(BQ) Part 1 book Robbins basic pathology presentation of content: Cell injury, cell death, and adaptations, inflammation and repair, diseases of the immune system, genetic and pediatric diseases, general pathology of infectious diseases, environmental and nutritional diseases, hematopoietic and lymphoid systems, blood vessels,... and other contents.
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Go to studentconsult.com; Sign in Click the “Activate Another Book” button Gently scratch off the surface of the sticker with the edge of a coin to reveal your Pin code Enter it into the “Pin code” box; select the title you’ve activated from the drop-down menu Click the “Activate Book” button REGISTER s 'OTOSTUDENTCONSULTCOMCLICKh2EGISTER.OWv s &ILLINYOURUSERINFORMATIONANDCLICKh!CTIVATEYOUR account” ACTIVATE YOUR BOOK s #LICKTHEh!CTIVATE!NOTHER"OOKvBUTTON s 'ENTLYSCRATCHOFFTHESURFACEOFTHESTICKERWITHTHE edge of a coin to reveal your Pin code s %NTERITINTOTHEh0INCODEvBOXSELECTTHETITLE you’ve activated from the drop-down menu s #LICKTHEh!CTIVATE"OOKvBUTTON Access to, and online use of, content through the Student Consult website is for individual use only; library and institutional access and use are strictly prohibited For information on products and services available for institutional access, please contact our Account Support Center at (+1) 877-857-1047 Important note: Purchase of this product includes access to the online version of this edition for use exclusively by the individual purchaser from the launch of the site This license and access to the online version operates strictly on the basis of a single user per PIN number The sharing of passwords is strictly prohibited, and any attempt to so will invalidate the password Access may not be shared, resold, or otherwise circulated, and will terminate 12 months after publication of the next edition of this product Full details and terms of use are available upon registration, and access will be subject to your acceptance of these terms of use For technical assistance: email online.help@elsevier.com call 800-401-9962 (inside the US) / call +1-314-995-3200 (outside the US) Robbins Basic Pathology This page intentionally left blank Basic Pathology ROBBINS NINTH EDITION Vinay Kumar, MBBS, MD, FRCPath Donald N Pritzker Professor Chair, Department of Pathology Biologic Sciences Division and Pritzker School of Medicine University of Chicago Chicago, Illinois Abul K Abbas, MBBS Distinguished Professor and Chair Department of Pathology University of California San Francisco San Francisco, California Jon C Aster, MD, PhD Professor of Pathology Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts ARTIST James A Perkins, MS, MFA 1600 John F Kennedy Blvd Ste 1800 Philadelphia, PA 19103-2899 ROBBINS BASIC PATHOLOGY 978-1-4377-1781-5 International Edition: 978-0-8089-2432-6 Copyright © 2013, 2007, 2003, 1997, 1992, 1987, 1981, 1976, 1971 by Saunders, an imprint of Elsevier Inc No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility With respect to any drug or pharmaceutical products identified, 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 practitioners, relying on their own experience and knowledge of their patients, 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 authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein Library of Congress Cataloging-in-Publication Data Robbins basic pathology / [edited by] Vinay Kumar, Abul K Abbas, Jon C Aster – 9th ed p ; cm Basic pathology Includes bibliographical references and index ISBN 978-1-4377-1781-5 (hardcover : alk paper) – ISBN 978-0-8089-2432-6 (International ed : hardcover : alk paper) I. Kumar, Vinay, 1944– II. Abbas, Abul K. III. Aster, Jon C. IV. Robbins, Stanley L (Stanley Leonard), 1915–2003. V. Title: Basic pathology [DNLM: 1. Pathology QZ 4] 616.07–dc23 2011048699 Executive Content Strategist: William Schmitt Content Development Manager: Rebecca Gruliow Publishing Services Manager: Patricia Tannian Senior Project Manager: Sarah Wunderly Design Direction: Louis Forgione Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org DEDICATION To Our children and a special grandchild Kiera Chapman Kumar This page intentionally left blank Contributors Charles E Alpers, MD Professor and Vice Chair Department of Pathology University of Washington Seattle, Washington Kidney and Its Collecting System Jonathan Epstein, MD Professor of Pathology, Urology, and Oncology The Reinhard Professor of Urological Pathology Director of Surgical Pathology The Johns Hopkins Medical Institutions Baltimore, Maryland Male Genital System and Lower Urinary Tract Mark W Lingen, DDS, PhD Associate Professor Department of Pathology The University of Chicago, Chicago, Illinois Oral Cavity and Gastrointestinal Tract Anirban Maitra, MBBS Professor of Pathology and Oncology The Johns Hopkins University School of Medicine Pathologist The Johns Hopkins Hospital Baltimore, Maryland Genetic and Pediatric Diseases; Pancreas; Endocrine System Agnes B Fogo, MD Alexander J McAdam, MD, PhD Matthew P Frosch, MD, PhD Richard N Mitchell, MD, PhD John L Shapiro Chair of Pathology Professor of Pathology, Microbiology, Immunology, Medicine, and Pediatrics Director, Renal/EM Division of Pathology Vanderbilt University School of Medicine Nashville, Tennessee Kidney and Its Collecting System Lawrence J Henderson Associate Professor of Pathology and Health Sciences & Technology Harvard Medical School Director, C.S Kubik Laboratory for Neuropathology Massachusetts General Hospital Boston, Massachusetts Central Nervous System Aliya Noor Husain, MBBS Professor Department of Pathology The University of Chicago Chicago, Illinois Lung Alexander J.F Lazar, MD, PhD Associate Professor Departments of Pathology and Dermatology The University of Texas M.D Anderson Cancer Center Houston, Texas Skin Associate Professor of Pathology Harvard Medical School Medical Director, Infectious Diseases Diagnostic Laboratory Children’s Hospital Boston, Massachusetts General Pathology of Infectious Diseases Lawrence J Henderson Professor of Pathology and Health Sciences & Technology Department of Pathology Harvard Medical School Staff Pathologist Brigham and Women’s Hospital Boston, Massachusetts Hemodynamic Disorders, Thromboembolism, and Shock; Blood Vessels; Heart Peter Pytel, MD Assistant Professor Department of Pathology The University of Chicago Chicago, Illinois Peripheral Nerves and Muscles Andrew E Rosenberg, MD Clinical Professor of Pathology Director, Bone and Soft Tissue Pathology Department of Pathology Miller School of Medicine University of Miami Miami, Florida Bones, Joints, and Soft Tissue Tumors viii Contributors Husain A Sattar, MD Assistant Professor of Pathology The University of Chicago Chicago, Illinois Female Genital System and Breast Arlene H Sharpe, MD, PhD Professor of Microbiology and Immunobiology, and Pathology Harvard Medical School and Brigham and Women’s Hospital Boston, Massachusetts General Pathology of Infectious Diseases Thomas Stricker, MD, PhD Instructor Department of Pathology The University of Chicago Chicago, Illinois Neoplasia Jerrold R Turner, MD, PhD Sara and Harold Lincoln Thompson Professor Associate Chair Department of Pathology The University of Chicago Chicago, Illinois Oral Cavity and Gastrointestinal Tract Wei-Lien Wang, MD Assistant Professor of Pathology Section of Soft Tissue and Dermatopathology The University of Texas M.D Anderson Cancer Center Houston, Texas Skin Neil D Theise, MD Professor Departments of Pathology and Medicine (Digestive Diseases) Beth Israel Medical Center of Albert Einstein College of Medicine New York, New York Liver, Gallbladder, and Biliary Tract Edward C Klatt, MD Professor and Academic Administrator Department of Pathology Florida State University College of Medicine Tallahassee, Florida Photographic Editor Raminder Kumar, MBBS, MD Chicago, Illinois Clinical Editor for Diseases of the Heart, Lung, Pancreas, Oral Cavity and Gastrointestinal Tract, and Liver Richard N Mitchell, MD, PhD Lawrence J Henderson Professor of Pathology and Health Sciences & Technology Department of Pathology Harvard Medical School Staff Pathologist Brigham and Women’s Hospital Boston, Massachusetts Targeted Therapy (Online) Editor 536 C H A P T E R 13 Kidney and Its Collecting System Blunted calyx Cortical scar or others that are similar in structure Serum IgE levels are increased in some persons, suggesting type I hypersensitivity In other cases the nature of the inflammatory infiltrate (discussed below) and the presence of positive skin tests to drugs suggest a T cell–mediated (type IV) hypersensitivity reaction The most likely sequence of pathogenic events is as follows: The drugs act as haptens that, during secretion by tubules, covalently bind to some cytoplasmic or extracellular component of tubular cells and become immunogenic The resultant tubulointerstitial injury is then caused by IgE- and cellmediated immune reactions to tubular cells or their basement membranes Cortical scar Figure 13–15 Typical coarse scars of chronic pyelonephritis associated with vesicoureteral reflux The scars are usually located at the upper or lower poles of the kidney and are associated with underlying blunted calyces Clinical Course Many persons with chronic pyelonephritis come to medical attention relatively late in the course of the disease, because of the gradual onset of renal insufficiency or because signs of kidney disease are noticed on routine laboratory tests In other cases, the renal disease is heralded by the development of hypertension The radiologic image is characteristic: The affected kidney is asymmetrically contracted, with some degree of blunting and deformity of the calyceal system (caliectasis) The presence or absence of significant bacteriuria is not particularly helpful diagnostically; its absence certainly should not rule out chronic pyelonephritis If the disease is bilateral and progressive, tubular dysfunction occurs with loss of concentrating ability, manifested by polyuria and nocturia As noted earlier, some persons with chronic pyelonephritis or reflux nephropathy ultimately develop secondary glomerulosclerosis, associated with proteinuria; eventually, these injuries all contribute to progressive chronic kidney disease M O R P H O LO G Y The abnormalities in acute drug-induced nephritis are in the interstitium, which shows pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages (Fig 13–16) Eosinophils and neutrophils may be present, often in large numbers With some drugs (e.g., methicillin, thiazides, rifampin), interstitial non-necrotizing granulomas with giant cells may be seen The glomeruli are normal except in some cases caused by nonsteroidal antiinflammatory agents, in which the hypersensitivity reaction also leads to podocyte foot process effacement and the nephrotic syndrome Clinical Course The disease begins about 15 days (range, to 40 days) after exposure to the drug and is characterized by fever, eosinophilia (which may be transient), a rash (in about 25% of persons), and renal abnormalities Urinary findings include hematuria, minimal or no proteinuria, and leukocyturia (sometimes including eosinophils) A rising serum creatinine or acute kidney injury with oliguria develops in about 50% of cases, particularly in older patients Clinical recognition of drug-induced kidney injury is imperative, because withdrawal of the offending drug is followed by recovery, Drug-Induced Interstitial Nephritis In this era of widespread antibiotic and analgesic use, drugs have emerged as an important cause of renal injury Acute drug-induced tubulointerstitial nephritis (TIN) occurs as an adverse reaction to any of an increasing number of drugs Acute drug-induced TIN is associated most frequently with synthetic penicillins (methicillin, ampicillin), other synthetic antibiotics (rifampin), diuretics (thiazides), nonsteroidal anti-inflammatory agents, and numerous other drugs (phenindione, cimetidine) PATHOGENESIS Many features of the disease suggest an immune mechanism Clinical evidence of hypersensitivity includes latent period, eosinophilia and rash, the idiosyncratic nature of the drug reaction (i.e., the lack of dose dependency), and the recurrence of hypersensitivity after reexposure to the same drug Figure 13–16 Drug-induced interstitial nephritis, with prominent eosinophilic and mononuclear infiltrate (Courtesy of Dr H Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.) Diseases Affecting Tubules and Interstitium although it may take several months for renal function to return to normal SUMMARY Tubulointerstitial Nephritis • TIN consists of inflammatory disease primarily involving the renal tubules and interstitium • Acute pyelonephritis is a bacterial infection caused either by ascending infection as a result of reflux, obstruction, or other abnormality of the urinary tract, or by hematogenous spread of bacteria; characterized by abscess formation in the kidneys, sometimes with papillary necrosis • Chronic pyelonephritis usually is associated with urinary obstruction or reflux; results in scarring of the involved kidney, and gradual renal insufficiency • Drug-induced interstitial nephritis is an IgE- and T cell– mediated immune reaction to a drug; characterized by interstitial inflammation, often with abundant eosinophils, and edema (3) acute drug-induced allergic interstitial nephritis, which often is not associated with tubular injury These other disorders involving acute kidney injury are discussed elsewhere in this chapter ATI arises in a variety of clinical settings, so it occurs relatively frequently Most of these clinical conditions, ranging from severe trauma to acute pancreatitis to septicemia, have in common a period of inadequate blood flow to all or regions of peripheral organs such as the kidney, sometimes in the setting of marked hypotension and shock The pattern of ATI associated with generalized or localized reduction in blood flow is called ischemic ATI Mismatched blood transfusions and other hemolytic crises, as well as myoglobinuria, also produce a clinical picture resembling that in ischemic ATI A second pattern, called nephrotoxic ATI, is caused by a variety of poisons, including heavy metals (e.g., mercury); organic solvents (e.g., carbon tetrachloride); and a multitude of drugs such as gentamicin and other antibiotics, and radiographic contrast agents ATI is often reversible, and proper recognition and management can mean the difference between full recovery and death PAT H O G E N E S I S Acute Tubular Injury Acute tubular injury (ATI) is a clinicopathologic entity characterized morphologically by damaged tubular epithelial cells and clinically by acute decline of renal function, with granular casts and tubular cells observed in the urine This constellation of changes, termed acute kidney injury, manifests clinically as decreased GFR When ATI is caused by acute kidney injury, there may be oliguria (defined as urine output of less than 400 mL/day) Other causes of acute kidney injury include (1) severe glomerular diseases manifesting clinically as RPGN; (2) acute tubular injury caused by diffuse renal vascular diseases, such as microscopic polyangiitis and thrombotic microangiopathies; and Ischemia Nephrotoxins (1) Renin-angiotensin PGI2 and NO The decisive events in both ischemic and nephrotoxic ATI are believed to be • Tubular injury Tubular epithelial cells are particularly sensitive to anoxia and are also vulnerable to toxins (Fig 13– 17) Several factors predispose the tubules to toxic injury, including elevated intracellular concentrations of various molecules that are resorbed or secreted across the proximal tubule, as well as exposure to high concentrations of luminal solutes that are concentrated by the resorption of water from the glomerular filtrate • Persistent and severe disturbances in blood flow resulting in diminished oxygen and substrate delivery to tubular Tubular damage (proximal tubules and ascending thick limb) (2) Obstruction by casts (3) Tubular backleak (4) Interstitial inflammation Vasoconstriction Intratubular pressure (5) ? Direct glomerular effect GFR Tubular fluid flow Oliguria Figure 13–17 Pathophysiologic mechanisms of acute kidney injury Various injuries can directly damage tubules, which in turn decreases GFR by multiple mechanisms and also promotes vasoconstriction Some injuries that cause tubular injury also directly decrease GFR by decreasing renal blood flow NO, nitric oxide; PGI2, prostaglandin I2 (prostacyclin) (Modified from Lameire N, et al: JASN 12:S20-S32, 2001.) 537 538 C H A P T E R 13 Kidney and Its Collecting System cells Ischemia causes numerous structural alterations in epithelial cells Loss of cell polarity is an early reversible event It leads to the redistribution of membrane proteins (e.g., Na+,K+-ATPase) from the basolateral to the luminal surface of tubular cells, resulting in decreased sodium reabsorption by proximal tubules and hence increased sodium delivery to distal tubules The latter, through a tubuloglomerular feedback system, contributes to preglomerular arteriolar vasoconstriction Redistribution or alteration of integrins that anchor tubular cells results in their detachment from the basement membranes and their shedding into the urine If sufficient tubular debris builds up it can block the outflow of urine (obstruction by casts), increasing intratubular pressure and thereby decreasing the GFR Additionally, fluid from the damaged tubules may leak into the interstitium (backleak), resulting in increased interstitial pressure and collapse of the tubules Ischemic tubular cells also express chemokines, cytokines, and adhesion molecules such as P-selectin that recruit leukocytes and can participate in tissue injury (interstitial inflammation) Ischemic renal injury also is characterized by severe hemodynamic alterations that cause reduced GFR The major one is intrarenal vasoconstriction, which results in both reduced glomerular plasma flow and reduced oxygen delivery to the tubules in the outer medulla (thick ascending limb and straight segment of the proximal tubule) (Fig 13–17) Although a number of vasoconstrictor pathways have been implicated in this phenomenon (e.g., renin-angiotensin, thromboxane A2, sympathetic nerve activity), the current opinion is that vasoconstriction is mediated by sublethal endothelial injury, leading to increased release of the endothelial vasoconstrictor endothelin and decreased production of vasodilatory nitric oxide and prostaglandins Finally, some evidence points to a direct effect of ischemia or toxins on the glomerulus, causing a reduced effective glomerular filtration surface In addition to vasoconstriction, the pathogenesis of ATI may involve apoptosis and necrosis of tubular cells Dead cells may elicit an inflammatory reaction (Chapter 2) that exacerbates the tubular injury and functional derangements MORPHOLOGY Ischemic ATI is characterized by lesions in the straight portions of the proximal tubule and the ascending thick limbs, but no segment of the proximal or distal tubules is spared There is often a variety of tubular injuries, including attenuation of proximal tubular brush borders, blebbing and sloughing of brush borders, vacuolization of cells, and detachment of tubular cells from their underlying basement membranes with sloughing of cells into the urine A striking additional finding is the presence of proteinaceous casts in the distal tubules and collecting ducts, which consist of Tamm-Horsfall protein (normally secreted by tubular epithelium) along with hemoglobin and other plasma proteins When crush injuries have produced ATI, the casts also contain myoglobin The interstitium usually shows generalized edema along with a mild inflammatory infiltrate consisting of polymorphonuclear leukocytes, lymphocytes, and plasma cells The histologic picture in toxic ATI is basically similar, with some differences Overt necrosis is most prominent in the proximal tubule, and the tubular basement membranes generally are spared If the patient survives for a week, epithelial regeneration becomes apparent in the form of a low cuboidal epithelial covering and mitotic activity in the surviving tubular epithelial cells Acute kidney injury with underlying acute tubular injury as its cause may result in fibrosis rather than repair if the proximal tubular cells are arrested at G2/M stage of the cell cycle after injury, as this arrest amplifies profibrotic mediators Clinical Course The clinical course of ischemic ATI initially is dominated by the inciting medical, surgical or obstetric event Affected patients often present with manifestations of acute kidney injury, including oliguria and decreased GFR Not all patients may manifest oliguria; some will have anuria, while in others, particularly if the injury is milder, the ATI may be nonoliguric During acute kidney injury, the clinical picture is dominated by electrolyte abnormalities, acidosis and the signs and symptoms of uremia and fluid overload Depending upon the severity and nature of the underlying injury and comorbid conditions, the prognosis varies In the absence of careful supportive treatment or dialysis, patients may die When the cause of acute kidney injury is ATI, repair and tubular regeneration lead to gradual clinical improvement With supportive care, patients who not die from the underlying precipitating problem have a good chance of recovering renal function unless kidney disease was present at the time of the acute insult In those with preexisting kidney disease complete recovery is less certain, and progression over time to end-stage renal disease is unfortunately too frequent S U M M A RY Acute Tubular Injury • ATI is the most common cause of acute kidney injury; its clinical manifestations are electrolyte abnormalities, acidosis, uremia, and signs of fluid overload, often with oliguria • ATI results from ischemic or toxic injury to renal tubules, and is associated with intrarenal vasoconstriction resulting in reduced GFR and diminished delivery of oxygen and nutrients to tubular epithelial cells • ATI is characterized morphologically by injury or necrosis of segments of the tubules (typically the proximal tubules), proteinaceous casts in distal tubules, and interstitial edema DISEASES INVOLVING BLOOD VESSELS Nearly all diseases of the kidney involve the renal blood vessels secondarily Systemic vascular diseases, such as various forms of vasculitis, also involve renal blood vessels, Diseases Involving Blood Vessels and often the effects on the kidney are clinically important (Chapter 9) The kidney is intimately involved in the pathogenesis of both essential and secondary hypertension This section covers the renal lesions associated with benign and malignant hypertension Arterionephrosclerosis Arterionephrosclerosis is the term used for the thickening and sclerosis of arterial walls and the renal changes associated with benign hypertension The characteristic morphologic alterations involve small arterioles and are called hyaline arteriolosclerosis Some degree of arterionephrosclerosis, albeit mild, is present at autopsy in many persons older than 60 years of age The frequency and severity of the lesions are increased at any age when hypertension is present PATHOGE NESIS Of note, many renal diseases cause hypertension, which in turn is associated with arterionephrosclerosis Thus, this renal lesion often is superimposed on other primary kidney diseases Similar changes in arteries and arterioles are seen in individuals with chronic thrombotic microangiopathies Whether hypertension causes the arterionephrosclerosis, or a subtle primary microvascular renal injury causes the hypertension, which in turn accelerates the sclerosis, is unknown Recent studies implicate mutation in the apolipoprotein L1 gene (the same gene implicated in increased risk for FSGS) as tightly linked to the high incidence of arterionephrosclerosis observed in African Americans The mechanisms of increased risk of kidney disease are unknown, but this mutation confers protection against trypanosomal disease, so its prevalence may have been influenced by natural selection MORPHOLOGY Grossly, the kidneys are symmetrically atrophic, each weighing 110 to 130 g Typically the renal surface shows diffuse, fine granularity that resembles grain leather Microscopically, the basic anatomic change is hyaline thickening of the walls of the small arteries and arterioles, known as hyaline arteriolosclerosis This appears as a homogeneous, pink hyaline thickening, at the expense of the vessel lumina, with loss of underlying cellular detail (Fig 13–18) The narrowing of the lumen results in markedly decreased blood flow through the affected vessels, with consequent ischemia in the organ served All structures of the kidney show ischemic atrophy In advanced cases of arterionephrosclerosis, the glomerular tufts may become sclerosed Diffuse tubular atrophy and interstitial fibrosis are present Often there is a scant interstitial lymphocytic infiltrate The larger blood vessels (interlobar and arcuate arteries) show reduplication of internal elastic lamina along with fibrous thickening of the media (fibroelastic hyperplasia) and the subintima Clinical Course This renal lesion alone rarely causes severe damage to the kidney except in persons with genetic susceptibility, such as African Americans, in whom it may lead to uremia and Figure 13–18 Benign nephrosclerosis High-power view of two arterioles with hyaline deposition, marked thickening of the walls, and a narrowed lumen (Courtesy of Dr M A Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, Texas.) death However, all patients with this lesion usually show some functional impairment, such as loss of concentrating ability or a variably diminished GFR A mild degree of proteinuria is a frequent finding Malignant Hypertension Malignant hypertension, defined as blood pressure usually greater than 200/120 mm Hg, is far less common in the United States than so-called “benign” hypertension and occurs in only about 5% of persons with elevated blood pressure It may arise de novo (i.e., without preexisting hypertension), or it may appear suddenly in a person who had mild hypertension The prevalence of malignant hypertension is higher in less developed countries PAT H O G E N E S I S The basis for this turn for the worse in hypertensive subjects is unclear, but the following sequence is suggested: The initial event seems to be some form of vascular damage to the kidneys This most commonly results from long-standing hypertension, with eventual injury to the arteriolar walls The result is increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, and platelet deposition This leads to the appearance of fibrinoid necrosis of arterioles and small arteries and intravascular thrombosis Mitogenic factors from platelets (e.g., plateletderived growth factor) and plasma cause intimal hyperplasia of vessels, resulting in the hyperplastic arteriolosclerosis typical of organizing injury of malignant hypertension and of morphologically similar thrombotic microangiopathies (see later) and further narrowing of the lumina The kidneys become markedly ischemic With severe involvement of the renal afferent arterioles, the renin-angiotensin system receives 539 540 C H A P T E R 13 Kidney and Its Collecting System a powerful stimulus This then sets up a self-perpetuating cycle in which angiotensin II causes intrarenal vasoconstriction and the attendant renal ischemia perpetuates renin secretion Aldosterone levels also are elevated, and the resultant salt retention exacerbates the elevation of blood pressure MORPHOLOGY The kidney may be essentially normal in size or slightly shrunken, depending on the duration and severity of the hypertensive disease Small, pinpoint petechial hemorrhages may appear on the cortical surface from rupture of arterioles or glomerular capillaries, giving the kidney a peculiar, flea-bitten appearance The microscopic changes reflect the pathogenetic events described earlier Damage to the small vessels is manifested as fibrinoid necrosis of the arterioles (Fig 13–19, A) The vessel walls show a homogeneous, granular eosinophilic appearance masking underlying detail In the interlobular arteries and larger arterioles, proliferation of intimal cells after acute injury produces an onion-skin appearance (Fig 13–19, B) This name is derived from the concentric arrangement of cells whose origin is believed to be intimal smooth muscle, although this issue has not been finally settled This lesion, called hyperplastic arteriolosclerosis, causes marked narrowing of arterioles and small arteries, to the point of total obliteration Necrosis also may involve glo meruli, with microthrombi within the glomeruli as well as necrotic arterioles Similar lesions are seen in persons with acute thrombotic microangiopathies (described later), and in patients with scleroderma in renal crisis before the eyes At the onset of rapidly mounting blood pressure there is marked proteinuria and microscopic, or sometimes macroscopic, hematuria but no significant alteration in renal function Soon, however, acute kidney injury develops The syndrome represents a true medical emergency that requires prompt and aggressive antihypertensive therapy before irreversible renal lesions develop About 50% of patients survive at least years, and further progress is still being made Ninety percent of deaths are caused by uremia and the other 10% by cerebral hemorrhage or cardiac failure Thrombotic Microangiopathies As described in Chapter 11, the term thrombotic microangiopathy refers to lesions seen in various clinical syndromes characterized morphologically by widespread thrombosis in the microcirculation and clinically by microangiopathic hemolytic anemia, thrombocytopenia, and, in certain instances, renal failure Common causes of thrombotic microangiopathy include • Childhood hemolytic uremic syndrome (HUS) • Various forms of adult HUS • Thrombotic thrombocytopenic purpura (TTP) • Various drugs • Malignant hypertension or scleroderma PAT H O G E N E S I S The major pathogenetic factors in the thrombotic microangiopathies are endothelial activation (the dominant abnormality in HUS) and platelet activation and aggregation (which is dominant in TTP) Both may be caused by a number of external insults and inherited mutations, and together they lead to excessive small vessel thrombosis, the hallmark of these diseases • Childhood HUS is the best-characterized of the renal syndromes associated with thrombotic microangiopathy As many as 75% of cases follow intestinal infection with Shiga toxin–producing E coli, such as occurs in epidemics Clinical Course The full-blown syndrome of malignant hypertension is characterized by papilledema, encephalopathy, cardiovascular abnormalities, and renal failure Most often, the early symptoms are related to increased intracranial pressure and include headache, nausea, vomiting, and visual impairment, particularly the development of scotomas, or “spots” A B Figure 13–19 Malignant hypertension A, Fibrinoid necrosis of afferent arteriole (periodic acid–Schiff stain) B, Hyperplastic arteriolosclerosis (onionskin lesion) (Courtesy of Dr H Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts.) Chronic Kidney Disease caused by ingestion of infected ground meat (e.g., in hamburgers) and infections with Shigella dysenteriae type I The pathogenesis of this syndrome is related to the effects of Shiga toxin, which is carried by neutrophils in the circulation Renal glomerular endothelial cells are targets because the cells express the membrane receptor for the toxin The toxin has multiple effects on the endothelium, including increased adhesion of leukocytes, increased endothelin production, and loss of endothelial nitric oxide (both favoring vasoconstriction), and (in the presence of cytokines, such as tumor necrosis factor) endothelial damage The toxin also gains entry to the cells and directly causes cell death The resultant endothelial damage leads to thrombosis, which is most prominent in glomerular capillaries, afferent arterioles, and interlobular arteries, as well as vasoconstriction, resulting in the characteristic thrombotic microangiopathy Approximately 10% of the cases of HUS in children are not preceded by diarrhea caused by Shiga toxin–producing bacteria In a subset of these patients, mutational inactivation of complement regulatory proteins (e.g., factor H) allows uncontrolled complement activation after minor vascular injuries These conditions promote the formation of thrombi • Adult HUS In typical (epidemic, classic, diarrheapositive) HUS, the trigger for endothelial injury and activation usually is a Shiga-like toxin, while in inherited forms of atypical HUS, the cause of endothelial injury appears to be excessive, inappropriate activation of complement Many other forms of exposures and conditions, including drug toxicities, can occasionally precipitate a HUS-like picture, presumably also by injuring the endothelium • TTP often is caused by an acquired defect in proteolytic cleavage of von Willebrand factor (vWF) multimers due to autoantibodies, or more rarely, an inherited defect as seen in familial TTP (Chapter 11) Pathogenic autoantibodies, whether arising in a context of autoimmunity or drug-induced, typically are directed against ADAMTS 13 (a disintegrin and metalloprotease with thrombospondinlike motifs), a plasma protease that cleaves vWF multimers into smaller sizes Autoantibody binding to ADAMTS 13 results in loss of function and increased levels of large vWF multimers in the circulation, which in turn can activate platelets spontaneously, leading to platelet aggregation and thrombosis Genetic defects in ADAMTS 13 lead to a similar pattern of disease MORPHOLOGY In childhood HUS, there are lesions of classic thrombotic microangiopathy with fibrin thrombi predominantly involving glomeruli, and extending into arterioles and larger arteries in severe cases Cortical necrosis may be present Morphologic changes in glomeruli resulting from endothelial injury include widening of the subendothelial space in glomerular capillaries, duplication or splitting of GBMs, and lysis of mesangial cells with mesangial disintegration Chronically, scarring of glomeruli may develop Clinical Course Typically, childhood HUS is characterized by the sudden onset, usually after a gastrointestinal or flulike prodromal episode, of bleeding manifestations (especially hematemesis and melena), severe oliguria, hematuria, microangiopathic hemolytic anemia, and (in some persons) prominent neurologic changes This disease is one of the main causes of acute kidney injury in children If the acute kidney injury is managed properly with dialysis, most patients recover in a matter of weeks The long-term prognosis (over 15 to 25 years), however, is not uniformly favorable, because in about 25% of these children, renal insufficiency eventually develops as a consequence of the secondary scarring Although HUS and TTP have some overlapping clinical features, such as microangiopathic hemolytic anemia and thrombocytopenia, TTP more often has dominant involvement of the central nervous system and the kidneys are less commonly involved compared to HUS S U M M A RY Vascular Diseases of the Kidney • Arterionephrosclerosis: Progressive, chronic renal damage associated with hypertension Characteristic features are hyaline arteriolosclerosis and narrowing of vascular lumina with resultant cortical atrophy • Malignant hypertension: Acute kidney injury associated with severe elevation of blood pressure Arteries and arterioles show fibrinoid necrosis and hyperplasia of smooth muscle cells; petechial hemorrhages on the cortical surface • Thrombotic microangiopathies: Disorders characterized by fibrin thrombi in glomeruli and small vessels resulting in acute kidney injury Childhood HUS is usually caused by endothelial injury by an E coli toxin; TTP is often caused by defects in von Willebrand factor leading to excessive thrombosis, with platelet consumption CHRONIC KIDNEY DISEASE Chronic kidney disease is the result of progressive scarring resulting from any type of kidney disease Alterations in the function of remaining initially intact nephrons are ultimately maladaptive and cause further scarring This eventually results in an end-stage kidney where glomeruli, tubules, interstitium and vessels are sclerosed, regardless of the primary site of injury Unless the disorder is treated with dialysis or transplantation, death from uremia results M O R P H O LO G Y Classically, the kidneys are symmetrically contracted, and their surfaces are red-brown and diffusely granular when the underlying disorder affects blood vessels or glo meruli Kidneys damaged by chronic pyelonephritis are typically unevenly involved and have deep scars Microscopically, the feature common to all cases is advanced scarring of the glomeruli, sometimes to the point of complete sclerosis (Fig 13–20) This obliteration of the glomeruli is the end point of many diseases, and it is impossible to ascertain from 541 542 C H A P T E R 13 Kidney and Its Collecting System • They are reasonably common and often present diagnostic problems for clinicians, radiologists, and pathologists • Some forms, such as adult polycystic disease, constitute major causes of chronic renal failure • Simple cysts can occasionally be confused with malignant tumors An emerging theme in the pathophysiology of the hereditary cystic diseases is that the underlying defect is in the cilia– centrosome complex of tubular epithelial cells Such defects may interfere with fluid absorption or cellular maturation, resulting in cyst formation A brief overview of simple cysts, the most common form, is presented next, followed by a more detailed discussion of polycystic kidney disease Figure 13–20 Chronic glomerulonephritis A Masson trichrome preparation shows complete replacement of virtually all glomeruli by bluestaining collagen (Courtesy of Dr M.A Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, Texas.) such kidneys the nature of the initial lesion There is also marked interstitial fibrosis, associated with atrophy and dropout of many of the tubules in the cortex, and diminution and loss of portions of the peritubular capillary network The small and medium-sized arteries frequently are thick-walled, with narrowed lumina, secondary to hypertension Lymphocytic (and, rarely, plasma cell) infiltrates are present in the fibrotic interstitial tissue As damage to all structures progresses, it may become difficult to ascertain whether the primary lesion was glomerular, vascular, tubular, or interstitial Such markedly damaged kidneys have been designated endstage kidneys Clinical Course Chronic kidney disease may sometimes develop insidiously and be discovered only late in its course, after the onset of renal insufficiency Frequently, renal disease is first detected with the discovery of proteinuria, hypertension, or azotemia on routine medical examination Diseasespecific findings may precede development of chronic kidney disease In patients with glomerular disease resulting in nephrotic syndrome, as the glomeruli undergo sclerotic changes, the avenue for protein loss is progressively closed, and the nephrotic syndrome thus becomes less severe with more advanced disease Some degree of proteinuria, however, is present in almost all cases Hypertension is very common, and its effects may dominate the clinical picture Although microscopic hematuria is usually present, grossly bloody urine is infrequent at this late stage Without treatment, the prognosis is poor; relentless progression to uremia and death is the rule The rate of progression is extremely variable CYSTIC DISEASES OF THE KIDNEY Cystic diseases of the kidney are a heterogeneous group comprising hereditary, developmental, and acquired disorders These diseases are important for several reasons: Simple Cysts Simple cysts are generally innocuous lesions that occur as multiple or single cystic spaces of variable size Commonly, they are to 5 cm in diameter; translucent; lined by a gray, glistening, smooth membrane; and filled with clear fluid On microscopic examination, these membranes are seen to be composed of a single layer of cuboidal or flattened cuboidal epithelium, which in many instances may be completely atrophic The cysts usually are confined to the cortex Rarely, massive cysts as large as 10 cm in diameter are encountered Simple cysts constitute a common postmortem finding that has no clinical significance The main importance of cysts lies in their differentiation from kidney tumors, when they are discovered either incidentally or during evaluation of hemorrhage and pain Radiographic studies show that in contrast with renal tumors, renal cysts have smooth contours, are almost always avascular, and produce fluid rather than solid tissue signals on ultrasonography Dialysis-associated acquired cysts occur in the kidneys of patients with end-stage kidney disease who have undergone prolonged dialysis They are present in both the cortex and the medulla and may bleed, causing hematuria Occasionally, renal adenomas or even papillary adenocarcinomas arise in the walls of these cysts Autosomal Dominant (Adult) Polycystic Kidney Disease Adult polycystic kidney disease is characterized by multiple expanding cysts affecting both kidneys that ultimately destroy the intervening parenchyma It is seen in approximately in 500 to 1000 persons and accounts for 10% of cases of chronic kidney disease This disease is genetically heterogeneous It can be caused by inheritance of one of at least two autosomal dominant genes of very high penetrance In 85% to 90% of families, PKD1, on the short arm of chromosome 16, is the defective gene This gene encodes a large (460-kDa) and complex cell membrane– associated protein, called polycystin-1 PAT H O G E N E S I S The polycystin molecule is mainly extracellular and has regions of homology with proteins involved in cell–cell or Cystic Diseases of the Kidney cell–matrix adhesion (e.g., domains that bind collagen, laminin, and fibronectin) It also has several other domains including those that can bind receptor tyrosine phosphatases The polycystins have been localized to the primary cilium of tubular cells, like the nephrocystins linked to medullary cystic disease that are discussed later on, giving rise to the concept of renal cystic diseases as a type of ciliopathy Cilia are hairlike organelles that project into the lumina from the apical surface of tubular cells, where they serve as mechanosensors of fluid flow Current evidence suggests that polycystin mutations produce defects in mechanosensing This in turn alters downstream signaling events involving calcium influx, leading to dysregulation of cell polarity, proliferation, and cell-cell and cell-matrix adhesion It is interesting to note that whereas germline mutations of the PKD1 gene are present in all renal tubular cells of affected persons, cysts develop in only some tubules This is most likely due to loss of both alleles of PKD1 Thus, as with tumor suppressor genes, a second “somatic hit” is required for expression of the disease The PKD2 gene, implicated in 10% to 15% of cases, resides on chromosome and encodes polycystin 2, a smaller, 110-kD protein Polycystin is thought to function as a calcium-permeable membrane channel, and is also expressed in cilia Although structurally distinct, polycystins and are believed to act together by forming heterodimers Thus, mutation in either gene gives rise to essentially the same phenotype, although patients with PKD2 mutations have a slower rate of disease progression as compared with patients with PKD1 mutations MORPHOLOGY In autosomal dominant adult polycystic kidney disease, the kidney may reach enormous size, and weights of up to 4 kg for each kidney have been recorded These very large kidneys are readily palpable abdominally as masses A extending into the pelvis On gross examination the kidney seems to be composed solely of a mass of cysts of various sizes up to or 4 cm in diameter with no intervening parenchyma The cysts are filled with fluid, which may be clear, turbid, or hemorrhagic (Fig 13–21) Cysts may arise at any level of the nephron, from tubules to collecting ducts, and therefore they have a variable, often atrophic, lining Occasionally, Bowman’s capsules are involved in the cyst formation, and in these cases glomerular tufts may be seen within the cystic space The pressure of the expanding cysts leads to ischemic atrophy of the intervening renal substance Some normal parenchyma may be dispersed among the cysts Evidence of superimposed hypertension or infection is common Asymptomatic liver cysts occur in one third of the patients Clinical Course Polycystic kidney disease in adults usually does not produce symptoms until the fourth decade of life, by which time the kidneys are quite large, although small cysts start to develop in adolescence The most common presenting complaint is flank pain or a heavy, dragging sensation Acute distention of a cyst, either by intracystic hemorrhage or by obstruction, may cause excruciating pain Sometimes attention is first drawn to the lesion on palpation of an abdominal mass Intermittent gross hematuria commonly occurs The most important complications, because of their deleterious effect on already marginal renal function, are hypertension and urinary infection Hypertension of variable severity develops in about 75% of persons with this disorder Saccular aneurysms of the circle of Willis (Chapter 22) are present in 10% to 30% of patients and are associated with a high incidence of subarachnoid hemorrhage Although the disease is ultimately fatal, the outlook is generally better than with most chronic kidney diseases The condition tends to be relatively stable and progresses B Figure 13–21 Autosomal dominant adult polycystic kidney, viewed from the external surface (A) and bisected (B) The kidney is markedly enlarged (centimeter rule is shown for scale), with numerous dilated cysts 543 544 C H A P T E R 13 Kidney and Its Collecting System very slowly End-stage kidney disease occurs at about age 50, but there is wide variation in the course of this disorder, and nearly normal life spans are reported Patients in whom the disease progresses to renal failure are treated by renal transplantation Death usually results from uremia or hypertensive complications Autosomal Recessive (Childhood) Polycystic Kidney Disease The childhood form of polycystic kidney disease is a rare autosomal recessive disorder that is genetically distinct from adult polycystic kidney disease It occurs in approximately in 20,000 live births Perinatal, neonatal, infantile, and juvenile subcategories have been defined, depending on age at presentation and the presence of associated hepatic lesions All types result from mutations in the PKHD1 gene, coding for a putative membrane receptor protein called fibrocystin, localized to the short arm of chromosome (6p) Fibrocystin is found in cilia in tubular epithelial cells, but its function remains unknown abnormalities, including retinitis pigmentosa, and even early-onset blindness in the most severe form Other abnormalities found in some persons include oculomotor apraxia, mental retardation, cerebellar malformations, and liver fibrosis In aggregate, the various forms of nephronophthisis are now thought to be the most common genetic cause of end-stage renal disease in children and young adults At least nine gene loci (NHP1-NHP9) have been identified for the autosomal recessive forms of the nephron ophthisis complex The majority of these genes encode proteins that are components of epithelial cilia, as is the case with other types of polycystic disease Two autosomal forms cause disease in adults; these are far less common M O R P H O LO G Y Pathologic features of medullary cystic disease include small contracted kidneys Numerous small cysts lined by flattened or cuboidal epithelium are present, typically at the corticomedullary junction Other pathologic changes are nonspecific, but most notably they include a chronic tubulointerstitial nephritis with tubular atrophy and thickened tubular basement membranes and progressive interstitial fibrosis MORPHOLOGY In autosomal recessive polycystic kidney disease, numerous small cysts in the cortex and medulla give the kidney a spongelike appearance Dilated, elongated channels at right angles to the cortical surface completely replace the medulla and cortex The cysts have a uniform lining of cuboidal cells, reflecting their origin from the collecting tubules The disease is invariably bilateral In almost all cases, findings include multiple epithelium-lined cysts in the liver and proliferation of portal bile ducts Clinical Course Perinatal and neonatal forms are most common; serious manifestations usually are present at birth, and young infants may die quickly from hepatic or renal failure Patients who survive infancy develop liver cirrhosis (congenital hepatic fibrosis) Medullary Diseases with Cysts There are two major types of cystic disease affecting the medulla: medullary sponge kidney, a relatively common and usually innocuous condition, occasionally associated with nephrolithiasis, which will not be discussed further, and nephronophthisis-medullary cystic disease complex, which is almost always associated with renal dysfunction Nephronophthisis–medullary cystic disease complex is an under-appreciated cause of chronic kidney disease that usually begins in childhood Four variants of this disease complex are recognized on the basis of the timing of onset: infantile, juvenile, and adolescent nephronophthisis and medullary cystic disease developing later in adult life The juvenile form is the most common Approximately 15% to 20% of children with juvenile nephronophthisis have extrarenal manifestations, which most often appear as retinal Clinical Course The initial manifestations are usually polyuria and polydipsia, a consequence of diminished tubular function Progression to end-stage kidney disease ensues over a 5- to 10-year period The disease is difficult to diagnose, since there are no serologic markers and the cysts may be too small to be seen with radiologic imaging Adding to this difficulty, cysts may not be apparent on renal biopsy if the corticomedullary junction is not well sampled A positive family history and unexplained chronic renal failure in young patients should lead to suspicion of nephronophthisis S U M M A RY Cystic Diseases • Adult polycystic kidney disease is a disease of autosomal dominant inheritance caused by mutations in the genes encoding polycystin-1 or -2 It accounts for about 10% of cases of chronic renal failure; kidneys may be very large and contain many cysts • Autosomal recessive (childhood) polycystic kidney disease is caused by mutations in the gene encoding fibrocystin It is less common than the adult form and strongly associated with liver abnormalities; kidneys contain numerous small cysts • Nephronophthisis–medullary cystic disease complex is being increasingly recognized as a cause of chronic kidney disease in children and young adults Of autosomal recessive inheritance, it is associated with mutations in several genes that encode epithelial cell proteins called nephrocystins that may be involved in ciliary function; kidneys are contracted and contain multiple small cysts Urinary Outflow Obstruction URINARY OUTFLOW OBSTRUCTION Renal Stones Urolithiasis is calculus formation at any level in the urinary collecting system, but most often the calculi arise in the kidney They occur frequently, and it is estimated that by the age of 70 years, 11% of men and 5.6% of women in the United States will have experienced a symptomatic kidney stone Symptomatic urolithiasis is more common in men than in women A familial tendency toward stone formation has long been recognized PATHOGE NESIS There are three major types of stones • About 80% of renal stones are composed of either calcium oxalate or calcium oxalate mixed with calcium phosphate • Ten percent are composed of magnesium ammonium phosphate • Six percent to 9% are either uric acid or cystine stones In all cases, an organic matrix of mucoprotein is present that makes up about 2.5% of the stone by weight (Table 13–3) The cause of stone formation is often obscure, particularly in the case of calcium-containing stones Probably involved is a confluence of predisposing conditions, including the concentration of the solute, changes in urine pH, and bacterial infections The most important cause is increased urinary concentration of the stone’s constituents, so that it exceeds their solubility in urine (supersaturation) As shown in Table 13–3, 50% of patients who develop calcium stones have hypercalciuria that is not associated with hypercalcemia Most in this group absorb calcium from the gut in excessive amounts (absorptive hypercalciuria) and promptly excrete it in the urine, and some have a primary renal defect of calcium reabsorption (renal hypercalciuria) The causes of the other types of renal stones are better understood Magnesium ammonium phosphate (struvite) stones almost always occur in persons with a M O R P H O LO G Y Stones are unilateral in about 80% of patients Common sites of formation are renal pelves and calyces and the bladder Often, many stones are found in one kidney They tend to be small (average diameter, to 3 mm) and may be smooth or jagged Occasionally, progressive accretion of salts leads to the development of branching structures known as staghorn calculi, which create a cast of the renal pelvis and calyceal system These massive stones usually are composed of magnesium ammonium phosphate Clinical Course Table 13–3 Prevalence of Various Types of Renal Stones Stone persistently alkaline urine resulting from UTIs In particular, infections with urea-splitting bacteria, such as Proteus vulgaris and staphylococci, predispose individuals to urolithiasis Moreover, bacteria may serve as particulate nidi for the formation of any kind of stone In avitaminosis A, desquamated cells from the metaplastic epithelium of the collecting system act as nidi Gout and diseases involving rapid cell turnover, such as the leukemias, lead to high uric acid levels in the urine and the possibility of uric acid stones About half of people with uric acid stones, however, have neither hyperuricemia nor increased urine urate but demonstrate an unexplained tendency to excrete a persistently acid urine (with a pH less than 5.5) This low pH favors uric acid stone formation—in contrast with the high pH that favors formation of stones containing calcium phosphate Cystine stones are almost invariably associated with a genetically determined defect in the renal transport of certain amino acids, including cystine Like uric acid stones, cystine stones are more likely to form when the urine is relatively acidic Urolithiasis also may result from the lack of substances that normally inhibit mineral precipitation Inhibitors of crystal formation in urine include Tamm-Horsfall protein, osteopontin, pyrophosphate, mucopolysaccharides, diphosphonates, and a glycoprotein called nephrocalcin, but no deficiency of any of these substances has been consistently demonstrated in persons with urolithiasis Distribution (%) Calcium oxalate and/or calcium phosphate Idiopathic hypercalciuria (50%) Hypercalcemia and hypercalciuria (10%) Hyperoxaluria (5%) Enteric (4.5%) Primary (0.5%) Hyperuricosuria (20%) No known metabolic abnormality (15% to 20%) 80 Struvite (Mg, NH3, PO4) Renal infection 10 Uric acid Associated with hyperuricemia Associated with hyperuricosuria Idiopathic (50% of uric acid stones) 6–7 Cystine 1–2 Others or unknown ±1–2 Stones may be present without producing either symptoms or significant renal damage This is particularly true with large stones lodged in the renal pelvis Smaller stones may pass into the ureter, where they may lodge, producing a typical intense pain known as renal or ureteral colic, characterized by paroxysms of flank pain radiating toward the groin Often at this time there is gross hematuria The clinical significance of stones lies in their capacity to obstruct urine flow or to produce sufficient trauma to cause ulceration and bleeding In either case, they predispose the sufferer to bacterial infection Fortunately, in most cases the diagnosis is readily made radiologically Hydronephrosis Hydronephrosis refers to dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma, caused by obstruction to the outflow of urine The 545 546 C H A P T E R 13 Kidney and Its Collecting System obstruction may be sudden or insidious, and it may occur at any level of the urinary tract, from the urethra to the renal pelvis The most common causes are categorized as follows: • Congenital: atresia of the urethra, valve formations in either ureter or urethra, aberrant renal artery compressing the ureter, renal ptosis with torsion, or kinking of the ureter • Acquired Foreign bodies: calculi, sloughed necrotic papillae Proliferative lesions: benign prostatic hyperplasia, carcinoma of the prostate, bladder tumors (papilloma and carcinoma), contiguous malignant disease (retroperitoneal lymphoma, carcinoma of the cervix or uterus) Inflammation: prostatitis, ureteritis, urethritis, retroperitoneal fibrosis Neurogenic: spinal cord damage with paralysis of the bladder Normal pregnancy: mild and reversible Bilateral hydronephrosis occurs only when the obstruction is below the level of the ureters If blockage is at the ureters or above, the lesion is unilateral Sometimes obstruction is complete, allowing no urine to pass; usually it is only partial PATHOGENESIS Even with complete obstruction, glomerular filtration persists for some time, and the filtrate subsequently diffuses back into the renal interstitium and perirenal spaces, whence it ultimately returns to the lymphatic and venous systems Because of the continued filtration, the affected calyces and pelvis become dilated, often markedly so The unusually high pressure thus generated in the renal pelvis, as well as that transmitted back through the collecting ducts, causes compression of the renal vasculature Both arterial insufficiency and venous stasis result, although the latter probably is more important The most severe effects are seen in the papillae, because they are subjected to the greatest increases in pressure Accordingly, the initial functional disturbances are largely tubular, manifested primarily by impaired concentrating ability Only later does glomerular filtration begin to diminish Experimental studies indicate that serious irreversible damage occurs in about weeks with complete obstruction, and in months with incomplete obstruction In addition to functional changes, the obstruction also triggers an interstitial inflammatory reaction, leading eventually to interstitial fibrosis MORPHOLOGY Bilateral hydronephrosis (as well as unilateral hydronephrosis when the other kidney is already damaged or absent) leads to renal failure, and the onset of uremia tends to abort the natural course of the lesion By contrast, unilateral involvement is associated with the full range of morphologic changes, which vary with the degree and speed of obstruction With Figure 13–22 Hydronephrosis of the kidney, with marked dilation of the pelvis and calyces and thinning of renal parenchyma subtotal or intermittent obstruction, the kidney may be massively enlarged (lengths in the range of 20 cm), and the organ may consist almost entirely of the greatly distended pelvicalyceal system The renal parenchyma itself is compressed and atrophied, with obliteration of the papillae and flattening of the pyramids (Fig 13–22) On the other hand, when obstruction is sudden and complete, glomerular filtration is compromised relatively early, and as a consequence, renal function may cease while dilation is still comparatively slight Depending on the level of the obstruction, one or both ureters may be dilated (hydroureter) On microscopic examination the early lesions show tubular dilation, followed by atrophy and fibrous replacement of the tubular epithelium with relative sparing of the glomeruli Eventually, in severe cases the glomeruli also become atrophic and disappear, converting the entire kidney into a thin shell of fibrous tissue With sudden and complete obstruction, there may be coagulative necrosis of the renal papillae, similar to the changes of papillary necrosis In uncomplicated cases the accompanying inflammatory reaction is minimal Superimposed pyelonephritis, however, is common Clinical Course Bilateral complete obstruction produces anuria, which is soon brought to medical attention When the obstruction is below the bladder, the dominant symptoms are those of bladder distention Paradoxically, incomplete bilateral obstruction causes polyuria rather than oliguria, as a result of defects in tubular concentrating mechanisms, and this may obscure the true nature of the disturbance Unfortunately, unilateral hydronephrosis may remain completely silent for long periods unless the other kidney is for some reason not functioning Often the enlarged kidney is discovered on routine physical examination Sometimes the basic cause of the hydronephrosis, such as renal calculi or an obstructing tumor, produces symptoms that indirectly draw attention to the hydronephrosis Removal of Tumors obstruction within a few weeks usually permits full return of function; however, with time the changes become irreversible TUMORS Many types of benign and malignant tumors occur in the urinary tract In general, benign tumors such as small (less than 0.5 cm in diameter) cortical papillary adenomas, which are found in 40% of adults, have no clinical significance The most common malignant tumor of the kidney is renal cell carcinoma, followed in frequency by nephroblastoma (Wilms tumor) and by primary tumors of the calyces and pelvis Other types of renal cancer are rare and need not be discussed here Tumors of the lower urinary tract are about twice as common as renal cell carcinomas They are described at the end of this section Tumors of the Kidney Oncocytoma Oncocytoma, a benign tumor that arises from the intercalated cells of collecting ducts, represents about 10% of renal tumors These tumors are associated with genetic changes— loss of chromosomes 1, 14, and Y—that distinguish them from other renal neoplasms Oncocytomas are histologically characterized by a plethora of mitochondria, providing the basis for their tan color and their finely granular eosinophilic cytoplasm that is seen histologically A central stellate scar, which is another feature of oncocytomas, provides a characteristic appearance on imaging studies Owing to their large size and clinical and radiologic similarity to some renal cell carcinomas, however, they are removed by nephrectomy, both to prevent such complications as spontaneous hemorrhage and to make a definitive diagnosis Renal Cell Carcinoma Renal cell carcinomas are derived from the renal tubular epithelium and hence they are located predominantly in the cortex These tumors represent 80% to 85% of all primary malignant tumors of the kidney and 2% to 3% of all cancers in adults These data translate into about 58,000 cases per year in the United States; 40% of patients die of the disease Carcinomas of the kidney are most common from the sixth to seventh decades, and men are affected about twice as commonly as women The risk of developing these tumors is higher in smokers, hypertensive or obese patients, and those who have had occupational exposure to cadmium The risk of developing renal cell cancer is increased 30-fold in persons who acquire polycystic disease as a complication of chronic dialysis The role of genetic factors in the causation of these cancers is discussed later on Renal cell cancers are classified on the basis of morphology and growth patterns However, recent advances in the understanding of the genetic basis of renal carcinomas have led to a new classification that takes into account the molecular origins of these tumors The three most common forms, discussed next, are clear cell carcinoma, papillary renal cell carcinoma, and chromophobe renal carcinoma Clear Cell Carcinomas Clear cell carcinomas are the most common type, accounting for 65% of renal cell cancers Histologically, they are composed of cells with clear cytoplasm Although most are sporadic, they also occur in familial forms or in association with von Hippel-Lindau (VHL) disease It is the study of VHL disease that has provided molecular insights into the causation of clear cell carcinomas VHL disease is inherited as an autosomal dominant trait and is characterized by predisposition to a variety of neoplasms, but particularly to hemangioblastomas of the cerebellum and retina Hundreds of bilateral renal cysts and bilateral, often multiple, clear cell carcinomas develop in 40% to 60% of affected persons Those with VHL syndrome inherit a germline mutation of the VHL gene on chromosomal band 3p25 and lose the second allele by somatic mutation Thus, the loss of both copies of this tumor suppressor gene is a key step in the development of clear cell carcinoma The VHL gene is also involved in the majority of sporadic clear cell carcinomas Cytogenetic abnormalities giving rise to loss of chromosomal segment 3p14 to 3p26 are often seen in sporadic renal cell cancers This region harbors the VHL gene (3p25.3) The second, nondeleted allele is inactivated by a somatic mutation or hypermethylation in 60% of sporadic cases Thus, homozygous loss of the VHL gene seems to be the common underlying molecular abnormality in both sporadic and familial forms of clear cell carcinomas The VHL protein causes the degradation of hypoxia-induced factors (HIFs), and in the absence of VHL, HIFs are stabilized HIFs are transcription factors that contribute to carcinogenesis by stimulating the expression of vascular endothelial growth factor (VEGF), an important angiogenic factor, as well as a number of other genes that drive tumor cell growth (Chapter 5) An uncommon familial form of clear cell carcinoma unrelated to VHL disease also is associated with cytogenetic abnormalities involving the short arm of chromosome (3p) In addition, recent deep sequencing of clear cell carcinoma genomes has revealed frequent loss-of-function mutations in SETD2, JARID1C, and UTX, all of which encode proteins that regulate histone methylation, suggesting that changes in the “epigenome” have a central role in the genesis of this subtype of renal carcinoma Papillary Renal Cell Carcinomas Papillary renal cell carcinomas account for 10% to 15% of all renal cancers As the name indicates, they show a papillary growth pattern These tumors are frequently multifocal and bilateral and appear as early-stage tumors Like clear cell carcinomas, they occur in familial and sporadic forms, but unlike these tumors, papillary renal cancers are not associated with abnormalities of chromosome The culprit in most cases of hereditary papillary renal cell cancers is the MET proto-oncogene, located on chromosomal sub-band 7q31 The MET gene is a tyrosine kinase receptor for the growth factor called hepatocyte growth factor The increased dosage of the MET gene due to duplications of chromosome seems to spur abnormal growth in the proximal tubular epithelial cell precursors of papillary carcinomas In familial cases, genetic analysis shows activating mutations of MET in the germline, along with increased gene dosage in the cancers Activating mutations of the MET gene also are found in a subset of 547 548 C H A P T E R 13 Kidney and Its Collecting System patients with sporadic forms of papillary renal cell carcinoma Chromophobe Renal Carcinomas Chromophobe renal carcinomas are the least common, representing 5% of all renal cell carcinomas They arise from intercalated cells of collecting ducts Their name derives from the observation that the tumor cells stain more darkly (i.e., they are less clear) than cells in clear cell carcinomas These tumors are unique in having multiple losses of entire chromosomes, including chromosomes 1, 2, 6, 10, 13, 17, and 21 Thus, they show extreme hypodiploidy Because of multiple losses, the “critical hit” has not been determined In general, chromophobe renal cancers have a good prognosis MORPHOLOGY Clear cell cancers (the most common form of these renal carcinomas) usually are solitary and large when symptomatic (spherical masses to 15 cm in diameter), but high-resolution radiographic techniques for investigation of unrelated problems sometimes detect smaller lesions incidentally They may arise anywhere in the cortex The cut surface of clear cell renal cell carcinomas is yellow to orange to gray-white, with prominent areas of cystic softening or of hemorrhage, either fresh or old (Fig 13–23) The margins of the tumor are well defined However, at times small processes project into the surrounding parenchyma and small satellite nodules are found, providing clear evidence of the aggressiveness of these lesions As the tumor enlarges, it may fungate through the walls of the collecting system, extending through the calyces and pelvis as far as the ureter Even more frequently, the tumor invades the renal vein and grows as a solid column within this vessel, sometimes extending in Figure 13–24 High-power detail of the clear cell pattern of renal cell carcinoma serpentine fashion as far as the inferior vena cava and even into the right side of the heart Occasionally, direct invasion into the perinephric fat and adrenal gland may be seen Depending on the amounts of lipid and glycogen present, the tumor cells of clear cell renal cell carcinoma may appear almost vacuolated or may be solid The classic vacuolated (lipid-laden), or clear cells are demarcated only by their cell membranes The nuclei are usually small and round (Fig 13–24) At the other extreme are granular cells, resembling the tubular epithelium, which have small, round, regular nuclei enclosed within granular pink cytoplasm Some tumors are highly anaplastic, with numerous mitotic figures and markedly enlarged, hyperchromatic, pleomorphic nuclei Between the extremes of clear cells and solid, granular cells, all intergradations may be found The cellular arrangement, too, varies widely The cells may form abortive tubules or may cluster in cords or disorganized masses The stroma is usually scant but highly vascularized Papillary renal cell carcinomas exhibit various degrees of papilla formation with fibrovascular cores They tend to be bilateral and multiple They also may show gross evidence of necrosis, hemorrhage, and cystic degeneration, but they are less vibrantly orange-yellow because of their lower lipid content The cells may have clear or, more commonly, pink cytoplasm Chromophobe-type renal cell carcinoma tends to be grossly tan-brown The cells usually have clear, flocculent cytoplasm with very prominent, distinct cell membranes The nuclei are surrounded by halos of clear cytoplasm Ultrastructurally, large numbers of characteristic macrovesicles are seen Clinical Course Figure 13–23 Renal cell carcinoma: Representative cross-section showing yellowish, spherical neoplasm in one pole of the kidney Note the tumor in the dilated, thrombosed renal vein Renal cell carcinomas have several peculiar clinical characteristics that create especially difficult and challenging diagnostic problems The signs and symptoms vary, but the most frequent presenting manifestation is hematuria, occurring in more than 50% of cases Macroscopic hematuria tends to be intermittent and fleeting, superimposed on a steady microscopic hematuria Less commonly the tumor may declare itself simply by virtue of its size, when it has grown large enough to produce flank pain and a palpable mass Because of the widespread use of imaging studies for Tumors unrelated conditions, even smaller tumors are detected Extra-renal effects are fever and polycythemia, which, because they are nonspecific, may be misinterpreted for some time before their association with the renal tumor is appreciated Polycythemia affects 5% to 10% of persons with this disease It results from elaboration of erythropoietin by the cancer cells Uncommonly, these tumors produce other hormone-like substances, resulting in hypercalcemia, hypertension, Cushing syndrome, or feminization or masculinization These, as noted in Chapter 5, are paraneoplastic syndromes In many patients, the primary tumor remains silent and is discovered only after its metastases have produced symptoms The prevalent locations for metastases are the lungs and the bones It must be apparent that renal cell carcinoma manifests in many ways, some quite devious, but the triad of painless hematuria, a palpable abdominal mass, and dull flank pain is characteristic SUMMARY Renal Cell Carcinoma Renal cell carcinomas account for 2% to 3% of all cancers in adults and are classified into three types: • Clear cell carcinomas are the most common and are associated with homozygous loss of the VHL tumor suppressor protein; tumors frequently invade the renal vein • Papillary renal cell carcinomas frequently are associated with increased expression and activating mutations of the MET oncogene; they tend to be bilateral and multiple and show variable papilla formation • Chromophobe renal cell carcinomas are less common; tumor cells are not as clear as in the other renal cell carcinomas Wilms Tumor Although Wilms tumor occurs infrequently in adults, it is the third most common organ cancer in children younger than 10 years of age These tumors contain a variety of cell and tissue components, all derived from the mesoderm Wilms tumor, like retinoblastoma, may arise sporadically or be familial, with the susceptibility to tumorigenesis inherited as an autosomal dominant trait This tumor is discussed in greater detail in Chapter along with other tumors of childhood Tumors and other lesions of the lower urinary tract (ureters, bladder, and urethra) are described in Chapter 17 BIBLIOGRAPHY Barratt J, Feehally J: IgA nephropathy J Am Soc Nephrol 16:2088, 2005 [A comprehensive update on the pathogenesis, clinical manifestations, and treatment of this disease.] Beck LH Jr, Bonegio RG, Lambeau G, et al: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy N Engl J Med 361:11, 2009 [A landmark study describing the discovery of the antigen in idiopathic membranous nephropathy.] D’Agati VD: The spectrum of focal segmental glomerulosclerosis: new insights Curr Opin Nephrol Hypertens 17:271, 2008 [A comprehensive review of mechanisms contributing to various forms of FSGS.] Genovese G, Friedman DJ, Ross MD, et al: Association of trypanolytic ApoL1 variants with kidney disease in African Americans Science 329:841, 2010 [A landmark study of natural selection, linking a genetic variant of 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bladder cancer: Jekyll and Hyde or chalk and cheese Carcinogenesis 27:371, 2006 [Comprehensive review of molecular changes in different types of bladder cancer.] Lionaki S, Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic (ANCA) and anti-glomerular basement membrane (GBM) autoantibodies in necrotizing and crescentic glomerulonephritis Semin Immunopathol 29:459, 2007 [A good summary of mechanisms of injury and clinical manifestations in ANCA and anti-GBM antibody–mediated disease.] Mathieson PW: Minimal change nephropathy and focal segmental glomerulosclerosis Semin Immunopathol 29:415, 2007 [An excellent overview of new insights into the pathogenesis and diagnosis of MCD versus FSGS.] Miller O, Hemphill RR: Urinary tract infection and pyelonephritis Emerg Med Clin North Am 19:655, 2001 [An excellent review of acute urinary tract infections.] Murray PT, Devarajan P, Levey AS, et al: A framework and key research questions in AKI diagnosis and staging in different environments Clin J Am Soc Nephrol 3:864, 2008 [An excellent review outlining recent advances in early diagnosis and consequences of acute kidney injury.] Nsar SH, Markowitz GS, Stokes MB, et al: Acute postinfectious glomerulonephritis in modern era: experience with 86 adults and review of the literature Medicine 87:21, 2008 [A contemporary review of postinfectious glomerulonephritis with an emphasis on clinicopathologic correlations and epidemiologic associations.] Ronco P, Debiec H: Membranous glomerulopathy: the evolving story Curr Opin Nephrol Hypertens 19:254, 2010 [An excellent review of recent insights into the etiology of membranous nephropathy.] Schrier RW, Wang W, Poole B, et al: Acute renal failure: definitions, diagnosis, pathogenesis, and therapy J Clin Invest 114:5, 2004 [An insightful review covering all aspects of acute renal failure.] Tryggvason K, Patrakka J, Wartiovaava J: Hereditary proteinuria syndromes and mechanisms of proteinuria N Engl J Med 354:1387, 2006 [An excellent review of the pathophysiology of defects in glomerular permeability.] Tsai HM: The molecular biology of thrombotic microangiopathy Kidney Int 70:16, 2006 [An excellent review of the pathogenesis of HUS and TTP.] Wilson PD, Goilav B: Cystic disease of the kidney Annu Rev Pathol 2:341, 2007 [Pathobiology of a common condition affecting the kidney.] Worcester EM, Coe FL: Calcium kidney stones N Engl J Med 363:954, 2010 [A comprehensive review of the pathophysiology and management of the most common types of kidney stones.] 549 This page intentionally left blank ... ROBBINS BASIC PATHOLOGY 978 -1- 4377 -17 81- 5 International Edition: 978-0-8089-2432-6 Copyright © 2 013 , 2007, 2003, 19 97, 19 92, 19 87, 19 81, 19 76, 19 71 by Saunders, an imprint of Elsevier Inc No part of... Vinay, 19 44– II. Abbas, Abul K. III. Aster, Jon C. IV. Robbins, Stanley L (Stanley Leonard), 19 15–2003. V. Title: Basic pathology [DNLM: 1. Pathology QZ 4] 616 .07–dc23 2 011 048699... online.help@elsevier.com call 800-4 01- 9962 (inside the US) / call +1- 314 -995-3200 (outside the US) Robbins Basic Pathology This page intentionally left blank Basic Pathology ROBBINS NINTH EDITION Vinay