Pathophysiology 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. All rights reserved. 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Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. 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).