Table Of ContentPathophysiology of Kidney
Disease and Hypertension
A. Vishnu Moorthy, MD Associate Editors:
Professor Bryan N. Becker, MD
Department of Medicine Professor
University of Wisconsin School of Medicine Department of Medicine
and Public Health University of Wisconsin School of Medicine
Madison, Wisconsin and Public Health
Madison, Wisconsin
Frederick J. Boehm III, MD
Postdoctoral Senior Fellow
Department of Biostatistics
University of Washington
Seattle, Washington
Arjang Djamali, MD, MS, FASN
Assistant Professor
Department of Medicine
University of Wisconsin School of Medicine
and Public Health
Madison, Wisconsin
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
PATHOPHYSIOLOGY OF KIDNEY DISEASE AND HYPERTENSION ISBN: 978-1-4160-4391-1
Copyright © 2009 by Saunders, an imprint of Elsevier Inc.
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The Publisher
Library of Congress Cataloging-in-Publication Data
Pathophysiology of kidney disease and hypertension / [edited by] A. Vishnu Moorthy ; associate
editors, Bryan N. Becker, Frederick J. Boehm III, Arjang Djamali.—1st ed.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-4160-4391-1
1. Kidneys—Pathophysiology. 2. Renal hypertension. I. Moorthy, A. Vishnu.
[DNLM: 1. Kidney Diseases—physiopathology. 2. Kidney Diseases—therapy. 3. Acid-Base Imbalance.
4. Hypertension, Renal. 5. Renal Replacement Therapy. 6. Water-Electrolyte Imbalance. WJ 300 P2977
2009]
RC903.9.P366 2009
616.6’107—dc22
2008021065
Acquisitions Editor: William Schmitt
Developmental Editor: Andrea Vosburgh
Project Manager: David Saltzberg
Design Direction: Louis Forgione
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
DEDICATION
“I want to beg you, as much as I can, dear sir, to be patient
toward all that is unsolved in your heart and to try to love the
questions themselves.”
Rainer Maria Rilke, Letters to a Young Poet.
This work is dedicated to all students and teachers of the
health sciences—past, present, and future. May you continue to
enjoy the questions.
Contributors
Bryan N. Becker, MD Theodore L. Goodfriend, MD
Professor Emeritus Professor
Department of Medicine Departments of Medicine and Pharmacology
University of Wisconsin School of Medicine and University of Wisconsin School of Medicine
Public Health and Public Health;
Madison, Wisconsin Associate Chief of Staff for Research
William S. Middleton Memorial Veterans Hospital
Yolanda T. Becker, MD Madison, Wisconsin
Associate Professor
Department of Surgery Claire Elliott Herrick, MD
University of Wisconsin School of Medicine Resident
and Public Health Department of Obstetrics, Gynecology,
Madison, Wisconsin and Reproductive Sciences
University of California, San Francisco
Tracy C. Blichfeldt, MD San Francisco, California
Resident
Department of Medicine Jonathan B. Jaffery, MD
Gundersen Lutheran Medical Foundation Assistant Professor
La Crosse, Wisconsin Department of Medicine
University of Wisconsin School of Medicine
Frederick J. Boehm III, MD and Public Health
Postdoctoral Senior Fellow Madison, Wisconsin
Department of Biostatistics
University of Washington Paul S. Kellerman, MD, FACP
Seattle, Washington Associate Professor
Department of Medicine
Peter C. Brazy, MD University of Wisconsin School of Medicine
Emeritus Professor of Medicine and Public Health
Department of Medicine Madison, Wisconsin;
University of Wisconsin School of Medicine Medical Director
and Public Health Wisconsin Dialysis, Inc.
Madison, Wisconsin Fitchburg, Wisconsin
Arjang Djamali, MD, MS, FASN Ryan Kipp, MD
Assistant Professor Resident
Department of Medicine Department of Medicine
University of Wisconsin School of Medicine University of Wisconsin School of Medicine
and Public Health and Public Health
Madison, Wisconsin Madison, Wisconsin
Joshua David Lindsey, MD
Resident
Department of Orthopaedics
University of Washington Affi liated Hospitals
Seattle, Washington
v
vi Contributors
Kristin M. Lyerly, MD Milagros D. Samaniego, MD
Master of Public Health Student Associate Professor
Department of Population Health Sciences Department of Medicine
University of Wisconsin School of Medicine University of Wisconsin School of Medicine
and Public Health and Public Health
Madison, Wisconsin Madison, Wisconsin
A. Vishnu Moorthy, MD Kelly Ann Traeger, MD
Professor Resident
Department of Medicine Department of Anesthesiology
University of Wisconsin School of Medicine Froedtert Hospital
and Public Health Milwaukee, Wisconsin
Madison, Wisconsin
Sung-Feng Wen, MD
Terry D. Oberley, MD, PhD Emeritus Professor
Professor and Vice Chairman Department of Medicine
Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine
University of Wisconsin School of Medicine and Public Health
and Public Health; Madison, Wisconsin
Chief, Electron Microscopy
Pathology and Laboratory Medicine Service Weixiong Zhong, MD, PhD
William S. Middleton Veterans Administration Assistant Professor
Hospital Department of Pathology and Laboratory Medicine
Madison, Wisconsin University of Wisconsin School of Medicine
and Public Health;
Byram H. Ozer, BA Staff Pathologist
MD/PhD Candidate Pathology and Laboratory Medicine Service
Department of Biomolecular Chemistry William S. Middleton Memorial Veterans Hospital
Medical Scientist Training Program Madison, Wisconsin
University of Wisconsin School of Medicine
and Public Health
Madison, Wisconsin
Preface
The goal of this project was to produce a text appro- a unique experience for the student and faculty
priate for an introductory study of the pathophysiol- authors in learning how to work together across
ogy of kidney diseases and hypertension for health knowledge and experiential gaps and still produce
professional students and medical students in a product worthy of use in any basic student course
particular. In many medical schools, including the addressing pathophysiology of kidney disorders
University of Wisconsin School of Medicine and and hypertension.
Public Health, students study kidney pathophysiol- The need for the text was apparent to all the
ogy during their pre-clinical years. When the Univer- contributors. Although the practicing nephrologist
sity of Wisconsin student authors, many of whom are could fi nd comprehensive and recently published
now resident physicians, began working on the text, books, review articles, and even outstanding
they had recently completed the kidney disease and online resources, an up-to-date and accessible
hypertension pathophysiology course offered during text targeted at health professional students was
their second year of medical school. They knew the unavailable. We hope that this text fulfi lls its pur-
course’s strengths and weaknesses and believed that pose of introducing the pathophysiology of kidney
they could make a difference in improving its impact diseases and hypertension to health professional
and ability to deliver comprehensive, understandable students and piques their interest and curiosity.
information about kidney and hypertensive diseases Finally, we hope that health professional students,
to students who were not yet overly familiar with the regardless of their discipline, will fi nd the text
clinical environment. The University of Wisconsin enlightening, enjoyable, and worthwhile.
students had studied other texts that had resulted
from student–faculty collaborations, and they be- A. Vishnu Moorthy, MD
lieved that their fi nal, much-needed product would Bryan N. Becker, MD
fi ll a vacancy in the medical school curriculum. Their Frederick J. Boehm III, MD
interest, perseverance, and determination resulted in Arjang Djamali, MD, MS, FASN
vii
Acknowledgments
We would like to acknowledge the administrators hours reading and commenting on many chapters in
and support staff in the Section of Nephrology, the this text other than the ones they contributed to
Department of Medicine, and the school infrastruc- themselves.
ture at the University of Wisconsin School of Medi- We would also like to expressly thank Bill Schmitt
cine and Public Health. We have been fortunate to and Andrea Vosburgh of Elsevier. They guided us
have their support for this project from its infancy. through the production process and continuously
Furthermore, we would like to thank our students offered advice, support, and encouragement. Their
and teachers, who continue to inspire us and to leadership in this project has been a key to its success.
enrich our lives. Last, but certainly not least, we wish to thank our
Special thanks go to Theodore L. Goodfriend, MD, families for their support and patience while we
and Sung-Feng Wen, MD, who spent numerous wrote and edited this text.
ix
Anatomy and Physiology
1
of the Kidney
A. Vishnu Moorthy
Tracy C. Blichfeldt
OUTLINE
I. Introduction C. Distal Convoluted Tubule
II. Anatomy of the Kidney D. Collecting Duct
A. The Nephron VI. Endocrine Functions of the Kidney
B. The Vascular System A. Renin–Angiotensin–Aldosterone System
C. The Glomerulus B. Erythropoietin
D. The Kidney Tubule C. 1,25-Dihydroxyvitamin D (Calcitriol)
3
III. Glomerular Filtration VII. Measurement of Kidney Function: The Glomerular
IV. Autoregulation and Tubuloglomerular Feedback Filtration Rate
V. Tubular Transport Processes A. Measurement of Creatinine Clearance
A. Proximal Tubule B. Estimation of Creatinine Clearance and the
B. Loop of Henle Glomerular Filtration Rate
Objectives medication is glipizide to lower his blood sugar, and his
• Know the anatomy of the kidney and its vasculature. serum creatinine level is 1.6 mg/dl.
• Know the structure of the glomerulus and the The patient is concerned that his kidney function
various segments of the nephron. might be impaired. How will you address his concerns?
• Understand the juxtaglomerular apparatus and
tubuloglomerular feedback.
I. INTRODUCTION
• Appreciate the factors that regulate glomerular
fi ltration. The kidneys regulate the excretion of excess ingested
• Review the major transport functions of the different water, electrolytes, and products of metabolism as
segments of the nephron. well as foreign substances, including drugs and toxins.
• Know the kidney as an endocrine organ, particu- The kidneys maintain the volume of body fl uid as
larly with regard to the production of renin, well as its electrolyte composition, pH, and osmolal-
1,25-dihydroxy vitamin D , and erythropoietin. ity. The stability of this milieu is necessary for the
3
• Know how to assess kidney function with the proper functioning of cells and organs. Various sens-
measurement of creatinine clearance, the Cockcroft– ing mechanisms that determine the extracellular fl uid
Gault equation to estimate creatinine clearance, and volume and the osmolality of the body fl uids help the
the Modifi cation of Diet in Renal Disease (MDRD) kidneys with this vital work. Hormones such as anti-
formula to estimate the glomerular fi ltration rate. diuretic hormone (ADH), aldosterone, angiotensin II,
and atrial natriuretic peptide (ANP) have important
Clinical Case roles in the functions of the kidneys. The kidneys are
A 62-year-old Caucasian man with a 10-year history of also important endocrine organs that produce a
diabetes mellitus type 2 visits the primary care clinic variety of hormones, including erythropoietin, renin,
where you, a second-year medical student, are working and 1,25-dihydroxyvitamin D (calcitriol), that are
3
with your preceptor. The patient tells you that he has necessary to sustain health.
no new symptoms and that he is visiting the doctor for
a routine health assessment and diabetes check. While
II. ANATOMY OF THE KIDNEY
reviewing the patient’s chart, you see that his most
recent visit to your preceptor was approximately 1 year The kidneys are located behind the peritoneal cavity
ago. His weight has been stable at 62 kg, and his (retroperitoneal) in the abdomen on either side of the
blood pressure is 130/80 mm Hg. His only prescription midline. Each kidney weighs approximately 150 g and
1
2 Anatomy and Physiology of the Kidney
measures 10 to 12 cm in length. The kidneys are B. The Vascular System
highly vascular organs, receiving 20% of the cardiac Each kidney is usually supplied by a single (at times
output (the greatest amount of blood per 100 g of double) renal artery, which arises from the aorta. The
tissue in the body) via the renal arteries that originate glomerular capillaries are unique in that they are situ-
from the abdominal aorta. Each kidney contains ated between two arterioles: the afferent arteriole,
400,000 to 1,200,000 functional units called nephrons. which arises from branches of the renal artery and
The arterial blood perfusing the kidney is later brings blood to the glomerular capillaries, and the
drained by the renal veins into the inferior vena efferent arteriole, which drains the glomerular
cava (Fig. 1-1). capillaries. After the glomerulus, the efferent arteriole
branches into a cluster of peritubular capillaries that
A. The Nephron intimately surrounds the tubules. Thus, there are two
The nephron is the functional unit of the kidney, capillary beds in series in the kidney parenchyma. This
and it consists of a glomerulus and a tubule. arrangement is vital for glomerular fi ltration and for
Glomeruli are clusters of specialized capillaries tubular reabsorption and secretion (Fig. 1-2).
contained within the Bowman’s capsule in the The segments of postglomerular capillaries, which
cortex of the kidney. Blood enters glomeruli are known as the vasa recta, supply the medullary por-
through the afferent arterioles and leaves through tion of the kidney. The vasa recta are hairpin-shaped
the efferent arterioles. The urine begins as a glo- blood vessels that arise in the cortex and descend into
merular ultrafi ltrate (blood minus plasma proteins) the medulla before turning back into the cortex and
that drains from the glomerulus to the tubule. The leading to the venous system. The medullary circula-
kidney tubule has distinct segments, namely the tion removes solutes and fl uid reabsorbed by the
proximal tubule, the hairpin-shaped loop of Henle, tubules. In the descending loops of the vasa recta,
and the distal tubule, all of which connect the water moves out of the vessels and solutes move in.
glomerulus to the collecting duct, which ultimately In the ascending loops of the vasa recta, this process
drains into the renal pelvis. As the glomerular is reversed: water moves into the vessel, and solutes
ultrafi ltrate traverses the tubules, its volume move out into the interstitium. By this process of
decreases, and its composition changes by the counter-current exchange, the vasa recta minimize the
processes of tubular reabsorption and secretion. removal of excessive medullary interstitial solutes and
Finally, the urine drains into the renal pelvis and maintain a high medullary tonicity. This high medul-
down the ureter into the urinary bladder, where it lary interstitial tonicity is essential for the production
is stored before elimination. of concentrated urine.
Figure 1-1. Anatomy of the kidney. Capsule
A coronal section through the kidney
showing the renal cortex and me-
Cortex
Medulla
dulla. The capsule surrounds the kid-
ney. The cortex contains the glomer-
uli and the medulla, which are Renal columns
mostly tubules that drain into the (of Bertin)
renal calyces and then into the pelvis
and connect to the ureter. The renal
blood vessels (the artery and the
vein) are shown in the hilum of the Papillae
kidney. (Modifi ed from Brenner B: Renal artery
Brenner and Rector’s The Kidney,
7th ed. Philadelphia, Saunders, Renal vein Renal pyramid
2004.)
Corticomedullary
Renal pelvis
junction
Perirenal fat
in renal sinus
Calyces
Ureter
Arcuate artery
Anatomy and Physiology of the Kidney 3
Figure 1-2. The structure of the kidney
Glomerular
showing the nephron and its vascular supply.
Proximal tubule capillaries
The nephron with its various components:
Glomerulus the glomerulus and the proximal tubule in the
Bowman’s cortex, the descending and ascending loops
capsule Cortex of Henle in the medulla, and the distal tubule
Efferent Afferent that returns to the glomerulus of its origin in
artery artery the cortex and ultimately connects to the col-
Juxtaglomerular lecting duct. The afferent artery supplies the
apparatus glomerulus. The efferent artery arises from
the glomerular capillaries, branches one
more time into the peritubular capillaries,
and descends into the renal medulla as the
vasa recta before connecting into the venous
Distal system. (Modifi ed from Andreoli T, Loscalzo J,
convoluted Carpenter C, Griggs R: Cecil Essentials of
tubule
Medicine, 6th ed. Philadelphia, Saunders,
Descending 2004.)
and ascending Medulla
loops of
Henle
Vasa recta
Collecting
duct
C. The Glomerulus fenestrated with the individual fenestra, and it mea-
Glomeruli are clusters of capillaries that are surrounded sures 70 to 100 nm in length. The glomerular base-
by Bowman’s capsules and lined with a single layer of ment membrane (GBM) is an acellular matrix about
epithelial cells called the parietal epithelium. The affer- 300-nm thick, with a central lamina densa and with
ent arteriole supplies the glomerulus, and the efferent the lamina rara interna and externa on either side. It is
arteriole drains it; the proximal tubule drains fi ltrate composed of extracellular matrix proteins, including
from the Bowman’s space. Glomerular capillaries are type IV collagen and laminin. It also contains nega-
unique in that they are placed between two arterioles tively charged glycoproteins, such as heparan and
(Box 1-1 and Fig. 1-3). chondroitin sulfates. The triple helical collagen type IV
Glomerular capillaries, like capillaries elsewhere in molecule in the GBM of adults contains (cid:2)-3, (cid:2)-4, and
the body, have a basement membrane with an endo- (cid:2)-5 chains of collagen (Box 1-2). The collagen chains
thelial cell lining. The glomerular endothelium is in the GBM are cross-linked, and they provide tensile
strength to the GBM.
The glomerular capillaries also have a unique cell
called the glomerular epithelial cell that is located ex-
Box 1-1. The Glomerulus
ternal to the GBM; this cell is also called the podocyte.
In the past, podocytes were known more commonly
The glomerulus is a cluster of capillaries that is sur-
as visceral epithelial cells. Podocytes are large cells that
rounded by Bowman’s capsule. The capillary wall has a
give rise to several interdigitating foot processes an-
central basement membrane with endothelial and epi-
chored to the GBM. The adjacent foot processes,
thelial cells (the podocyte) on either side. Mesangial
which arise from different podocytes, are attached to
cells with matrix surround the capillaries. The podocyte
one another through cytoplasmic connections called
is anchored to the basement membrane with fi ngerlike
slit diaphragms. The slit diaphragm forms a zipper-like
foot processes. Slit diaphragms connect adjacent foot
structure between adjacent podocytes. It has pores
processes. The glomerular capillary wall and the podo-
that are about 40 nm across, and it serves as a size-
cyte serve as barriers to exclude cells and protein in
selective barrier to prevent molecules from entering
the blood from entering the Bowman’s space.
Bowman’s urinary space (Figs. 1-4 and 1-5).
