
ence of red cell casts is suggestive of another diag- 
nosis. The presence of nephrotic range proteinuria 
in the diabetic patient with a preserved GFR 
should also raise concern that another glomerular 
lesion is the cause of the nephrotic syndrome. In 
general, proteinuria is initially mild and pro- 
gresses to the nephrotic syndrome as the GFR 
declines in patients with diabetic nephropathy. 
Treatment of diabetic nephropathy requires a 
multidrug regimen including tight glucose con- 
trol, BP control with medications that modulate 
the RAAS, and statin therapy to reduce lipids. This 
was reviewed in more detail in Chapter 16. 



Systemic Amyloidosis 

More than 90% of patients with primary and sec- 
ondary amyloidosis have renal involvement, 
approximately 60% have nephrotic syndrome. In 
patients over the age of 60 with nephrotic syn- 
drome 10% have amyloidosis. On LM diffuse amor- 
phous hyaline material is deposited in glomeruli 
(Figure 17.9). Amyloid deposits may also be 



Figure 17.9 



*$ 7 



t * i 








Amyloid (light microscopy). Illustrated by the arrow is a dif- 
fuse increase in amorphous hyaline material (amyloid) 
deposited in the glomerulus. 



286 



Chapter 17 ♦ Glomerular Diseases 



Figure 17.10 







V 



Amyloid (electron microscopy). Shown in the glomerulus is 
the deposition of nonbranching 8-12 nm fibers that are char- 
acteristic of amyloid. 



present in tubular basement membranes, arteri- 
oles, and small arteries. In more advanced cases 
nodule formation occurs and the LM picture can 
resemble advanced diabetic nephropathy. The 
diagnosis is confirmed by special stains (Congo 
red, thioflavin-T) and electron microscopy. 
Amyloid deposits have a characteristic applegreen 
birefringence under polarized light with Congo red 
staining. The demonstration of 8-12 nm non- 
branching fibrils on EM is diagnostic (Figure 17.10). 
Patients present with nephrotic syndrome, 
decreased GFR, and an unremarkable urinary sed- 
iment. Clinically apparent extrarenal involvement 
is often absent. A monoclonal light chain is present 
in urine in approximately 90% of patients with pri- 
mary amyloidosis. The diagnosis can be estab- 
lished on biopsy of the rectum, gingiva, abdominal 
fat pad and skin, as well as on renal biopsy. 

In primary amyloidosis (AL amyloid) fibrils con- 
sist of the N-terminal amino acid residues of the 
variable portion of monoclonal light chains. 
Lambda light chains more commonly form amy- 
loid fibrils (75%) than kappa light chains (25%). 
Primary amyloid commonly involves heart, 
kidney, and peripheral nerves. The vast majority 
of patients have a paraprotein detected in serum 
or urine (90%). Prognosis is poor with a mean 
survival of less than 2 years and only a 20% 5-year 



survival. Cardiac disease, renal dysfunction, and 
interstitial fibrosis on kidney biopsy are associated 
with a worse prognosis. The goal of therapy is to 
reduce light chain production with chemotherapy. 
The combination of melphalan and prednisone is 
most commonly employed with stabilization of 
renal function and improvement in organ system 
involvement in some patients. The best results are 
found with high-dose melphalan followed by 
bone marrow or stem cell transplant. Toxicity of 
this regimen is considerable and only a small 
subset of patients are candidates. 

In one study of 350 patients who carried a clinical 
diagnosis of AL amyloid, 10% had mutations result- 
ing in the formation of amyloidogenic proteins that 
were responsible for the syndrome. Mutated genes 
included transthyretin, fibrinogen A alpha-chain, 
lysozyme, and apolipoprotein A-I. None of these 
patients had a positive family history. A genetic 
cause should be suspected in those whose fluores- 
cence staining is negative for light chains and serum 
amyloid-associated protein A. 

In secondary amyloidosis (AA amyloid) fibrils 
are made up of the N-terminus of serum amyloid- 
associated protein A. Chronic inflammation 
(rheumatoid arthritis, inflammatory bowel dis- 
ease, bronchiectasis, heroin addicts who inject 
subcutaneously), some malignancies (Hodgkin's 
disease and renal cell carcinoma), and familial 
Mediterranean fever stimulate hepatic production 
of serum amyloid-associated protein A, an acute 
phase reactant. Monocytes and macrophages take 
up the protein and cleave it into smaller fragments 
called AA protein (the major component of sec- 
ondary amyloid fibrils). Treatment is directed at 
the underlying process. Correction of the inflam- 
matory or infectious process may improve pro- 
teinuria in patients with secondary amyloidosis. 
Colchicine in high doses is effective in patients 
with familial Mediterranean fever. Those with pre- 
served renal function are more likely to respond 
with decreases in proteinuria. 

Nonamyloid fibrillar deposits can also cause 
glomerular disease. They occur most commonly 
in elderly Caucasians. These diseases, fibrillary 
glomerulonephritis and immunotactoid glomeru- 
lonephritis, are only diagnosed by renal biopsy. 



Chapter 17 



Glomerular Diseases 



287 



A variety of LM patterns are described including 
diffuse proliferative glomerulonephritis, mesan- 
gial proliferation, membranous glomerulonephritis, 
and membranoproliferative glomerulonephritis. 
The diagnosis is established based on EM. In fib- 
rillary glomerulonephritis, fibrils average 20 nm in 
diameter and are randomly arranged. Immuno- 
fluorescence microscopy is positive for IgG, C3, 
and kappa and lambda light chains. Fibrillary 
glomerulonephritis is responsible for >90% of 
nonamyloid fibrillary diseases. 

Immunotactoid glomerulonephritis is character- 
ized by fibrils that are 30-50 nm in size. On LM an 
MPGN type I or diffuse proliferative pattern are 
most common. Immunofluorescence microscopy 
is positive for IgG. IgM, IgA, C3, and Clq may also 
be seen. Some patients have a circulating parapro- 
tein and hypocomplementemia is often present. 
An association with chronic lymphoproliferative 
disease was described. 

Patients with nonamyloid fibrillar deposits com- 
monly present with nephrotic syndrome, micro- 
scopic hematuria, hypertension, and a progressive 
decline in GFR. There is no proven effective ther- 
apy although corticosteroids, cyclophosphamide, 
and cyclosporin were employed. Some advocate 
tailoring therapy based on the LM pattern. There is 
a high rate of recurrence after renal transplantation. 



Monoclonal Immunoglobulin 
Deposition Diseases 

Monoclonal immunoglobulin deposition diseases 
result from the deposition of light chains, heavy 
chains, or the combination of both in a variety of 
organs including kidney. In light chain deposition 
disease (LCDD) immunoglobulin light chains 
deposit in the glomerulus and do not form fibrils. 
The deposits in most cases are derived from the 
constant region of kappa light chains. A parapro- 
tein is detected in the urine or serum by immunofix- 
ation electrophoresis in 85% of patients. The most 
common presentation is nephrotic syndrome asso- 
ciated with hypertension and a decreased GFR. 
Other organs such as heart, liver, and peripheral 
nerves may be affected. Light microscopy reveals 



eosinophilic mesangial nodules. Immunofluores- 
cence microscopy is positive for monoclonal light 
chains in a linear pattern in the glomerular and 
tubular basement membrane. Mesangial nodules 
also stain positive. A subset of patients have associ- 
ated myeloma cast nephropathy. The prognosis of 
patients with LCDD is poor and renal dysfunction 
predicts a poor prognosis. Some patients respond 
to the combination of melphalan and prednisone. 
Heavy chains may also deposit in the glomeru- 
lus with a similar clinical presentation and result 
in heavy chain deposition disease (HCDD). The 
diagnosis is established by immunofluorescence 
with antiheavy chain antibodies. Patients with 
HCDD secrete an abnormal heavy chain with a 
deletion in the CHI domain. If the patient pro- 
duces a heavy chain that fixes complement (IgG 1 
or 3) hypocomplementemia may be present. 



Systemic Lupus Erythematosis 

Renal involvement is common in SLE with half of 
patients having an abnormal urinalysis or a 
decreased GFR at the time of initial diagnosis, and 
75% eventually manifesting kidney disease. Renal 
involvement includes mild mesangial proliferation, 
focal or diffuse proliferative glomerulonephritis, 
membranous glomerulonephritis, and chronic 
glomerulonephritis. Although SLE may present as 
nephrotic syndrome (membranous glomeru- 
lonephritis), it more commonly presents as 
nephritis and is discussed in the following sec- 
tion. Patients may change from one form of renal 
involvement to another. 



Key Points 



Secondary Renal Diseases Commonly Associated 
with Nephrotic Syndrome in Adults 



Diabetic nephropathy is the most common 
cause of the nephrotic syndrome and ESRD 
in the United States. The natural history 
of diabetic nephropathy is divideci into 



Chapter 17 ♦ Glomerular Diseases 



five stages. The rate of progression can be 
slowed by antihypertensive therapy. 
Nephrotic syndrome may occur in up to 
60% of patients with primary and secondary 
amyloid. The demonstration of amyloid fib- 
rils on EM is diagnostic. 
Monoclonal immunoglobulins (light chains 
and heavy chains) can deposit in the 
glomerulus and cause nephrotic syndrome. 
IF staining with the appropriate anti-sera 
will be positive. 




Nephritic Syndrome 
(Glomerulonephritis) 



Acute nephritic syndrome or glomerulonephritis 
is characterized by the abrupt onset of hematuria, 
proteinuria, and a rise in serum BUN and creatinine 
concentrations. Patients are often hypertensive and 
may have peripheral edema. In glomerulonephritis 
there is an inflammatory lesion of the glomerular 
capillary bed that is often immune-mediated. This is 
manifested clinically by red cell casts, hematuria, 
and proteinuria. The hallmark of glomerulonephri- 
tis on urinalysis is the presence of red cell casts. 
Decreased glomerular capillary perfusion decreases 
GFR and results secondarily in increased reabsorp- 
tion of sodium and water. Hypertension, oliguria, 
edema formation, and rising serum BUN and creati- 
nine concentrations are the clinical sequellae. 



Postinfectious Glomerulonephritis 

Acute postinfectious glomerulonephritis occurs 
most often in children but can be seen in adults. It 
generally occurs 2 weeks after pharyngeal infec- 
tion with specific nephritogenic strains of group A 
^-hemolytic streptococcal infection. The clinical 



presentation can vary from microscopic hematuria 
and proteinuria on urinalysis to the nephritic syn- 
drome with the abrupt onset of periorbital and 
lower extremity edema, mild-to-moderate hyper- 
tension, microscopic hematuria, red cell casts, 
gross hematuria, and oliguria. The latent interval 
from the time of infection to the onset of symp- 
toms is not less than 5 days and not more than 
28 days (average 10-21 days). Documentation of a 
preceding streptococcal infection may be by throat 
or skin culture or serologic changes in strepto- 
coccal antigen titers. Antistreptolysin O (ASO) 
titers are not as sensitive in patients with skin infec- 
tion and anti-DNAse B is often used in this setting. 
Laboratory evaluation reveals an elevated serum 
BUN and creatinine concentration, and low 
serum complement concentration (C3). The vast 
majority of children recover spontaneously. The 
recovery rate is lower in adults. In the rare patient 
RPGN may develop. The serum creatinine concen- 
tration usually returns to baseline within 4 weeks, 
C3 concentration returns to normal in 6-12 weeks, 
hematuria generally resolves within 6 months, 
however, proteinuria may persist for years. There 
is no evidence that immunosuppressive therapy 
with corticosteroids is of benefit. 

In kidney there is endothelial and mesangial cell 
proliferation with leukocytic infiltration resulting in 
a picture of diffuse proliferative glomerulonephri- 
tis. Electron microscopy reveals large immune 
deposits in the subepithelial space. Subendothelial 
deposits can occur early in the course of the dis- 
ease. Immunofluorescence demonstrates comple- 
ment and IgG. The disease is secondary to an 
immunologic process. Many patients have circulat- 
ing immune complexes while others may develop 
in situ immune complexes in the GBM due to 
planted bacterial antigens. Treatment includes 
antimicrobial agents, blood pressure control, and 
supportive therapy. 



Systemic Lupus Erythematosis 

Renal disease in patients with SLE is associated 
with a number of different lesions that involve the 



Chapter 17 



Glomerular Diseases 



289 



Table 17.1 



WHO Classification of Lupus Nephritis 



Type 


Name 


Light Microscopy 


IF 


EM 


I 


Normal 


Normal 


Mild mesangial 
staining 


Few mesangial 
deposits 


II 


Mesangial prolifera- 
tive 


Mesangial prolifera- 
tion with increased 
mesangial matrix 


Mesangial staining 


Mesangial deposits 


III 


Focal proliferative 


Focal and segmental 


Mesangial and capil- 


Mesangial deposits, 






mesangial and 


lary loop staining 


some deposits in 






endothelial prolif- 




subendothelial and 






eration, few areas 




subepithelial space 






of necrosis 






IV 


Diffuse proliferative 


Diffuse proliferative 


Mesangial and capil- 


Deposits in all sites, 






and necrotizing 


lary loop staining 


deposits are larger 






lesion, wire loops 




and more numer- 






and crescents 




ous 


V 


Membranous 


Diffuse basement 


Capillary loop stain- 


Subepithelial and 






membrane thicken- 


ing 


often mesangial 






ing 




deposits 


VI 


Sclerosing 


Diffuse sclerosis of 
glomeruli 







Abbreviations: WHO, World Health Organization; TF, immunofluorescence microscopy; FM, electron microscopy. 



glomerulus, blood vessels, and tubulointerstitium. 
This section focuses on glomerular disease. 
Immune complex formation underlies the patho- 
genesis of SLE nephritis. The World Health 
Organization (WHO) classification divides the 
lesions associated with SLE into six different 
patterns or types (Table 17.1). Type I is normal 
LM with evidence of mesangial deposits on 
EM and mesangial immunoglobulin staining on 
IF microscopy. Type II is characterized by mesan- 
gial proliferation, defined as increased mesangial 
matrix and hypercellularity (LM), mesangial 
immunoglobulin staining (IF), and dense deposits 
(EM) within the mesangium. Focal proliferative 
glomerulonephritis constitutes type III WHO SLE 
nephritis. On LM, "focal" represents disease in 
some but not all glomeruli, whereas "segmental" 
means that less than 50% of glomeruli have evident 



disease. As such, focal and segmental mesangial 
and endothelial proliferation is seen; necrosis 
(cell death) may also be present in these areas. 
Immune staining is seen in the mesangium and 
capillary loops on IF. Deposits in the mesangium, 
subendothelial, and subepithelial areas are often 
visualized on EM. Type IV lupus nephritis is a 
diffuse proliferative glomerulonephritis. Light 
microscopy demonstrates proliferative changes 
and necrosis diffusely throughout the glomerulus. 
Crescents and thickening of capillary loops (wire 
loops) may also be seen (Figure 17.11). Immune 
staining is noted in the mesangium and capillary 
loops on IF, while EM shows deposits in all sites. 
The EM deposits are typically more numerous 
and larger with type IV disease. Type V nephritis 
is a membranous lesion. It is characterized by 
diffuse thickening of the GBM without cellular 



290 



Chapter 17 ♦ Glomerular Diseases 



Figure 17.11 







Lupus nephritis (light microscopy). There is an increase in 
cellularity due to mesangial and endothelial proliferation, as 
well as an accumulation of mesangial matrix. An early cres- 
cent is seen at the arrow on the left. The arrow on the right 
shows an infiltration of mononuclear cells in the interstitium. 
The association of interstitial nephritis with glomerulonephri- 
tis is suggestive of the diagnosis of vasculitis. 



proliferation. A granular pattern of staining is 
noted on IF. Subepithelial immune deposits are 
present on EM, although mesangial deposits are 
often found as well. A sclerosing glomerular 
lesion is seen with type VI lupus nephritis. This 
represents an end-stage kidney lesion. 

An abnormal urinalysis (hematuria and pro- 
teinuria) is typically seen at the time of diagnosis 
of SLE. Approximately 50% of patients with newly 
diagnosed SLE will have an abnormal urinalysis 
with or without renal dysfunction. In this setting, 
proteinuria is the most common urinary abnor- 
mality, noted in 80% of patients. Hematuria 
and/or pyuria develop in nearly 40% of patients at 
sometime during the course of disease. In gen- 
eral, lupus nephritis develops early following 
diagnosis, although decreased kidney function 
(increased serum creatinine concentration) is rel- 
atively uncommon within the first few years of 
diagnosis. Younger patients appear to develop 
renal disease earlier. While SLE is associated 
more commonly with certain HLA genotypes 
(HLA-B8, DR2, DR3, and DQW1) and complement 



component deficiencies (C2 and C4 deficiencies), 
nephritis tends to be more severe in African 
Americans, children, and in those patients with 
genetic abnormalities of Fc receptors. The course 
of renal disease is typically benign for types I and 
II SLE nephritis. Often there are no obvious signs 
of renal disease, although hematuria and/or pro- 
teinuria with preserved kidney function is seen. 
In type III, proteinuria and hematuria are com- 
monly present, rarely patients may develop 
nephrotic range proteinuria. Mild renal dysfunc- 
tion and hypertension can occur. Diffuse prolifer- 
ative nephritis (type IV) is universally complicated 
by hematuria and proteinuria. Renal failure, 
which can be severe, hypertension, and nephrotic 
range proteinuria are common. Type III and, in 
particular, type IV nephritis are both associated 
with severe and rapid loss of kidney function 
when left untreated. In addition to type III and 
type IV lesions, poor renal prognosis is associated 
with high activity index and chronicity index, 
presence of cellular crescents and interstitial fibro- 
sis, and severe vascular lesions. The activity index 
is based on six histologic categories of active 
lesions that may be reversible (cellular prolifera- 
tion, leukocyte infiltration, fibrinoid necrosis, cel- 
lular crescents, hyaline thrombi or wire loops, and 
mononuclear cell interstitial infiltration), whereas 
chronicity index measures four histologic compo- 
nents of irreversible damage (glomerular sclero- 
sis, fibrous crescents, interstitial fibrosis, and 
tubular atrophy). Membranous nephropathy, which 
has a variable course of disease, is associated with 
high-grade proteinuria, and 90% develop nephrotic 
syndrome at some point in the disease course. 
Hematuria, hypertension, and renal failure may 
be seen. 

As an immune complex disease, the pattern of 
SLE-associated glomerular injury that develops is 
related to the site of formation of the immune 
deposits. Loss of self-tolerance and generation of 
an autoimmune response are associated with 
alterations in cytotoxic, suppressor, and helper T 
cells numbers. Altered T cell signaling, cytokine 
production, and polyclonal activation of B cells 
results in the production of idiotypic autoantibodies 



Chapter 17 



Glomerular Diseases 



291 



against nuclear antigens, DNA, Sm, RNA, Ro, La, 
and other nuclear antigens. Thus, the complexes 
are composed of nuclear antigens and comple- 
ment fixing IgGl antibodies. Immune complex 
deposition in kidney results from either com- 
plexes formed in the circulation (mesangial and 
proliferative) or binding of circulating antibodies 
to antigens previously planted in the subepithelial 
space (membranous). Location of deposits deter- 
mines the type of inflammatory response. 
Deposits in the mesangium or subendothelial 
space are close to the vascular space, and, as a 
result activate complement. This generates the 
chemoattractants C3a and C5a, stimulating influx 
of neutrophils and mononuclear cells. A prolifer- 
ative glomerular lesion, including mesangial, 
focal, and diffuse proliferative nephritis, is cre- 
ated. In contrast, deposits on the subepithelial 
space activate complement but do not attract 
inflammatory cells due to their separation from 
the vascular space. A nonproliferative lesion com- 
plicated by proteinuria (membranous) with dis- 
ease limited to the glomerular epithelial cell 
develops. 

Diagnosis of SLE nephritis most often occurs 
following identification of extrarenal disease. 
Occasionally, renal manifestations and renal his- 
tology precede systemic disease, or recognition of 
atypical symptoms of SLE. In addition to urinary 
findings such as hematuria (with or without red 
blood cell casts) and proteinuria (both low and 
high grade), blood testing, such as serum creati- 
nine concentration, antinuclear antibody titer, 
antidouble stranded DNA, and serum comple- 
ment concentration are also useful. Renal biopsy is 
the gold standard test to diagnose and direct ther- 
apy in lupus nephritis. In addition, biopsy allows 
for prediction of prognosis. Histologic features 
such as WHO class, activity and chronicity indices, 
and other findings when employed with clinical 
features can help guide therapy. For example, 
aggressive cytotoxic treatment is employed for 
lesions that are potentially reversible and less 
aggressive approaches, employing supportive 
therapy in those with advanced, irreversible 
histopathology. 



Therapy of lupus nephritis is based primarily 
on WHO classification, with types III and IV 
undergoing treatment. A combination of intra- 
venous "pulse" cyclophosphamide and intra- 
venous methylprednisolone are more effective 
than either alone. Cyclophosphamide is infused 
monthly (0.5-1.0 g/m 2 , titrated to maintain white 
blood cell count above 3000 cells/mm 3 ) for 6 months 
followed by every 3 months for an additional 
24 months. Prolonged maintenance therapy is 
associated with the best outcome. Due to toxicity, 
a shorter maintenance course is recommended for 
patients with diffuse proliferative lupus nephritis 
with mild clinical disease. Corticosteroids are often 
tapered over a period of months to doses optimal 
to control extrarenal manifestations of SLE. Oral 
azathioprine (0.5-4 mg/kg/day) and mycopheno- 
late mofetil (500-3000 mg/day) were employed 
successfully as maintenance therapies for lupus 
nephritis. Plasmapheresis appears to add little 
benefit to routine immunosuppressive therapy, 
although some patients with resistant disease 
garner some benefit. Patients should be moni- 
tored for both remission (during therapy) and 
relapse of lupus nephritis (following therapy) 
with the same clinical tools used to diagnose renal 
disease. 

When routine treatment of lupus nephritis is 
unsuccessful, other modalities were employed for 
both initial and maintenance therapy. African- 
American race is associated with resistance to rou- 
tine immunosuppressive regimens for diffuse 
proliferative glomerulonephritis. Limited evidence 
supports use of mycophenolate mofetil (versus 
cyclophosphamide) as an initial therapy for dif- 
fuse proliferative lupus nephritis. Mycophenolate 
mofetil reduced both serum creatinine concentra- 
tion and proteinuria at 1 year in a small number of 
patients who failed cyclophosphamide. At this time, 
it might be best to reserve this drug for female 
patients who are concerned about fertility. 
Cyclosporin stabilized renal function and reduced 
proteinuria in a small number of patients with type 
IV lupus nephritis that were resistant to cyclophos- 
phamide. Intravenous immunoglobulin promoted 
histologic, immunologic, and clinical improvement 



292 



Chapter 17 ♦ Glomerular Diseases 



in nine patients resistant to routine therapy. The 
efficacy of this therapy needs further evaluation in 
controlled studies. High-dose chemotherapy with 
stem cell transplantation was examined in patients 
with active diffuse proliferative nephritis and other 
severe extrarenal manifestations of SLE refractory to 
aggressive immunosuppressive treatment. Seven 
patients with this type of disease underwent this 
regimen. At 25 months of follow-up, all patients had 
no clinical or serologic evidence of SLE. Other 
experimental therapies for lupus nephritis on the 
horizon include immunoadsorption, anti-CD 40 
ligand (to block costimulatory pathways between 
T and B cells), and LJP-394, a small molecule that 
blocks production of anti-DNA antibodies. Large, 
randomized studies are required to fully test these 
interventions. 

Treatment of lupus-associated membranous 
nephropathy is unclear as the renal prognosis and 
natural history of this lesion are uncertain. 
Treatment is probably indicated if renal function 
declines or nephrotic syndrome is severe and 
associated with complications. Prednisone alone 
or in combination with other immunosuppressive 
regimens (cyclophosphamide, cyclosporin, or 
chlorambucil) was employed. Cyclophosphamide 
and cyclosporin appeared superior to prednisone 
alone in small studies of patients with this lesion. 
Combination therapy with corticosteroids plus 
chlorambucil was better than corticosteroids 
alone for inducing either complete or partial 
remission. 



Thrombotic Microangiopathies 

The thrombotic microangiopathies consist of 
a spectrum of diseases that are characterized by 
the formation of platelet microthrombi within ves- 
sels, thrombocytopenia, and microangiopathic 
hemolytic anemia. Formation of microthrombi in 
the microcirculation leads to multisystem end- 
organ ischemia and one of two clinical presenta- 
tions (Table 17.2), consistent with either hemolytic 
uremic syndrome (HUS) or thrombotic thrombo- 
cytopenic purpura (TTP). There is, however, 



Table 17.2 



Clinical Features of the Thrombotic Microangiopathies 





D+HUS 


TTP 


CNS symptoms 


+ 


+++ 


Fever 


+ 


+++ 


Colitis 


+++ 


+ 


Multiorgan disease 


+ 


+++ 


Hematuria/proteinuria 


+++ 


++ 


Renal failure 


+++ 


+ 


Death despite treatment 


5% 


15% 


Recurrences 


1% 


20% 



Abbreviations: +, rare; +++, common; D+HUS, hemolytic uremic syn- 
drome associated with diarrhea; TTP, thrombotic thrombocytopenic 
purpura; CNS, central nervous system. 



overlap between the two with regard to the clin- 
ical manifestations of the thrombotic microan- 
giopathy. Hemolytic uremic syndrome and TTP 
can also be separated based on pathogenesis of 
the coagulation disorder. Thrombotic thrombo- 
cytopenic purpura is most often associated 
with either a congenital or acquired defect in a 
metalloproteinase-converting enzyme (ADAMTS13) 
for von Willebrand's factor (vWF). Absence of or 
reduced activity of this enzyme leads to abnormally 
large vWF in the circulation, which promotes aggre- 
gation of platelets and formation of microthrombi. 
In contrast, with HUS endothelial cell damage in 
the vasculature is thought to be the primary event 
that precipitates coagulation and microthrombi for- 
mation. It is not associated with a defect in the 
vWF-cleaving protease, but can have abnormal 
vWF in the circulation during acute illness. 

Renal histology in the thrombotic microan- 
giopathies is characterized by microthrombi within 
small vessels, including small arteries, arterioles 
(including afferent arterioles), and glomerular cap- 
illary loops. Ischemic retraction of glomeruli and 
ischemic injury in the tubulointerstitium is present. 
Over time, glomerulosclerosis and tubulointersti- 
tial fibrosis are seen. Electron microscopy demon- 
strates small vessel microthrombi consisting of 
platelets and fibrin. No immune deposits are seen. 



Chapter 17 



Glomerular Diseases 



293 



Immunofluorescence staining is also negative 
except for fibrin deposition in vessel •walls. 

Hemolytic Uremic Syndrome 

Hemolytic uremic syndrome develops from vari- 
ous disease processes. The sporadic or endemic 
variety associated with diarrhea (D+HUS) is 
linked to Shiga toxin exposure. The classic exam- 
ple is Escherichia coli strain 0-157:H7. This bac- 
terium produces the culprit toxin, which is 
associated with acute endothelial inflammation 
and injury, as well as accelerated thrombogenesis, 
resulting in bloody diarrhea and HUS. Other 
organisms produce neuraminidase, a promoter of 
diffuse endothelial injury, and may also cause 
HUS. Atypical, non-diarrhea-associated HUS 
(D-HUS) is more heterogeneous. It consists of famil- 
ial forms, including both autosomal dominant and 
recessive disorders that can frequently relapse. 
Non-diarrhea-associated HUS can also occur fol- 
lowing exposure to various drugs and therapeutic 
agents. Included are cyclosporin, tacrolimus, 
mitomycin-C, gemcitabine, methotrexate, oral 
contraceptives, ticlodipine, irradiation, quinine, 
and anti-T-cell antibodies. Pregnancy (HELLP — 
hemolysis-elevated liver enzymes-low platelets 
syndrome), certain malignancies, systemic dis- 
eases (scleroderma, SLE, antiphospholipid anti- 
body syndrome), malignant hypertension, HIV 
infection, and bone marrow transplantation are 
associated with D-HUS. Hereditary complement 
deficiency (Factor H deficiency) was also described 
to cause this form of HUS. Finally, an idiopathic 
form of D-HUS can occur. 

The majority of HUS in children is associated with 
diarrhea (D+HUS), whereas less than 50% of adult 
cases are D+HUS. Vectors for toxin-producing bac- 
teria are beef, fermented salami, as well as contami- 
nated water, fruit, and vegetables. Unpasteurized 
apple cider, apple juice, and dairy products are also 
sources. Numerous outbreaks are due to person-to- 
person contact. Development of HUS occurs during 
the warmer months. In children, bloody diarrhea 
from colitis is common and abdominal pain, which 
can be associated with intussception, bowel necrosis, 



and rectal prolapse can occur. The onset of HUS 
occurs approximately 1 week after diarrhea, pre- 
senting as pallor, lethargy, irritability, severe hyper- 
tension, and decreased urine output. Clinical or 
chemical pancreatitis, seizures, and other end-organ 
disturbances occur less commonly. 

Treatment is supportive as most interventions 
are too risky and often with marginal or no bene- 
fit. In particular, the benefit of plasma exchange is 
unclear; however, anecdotal reports suggest some 
modest benefit in those with D-HUS. Blood pres- 
sure control and optimal management of renal 
failure, often using dialysis, are key to improved 
outcomes. Children with HUS have a good prog- 
nosis. Approximately 90% experience functional 
recovery whereas 5% die in the acute phase of ill- 
ness. In those who recover, 10% are left with some 
form of chronic kidney disease. In contrast, adults 
have worse outcomes. Overall mortality is up to 
30%, and chronic kidney disease occurs in 
approximately 20-30% of survivors, many requir- 
ing renal replacement therapy for end-stage renal 
disease. Mortality is highest (greater than 50%) in 
those with postpartum, cancer, or mitomycin-C- 
associated HUS. Recurrence develops in 25% of 
cases. The poor outcome is likely explained by 
the much higher incidence of D-HUS in adults. 

Thrombotic Thrombocytopenic Purpura 

Thrombotic thrombocytopenic purpura occurs 
most often from either congenital or acquired 
abnormalities in the vWF-cleaving protease 
(ADAMST13). The primary defect is abnormal 
(enhanced) platelet aggregation due to large, cir- 
culating vWFs present due to reduced protease 
activity, resulting in microthrombi formation. 
Congenital forms may be acute and nonrelapsing 
or, more commonly, chronic and relapsing. The 
chronic, relapsing form of TTP may be familial 
(autosomal recessive) or sporadic, both associated 
with a deficiency of vWF-cleaving protease. 
Acquired forms occur following exposure to vari- 
ous drugs such as ticlopidine, mitomycin-C, oral 
contraceptives, quinine, cyclosporin, and cocaine. 
Scleroderma, pregnancy, HIV infection, and SLE 



294 



Chapter 17 ♦ Glomerular Diseases 



are also associated with TTP. Acute, nonrelapsing 
forms of TTP are more commonly acquired. An 
autoantibody directed against the vWF-cleaving 
protease, that is able to inactivate the enzyme, 
occurs with most acquired forms of TTP. 

In contrast to HUS, TTP occurs predominantly 
in women (70%) and is not seasonal. Peak inci- 
dence is in the third and fourth decades and TTP 
is rare in infants and the elderly. This is probably 
due to the more common association with 
acquired causes of TTP, which outnumber con- 
genital forms. Fever and bleeding are common 
presenting features of TTP. Central nervous 
system (CNS) manifestations occur initially in 
approximately 50% of patients, but eventually 
develop in nearly 90% of those with TTP, and are 
the most prominent feature of the syndrome. 
Headache, visual symptoms, somnolence, and 
focal neurologic findings occur commonly. 
Seizures develop in 30% of patients. The CNS 
changes can fluctuate and be fleeting. Purpura is 
common, while gastrointestinal bleeding occurs 
from severe thrombocytopenia. Renal manifesta- 
tions include hematuria, proteinuria, and azotemia. 
Severe renal failure, in contrast to HUS, is much 
less common but can occur. Heart and lung may 
also suffer thrombotic complications of TTP. 

The rationale of plasma infusion and plasma 
exchange in TTP is based on targeting the vWF- 
cleaving protease abnormality. Treatment with 
fresh frozen plasma infusion is very effective for 
TTP-associated with a deficiency of the vWF pro- 
tease. Alternatively, intensive plasmapheresis with 
plasma infusion is appropriate for disorders associ- 
ated with an autoantibody to the vWF protease. 
Plasma exchange is associated with a response in 
70-90% of patients with TTP. Treatment should be 
continued until remission is achieved. In general, at 
least seven consecutive daily treatments followed 
by alternate day exchanges for those improving are 
recommended. Therapies for those who fail plasma 
exchange are vincristine, corticosteroids, intra- 
venous immunoglobulin, and antiplatelet agents. 
Except for vincristine, the efficacy of these treat- 
ments for TTP is unclear. Splenectomy is risky and 
its benefit is marginal. Platelet transfusions are 



generally felt to be contraindicated because they 
may worsen clinical signs and symptoms. 



Key Points 



Nephritic Syndrome (Glomerulonephritis) 



1 . Nephritis or the nephritic syndrome is char- 
acterized by the abrupt onset of hematuria, 
proteinuria and acute renal failure. Patients 
often have associated hypertension and 
peripheral edema. The hallmark of glomeru- 
lonephritis on urinalysis is the presence of 
red cell casts. 

2. Acute postinfectious glomerulonephritis 
occurs most often in children after pharyn- 
geal infection with specific nephritogenic 
strains of group A /{-hemolytic streptococcal 
infection. 

3. Immune complex formation underlies the 
pathogenesis of SLE nephritis. Location of 
deposits determines the type of inflamma- 
tory response. 

4. The WHO classification divides the lesions 
associated with SLE into six different types. 
Type III (focal proliferative glomerulonephri- 
tis) and, in particular, type IV nephritis 
(diffuse proliferative glomerulonephritis) are 
both associated with severe and rapid loss 
of kidney function when left untreated. 

5. Therapy of lupus nephritis is based pri- 
marily on WHO classification. 

6. The thrombotic microangiopathies consist of 
a spectrum of diseases that are characterized 
by the formation of platelet microthrombi 
within vessels, thrombocytopenia and 
microangiopathic hemolytic anemia. 

7. Hemolytic uremic syndrome develops from 
various disease processes. The sporadic or 
endemic variety associated with diarrhea is 
linked to Shiga toxin exposure. The onset 
occurs approximately 1 week after diarrhea, 
presenting with severe hypertension and 
decreased urine output. 



Chapter 17 



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295 



Thrombotic thrombocytopenic purpura is 
associated with either a congenital or 
acquired defect in a metalloproteinase- 
converting enzyme for von Willebrand 
factor. Central nervous system manifesta- 
tions are the most prominent feature. 
Purpura is common, while gastrointestinal 
bleeding occurs from severe thrombocy- 
topenia. Renal manifestations include hema- 
turia, proteinuria, and azotemia. 




Rapidly Progressive 
Glomerulonephritis 



RPGN is characterized by crescent formation and 
a rapid decline in renal function. A crescent is 
made up of proliferating epithelial cells that line 
Bowman's capsule and infiltrating macrophages 
(Figure 17.12). Crescents result when the GBM is 
severely damaged with breaks observed on EM. 
This allows fibrin, plasma proteins, macrophages, 
monocytes, plasma cells, and platelets to gain 



mire 17.12 




Crescent (light microscopy). A cellular crescent is seen by the 
arrow. 



access to Bowman's space. Patients present with 
rising serum BUN and creatinine concentrations 
and may have oliguria. Without adequate treat- 
ment irreversible renal failure may develop in 
weeks. Rapidly progressive glomerulonephritis is 
subdivided into three types based on immunoflu- 
orescence microscopy: (1) anti-GBM antibody 
disease; (2) pauci-immune glomerulonephritis; 
and (3) immune complex disease. 

Type 1 -Anti-GBM Antibody Disease 
(Goodpasture Syndrome) 

Goodpasture syndrome is characterized by circu- 
lating antibodies to the GBM in association with 
glomerulonephritis and pulmonary hemorrhage. 
Rarely, clinical evidence of an anti-neutrophil 
cytoplasmic antibody (ANCA)-associated vas- 
culitis may be seen concurrently with anti-GBM 
disease. Hemoptysis, pulmonary infiltrates, and 
pulmonary hemorrhage result from cross-reactivity 
of anti-GBM antibody to the alveolar capillary 
basement membrane. The autoantibodies recog- 
nize an epitope in the alpha-3 chain of type IV 
collagen. The binding of antibody to antigen 
induces an inflammatory response that results in 
glomerular injury. The initial injury is a focal and 
segmental necrosis followed by extensive cres- 
cent formation. Immunofluorescence microscopy 
shows linear deposition of IgG in the GBM 
(Figure 17.13). Electron microscopy does not 
reveal dense deposits, excluding immune com- 
plex disease. 

Anti-GBM disease is uncommon; the annual 
incidence is one to two cases per million popula- 
tion/year. It makes up less than 10% of all cases of 
crescentic glomerulonephritis seen on renal 
biopsy. The disease incidence has two peaks, the 
first is in the third decade in men, and the second 
in the sixth and seventh decades with men and 
women equally affected. Young males more often 
present with the pulmonary renal syndrome 
while elderly females more commonly develop 
renal-limited disease. Smoking predisposes to the 
development of pulmonary hemorrhage. Dyspnea, 



296 



Chapter 17 ♦ Glomerular Diseases 



Figure 17.13 




Goodpasture syndrome (immunofluorescence microscopy). 
Immunofluorescence staining in this patient with Goodpasture 
syndrome shows the classic linear IgG staining pattern. Note 
that there is no granularity as in Figure 17.5. 



either intermittent or continuous, cough, and 
hemoptysis are the major symptomatic features of 
Goodpasture syndrome. Hemoptysis can be mas- 
sive, minor, or absent. Lack of hemoptysis does 
not exclude pulmonary disease or hemorrhage. 
Pulmonary symptoms may develop over hours or 
slowly over weeks. Tachypnea, cyanosis, and 
inspiratory rales are signs of pulmonary disease. 
Arterial blood gas may demonstrate hypoxemia 
from alveolar hemorrhage. Occasionally, subclin- 
ical bleeding in the lungs results in iron deficiency 
anemia. Nephritis from anti-GBM disease is asso- 
ciated with hematuria, dysmorphic red cells, and 
red blood cell casts on urine sediment. Proteinuria 
and an elevated serum creatinine concentration 
are often present at the time of diagnosis. Renal 
function can deteriorate rapidly in the absence of 
therapy. Some patients, especially the elderly, 
present with renal manifestations and no pul- 
monary symptoms. In the absence of pulmonary 
hemorrhage, patients are considered to have 
renal-limited anti-GBM disease. 

The diagnosis is suspected based on clinical 
and laboratory findings. The chest radiograph 



demonstrates patchy or diffuse infiltrates in the 
central lung fields. The changes are most often 
symmetric, but rarely can occur asymmetrically. 
Renal ultrasound typically appears normal. Anti- 
GBM antibodies may be detected in serum, but 
this is not a sensitive test (excessive number of 
false-negative results). Circulating anti-GBM anti- 
bodies are detected in serum using a specific 
enzyme-linked immunosorbent assay (ELISA) or 
radioimmunoassay. The test is based on the prin- 
ciple that purified GBM components are coated 
on plastic microtiter plates, diluted serum is 
applied, and anti-GBM antibodies bind the GBM 
components. Antibody binding is detected by 
using a secondary antibody that binds to human 
IgG. In general, the ANCA test is negative, but may 
be positive when a vasculitis occurs concurrently 
with anti-GBM disease. Although rarely per- 
formed, lung biopsy is diagnostic when it reveals 
linear IgG staining along the pulmonary basement 
membrane. Alveoli are often filled with red blood 
cells and hemosiderin-laden macrophages. Renal 
histology is typically obtained in these cases and, 
as described above, is diagnostic. 

Anti-GBM disease is a true autoimmune dis- 
ease of the kidney and lung. The pathogenesis is 
thought to be due to both the presence of anti- 
GBM antibodies and T-cell-mediated immunity to 
GBM antigens. Glomerular basement membrane 
antigens are expressed in thymus, and autoreac- 
tive CD4 + T cells are increased. These T cells pro- 
vide help to autoreactive B cells in the production 
of anti-GBM antibodies. These autoantibodies are 
directed against the noncollagenous 1 domain of 
the alpha-3 chain of type IV collagen in kidney 
and lung. Antibody binding leads to inflammation 
with complement deposition, leukocyte recruit- 
ment, and tissue injury and destruction. Genetic 
factors may play a role, as HLA-DR2 is associated 
with the development of anti-GBM disease. 
Environmental influences such as smoking, infec- 
tion, certain geographical locations, and organic 
solvents or hydrocarbons are associated with 
Goodpasture syndrome. 

Treatment is directed at removing culprit autoan- 
tibodies and suppressing their production. To this 



Chapter 17 



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297 



end, intensive plasma exchange, glucocorticoids, 
and immunosuppressive agents such as cyclophos- 
phamide and azathioprine are employed. Most 
therapeutic protocols use a combination regimen 
consisting of prednisolone, cyclophosphamide, 
and plasma exchange. Prednisolone is employed 
at 1 mg/kg/day (maximum 80 mg/day) with a 
weekly dose reduction to 20 mg/day, followed 
by a slow taper over the next 1-2 years. Oral 
cyclophosphamide at 2.5 mg/kg/day (maximum 
150 mg/day) is given for 4 months (dose adjusted 
based on white blood cell count) and converted 
to azathioprine for the next 1—2 years. Daily 4 L 
exchanges with 4.5% albumin for 2 weeks (or 
until no detectable anti-GBM antibodies) is the 
plasma exchange regimen. Key to success is initi- 
ation of therapy prior to the serum creatinine con- 
centration reaching 5.7 mg/dL. The probability of 
achieving a 5-year survival without dialysis was 
94% in these patients, where it decreased to 50% 
in patients with higher serum creatinine concen- 
trations not yet requiring dialysis. Dialysis depen- 
dence at the time of therapy was associated with 
a dismal 13% chance of dialysis-free survival. 
Interestingly, there was no influence of anti-GBM 
titer on outcome, although 100% glomerular cres- 
cents on biopsy portended a poor renal prognosis. 



Type 2-Pauci-Immune Glomerulonephritis 

Pauci-immune glomerulonephritis is characterized 
by no or very little immunoglobulin deposition on 
immunofluorescence. This group of diseases is 
associated with ANCA. Most patients have evi- 
dence of a systemic vasculitis such as Wegener's 
granulomatosis, microscopic polyarteritis, or 
Churg-Strauss syndrome. 



Wegener's Granulomatosis 

Wegener's granulomatosis is a necrotizing vasculi- 
tis involving small-sized vessels. Although 
Wegener's granulomatosis can affect any organ 
system, it classically involves the kidney, as well as 
the upper and lower respiratory tract. Pathologic 



examination of lesions in the nasopharynx and 
lung reveals a necrotizing granulomatous vasculitis. 
In kidney the vasculitis manifests as a necrotizing 
glomerulonephritis with crescent formation. 
Granulomas are rarely seen on renal biopsy. 

The disease most commonly develops in 
middle aged or elderly adults but can occur at any 
age. The initial presentation is often nonspecific 
with a variety of prominent constitutional symp- 
toms including fever, night sweats, anorexia, 
weight loss, and fatigue. Upper respiratory and 
pulmonary symptoms are prominent early on 
such as rhinorrhea, sinusitis, otitis media, epi- 
staxis, cough, and hemoptysis. A "limited" form of 
Wegener's is described that affects the upper and 
lower respiratory tract and not the kidneys. Renal 
involvement generally, but not always, follows 
the development of extrarenal involvement. 
Microscopic hematuria, red blood cell casts, pro- 
teinuria, and an elevated serum creatinine con- 
centration are often present at the time of diagnosis. 
Some patients present with the renal lesion and 
nondiagnostic systemic symptoms. In the absence 
of upper and lower respiratory involvement these 
patients are often considered to have microscopic 
polyarteritis. It is likely that Wegener's granulo- 
matosis, "limited" Wegener's, and microscopic 
polyarteritis are all part of a spectrum of the same 
disease since patients with "limited" Wegener's 
often develop renal involvement, patients with 
microscopic polyarteritis often subsequently 
develop pulmonary involvement, and the ANCA 
test is typically positive in all three syndromes. A 
variety of other organ systems may also be 
involved including the musculoskeletal system 
(myalgias, arthralgias), peripheral and central 
nervous system (mononeuritis multiplex, cranial 
nerve abnormalities), cardiovascular (pericarditis, 
myocarditis), skin (palpable purpura, ulcerative 
lesions), and eyes (conjunctivitis, episcleritis, 
uveitis, proptosis). 

The diagnosis is suspected based on clinical 
and laboratory findings. The chest radiograph 
shows solitary or multiple nodules in the middle 
or lower lung fields. The nodules are poorly 
defined and often undergo central necrosis. 



298 



Chapter 17 ♦ Glomerular Diseases 



The ANCA test is frequently positive in a cyto- 
plasmic pattern (cANCA) and has a high sensitiv- 
ity and specificity in the presence of active classic 
Wegener's granulomatosis (>90%) but is not suffi- 
cient to either rule in or rule out the diagnosis. In 
"limited" Wegener's the ANCA may be negative in 
as many as 40% of patients. 

The ANCA test is performed by incubating the 
patient's serum with ethanol-fixed human neu- 
trophils. Indirect immunofluorescence is carried out 
and two patterns are observed. A diffuse cytoplas- 
mic pattern is caused by antibodies directed against 
proteinase 3 and a perinuclear pattern is caused 
by antibodies directed against myeloperoxidase. 
A positive immunofluoresence should be fol- 
lowed by an ELISA for proteinase 3 and myeloper- 
oxidase. Approximately 70% of patients with 
microscopic polyarteritis will have a positive 
pANCA. The pANCA pattern is, however, nonspe- 
cific and is seen in a wide variety of inflammatory 
diseases. It can also be caused by antibodies 
against a host of azurophilic granule proteins 
including catalase, lysozyme, lactoferrin, and elas- 
tase. The pANCA can also be falsely positive in 
patients with positive antinuclear antibodies 
(ANA). 

Wegener's granulomatosis is an immune-medi- 
ated disorder. It likely results from an inciting 
inflammatory stimulus and a pathologic immune 
reaction to shielded antigens on neutrophil gran- 
ule proteins. These anti-neutrophil cytoplasmic 
antibodies interact with activated neutrophils and 
endothelial cells and cause tissue damage. The 
inciting inflammatory event remains unclear. 
Given that the initial symptoms often involve the 
respiratory tract, research has focused on infec- 
tious and noninfectious inhaled agents without 
identifying a causal agent. It is possible that an 
inflammatory event exposes neoepitopes on 
granule proteins that generate an immune 
response that then undergoes epitope spreading. 
Activated neutrophils have increased surface 
expression of proteinase 3, are more likely to 
degranulate and release reactive oxygen species, 
and have increased binding to endothelial cells 
resulting in tissue damage. 



Confirmation of the diagnosis requires histo- 
logic examination of tissue. If lesions are present 
in the nasopharynx these should be biopsied 
because of the low morbidity. Granulomatous 
inflammation is often observed but granuloma- 
tous vasculitis is seen in only one-third of 
patients. If there are no nasopharyngeal lesions 
the kidney is often biopsied since it is less inva- 
sive than an open lung biopsy (transbronchial 
biopsy often does not provide sufficient tissue to 
exclude the diagnosis). A kidney biopsy will not 
differentiate between Wegener's granulomatosis 
and microscopic polyarteritis since granulomas 
are rarely seen on renal biopsy. The characteris- 
tic finding in both disorders is a focal necrotizing 
glomerulonephritis with or without crescent 
formation. Immunofluorescence studies are 
negative. Serum complement concentrations 
are normal. This distinction is often not important 
clinically given that the treatment of both condi- 
tions is the same. 

The mortality rate in untreated Wegener's gran- 
ulomatosis is high, 80% within 1 year and 90% 
within 2 years. Mean survival in untreated patients 
is only 5 months. Although corticosteroids alone 
may yield transient improvement, this is generally 
only temporary. One -year survival with cortico- 
steroids alone is 33%. Long-term remissions are 
obtained in those treated with cyclophosphamide. 
One-year survival with cyclophosphamide is 
80-95%. Early institution of therapy is paramount. 
The presence of severe dialysis requiring acute 
renal failure during the acute phase of illness does 
not preclude aggressive therapy. Enough renal 
function can return to allow the discontinuation 
of dialysis. Patients with respiratory involvement or 
fulminant disease are begun on 4 mg/kg/day of 
oral cyclophosphamide for the first 3 or 4 days. 
When disease is active but relatively stable one 
can use 2 mg/kg/day orally. Intermittent IV pulse 
cyclophosphamide given at monthly intervals 
(0.5-1 g/m 2 ) was also employed. Oral prednisone 
(1 mg/kg/day in divided doses) is given and is 
especially helpful in reducing acute inflammation 
in the pericardium, eye, and skin. Intravenous 
pulse methylprednisolone (1 g for 3 days) is used 



Chapter 17 



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299 



in patients with rapidly progressive renal failure or 
respiratory disease. Corticosteroids are continued 
until the disease is controlled and then tapered to 
an alternate-day schedule. Cyclophosphamide is 
continued until there is no evidence of disease 
activity. Patients in remission after 3 or 4 months 
can be switched to oral azothiaprine or methotrex- 
ate to reduce the incidence of complications pro- 
viding the ANCA is negative. Approximately 
80-90% of patients can be placed into remission. 
Maintenance therapy is generally continued 
for 12-24 months after complete remission is 
induced. Systemic symptoms often improve 
quickly. The pulmonary and renal abnormalities 
require 3—6 months after cyclophosphamide begins 
to remit. Late relapses can occur. Given the toxic- 
ity of oral cyclophosphamide, monthly pulse 
intravenous dosing was evaluated with mixed 
results. Some studies showed equal and others 
reduced efficacy. Plasmapheresis is of limited 
benefit but may be of value in those with pul- 
monary hemorrhage, patients who require dialy- 
sis during the initial phase, and those with 
anti-GBM antibodies. 

Classic Polyarteritis Nodosa 

Classic polyarteritis nodosa (PAN) involves small 
and medium-sized muscular arteries. Lesions tend 
to be segmental and commonly occur at arterial 
bifurcations with distal spread occasionally 
involving arterioles. There is prominent neu- 
trophilic infiltration with destruction of the vascu- 
lar wall. Fibrinoid necrosis occurs with disruption 
of the internal elastic lamina, ischemia, and infarc- 
tion. Aneurysm formation develops in the weak- 
ened vessel wall, and scarring during the 
healing process leads to further obliteration of 
the vascular lumen. The arcuate and interlobular 
arteries are primarily involved in the kidney. The 
glomerular lesion is a focal, segmental necrotizing 
glomerulonephritis. Changes are primarily ischemic, 
with fibrinoid necrosis and minimal proliferation. 
Immunofluorescence microscopy is usually neg- 
ative. In the healing phase, thickening of the 
vessel wall may resemble that induced by chronic 



hypertension; however, in hypertension the inter- 
nal elastic lamina is preserved. 

Patients present with systemic symptoms 
including fever, "weight loss, arthralgias, and loss 
of appetite. Males are more commonly affected 
than females "with a peak incidence in the sixth 
decade. There is a lack of eosinophilia or significant 
pulmonary involvement, which differentiates 
PAN from Churg-Strauss syndrome. Asymmetric 
polyneuropathy (mononeuritis multiplex — due to 
involvement of the vasa vasorum) strongly sug- 
gests the diagnosis of PAN. The only other disease 
causing mononeuritis multiplex is diabetes melli- 
tus. Testicular pain is another common feature. 
Renal involvement is characterized by azotemia 
and hypertension. In general progressive renal 
failure is a late manifestation. Urine sediment is 
variable, and may be relatively benign if only 
larger vessels are involved, a setting in which 
there may be glomerular ischemia without signif- 
icant necrosis. Dysmorphic red blood cells, red 
blood cell casts, and mild proteinuria are typically 
seen when there is focal proliferative glomeru- 
lonephritis. Nephrotic range proteinuria is unusual. 
Serum complement concentration is usually 
normal. Hepatitis B infection has been associated 
with the development of PAN. 

The diagnosis is most commonly made by 
demonstrating typical vascular lesions on angiogra- 
phy of the celiac and renal arteries. Microaneurysms 
and irregular segmental constrictions are seen in 
larger vessels, with tapering and occlusion of 
smaller intrarenal arteries. Renal biopsy may be 
required if the angiogram is negative, and if no 
other easily biopsied affected tissue such as muscle 
or peripheral nerve can be identified. 

The prognosis of untreated PAN is poor with 
survival rates of only 33% at 1 year, and 10% at 
5 years. This improved dramatically with the 
advent of corticosteroids (50% 5-year survival). 
Mortality remains high secondary to renal failure, 
congestive heart failure, stroke, and mesenteric 
infarction. Long-term remissions are induced with 
cyclophosphamide in doses similar to those used 
for Wegener's granulomatosis. Patients with 
RPGN should also be given pulse corticosteroids. 



300 



Chapter 17 ♦ Glomerular Diseases 



As with Wegener's granulomatosis, improvement 
in renal function can be seen even in patients with 
far-advanced disease. Maintenance therapy should 
be continued for 1-2 years after remission. 

Churg— Strauss Syndrome 

Churg-Strauss syndrome is characterized by 
extravascular granulomas, eosinophilic infiltra- 
tion of arteries and venules, and kidney involve- 
ment. Clinically the disease progresses through 
three stages. An allergic diathesis is usually the 
first clinical manifestation, beginning between 
age 20 and 30. Asthmatic symptoms are frequent 
in this stage. This is followed by peripheral 
eosinophilia. The final stage is systemic vasculitis. 
The time course required to progress from one 
stage to another is variable. The shorter the inter- 
val, the worse the prognosis. As systemic vasculi- 
tis develops, lung involvement becomes more 
prominent with noncavitating pulmonary infil- 
trates on chest radiograph. Often allergic and 
asthmatic symptoms improve as vasculitis devel- 
ops. Coronary vasculitis is common, and the heart 
is often the most severely affected organ (result- 
ing in 50% of deaths). Renal involvement is gen- 
erally mild, with renal failure developing in less 
than 10% of patients. Despite the paucity of renal 
findings hypertension is relatively common (75%). 
The characteristic LM finding on renal biopsy is a 
focal segmental necrotizing glomerulonephritis. 
The interstitium is also involved with either a focal 
or diffuse interstitial nephritis with granuloma for- 
mation and eosinophilic infiltration. Patients with 
Churg-Strauss syndrome often respond to corti- 
costeroids alone and generally are treated for 
1 year; relapses are uncommon. 



Type ^-Immune Complex Diseases 

A variety of immune complex diseases can result 
in RPGN including postinfectious glomerulonephri- 
tis, lupus nephritis, IgA nephropathy, Henoch- 
Schonlein purpura, membranoproliferative 



glomerulonephritis, and membranous glomeru- 
lonephritis. Many of these disorders are covered 
in other sections of this chapter. 

Hypersensitivity Vasculitis 

Hypersensitivity vasculitis primarily involves post- 
capillary venules. Skin lesions (palpable purpura) 
are the most predominant abnormality observed. 
Lesions vary in size from a few millimeters to 
centimeters and in severe cases ulceration may 
occur. Biopsy of affected skin reveals an intense 
neutrophilic infiltrate surrounding dermal blood 
vessels that is associated with hemorrhage and 
edema (leukocytoclastic vasculitis). Hypersensitivity 
vasculitis is often confined to skin but other organ 
systems including kidney may be involved. 
Vascular involvement in kidney occurs in the distal 
interlobular arteries and glomerular arterioles. In 
contrast to pauci-immune forms of glomeru- 
lonephritis such as Wegener's granulomatosis, IF 
shows diffuse granular deposition of immunoglob- 
ulin and complement. When the kidney is affected 
this is manifested as either Henoch-Schonlein 
purpura (HSP), essential mixed cryoglobulinemia 
(EMC), or serum sickness. 

Henoch-Schonlein Purpura 

HSP is characterized by IgA-containing immune 
deposits at sites of involvement. Presenting symp- 
toms include the characteristic tetrad of abdominal 
pain, arthritis or arthralgias, purpuric skin lesions, 
and kidney disease. Its annual incidence is 20 per 
100,000 children. Skin lesions are most commonly 
seen on the extensor surfaces of the arms, legs, 
and buttocks. They are ultimately seen in all 
patients but on occasion are absent at initial pre- 
sentation. Lesions can begin as urticaria and evolve 
into purpura. The most common joints involved 
are the ankles and knees. Gastrointestinal mani- 
festations include vomiting, abdominal pain, and 
bleeding. Renal involvement is common and gener- 
ally evident within days to months after the onset of 
initial symptoms. The urinalysis reveals microscopic 



Chapter 17 



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301 



hematuria, red cell casts, and mild proteinuria. On 
presentation the serum creatinine concentration is 
often normal or slightly elevated. Patients with 
more severe disease have nephrotic range pro- 
teinuria, hypertension, and elevated serum BUN 
and creatinine concentrations. 

Immunofluorescence staining of purpuric skin 
lesions and occasionally normal skin is positive for 
IgA in endothelial cells of superficial blood vessels. 
Immune complexes may be absent from the vessel 
wall in older lesions. Therefore, the absence of 
immune complexes does not rule out Henoch- 
Schonlein purpura. Morphologic changes in the 
kidney are identical to those seen in IgA nephropa- 
thy. The most common lesion is a mild prolifera- 
tive glomerulonephritis. In severe cases crescent 
formation and fibrinoid necrosis are observed. 
IgA and complement containing immune deposits 
are present on IF. 

The diagnosis should be considered in a patient 
with skin lesions of hypersensitivity vasculitis, par- 
ticularly in the presence of arthralgias and abdom- 
inal pain. Skin biopsy with immunoflourescence is 
often diagnostic. IgA deposition is found in dermal 
vessels in up to 75% of cases, however, early 
lesions must be biopsied. The absence of IgA in 
dermal vessels does not rule out HSP. Serum com- 
plement concentration is usually normal. Renal 
biopsy is only performed in patients with pro- 
gressive increases in serum BUN and creatinine 
concentrations. 

Henoch-Schonlein purpura is generally a 
benign self-limited disorder that resolves sponta- 
neously. Adults tend to have more severe disease 
than children. Recurrences of purpuric skin 
lesions or glomerulonephritis can occur and 
recurrent disease does not imply a worse progno- 
sis. The degree of renal involvement is the most 
important long-term prognostic factor. Prognosis 
is excellent in those with asymptomatic hematuria 
and proteinuria or focal glomerulonephritis. Poor 
prognostic signs include nephrotic range protein- 
uria and >50% crescents on renal biopsy. This 
group of patients is less likely to completely 
recover kidney function. In one study, patients 



with greater than 50% crescents had a 37% 
incidence of progressing to ESRD. Progressive 
kidney disease is uncommon in patients who 
present initially with mild disease. Skin lesions 
and kidney disease do not respond to corticos- 
teroids alone. Therapy is often attempted with 
pulse steroids, cyclophosphamide, and plasma- 
pheresis in patients with severe or progressive 
disease and crescentic glomerulonephritis. Its effi- 
cacy remains unproven due to the lack of rando- 
mized trials and the high spontaneous remission 
rate even in those with severe disease. 

Essential Mixed Cryoglobulinemia (Type II) 

Cryoglobulins are antibodies that precipitate in 
cold and redissolve on warming. The biochemi- 
cal characteristics responsible for this are not 
■well understood. There are three different types 
of cryoglobulins. Type I cryoglobulins are mono- 
clonal and are usually the result of multiple 
myeloma or Waldenstrom's macroglobulinemia. 
Type II cryoglobulins (essential mixed cryoglob- 
ulinemia) contain a polyclonal IgG and a mono- 
clonal IgM rheumatoid factor directed against the 
immunoglobulin. Most cases are the result of 
infection with hepatitis C. Cryoglobulins are 
abnormally glycosylated and this may play a 
role in their cryoprecipitation. Type III cryo- 
globulins are composed of a polyclonal IgG 
and a polyclonal IgM rheumatoid factor. This 
may be the result of hepatitis C infection but can 
also be seen with SLE and lymphoproliferative 
malignancies. 

Hepatitis C virus can bind to B lymphocytes 
and lower their activation threshold resulting in 
the production of autoantibodies. Cryoglobulins 
are also present in other forms of chronic liver dis- 
ease including infection with hepatitis B and 
patients with other forms of cirrhosis. Liver disease 
may contribute to the development or persistence 
of cryoglobulinemia due to the fact that the liver is 
the primary clearance site of cryoglobulins. 

Patients often present with systemic symptoms 
including fatigue and lethargy, as well as arthralgias. 



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Chapter 17 ♦ Glomerular Diseases 



Palpable purpura can also be the presenting com- 
plaint and commonly involves the lower extremi- 
ties. Hepatosplenomegaly, lymphadenopathy, 
peripheral neuropathy, and Raynaud's phenome- 
non may be present. Serum complement concen- 
trations are generally low. Renal involvement is 
present in approximately half of patients and 
ranges from asymptomatic hematuria and protein- 
uria to acute oliguric renal failure. Azotemia is 
present at onset of disease in a minority of 
patients. Hepatic enzymes are often elevated 
and may reflect underlying hepatitis B or C 
infection. 

EMC should be considered in any patient with 
palpable purpura, especially if hypocomple- 
mentemia is present. The diagnosis is established 
by the presence of an IgM-IgG cryoglobulin with 
a monoclonal component by immunofixation 
electrophoresis. To test for the presence of cryo- 
globulins 20 mL of blood must be drawn in the 
fasting state and collected in a tube without anti- 
coagulants. The tube is then placed in warm water 
for transportation to the lab. After serum is sepa- 
rated via centrifugation the sample is placed at 
4°C and observed for cryoprecipitation. 

The principal pathologic findings are found in 
skin and kidney. Skin biopsy reveals a leukocyto- 
clastic vasculitis without IgA deposition. In the 
kidney LM resembles MPGN type I with lobular 
accentuation, diffuse mesangial and endothelial cell 
proliferation, and basement membrane thickening. 
On EM mesangial and subendothelial deposits are 
seen. The subendothelial deposits often have a 
characteristic "fingerprint" appearance. There are 
numerous intraluminal thrombi composed of pre- 
cipitated cryoglobulin distinguishing EMC from 
MPGN type I, Immunofluorescence microscopy 
reveals the deposition of IgM and C3 in the 
glomerular basement membrane. 

In most patients renal involvement is slowly 
progressive, with renal failure developing over 
months to years. Neither the cryoglobulin or 
complement concentration predicts those that 
will develop ESRD. Hypocomplementemia in the 
presence of renal failure, hypertension, and ele- 
vated serum BUN and creatinine concentrations 



are poor prognostic signs. The efficacy of treat- 
ment remains a question. Patients with fulminant 
disease (acute renal failure, progressive neu- 
ropathy, or distal necrosis requiring amputation) 
were often treated with plasmapheresis, pred- 
nisone, and cyclophosphamide before it became 
apparent that the majority of cases were related 
to hepatitis C infection. This regimen was suc- 
cessful in inducing remission in some patients. 
Reinfused plasma must be warmed or acute 
renal failure will be induced. Plasmapheresis is 
generally done three times per week for several 
weeks. Immunosuppressive therapy carries the 
risk of worsening viral replication and may fur- 
ther increase the risk of inducing non-Hodgkin's 
lymphoma. More recently combinations of inter- 
feron a and ribavirin were employed. Although 
this regimen is effective for the treatment of skin 
and joint involvement, there is little evidence 
that it is beneficial for the treatment of the renal 
lesion. In general ribavirin should not be used in 
patients with a GFR below 50 mL/minute. There 
is a high rate of recurrence of EMC in the renal 
allograft. 



Key Points 

Rapidly Progressive Glomerulonephritis 



1 . Rapidly progressive glomerulonephritis is 
characterized by a rapid decline in renal 
function and crescent formation on renal 
biopsy. It is important to recognize since 
irreversible renal damage can occur over a 
span of weeks. 

2. Rapidly progressive glomerulonephritis is 
subdivided into three types based on 
immunofluorescence microscopy: (1) anti- 
GBM antibody disease; (2) pauci-immune 
glomerulonephritis; and (3) immune 
complex disease. 

3. Goodpasture syndrome is characterized by 
circulating antibodies to the GBM, glomeru- 
lonephritis and pulmonary hemorrhage. 



Chapter 17 



Glomerular Diseases 



303 



Immunofluorescence microscopy reveals a 
linear deposition of IgG. 

4. Pauci-immune glomerulonephritis is char- 
acterized by no or very little immunoglo- 
bulin deposition on immunofluorescence. 
This group of diseases is associated with 
ANCA and includes Wegener's granulo- 
matosis, microscopic polyarteritis, classic 
polyarteritis nodosum, and Churg-Strauss 
syndrome. 

5. Wegener's granulomatosis classically 
involves the kidney, as well as the upper 
and lower respiratory tract. Pathologic 
examination of lesions in the nasopharynx 
and lung reveals a necrotizing granuloma- 
tous vasculitis. 

6. Classic polyarteritis nodosa is diagnosed by 
demonstrating typical vascular lesions on 
angiography of the celiac and renal arteries. 
Microaneurysms and irregular segmental 
constrictions are seen in larger vessels, with 
tapering and occlusion of smaller intrarenal 
arteries. 

7. Churg-Strauss syndrome is characterized 
by extravascular granulomas, eosinophilic 
infiltration of arteries and venules, and 
kidney involvement. Clinically the disease 
progresses through three stages: an allergic 
diathesis; peripheral eosinophilia; and sys- 
temic vasculitis. 

8. Henoch-Schonlein purpura presents with 
the characteristic tetrad of abdominal pain, 
arthritis or arthralgias, purpuric skin lesions, 
and kidney disease. Morphologic changes in 
kidney are identical to those seen in IgA 
nephropathy. 

9. Essential mixed cryoglobulinemia 
should be considered in any patient with 
palpable purpura, especially if hypocom- 
plementemia is present. The diagnosis is 
established by the presence of an 
IgM-IgG cryoglobulin with a monoclonal 
component by immunofixation 
electrophoresis. 




Asymptomatic Abnormalities 
on Urinalysis 



Abnormalities on urinalysis such as microscopic 
hematuria and proteinuria may also be the initial 
presentation of glomerular disease. Microscopic 
hematuria may result from bleeding anywhere in 
the urinary tract. The most common causes are 
nephrolithiasis, urinary tract infection, and malig- 
nancies. These disorders do not result in signifi- 
cant proteinuria. Hematuria in association with 
proteinuria is suggestive of a glomerular disease. 
Although any glomerular disease can initially 
present with an abnormal urinalysis, IgA nephropa- 
thy, Alport syndrome, and thin basement mem- 
brane disease are common glomerular lesions that 
often present initially with an abnormal urinalysis. 



IgA Nephropathy 

IgA nephropathy is the most common cause of 
glomerulonephritis worldwide. It is most common 
in Asians and Caucasians and relatively uncom- 
mon in African Americans. IgA nephropathy is 
unique among glomerular diseases in that it is 
defined not by its LM features but rather by the 
finding of immune deposits containing IgA in the 
mesangium and occasionally in the GBM on IF 
microscopy. 

Approximately one-third to half of patients 
present prior to the age of 40 with intermittent 
macroscopic hematuria after respiratory infection. 
The majority of the remainder have asymptomatic 
abnormalities on urinalysis. Nephrotic syndrome 
and RPGN occur in a small percentage of patients. 
IgA nephropathy is associated with chronic liver 
disease, viral infections such as HIV and hepatitis B, 
rheumatoid arthritis, Reiter's syndrome, dermatitis 
herpetiformis, and gluten enteropathy. 

Light microscopic findings vary from minimal 
changes to segmental or diffuse mesangial hyper- 
cellularity with an increase in mesangial matrix to 



304 



Chapter 17 ♦ Glomerular Diseases 



segmental sclerosis. On IF microscopy the hall- 
mark is the detection of IgA. Other immunoglobu- 
lins including IgG and IgM can also be seen, as 
well as C3. Focal thinning of the GBM is a common 
feature on electron microscopic examination. The 
only other glomerular disease associated with 
extensive glomerular deposition of IgA is lupus 
nephritis. In lupus nephritis, however, IgG deposi- 
tion is often more prominent than IgA and Clq is 
detected due to activation of the classical comple- 
ment pathway. In IgA nephropathy immune com- 
plexes activate the alternative pathway and do not 
bind CI. 

Abnormal glycosylation of IgAl plays a role in 
its deposition in the mesangium. IgA binds to 
mesangial cells and can induce proliferation and 
cytokine production. It also binds complement 
via the alternative pathway. Sublytic concentra- 
tions of C5b-9 are generated resulting in increased 
secretion of inflammatory cytokines, as well as the 
production of mesangial matrix. 

End-stage renal disease develops in 20% of 
patients at 20 years. Predictors of a poor outcome 
include an elevated serum creatinine concentra- 
tion, proteinuria >1 g/24 hours, hypertension, 
male sex, persistent microscopic hematuria, and 
young age at onset. On renal biopsy the presence 
of tubulointerstitial disease and crescents por- 
tends a poor prognosis. Treatment is generally 
reserved for patients with an elevated serum 
creatinine concentration, hypertension, and/or 
proteinuria greater than 1 g/24 hours. Angiotensin- 
converting enzyme inhibitors are more effective 
than other antihypertensive agents in slowing the 
progression of renal failure in patients with IgA 
nephropathy. Proteinuria can be further reduced 
with the addition of an ARB. Fish oil can be tried 
but studies are conflicting as to whether it is of 
benefit. Corticosteroids also reduce proteinuria 
and may improve outcomes in those with 
nephrotic syndrome and progressive disease 
despite ACE inhibitors or ARBs. Those patients 
with LM features typical of minimal change dis- 
ease may be especially responsive to cortico- 
steroids. Patients with RPGN are treated "with 



intravenous pulse methylprednisolone, oral pred- 
nisone, and cyclophosphamide with or without 
plasmapheresis. 



Alport Syndrome 

Alport syndrome is an inherited disorder that 
results in the production of defective type IV 
collagen. Its incidence is approximately 1 in 
50,000. Type IV collagen is a triple helix of alpha 
chains. Abnormalities in any one of the three 
chains results in an abnormal collagen molecule. 
Six alpha chains, COL4A1 through COL4A6, have 
been identified in humans. COL4A3, COL4A4, and 
COL4A5 are expressed in the glomerular base- 
ment membrane. Renal involvement (microscopic 
and gross hematuria, progressive rise in the serum 
BUN and creatinine concentrations, hypertension, 
proteinuria) is associated with sensorineural hear- 
ing loss and eye abnormalities (perimacular flecks 
and anterior lenticonus). The earliest change on 
renal biopsy is thinning of the GBM. As the dis- 
ease progresses the GBM splits developing a lam- 
inated appearance. 

In 85% of cases the mode of inheritance is X- 
linked dominant and is caused by mutations in 
COL4A5. Heterozygous females generally have 
mild disease. In 10-15% of cases inheritance is 
autosomal recessive and due to mutations in 
COL4A3 and COL4A4. Carriers generally have 
microscopic hematuria but rarely progress to 
renal failure or have hearing loss. In a few cases 
an autosomal dominant mode of inheritance is 
described. 

Large deletions and frame shift mutations are 
associated with a more severe phenotype. 
Greater than 90% of these patients develop ESRD 
and deafness by age 30. The abnormality of 
alpha-5 chain synthesis leads to an abnormal 
GBM that is also deficient in the alpha-3 chain 
(Goodpasture's antigen). A deficiency of both 
alpha-3 and alpha-5 results in a higher incidence 
of ESRD and a higher risk of anti-GBM nephritis 
after renal transplant. 



Chapter 17 



Glomerular Diseases 



305 



Thin Basement Membrane Disease 



Additional Reading 



Thin basement membrane disease or benign 
familial hematuria is manifested by persistent 
microscopic hematuria, minimal proteinuria, 
and the absence of ear or eye involvement. 
Rarely do patients progress to renal failure. 
Inheritance is autosomal dominant. There is dif- 
fuse thinning of the lamina densa of the GBM 
(<200 nm). Some of these patients are heterozy- 
gous for mutations in COL4A3 and COL4A4 sug- 
gesting that thin basement membrane disease is 
the heterozygous state of autosomal recessive 
Alport syndrome. 



Key Points 



Abnormal Urinalysis 



1 . IgA nephropathy is the most common cause 
of glomerulonephritis worldwide. 

2. IgA nephropathy is unique among glomerular 
diseases in that it is defined not by its LM 
features but by the finding of immune 
deposits containing IgA on IF microscopy. 

3. Abnormal glycosylation of IgAl plays a role 
in its deposition in the mesangium. IgA 
binds to mesangial cells, induces prolifera- 
tion and cytokine production, and bincis 
complement via the alternative pathway. 

4. Alport syndrome is an inheriteci disorder 
that results in the production of defective 
type IV collagen. The earliest change on 
renal biopsy is thinning of the GBM. 

5. Thin basement membrane disease or benign 
familial hematuria is manifested by persist- 
ent microscopic hematuria, minimal protein- 
uria, and the absence of ear or eye 
involvement. 



Cameron, J.S. Lupus nephritis. / Am Soc Nephrol 
10:413-424, 1999. 

Cattran, D.C. Idiopathic membranous glomeru- 
lonephritis. Kidney Int 59: 1983-1994, 2001. 

Floege, J., Feehally, J. IgA nephropathy: recent devel- 
opments. J Am Soc Nephrol 11:2395-2403, 2000. 

Hricik, D.E., Chung-Park, M., Sedor, J.R. Glomeru- 
lonephritis. N Engl J Med 339:888-899, 1998. 

Kamesh, L., Harper, L., Savage, CO. ANCA-positive 
vasculitis. J Am Soc Nephrol 13:1953-1960, 2002. 

Kluth, D.C, Rees, A.J. Anti-glomerular basement mem- 
brane disease. / Am Soc Nephrol 10:2446-2453, 
1999. 

Korbet, S.M. Treatment of primary focal segmental 
glomerulosclerosis. Kidney Int 62:2301-2310, 2002. 

Lin, J., Markowitz, G.S., Valeri, A.M., Kambham, N., 
Sherman, W.H., Appel, G.B., DAgati, V.D. Renal 
monoclonal immunoglobulin deposition disease: 
the disease spectrum. J Am Soc Nephrol 12:1482- 
1492, 2001. 

Moake, J.L. Thrombotic microangiopathies. N Engl J 
Med 347:589-600, 2002. 

Remuzzi, G., Schieppati, A., Ruggenenti, P. Clinical 
practice. Nephropathy in patients with type 2 dia- 
betes. N Engl] Med 346:1145-1151, 2002. 

Ritz, E., Orth, S.R. Nephropathy in patients with type 2 
diabetes mellitus. N Engl] Med 341:1127-1133, 1999. 

Rosenstock, J.L., Markowitz, G.S., Valeri, A.M., Sacchi, 
G., Appel, G.B., DAgati, V.D. Fibrillary and immuno- 
tactoid glomerulonephritis: distinct entities with dif- 
ferent clinical and pathologic features. Kidney Int 
63:1450-1461, 2003. 

Ross, M.J., Klotman, P.E. Recent progress in HIV- 
associated nephropathy. J Am Soc Nephrol 13:2997- 
3004, 2002. 

Schwarz, A. New aspects of the treatment of nephrotic 
syndrome. J Am Soc Nephrol 12(Suppl. 17):S44-S47, 
2001. 

Vora, J.P., Ibrahim, H.A., Bakris, G.L. Responding to the 
challenge of diabetic nephropathy: the historic evo- 
lution of detection, prevention and management. / 
Hum Hypertens 14:667-685, 2000. 



Mark A. Perazella 



Tubulointerstitial 
Diseases 




Recommended Time to Complete: 1 day 

1. How does one diagnose tubulointerstitial disease? 

2. The development of tubulointerstitial disease is characterized by 
what two circumstances? 

Z. Tubulointerstitial disease is characterized by what histopathologic 

findings? 
<4. What are the common chnical manifestations of tubulointerstitial 

disease? 

5. Are there laboratory tests that suggest a diagnosis of tubulointerstitial 
disease? 

6. What are the common categories of tubulointerstitial disease? 
7- What is the basic model of the pathogenesis of tubulointerstitial 

disease? 



306 



Chapter 18 



Tubulointerstitial Diseases 



307 




Introduction 



Structural abnormalities of the renal parenchyma 
that involve primarily the tubules and interstitium 
are called tubulointerstitial disease. In contrast to 
acute interstitial nephritis (AIN), diseases that cause 
tubulointerstitial disease, discussed in this section, 
are more often chronic processes (Table 18.1). 
Diseases of the tubulointerstitium are best thought 
of as either primary or secondary processes. Primary 
causes of tubulointerstitial nephritis typically 
occur due to systemic diseases or following expo- 
sure to environmental or therapeutic agents. In 
this circumstance, the glomeruli and vasculature 
are typically spared or have only minor structural 
changes until late in the course of disease. In gen- 
eral, approximately 10-20% of end-stage renal 
disease (ESRD) in the United States occurs from 
primary chronic tubulointerstitial disease. A sec- 
ondary form of chronic tubulointerstitial disease 
may also result from progressive glomerular dis- 
ease or vascular injury with associated renal 
parenchymal ischemia. A significant number of 
disease states cause this form of chronic tubuloin- 
terstitial injury, with diabetic nephropathy and 
hypertensive nephrosclerosis being most common. 
Tubulointerstitial disease with fibrosis and scarring 
significantly determine the progressive nature of 
these lesions and their ultimate outcome, the out- 
come being chronic kidney disease (CKD) and 
ESRD requiring renal replacement therapy. 




Histopathology of 
Tubulointerstitial Disease 



In chronic tubulointerstitial disease, a cellular 
infiltrate and variable amounts of fibrosis are 
noted within the architecture of the interstitium. 



Table 18.1 

Etiologies of Tubulointerstitial Disease 



Immunologic causes 

Systemic lupus erythematosis 

Vasculitis 

Amyloidosis 

Cryoglobulinemia 

Sjogren's syndrome 

Therapeutic agents 

Analgesics 

NSAIDs 

Chemotherapy (cisplatin, nitrosoureas) 

Immunosuppressive agents (calcineurin inhibitors) 

Lithium 

Chinese herbs (aristolochic acid) 

Occupational/environmental agents 

Heavy metals (lead, cadmium, mercury) 

Mycotoxins 

Neoplastic/hematopoietic diseases 

Lymphoma/leukemia 

Multiple myeloma 

Light chain deposition disease 

Sickle cell disease 

Hereditary diseases 

Medullary cystic disease 

Polycystic kidney disease 

Karyomegalic interstitial nephritis 

Vascular diseases 

Renal atheroemboli 

Radiation nephritis 

Hypertensive nephrosclerosis 

Infections 

Bacterial pyelonephritis 

Xanthogranulomatous pyelonephritis 

Malacoplakia 

Metabolic disorders 

Hypercalcemia 

Hypokalemia 

Hyperoxaluria/oxalosis 

Hyperuricemia 

Cystinosis 

Other conditions 

Sarcoidosis 

Obstructive uropathy 

Balkan nephropathy 

Tubulointerstitial nephritis uveitis (TINU) 



Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs. 



308 



Chapter 18 ♦ Tubulointerstitial Diseases 



The characteristic lesion is an inflammatory cellular 
infiltrate composed of lymphocytes, usually T cells 
and, to a lesser degree, plasma cells. Early in the 
course of disease, the acute cellular infiltrate is 
accompanied by interstitial edema, tubulitis with 
tubular basement membrane disruption, and disso- 
lution of the normal tubulointerstitial architecture. 
Over time, the acute process transitions to a chronic 
tubulointerstitial lesion. The chronic histology is 
characterized by interstitial fibrosis with increased 
extracellular matrix, tubular ectasia and atrophy, 
and tubular dropout. The severity of this process 
typically advances over time until the entire tubu- 
lointerstitium is overtaken by fibrosis. In far 
advanced disease, glomerulosclerosis develops and 
blood vessels become involved by fibrosis and scle- 
rosis. At this point in time, the patient often mani- 
fests clinically advanced CKD. 



Key Points 

Histopathology of Tubulointerstitial Disease 



1 . Tubulointerstitial disease is classified as pri- 
mary or secondary to another disease 
process. 

2. In primary tubulointerstitial disease, the 
glomeruli and vasculature are normal early 
in the course of disease. 

3. The characteristic lesion is a lymphocytic 
infiltrate. 

4. Early in tubulointerstitial disease, interstitial 
edema accompanies the cellular infiltrate 
while tubular injury and interstitial fibrosis 
develop as the process progresses. 




Clinical Presentation 



More often than not, patients with tubulointerstitial 
disease have few clinical symptoms suggestive of 



CKD. In general, symptoms and signs reflect the 
extent of tubulointerstitial disease. For example, 
focal areas of injury are minimally symptomatic, 
whereas diffuse disease causes several tubular 
defects in electrolyte, acid-base, and mineral han- 
dling. Also, the area of the kidney involved by dis- 
ease leads to disturbances characteristic of the loss 
of function of the injured tubular segment. Injury to 
the proximal tubule is associated with impaired 
absorption of sodium, glucose, phosphorus, amino 
acids, potassium, uric acid, and several low molec- 
ular weight proteins. In contrast, disease of the 
loop of Henle and distal convoluted tubule causes 
sodium and potassium wasting (salt wasting, 
hypokalemia, and hypotension). Involvement of 
the cortical and medullary collecting ducts may be 
associated with hyperkalemia and metabolic aci- 
dosis (hyperkalemic distal renal tubular acidosis) 
due to defects in potassium and ammonia (buffers 
acid) secretion by this segment. Another important 
determinate of the clinical manifestations of tubu- 
lointerstitial disease is the degree of compensation 
by the remaining normal (or less severely impaired) 
nephron segments. With mild-to-moderate disease, 
compensatory hypertrophy may eliminate or sub- 
stantially reduce symptoms of renal disease. 

Often times, chronic tubulointerstitial disease 
is discovered "when blood testing reveals abnor- 
mal kidney function (increased blood urea nitro- 
gen [BUN] and serum creatinine concentration) 
that is otherwise fairly asymptomatic. The pres- 
ence of certain systemic diseases may also prompt 
investigation of kidney function and potential 
kidney disease. As is discussed later, several sys- 
temic diseases promote the development of 
chronic tubulointerstitial disease. The most common 
symptom associated with disease of the tubuloin- 
terstitium is polyuria. Two mechanisms account 
for this symptom including salt wasting and the 
inability to maximally concentrate the urine. 
Dizziness from low blood pressure (salt wasting), 
weakness from either severe hypokalemia or hyper- 
kalemia, and bone pain/fractures from osteopenia 
induced by metabolic acidosis can also occur. 
Advanced chronic tubulointerstitial disease results 
in the development of usual manifestations of CKD 



Chapter 18 



Tubulointerstitial Diseases 



309 



approaching ESRD. These include anorexia, nausea, 
vomiting, lethargy, somnolence, fatigue, restless 
legs, and other uremic manifestations. 



Laboratory Findings 

As noted in the previous section, tubulointerstitial 
disease often manifests with various renal tubular 
and urinary disorders (Table 18.2). Examination 
of blood and urine chemistries often provide 
insight into the disease. Proximal renal tubular 
acidosis (RTA), as noted by a hypokalemic, 
nonanion gap metabolic acidosis, may occur in 
this setting. In this case, the urine is acid (pH <5.5) 
in steady state acidosis, but becomes alkaline (pH 
>7.0) when therapy to correct the metabolic aci- 
dosis with bicarbonate is attempted. A full-blown 
Fanconi's syndrome can develop with chronic 
tubulointerstitial disease involving the proximal 



Table 18.2 

Laboratory Manifestations of Tubulointerstitial Disease 



Proximal tubular defects 

Proximal renal tubular acidosis 
Fanconi's syndrome 
Distal tubular defects 

Hypokalemic distal renal tubular acidosis 

Hyperkalemic distal renal tubular acidosis 

Concentrating defect 

Salt wasting nephropathy 

Sterile pyuria 

White blood cells 

White blood cell casts 

Tubular proteinuria 

Albuminuria (<1 g/day) 

/3-,-microglobulinuria 

Retinol-binding protein excretion 

Enzymuria 

Af-acetyl-/5-glucosaminidase excretion 

Alanine aminopeptidase excretion 

Intestinal alkaline phosphatase excretion 



tubule. This syndrome is characterized by the pres- 
ence of a proximal RTA that also demonstrates 
phosphaturia, aminoaciduria, glycosuria, enzy- 
muria, and uricosuria. Salt wasting (urinary sodium 
>20 meq/L) despite hypotension may indicate 
tubulointerstitial disease of the loop of Henle. 
Hypokalemia due to urinary potassium wasting 
may also occur with a lesion in this segment. An 
acidification defect in the distal nephron may 
cause a hypokalemic distal RTA that is character- 
ized by hypokalemia, nonanion gap metabolic 
acidosis, and alkaline urine (first morning void pH 
>5.5). A hyperkalemic distal RTA (hyperkalemia 
with nonanion gap metabolic acidosis) may be 
seen with tubulointerstitial disease. Inability to 
concentrate the urine leads to a low urine osmo- 
lality and, if the patient is unable to gain free water 
access, may cause hypernatremia. 

The urinalysis yields variable results in the set- 
ting of chronic tubulointerstitial disease. A couple 
of generalizations, however, can be made. 
Tubulointerstitial disease rarely has marked pro- 
teinuria, most often there is trace to 1+ protein on 
quantitative examination of the urine. A 24-hour 
urine collection or spot protein/creatinine ratio 
usually contains less than 1 g of total protein. 
Examination of the urine sediment under the 
microscope often reveals a preponderance of 
white blood cells (WBCs), occasionally with some 
WBC and granular casts. Red blood cells (RBCs) 
and RBC casts are extremely unusual. Urinary 
crystals may be present with certain disorders 
associated with chronic tubulointerstitial disease 
(calcium oxalate crystals with hyperoxaluria, uric 
acid crystals with uric acid nephropathy). 

Examination of proteinuria (low molecular 
weight proteins) and enzymuria may provide 
insight into disease limited to the tubulointersti- 
tium, however, they are not widely employed as 
clinical tools. High molecular weight proteins 
(>40, 000-50, 000 Da) in the urine are typically a 
marker of glomerular disease. Included in this 
group is albumin (69,000 Da), transferrin 
(77,000 Da), and IgG (146,000 Da). In contrast, 
small amounts of low molecular weight proteins 
are normally excreted in the urine. They are 



310 



Chapter 18 ♦ Tubulointerstitial Diseases 



considered markers of "tubular" proteinuria 
(versus glomerular proteinuria), /^-microglobulin 
(11,800 Da) and retinol-binding protein (21,400 Da) 
are the markers of tubular injury most com- 
monly employed. Both substances are freely fil- 
tered; approximately 99.9% is reabsorbed in the 
proximal tubule where they are catabolized. 
When the reabsorptive capacity of proximal 
tubular cells is impaired, increased amounts of 
various low molecular weight proteins can be 
demonstrated in the urine. Thus, levels increase 
in urine when disease injures proximal tubular 
cells. Although both /^-microgl