Kidney and Its Collecting System Chapter 13 PDF

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See Targeted Therapy available online at studentconsult.com C H A P T E R Kidney and Its Collecting System 13 C H A P T E R CO N T E N T S Clinical Manifestations of Renal Acute Tubular Injury 537 Autosomal Recessive (Childhood) Polycystic Diseases 517 Diseases Involving Blood Kidney Disease 544 Glomerular Diseases 518 Vessels 538 Medullary Diseases with Cysts 544 Mechanisms of Glomerular Injury and Arterionephrosclerosis 539 Urinary Outflow Obstruction 545 Disease 519 Malignant Hypertension 539 Renal Stones 545 The Nephrotic Syndrome 523 Thrombotic Microangiopathies 540 Hydronephrosis 545 The Nephritic Syndrome 529 Chronic Kidney Disease 541 Tumors 547 Rapidly Progressive Glomerulonephritis 531 Cystic Diseases of the Kidney 542 Tumors of the Kidney 547 Diseases Affecting Tubules and Simple Cysts 542 Interstitium 533 Autosomal Dominant (Adult) Polycystic Tubulointerstitial Nephritis 533 Kidney Disease 542 The kidney is a structurally complex organ that has evolved CLINICAL MANIFESTATIONS to carry out a number of important functions: excretion of the waste products of metabolism, regulation of body OF RENAL DISEASES water and salt, maintenance of acid balance, and secretion of a variety of hormones and prostaglandins. Diseases of The clinical manifestations of renal disease can be grouped the kidney are as complex as its structure, but their study into reasonably well-defined syndromes. Some are peculiar is facilitated by dividing them into those that affect its four to glomerular diseases and others are shared by several components: glomeruli, tubules, interstitium, and blood renal disorders. Before we list the syndromes, a few terms vessels. This traditional approach is useful because the must be defined. early manifestations of diseases that affect each of these Azotemia is an elevation of blood urea nitrogen and cre- components tend to be distinctive. Furthermore, some atinine levels and usually reflects a decreased glomerular structures seem to be more vulnerable to specific forms of filtration rate (GFR). GFR may be decreased as a conse- renal injury; for example, glomerular diseases are often quence of intrinsic renal disease or extrarenal causes. Prer- immunologically mediated, whereas tubular and intersti- enal azotemia is encountered when there is hypoperfusion tial disorders are more likely to be caused by toxic or infec- of the kidneys, which decreases GFR in the absence of paren- tious agents. However, some disorders affect more than chymal damage. Postrenal azotemia results when urine flow one structure, and functional interdependence of struc- is obstructed below the level of the kidney. Relief of the tures in the kidney means that damage to one component obstruction is followed by correction of the azotemia. almost always secondarily affects the others. Thus, severe When azotemia gives rise to clinical manifestations and glomerular damage impairs the flow through the peritubu- systemic biochemical abnormalities, it is termed uremia. lar vascular system; conversely, tubular destruction, by Uremia is characterized not only by failure of renal excre- increasing intraglomerular pressure and inducing cyto- tory function but also by a host of metabolic and endocrine kines and chemokines, may induce glomerular sclerosis. alterations incident to renal damage. There is, in addition, Whatever the origin, there is a tendency for chronic renal secondary gastrointestinal (e.g., uremic gastroenteritis); disease ultimately to damage all four components of the neuromuscular (e.g., peripheral neuropathy); and cardio- kidney, culminating in end-stage kidney disease. For these vascular (e.g., uremic fibrinous pericarditis) involvement. reasons, the early signs and symptoms of renal disease are We now turn to a brief description of the major renal particularly important in discerning the initiating cause of syndromes: the disease, and therefore are referred to in the discussion Nephritic syndrome results from glomerular injury and is of individual diseases. The functional reserve of the kidney dominated by the acute onset of usually grossly visible is large, and much damage may occur before renal dys- hematuria (red blood cells and red cell casts in urine), function becomes evident. proteinuria of mild to moderate degree, azotemia, 518 C H A P T E R 13 Kidney and Its Collecting System edema, and hypertension; it is the classic presentation of Podocytes, which are structurally complex cells that acute poststreptococcal glomerulonephritis. possess interdigitating processes embedded in and Nephrotic syndrome is a glomerular syndrome character- adherent to the lamina rara externa of the basement ized by heavy proteinuria (excretion of greater than membrane. Adjacent foot processes are separated by 20- to 3.5 g of protein/day in adults), hypoalbuminemia, 30-nm-wide filtration slits, which are bridged by a thin severe edema, hyperlipidemia, and lipiduria (lipid in slit diaphragm composed in large part of nephrin (see the urine). further on). Asymptomatic hematuria or non-nephrotic proteinuria, or The glomerular tuft is supported by mesangial cells a combination of these two, is usually a manifestation of lying between the capillaries. Basement membrane–like subtle or mild glomerular abnormalities. mesangial matrix forms a meshwork through which Rapidly progressive glomerulonephritis is associated with the mesangial cells are scattered. These cells, of mesen- severe glomerular injury and results in loss of renal chymal origin, are contractile and are capable of pro­ function in a few days or weeks. It is manifested by liferation, of laying down collagen and other matrix microscopic hematuria, dysmorphic red blood cells and components, and of secreting a number of biologically red cell casts in the urine sediment, and mild to moder- active mediators. ate proteinuria. Normally, the glomerular filtration system is extraordi- Acute kidney injury is dominated by oliguria or anuria narily permeable to water and small solutes and almost (no urine flow), and recent onset of azotemia. It can completely impermeable to molecules of the size and result from glomerular injury (such as rapidly proges- molecular charge of albumin (a 70,000-kDa protein). This sive glomerulonephritis), interstitial injury, vascular selective permeability, called glomerular barrier function, injury (such as thrombotic microangiopathy), or acute discriminates among protein molecules according to their tubular injury. size (the larger, the less permeable), their charge (the more Chronic kidney disease, characterized by prolonged symp- cationic, the more permeable), and their configuration. The toms and signs of uremia, is the result of progressive characteristics of the normal barrier depend on the complex scarring in the kidney from any cause and may culmi- structure of the capillary wall, the integrity of the GBM, nate in end-stage kidney disease, requiring dialysis or and the many anionic molecules present within the wall, transplantation. including the acidic proteoglycans of the GBM and the Urinary tract infection is characterized by bacteriuria sialoglycoproteins of epithelial and endothelial cell coats. and pyuria (bacteria and leukocytes in the urine). The The podocyte is also crucial to the maintenance of glomerular infection may be symptomatic or asymptomatic, and it barrier function. Podocyte slit diaphragms are important may affect the kidney (pyelonephritis) or the bladder diffusion barriers for plasma proteins, and podocytes (cystitis) only. are also largely responsible for synthesis of GBM Nephrolithiasis (renal stones) is manifested by renal colic, components. hematuria (without red cell casts), and recurrent stone In the past few years, much has been learned about the formation. molecular architecture of the glomerular filtration barrier. In addition to these renal syndromes, urinary tract obstruc- Nephrin, a transmembrane glycoprotein, is the major com- tion and renal tumors also commonly present with signs and ponent of the slit diaphragms between adjacent foot pro- symptoms related to renal dysfunction and are discussed cesses. Nephrin molecules from adjacent foot processes later. bind to each other through disulfide bridges at the center of the slit diaphragm. The intracellular part of nephrin interacts with several cytoskeletal and signaling proteins (Fig. 13–1). Nephrin and its associated proteins, including GLOMERULAR DISEASES podocin, have a crucial role in maintaining the selective permeability of the glomerular filtration barrier. This role Disorders affecting the glomerulus encompass a clinically is dramatically illustrated by rare hereditary diseases in important category of renal disease. The glomerulus con- which mutations of nephrin or its partner proteins are asso- sists of an anastomosing network of capillaries invested by ciated with abnormal leakage into the urine of plasma pro- two layers of epithelium. The visceral epithelium (com- teins, giving rise to the nephrotic syndrome (discussed posed of podocytes) is an intrinsic part of the capillary later). This observation suggests that acquired defects in wall, whereas the parietal epithelium lines Bowman space the function or structure of slit diaphragms constitute an (urinary space), the cavity in which plasma ultrafiltrate important mechanism of proteinuria, the hallmark of the first collects. The glomerular capillary wall is the filtration nephrotic syndrome. unit and consists of the following structures (Figs. 13–1 Glomeruli may be injured by diverse mechanisms and 13–2): and in the course of a number of systemic diseases (Table A thin layer of fenestrated endothelial cells, each fenestra 13–1). Immunologically mediated diseases such as sys- being 70 to 100 nm in diameter. temic lupus erythematosus, vascular disorders such as A glomerular basement membrane (GBM) with a thick, hypertension and hemolytic uremic syndrome, metabolic electron-dense central layer, the lamina densa, and diseases such as diabetes mellitus, and some purely heredi- thinner, electron-lucent peripheral layers, the lamina rara tary conditions such as Alport syndrome often affect the interna and lamina rara externa. The GBM consists of col- glomerulus. These are termed secondary glomerular diseases lagen (mostly type IV), laminin, polyanionic proteogly- to differentiate them from those in which the kidney is the cans, fibronectin, and several other glycoproteins. only or predominant organ involved. The latter constitute  Glomerular Diseases 519 GLOMERULUS Capillary Urinary space loops Mesangium Mesangial cell Mesangial matrix Red cell Parietal epithelium Fenestrae in Proximal endothelium tubule Urinary space Capillary lumen Parietal epithelium Basement membrane Visceral epithelium Foot (podocytes) processes Basement Endothelium membrane Endothelium BLOOD Basement membrane Red cell Foot processes Complex of signaling and cytoskeletal proteins Podocyte foot process URINE Nephrin molecules from adjacent foot processes forming slit diaphragm Figure 13–1 Schematic diagram of a lobe of a normal glomerulus. the various types of primary glomerular diseases, which are experimental conditions, glomerulonephritis (GN) can be discussed later in this section. The glomerular alterations readily induced by antibodies, and deposits of immuno- in systemic diseases are discussed elsewhere. globulins, often with various components of complement, are found frequently in patients with GN. Cell-mediated immune mechanisms may also play a role in certain glo- Mechanisms of Glomerular Injury and Disease merular diseases. Two forms of antibody-associated injury have been Although little is known about the etiologic agents or established: (1) injury resulting from deposition of soluble triggering events, it is clear that immune mechanisms circulating antigen-antibody complexes in the glomerulus underlie most types of primary glomerular diseases and (2) injury by antibodies reacting in situ within and many of the secondary glomerular diseases. Under the glomerulus, either with insoluble fixed (intrinsic) 520 C H A P T E R 13 Kidney and Its Collecting System of glomerular origin. It may be endogenous, as in the GN associated with systemic lupus erythematosus, or it may be exogenous, as is probable in the GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic (Plas- modium falciparum malaria), and spirochetal (Treponema pal- lidum) infections. Often the inciting antigen is unknown, as in most cases of membranoproliferative GN (MPGN). Whatever the antigen may be, antigen–antibody complexes are formed in situ or in the circulation and are then trapped in the glomeruli, where they produce injury, in large part through the activation of complement and the recruitment of leukocytes. Injury also may occur through the engagement of Fc receptors on leukocytes independent of complement activation, as cross-linking of Fc receptors by IgG antibod- ies also results in leukocyte activation and degranulation. Regardless of the mechanism, the glomerular lesions usually consist of leukocytic infiltration (exudation) into Figure 13–2 Low-power electron micrograph of rat glomerulus. B, basement membrane; CL, capillary lumen; End, endothelium; Ep, visceral glomeruli and variable proliferation of endothelial, mesan- epithelial cells (podocytes) with foot processes; Mes, mesangium; US, gial, and parietal epithelial cells. Electron microscopy urinary space. reveals the immune complexes as electron-dense deposits or clumps that lie at one of three sites: in the mesangium, between the endothelial cells and the GBM (subendothelial glomerular antigens or with molecules planted within the deposits), or between the outer surface of the GBM and the glomerulus (Fig. 13–3). In addition, antibodies directed podocytes (subepithelial deposits). Deposits may be located against glomerular cell components may cause glomerular at more than one site in a given case. The presence of injury. These pathways are not mutually exclusive, and in immunoglobulins and complement in these deposits can humans all may contribute to injury. be demonstrated by immunofluorescence microscopy (Fig. 13–4, A). The pattern and location of immune complex deposition Glomerulonephritis Caused by Circulating are helpful in distinguishing among various types of GN. Once deposited in the kidney, immune complexes may Immune Complexes eventually be degraded or phagocytosed, mostly by infil- The pathogenesis of immune complex diseases is discussed trating leukocytes and mesangial cells, and the inflamma- in detail in Chapter 4. Presented here is a brief review of tory changes may then subside. Such a course occurs when the salient features that relate to glomerular injury in GN. the exposure to the inciting antigen is short-lived and With circulating immune complex–mediated disease, limited, as in most cases of poststreptococcal or acute the glomerulus may be considered an “innocent bystander” infection-related GN. However, if exposure to antigen is because it does not incite the reaction. The antigen is not sustained over time, repeated cycles of immune complex formation, deposition, and injury may occur, leading to chronic GN. In some cases the source of chronic antigenic Table 13–1 Glomerular Diseases exposure is clear, such as in hepatitis B virus infection and Primary Glomerular Diseases self nuclear antigens in systemic lupus erythematosus. In Minimal-change disease other cases, however, the antigen is unknown. Circulating Focal segmental glomerulosclerosis immune complex deposition as a mechanism of injury is Membranous nephropathy well studied in animal models but is uncommonly identi- Acute postinfectious GN fied in human disease. Membranoproliferative GN IgA nephropathy Glomerulopathies Secondary to Systemic Diseases Glomerulonephritis Caused by In Situ Immune Complexes Lupus nephritis (systemic lupus erythematosus) Antibody deposition in the glomerulus is a major pathway Diabetic nephropathy of glomerular injury. As noted, antibodies in this form of Amyloidosis injury react directly with fixed or planted antigens in the GN secondary to multiple myeloma glomerulus. Immune reactions in situ, trapping of circulat- Goodpasture syndrome ing complexes, interactions between these two events, and Microscopic polyangiitis local hemodynamic and structural determinants in the Wegener granulomatosis glomerulus all contribute to the morphologic and func- Henoch-Schönlein purpura Bacterial endocarditis–related GN tional alterations in GN. Antibodies also may react in Thrombotic microangiopathy situ with previously “planted” nonglomerular antigens, which may localize in the kidney by interacting with Hereditary Disorders various intrinsic components of the glomerulus. Planted Alport syndrome antigens include nucleosomal complexes (in patients Fabry disease with systemic lupus erythematosus); bacterial products, Podocyte/slit-diaphragm protein mutations such as endostroptosin, a protein expressed by group A GN, glomerulonephritis; IgA, immunoglobulin A. streptococci; large aggregated proteins (e.g., aggregated  Glomerular Diseases 521 CIRCULATING IN SITU IMMUNE COMPLEX DEPOSITION ANTI-GBM ANTIBODY ANTIBODY AGAINST GLOMERULAR ANTIGEN Epithelial cell Foot processes Endothelium (MEMBRANOUS NEPHROPATHY) Subepithelial deposit Basement membrane Endothelium Circulating complex Subendothelial deposit A Antibody Antigen B Antibody Antigen C Figure 13–3 Antibody-mediated glomerular injury. Injury can result either from the deposition of circulating immune complexes or from formation of complexes in situ. A, Deposition of circulating immune complexes gives a granular immunofluorescence pattern. B, Anti-glomerular basement membrane (anti-GBM) antibody glomerulonephritis is characterized by a linear immunofluorescence pattern. C, Antibodies against some glomerular components deposit in a granular pattern. immunoglobulin G [IgG]), which tend to deposit in the proliferation of glomerular resident cells. By contrast, anti- mesangium; and immune complexes themselves, because bodies directed to the subepithelial region of glomerular they contain reactive sites for further interactions with capillaries are largely noninflammatory and elicit lesions free antibody, free antigen, or complement. Most of these similar to those of Heymann nephritis or membranous planted antigens induce a granular pattern of immuno- nephropathy (discussed later). globulin deposition as seen by immunofluorescence microscopy. The following factors affect glomerular localization of Anti-Glomerular Basement Membrane Antibody–Mediated antigen, antibody, or immune complexes: the molecular Glomerulonephritis charge and size of the reactants; glomerular hemodynam- The best-characterized disease in this group is classic anti- ics; mesangial function; and the integrity of the charge- GBM antibody–mediated crescentic GN (Fig. 13–3, B). In selective glomerular barrier. The localization of antigen, this type of injury, antibodies are directed against fixed antibody, or immune complexes in turn determines the antigens in the GBM. It has its experimental counterpart in glomerular injury response. Studies in experimental models the nephritis of rodents called nephrotoxic serum nephritis. have shown that complexes deposited in the endothelium This is produced by injecting rats with anti-GBM antibod- or subendothelium elicit an inflammatory reaction in the ies produced by immunization of rabbits or other species glomerulus with infiltration of leukocytes and exuberant with rat kidney. Antibody–mediated GN in humans results 522 C H A P T E R 13 Kidney and Its Collecting System A B Figure 13–4 Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy. A, Granular, characteristic of circulating and in situ immune complex deposition. B, Linear, characteristic of classic anti-glomerular basement membrane (anti-GBM) antibody glomerulonephritis. (A, Courtesy of Dr. J. Kowalewska, Department of Pathology, University of Washington, Seattle, Washington.) from the formation of autoantibodies directed against the GBM. Deposition of these antibodies creates a linear pattern of Mediators of Immune Injury staining when the bound antibodies are visualized with Once immune reactants are localized in the glomerulus, immunofluorescence microscopy, in contrast with the how does glomerular damage ensue? A major pathway of granular pattern described for other forms of immune antibody-initiated injury involves complement activation complex–mediated nephritis (Fig. 13–4, B). This distinction and recruitment of leukocytes (Fig. 13–5). Activation of is useful in the diagnosis of glomerular disease. A confor- complement via the classical pathway leads to the genera- mational change in the α3 chain of the type IV collagen of tion of chemotactic agents (mainly C5a) for neutrophils the GBM appears to be key in inciting autoimmunity. and monocytes. Neutrophils release proteases, which cause Sometimes the anti-GBM antibodies cross-react with base- GBM degradation; oxygen-derived free radicals, which ment membranes of lung alveoli, resulting in simultaneous cause cell damage; and arachidonic acid metabolites, which lung and kidney lesions (Goodpasture syndrome). Although contribute to reduction in GFR. This mechanism applies anti-GBM antibody–mediated GN accounts for less than only to some types of GN, however, because many types 1% of human GN cases, the resulting disease can be very show few neutrophils in the damaged glomeruli. In these serious. Many instances of anti-GBM antibody–mediated cases neutrophil-independent but complement-dependent crescentic GN are characterized by very severe glomerular injury may occur, possibly caused by the C5b-C9 mem- damage with necrosis and crescents and the development brane attack complex, which is formed on the GBM and of the clinical syndrome of rapidly progressive GN (see may induce sublytic epithelial cell injury and stimulate below). the secretion of various inflammatory mediators from NORMAL PODOCYTE FOOT PROCESS EFFACEMENT AND DETACHMENT Filtration slit Podocyte Effacement foot processes Antibody Complement Adhesion proteins Cytokine Protein molecule Endothelium Toxin Basement membrane Figure 13–5 Podocyte injury. The postulated sequence may be initiated by antibodies to podocyte antigens, toxins, cytokines, or other factors. The common features are podocyte injury leading to foot process effacement and variable degrees of podocyte detachment, and degradation of the base- ment membrane. These defects permit plasma proteins to be lost into the urinary space.  Glomerular Diseases 523 mesangial and epithelial cells. The alternative and mannose- Nephron Loss binding lectin pathways of complement can be activated Once renal disease, glomerular or otherwise, destroys by cell injury or apoptosis, also leading to glomerular sufficient nephrons to reduce the GFR to 30% to 50% of injury (Fig. 13–5). normal, progression to end-stage kidney disease proceeds Antibodies against glomerular cell antigens also inexorably at varying rates. Affected persons have protein- may directly damage glomerular cells or slit diaphragms. uria, and their kidneys show widespread glomerulosclerosis. Such antibodies are suspected of being involved in certain Such progressive sclerosis may be initiated, at least in part, disorders in which immune complexes are not found. by the adaptive changes that occur in the remaining glom- Other mediators of glomerular damage include the eruli not destroyed by the initial disease. These remaining following: glomeruli undergo hypertrophy to maintain renal func- Monocytes and macrophages, which infiltrate the glomeru- tion. This hypertrophy is associated with hemodynamic lus in antibody- and cell-mediated reactions and, when changes, including increases in single-nephron GFR, blood activated, release diverse mediators flow, and transcapillary pressure (capillary hypertension). Sensitized T cells, formed during the course of a cell- These alterations ultimately become “maladaptive” and mediated immune reaction, can cause experimental lead to further endothelial and podocyte injury, increased glomerular injury. In some forms of experimental GN, glomerular permeability to proteins, and accumulation of the disease can be induced by transfer of sensitized T proteins and lipids in the mesangial matrix. This is fol- cells. T cell–mediated injury may account for the lowed by capillary obliteration, increased deposition of instances of GN in which either there are no deposits of mesangial matrix and plasma proteins, and ultimately by antibodies or immune complexes or the deposits do not segmental (affecting a portion) or global (complete) sclero- correlate with the severity of damage. However, it has sis of glomeruli. The latter results in further reductions been difficult to establish a causal role for T cells or cell- in nephron mass and a vicious circle of progressive mediated immune responses in human GN. glomerulosclerosis. Platelets, which aggregate in the glomerulus during immune-mediated injury and release prostaglandins and growth factors S U M M A RY Resident glomerular cells (epithelial, mesangial, and endothelial), which can be stimulated to secrete Glomerular Injury mediators such as cytokines (interleukin-1), arachidonic Antibody-mediated immune injury is an important mecha- acid metabolites, growth factors, nitric oxide, and nism of glomerular damage, mainly by way of complement- endothelin and leukocyte-mediated pathways. Antibodies also may Thrombin, produced as a consequence of intraglomerular be directly cytotoxic to cells in the glomerulus. thrombosis, which causes leukocyte infiltration and glo- The most common forms of antibody-mediated GN are merular cell proliferation by triggering protease-acti- caused by the formation of immune complexes, whether vated receptors (PARs) occurring in situ or by deposition of circulating immune In essence, virtually all of the mediators described in the complexes. These immune complexes may contain exog- discussion of inflammation in Chapter 2 may contribute to enous (e.g. microbial) circulating antigens or endogenous glomerular injury. antigens (e.g. in membranous nephropathy). Immune com- plexes show a granular pattern of deposition. Other Mechanisms of Glomerular Injury Autoantibodies against components of the GBM are the cause of anti-GBM-antibody–mediated disease, often Other mechanisms contribute to glomerular damage in associated with severe injury. The pattern of antibody certain primary renal disorders. Two that deserve special deposition is linear. mention due to their importance are podocyte injury and Immune complexes and antibodies cause injury by com- nephron loss. plement activation and leukocyte recruitment, with release of various mediators, and sometimes by direct podocyte Podocyte Injury damage. Podocyte injury can be induced by antibodies to podocyte antigens; by toxins, as in an experimental model of protein- uria induced by the ribosome poison puromycin; conceiv- ably by certain cytokines; or by still poorly characterized We now turn to a consideration of specific types of GN circulating factors, as in some cases of focal segmental glo- and the glomerular syndromes they produce. merulosclerosis (see later). Podocyte injury is reflected by morphologic changes, which include effacement of foot processes, vacuolization, and retraction and detachment of The Nephrotic Syndrome cells from the GBM, and clinically by proteinuria. In most forms of glomerular injury, loss of normal slit diaphragms The nephrotic syndrome refers to a clinical complex that is key in the development of proteinuria (Fig. 13–5). Func- includes tional abnormalities of the slit diaphragm also may result Massive proteinuria, with daily protein loss in the urine from mutations in its structural components, such as of 3.5 g or more in adults nephrin and the associated podocin. Such mutations cause Hypoalbuminemia, with plasma albumin levels less than rare hereditary forms of the nephrotic syndrome. 3 g/dL 524 C H A P T E R 13 Kidney and Its Collecting System Generalized edema, the most obvious clinical mani­­ The relative frequencies of the several causes of the festation nephrotic syndrome vary according to age (Table 13–2). In Hyperlipidemia and lipiduria. children 1 to 7 years of age, for example, the nephrotic The nephrotic syndrome has diverse causes that share a syndrome is almost always caused by a lesion primary to common pathophysiology (Table 13–2). In all there is a the kidney, whereas among adults it often is due to renal derangement in the capillary walls of the glomeruli that manifestations of a systemic disease. The most frequent results in increased permeability to plasma proteins. Any systemic causes of the nephrotic syndrome in adults are increased permeability resulting from either structural diabetes, amyloidosis, and systemic lupus erythematosus. or physicochemical alterations in the GBM allows protein The renal lesions produced by these disorders are described to escape from the plasma into the glomerular filtrate. in Chapter 4. The most important of the primary glomeru- With long-standing or extremely heavy proteinuria, serum lar lesions that characteristically lead to the nephrotic syn- albumin is decreased, resulting in hypoalbuminemia and a drome are focal and segmental glomerulosclerosis and drop in plasma colloid osmotic pressure. As discussed in minimal-change disease. The latter is more important in Chapter 3, the resulting decrease in intravascular volume children; the former, in adults. Two other primary lesions, and renal blood flow triggers increased release of renin membranous nephropathy and membranoproliferative from renal juxtaglomerular cells. Renin in turn stimulates glomerulonephritis, also commonly produce the nephrotic the angiotensin-aldosterone axis, which promotes the syndrome. These four lesions are discussed individually retention of salt and water by the kidney. This tendency is next. exacerbated by reductions in the cardiac secretion of natri- uretic factors. In the face of continuing proteinuria, these Minimal-Change Disease alterations further aggravate the edema and if unchecked Minimal-change disease, a relatively benign disorder, is the may lead to the development of generalized edema (termed most frequent cause of the nephrotic syndrome in children. anasarca). At the onset, there is little or no azotemia, hema- Characteristically, the glomeruli have a normal appearance by turia, or hypertension. light microscopy but show diffuse effacement of podocyte foot The genesis of the hyperlipidemia is more obscure. Pre- processes when viewed with the electron microscope. Although sumably, hypoalbuminemia triggers increased synthesis of it may develop at any age, this condition is most common lipoproteins in the liver or massive proteinuria causes loss between the ages of 1 and 7 years. of an inhibitor of their synthesis. There is also abnormal The pathogenesis of proteinuria in minimal-change transport of circulating lipid particles and impairment of disease remains to be elucidated. On the basis of some peripheral breakdown of lipoproteins. The lipiduria, in experimental studies, the proteinuria has been attributed turn, reflects the increased permeability of the GBM to to a circulating, possibly T cell–derived, factor that causes lipoproteins. podocyte damage and effacement of foot processes. Neither the nature of such a putative factor nor a causal role of T cells, however, is established in the human disease. Table 13–2 Causes of Nephrotic Syndrome M O R P H O LO G Y Cause Prevalence (%)* Under the light microscope, the glomeruli appear normal, Children Adults thus giving rise to the name “minimal-change disease” (Fig. Primary Glomerular Disease 13–6, A). The cells of the proximal convoluted tubules often Membranous nephropathy 5 30 are heavily laden with protein droplets and lipids, but this Minimal-change disease 65 10 feature is secondary to tubular reabsorption of the lipopro- Focal segmental glomerulosclerosis 10 35 teins passing through the diseased glomeruli. Even under the electron microscope, the GBM appears normal. The only Membranoproliferative glomerulonephritis 10 10 obvious glomerular abnormality is the uniform and diffuse IgA nephropathy and others 10 15 effacement of the foot processes of the podocytes Systemic Diseases with Renal Manifestations (Fig. 13–6, B). The cytoplasm of the podocytes thus appears Diabetes mellitus flattened over the external aspect of the GBM, obliterating Amyloidosis the network of arcades between the podocytes and the Systemic lupus erythematosus GBM. There are also epithelial cell vacuolization, microvillus formation, and occasional focal detachments, suggesting Ingestion of drugs (gold, penicillamine, “street heroin”) some form of podocyte injury. With reversal of the changes in the podocytes (e.g., in response to corticosteroids), the Infections (malaria, syphilis, hepatitis B, HIV infection) proteinuria remits. Malignancy (carcinoma, melanoma) Miscellaneous (bee sting allergy, hereditary nephritis) Clinical Course *Approximate prevalence of primary disease is 95% of the cases in children, The disease manifests with the insidious development of 60% in adults. Approximate prevalence of systemic disease is 5% of the the nephrotic syndrome in an otherwise healthy child. cases in children, 40% in adults. There is no hypertension, and renal function is preserved HIV, human immunodeficiency virus. in most of these patients. The protein loss usually is  Glomerular Diseases 525 nephrotic syndrome. FSGS may be primary (idiopathic) or secondary to one of the following conditions: In association with other conditions, such as HIV infection (HIV nephropathy) or heroin abuse (heroin nephropathy) As a secondary event in other forms of GN (e.g., IgA nephropathy) As a maladaptation to nephron loss (as described earlier) In inherited or congenital forms. Autosomal dominant forms are associated with mutations in cytoskeletal pro- teins and podocin, both of which are required for the integrity of podocytes. In addition, a sequence variant in the apolipoprotein L1 gene (APOL1) on chromosome A 22 appears to be strongly associated with an increased risk of FSGS and renal failure in individuals of African descent. Podocyte with effaced foot processes Primary FSGS accounts for approximately 20% to 30% of all cases of the nephrotic syndrome. It is an increasingly common cause of nephrotic syndrome in adults and remains a frequent cause in children. PAT H O G E N E S I S The pathogenesis of primary FSGS is unknown. Some inves- tigators have suggested that FSGS and minimal-change disease Normal are part of a continuum and that minimal-change disease basement may transform into FSGS. Others believe them to be membrane distinct clinicopathologic entities from the outset. In any case, injury to the podocytes is thought to represent the B initiating event of primary FSGS. As with minimal- change disease, permeability-increasing factors produced by Figure 13–6 Minimal-change disease. A, Under the light microscope lymphocytes have been proposed. The deposition of hyaline the silver methenamine–stained glomerulus appears normal, with a deli- masses in the glomeruli represents the entrapment of plasma cate basement membrane. B, Schematic diagram illustrating diffuse proteins and lipids in foci of injury where sclerosis develops. effacement of foot processes of podocytes with no immune deposits. IgM and complement proteins commonly seen in the lesion are also believed to result from nonspecific entrapment in damaged glomeruli. The recurrence of proteinuria and sub- sequent FSGS in a renal transplant in some patients who had confined to the smaller plasma proteins, chiefly albumin FSGS, sometimes within 24 hours of transplantation, sup- (selective proteinuria). The prognosis for children with this ports the idea that a circulating mediator is the cause of the disorder is good. More than 90% of children respond to a podocyte damage in some cases. short course of corticosteroid therapy; however, proteinuria recurs in more than two thirds of the initial responders, some of whom become steroid-dependent. Less than 5% develop chronic kidney disease after 25 years, and it is likely that most persons in this subgroup had nephrotic M O R P H O LO G Y syndrome caused by focal and segmental glomerulosclero- sis not detected by biopsy. Because of its responsiveness In FSGS, the disease first affects only some of the glomeruli to therapy in children, minimal-change disease must be (hence the term focal) and, in the case of primary FSGS, differentiated from other causes of the nephrotic syndrome initially only the juxtamedullary glomeruli. With progression, in nonresponders. Adults with this disease also respond to eventually all levels of the cortex are affected. On histologic steroid therapy, but the response is slower and relapses are examination, FSGS is characterized by lesions occurring in more common. some tufts within a glomerulus and sparing of the others (hence the term segmental). Thus, the involvement is Focal Segmental Glomerulosclerosis both focal and segmental (Fig. 13–7). The affected glomeruli Focal segmental glomerulosclerosis (FSGS) is character- exhibit increased mesangial matrix, obliterated ized histologically by sclerosis affecting some but not capillary lumina, and deposition of hyaline masses all glomeruli (focal involvement) and involving only (hyalinosis) and lipid droplets. In affected glomeruli, segments of each affected glomerulus (segmental involve- immunofluorescence microscopy often reveals nonspecific ment). This histologic picture often is associated with the trapping of immunoglobulins, usually IgM, and complement 526 C H A P T E R 13 Kidney and Its Collecting System expressed by podocytes. In the remainder (secondary membranous nephropathy), it occurs secondary to other disorders, including Infections (chronic hepatitis B, syphilis, schistosomiasis, malaria) Malignant tumors, particularly carcinoma of the lung and colon and melanoma Systemic lupus erythematosus and other autoimmune conditions Exposure to inorganic salts (gold, mercury) Drugs (penicillamine, captopril, nonsteroidal anti- inflammatory agents) Figure 13–7 High-power view of focal and segmental glomerulosclero- PAT H O G E N E S I S sis (periodic acid–Schiff stain), seen as a mass of scarred, obliterated capillary lumens with accumulations of matrix material that has replaced Membranous nephropathy is a form of chronic a portion of the glomerulus. immune complex glomerulonephritis induced by anti- (Courtesy of Dr. H. Rennke, Department of Pathology, Brigham and Women’s Hospital, Boston, bodies reacting in situ to endogenous or planted glomerular Massachusetts.) antigens. An endogenous podocyte antigen, the phospholi- pase A2 receptor, is the antigen that is most often recognized by the causative autoantibodies. in the areas of hyalinosis. On electron microscopy, the podo- The experimental model of membranous nephropathy is cytes exhibit effacement of foot processes, as in minimal- Heymann nephritis, which is induced in animals by immuniza- change disease. tion with renal tubular brush border proteins that also are In time, progression of the disease leads to global sclerosis present on podocytes. The antibodies that are produced of the glomeruli with pronounced tubular atrophy and inter- react with an antigen located in the glomerular capillary wall, stitial fibrosis. This advanced picture is difficult to differentiate resulting in granular deposits (in situ immune complex from other forms of chronic glomerular disease, described formation) and proteinuria without severe inflammation. later on. A puzzling aspect of the disease is how antigen-antibody A morphologic variant called collapsing glomerulopa- complexes cause capillary damage despite the absence of thy is being increasingly reported. It is characterized by col- inflammatory cells. The likely answer is by activating comple- lapse of the glomerular tuft and podocyte hyperplasia. This ment, which is uniformly present in the lesions of membra- is a more severe manifestation of FSGS that may be idiopathic nous nephropathy. It is hypothesized that complement or associated with HIV infection, drug-induced toxicities, and activation leads to assembly of the C5b-C9 membrane attack some microvascular injuries. It carries a particularly poor complex, which damages mesangial cells and podocytes prognosis. directly, setting in motion events that cause the loss of slit filter integrity and proteinuria. Clinical Course In children it is important to distinguish FSGS as a cause of the M O R P H O LO G Y nephrotic syndrome from minimal-change disease, because the clinical courses are markedly different. The incidence of Histologically, the main feature in membranous nephropathy hematuria and hypertension is higher in persons with is diffuse thickening of the capillary wall (Fig. 13–8, A). FSGS than in those with minimal-change disease; the FSGS- Electron microscopy reveals that this thickening is caused in associated proteinuria is nonselective; and in general the part by subepithelial deposits, which nestle against the response to corticosteroid therapy is poor. At least 50% of GBM and are separated from each other by small, spikelike patients with FSGS develop end-stage kidney disease protrusions of GBM matrix that form in reaction to the within 10 years of diagnosis. Adults typically fare even less deposits (spike and dome pattern) (Fig. 13–8, B). As the well than children. disease progresses, these spikes close over the deposits, incorporating them into the GBM. In addition, as in other Membranous Nephropathy causes of nephrotic syndrome, the podocytes show efface- ment of foot processes. Later in the disease, the incor- Membranous nephropathy is a slowly progressive disease, porated deposits may be broken down and eventually most common between 30 and 60 years of age. It is char­ disappear, leaving cavities within the GBM. Continued deposi- acterized morphologically by the presence of subepithelial tion of basement membrane matrix leads to progressive immunoglobulin-containing deposits along the GBM. Early in thickening of basement membranes. With further progres- the disease, the glomeruli may appear normal by light sion, the glomeruli can become sclerosed. Immunofluores- microscopy, but well-developed cases show diffuse thicken- cence microscopy shows typical granular deposits ing of the capillary wall. of immunoglobulins and complement along the GBM In about 85% of cases, membranous nephropathy is (Fig. 13–4, A). caused by autoantibodies that cross-react with antigens  Glomerular Diseases 527 Membranoproliferative Glomerulonephritis and Dense Deposit Disease Membranoproliferative GN (MPGN) is manifested histo- logically by alterations in the GBM and mesangium and by proliferation of glomerular cells. It accounts for 5% to 10% of cases of idiopathic nephrotic syndrome in children and adults. Some patients present only with hematuria or proteinuria in the non-nephrotic range; others exhibit a combined nephrotic–nephritic picture. Two major types of MPGN (I and II) have traditionally been recognized on the basis of distinct ultrastructural, immunofluorescence, microscopic, and pathogenic findings, but these are now recognized to be separate entities, termed MPGN type I and dense deposit disease (formerly MPGN type II). Of the two types of disease, MPGN type I is far more common A (about 80% of cases). Podocyte with effaced foot processes PAT H O G E N E S I S Different pathogenic mechanisms are involved in the devel- opment of MPGN and dense deposit disease. Some cases of type I MPGN may be caused by circulating immune complexes, akin to chronic serum sickness, or may be due to a planted antigen with subsequent in situ immune complex formation. In either case, the inciting antigen is not known. Type I MPGN also occurs in association with hepatitis B and C antigenemia, systemic lupus erythematosus, infected atrioventricular shunts, and extrarenal infections with persistent or epi- Thickened basement sodic antigenemia. membrane The pathogenesis of dense deposit disease is less clear. The fundamental abnormality in dense deposit disease appears to be excessive complement acti- vation. Some patients have an autoantibody against C3 Subepithelial convertase, called C3 nephritic factor, which is believed deposits to stabilize the enzyme and lead to uncontrolled cleavage of C3 and activation of the alternative complement "Spikes" pathway. Mutations in the gene encoding the complement B regulatory protein factor H or autoantibodies to factor H have been described in some patients. These abnor- Figure 13–8 Membranous nephropathy. A, Diffuse thickening of the malities result in excessive complement activation. Hypo- glomerular basement membrane (periodic acid–Schiff stain). B, Sche- matic diagram illustrating subepithelial deposits, effacement of foot pro- complementemia, more marked in dense deposit disease, cesses, and the presence of spikes of basement membrane material is produced in part by excessive consumption of C3 and between the immune deposits. in part by reduced synthesis of C3 by the liver. It is still not clear how the complement abnormality induces the glomerular changes. Clinical Course Most cases of membranous nephropathy present as full- blown nephrotic syndrome, usually without antecedent illness; other individuals may have lesser degrees of pro- M O R P H O LO G Y teinuria. In contrast with minimal-change disease, the pro- By light microscopy, type I MPGN and many cases of dense teinuria is nonselective, with urinary loss of globulins as deposit disease are similar. The glomeruli are large, with an well as smaller albumin molecules, and does not usually accentuated lobular appearance, and show prolifera- respond to corticosteroid therapy. Secondary causes of tion of mesangial and endothelial cells as well as infil- membranous nephropathy should be ruled out. Membra- trating leukocytes (Fig. 13–9, A). The GBM is thickened, nous nephropathy follows a notoriously variable and often and the glomerular capillary wall often shows a double indolent course. Overall, although proteinuria persists in contour, or “tram track,” appearance, especially evident with greater than 60% of patients with membranous nephropa- use of silver or periodic acid–Schiff (PAS) stains. This “split- thy, only about 40% suffer progressive disease terminating ting” of the GBM is due to extension of processes of in renal failure after 2 to 20 years. An additional 10% to mesangial and inflammatory cells into the peripheral capillary 30% have a more benign course with partial or complete loops and deposition of mesangial matrix (Fig. 13–9, B). remission of proteinuria. 528 C H A P T E R 13 Kidney and Its Collecting System Type I MPGN Subendothelial deposit Interposed mesangial cell process A Intramembranous deposit Dense Deposit Disease B Figure 13–9 A, Membranoproliferative glomerulonephritis (MPGN), showing mesangial cell proliferation, basement membrane thickening, leukocyte infiltration, and accentuation of lobular architecture. B, Schematic representation of patterns in the two types of MPGN. In type I there are subendo- thelial deposits; in type II, now called dense deposit disease, intramembranous characteristically dense deposits are seen. In both types, mesangial interposition gives the appearance of split basement membranes when viewed by light microscopy. recipients. MPGN type I may occur in association with Type I MPGN is characterized by discrete subendothe- other disorders (secondary MPGN), such as systemic lupus lial electron-dense deposits (Fig. 13–9, B). By immuno- erythematosus, hepatitis B and C, chronic liver disease, and fluorescence microscopy, C3 is deposited in an irregular chronic bacterial infections. Indeed, many so-called idio- granular pattern, and IgG and early complement components pathic cases are believed to be associated with hepatitis C (C1q and C4) often are also present, indicative of an immune and related cryoglobulinemia. complex pathogenesis. By contrast, in the aptly named dense deposit disease the lamina densa and the subendothelial space of the GBM are transformed into an irregular, ribbon-like, extremely S U M M A RY electron-dense structure, resulting from the deposition of material of unknown composition. C3 is present in irregular The Nephrotic Syndrome chunky and segmental linear foci in the basement membranes The nephrotic syndrome is characterized by proteinuria, and in the mesangium. IgG and the early components of the which results in hypoalbuminemia and edema. classical complement pathway (C1q and C4) are usually Podocyte injury is an underlying mechanism of proteinuria, absent. and may be the result of nonimmune causes (as in minimal- change disease and FSGS) or immune mechanisms (as in membranous nephropathy). Minimal-change disease is the most frequent cause of Clinical Course nephrotic syndrome in children; it is manifested by pro- The principal mode of presentation (in approximately 50% teinuria and effacement of glomerular foot processes of cases) is the nephrotic syndrome, although MPGN or without antibody deposits; the pathogenesis is unknown; dense deposit disease may begin as acute nephritis or mild the disease responds well to steroid therapy. proteinuria. The prognosis of MPGN type I generally is FSGS may be primary (podocyte injury by unknown mech- poor. In one study, none of the 60 patients followed for 1 anisms) or secondary (e.g., as a consequence of previous to 20 years showed complete remission. Forty percent pro- glomerulonephritis, hypertension, or infection such as gressed to end-stage renal failure, 30% had variable degrees with HIV); glomeruli show focal and segmental oblitera- of renal insufficiency, and the remaining 30% had persis- tion of capillary lumina, and loss of foot processes; the tent nephrotic syndrome without renal failure. Dense disease often is resistant to therapy and may progress to deposit disease carries an even worse prognosis, and it end-stage renal disease. tends to recur more frequently in renal transplant  Glomerular Diseases 529 Membranous nephropathy is caused by an autoimmune PAT H O G E N E S I S response, most often directed against the phospholipase A2 receptor on podocytes; it is characterized by granular Poststreptococcal GN is an immune complex disease subepithelial deposits of antibodies with GBM thickening in which tissue injury is primarily caused by complement and loss of foot processes but little or no inflammation; activation by the classical pathway. Typical features of immune the disease often is resistant to steroid therapy. complex disease, such as hypocomplementemia and granular deposits of IgG and complement on the GBM, are seen. The MPGN and dense deposit disease are now recognized to relevant antigens probably are streptococcal proteins. Spe- be distinct entities. MPGN is caused by immune complex cific antigens implicated in pathogenesis include streptococcal deposition; dense deposit disease is a consequence exotoxin B (Spe B) and streptococcal GAPDH. Both activate of complement dysregulation. Both may present with the alternative complement pathway and have affinity for nephrotic and/or nephritic features. glomerular proteins and plasmin. It is not clear if immune complexes are formed mainly in the circulation or in situ (the latter by binding of antibodies to bacterial antigens “planted” in the GBM). The Nephritic Syndrome The nephritic syndrome is a clinical complex, usually of acute onset, characterized by (1) hematuria with dysmor- M O R P H O LO G Y phic red cells and red cell casts in the urine; (2) some degree By light microscopy, the most characteristic change in postin- of oliguria and azotemia; and (3) hypertension. fectious GN is increased cellularity of the glomerular tufts Although proteinuria and even edema also may be that affects nearly all glomeruli—hence the term diffuse (Fig. present, these usually are not as severe as in the nephrotic 13–10, A). The increased cellularity is caused both by prolif- syndrome. The lesions that cause the nephritic syndrome eration and swelling of endothelial and mesangial cells and by have in common proliferation of the cells within the glo­ infiltrating neutrophils and monocytes. Sometimes there is meruli, often accompanied by an inflammatory leukocytic necrosis of the capillary walls. In a few cases, “crescents” infiltrate. This inflammatory reaction severely injures the (described later) may be observed within the urinary capillary walls, permitting blood to pass into the urine and space, formed in response to the severe inflammatory injury. inducing hemodynamic changes that lead to a reduction Electron microscopy shows deposited immune complexes in the GFR. The reduced GFR is manifested clinically by arrayed as subendothelial, intramembranous, or, most oliguria, fluid retention, and azotemia. Hypertension often, subepithelial “humps” nestled against the GBM pro­bably is a result of both the fluid retention and some (Fig. 13–10, B). Mesangial deposits also are occasionally augmented renin release from the ischemic kidneys. present. Immunofluorescence studies reveal scattered gran- The acute nephritic syndrome may be produced by sys- ular deposits of IgG and complement within the capil- temic disorders such as systemic lupus erythematosus, or lary walls and some mesangial areas, corresponding to the it may be secondary to primary glomerular disease. The deposits visualized by electron microscopy. These deposits latter is exemplified by acute postinfectious GN. usually are cleared over a period of about 2 months. Acute Postinfectious (Poststreptococcal) Glomerulonephritis Acute postinfectious GN, one of the more frequently occurring Clinical Course glomerular disorders, is caused by glomerular deposition of The onset of the kidney disease tends to be abrupt, her- immune complexes resulting in proliferation of and damage to alded by malaise, a slight fever, nausea, and the nephritic glomerular cells and infiltration of leukocytes, especially neutro- syndrome. In the usual case, oliguria, azotemia, and hyper- phils. The inciting antigen may be exogenous or endoge- tension are only mild to moderate. Characteristically, there nous. The prototypic exogenous pattern is seen in is gross hematuria, the urine appearing smoky brown poststreptococcal GN. Infections by organisms other than rather than bright red. Some degree of proteinuria is a streptococci may also be associated with postinfectious constant feature of the disease, and as mentioned earlier it GN. These include certain pneumococcal and staphylococ- occasionally may be severe enough to produce the nephrotic cal infections as well as several common viral diseases such syndrome. Serum complement levels are low during the as mumps, measles, chickenpox, and hepatitis B and C. active phase of the disease, and serum anti–streptolysin O Endogenous antigens, as occur in systemic lupus erythe- antibody titers are elevated in poststreptococcal cases. matosus, also may cause a proliferative GN but more com- Recovery occurs in most children in epidemic cases. monly result in a membranous nephropathy (see earlier) Some children develop rapidly progressive GN owing to lacking the neutrophil infiltrates that are characteristic of severe injury with formation of crescents, or chronic renal postinfectious GN. disease from secondary scarring. The prognosis in sporadic The classic case of poststreptococcal GN develops in a cases is less clear. In adults, 15% to 50% of affected persons child 1 to 4 weeks after they recover from a group A strep- develop end-stage renal disease over the ensuing few years tococcal infection. Only certain “nephritogenic” strains of or 1 to 2 decades, depending on the clinical and histologic β-hemolytic streptococci evoke glomerular disease. In most severity. By contrast, in children, the prevalence of chronic- cases, the initial infection is localized to the pharynx or ity after sporadic cases of acute postinfectious GN is much skin. lower. 530 C H A P T E R 13 Kidney and Its Collecting System A B Figure 13–10 Poststreptococcal glomerulonephritis. A, Glomerular hypercellularity is caused by intracapillary leukocytes and proliferation of intrinsic glomerular cells. Note the red cell casts in the tubules. B, Typical electron-dense subepithelial “hump” (arrow) and intramembranous deposits. BM, basement membrane; CL, capillary lumen; E, endothelial cell; Ep, visceral epithelial cells (podocytes). IgA Nephropathy abnormal IgA1 may also elicit glycan-specific IgG antibodies. This condition usually affects children and young adults The prominent mesangial deposition of IgA may stem from and begins as an episode of gross hematuria that occurs entrapment of IgA immune complexes, and the absence of within 1 or 2 days of a nonspecific upper respiratory tract C1q and C4 in glomeruli points to activation of the alterna- infection. Typically, the hematuria lasts several days and tive complement pathway. Taken together, these clues then subsides, only to recur every few months. It may be suggest that in genetically susceptible individuals, respiratory associated with local pain. IgA nephropathy is one of the most or gastrointestinal exposure to microbial or other antigens common causes of recurrent microscopic or gross hematuria and (e.g., viruses, bacteria, food proteins) may lead to increased is the most common glomerular disease revealed by renal biopsy IgA synthesis, some of which is abnormally glycosylated, and worldwide. deposition of IgA and IgA-containing immune complexes in The hallmark of the disease is the deposition of IgA in the the mesangium, where they activate the alternative comple- mesangium. Some workers have considered IgA nephropa- ment pathway and initiate glomerular injury. In support of this thy to be a localized variant of Henoch-Schönlein purpura, scenario, IgA nephropathy occurs with increased frequency also characterized by IgA deposition in the mesangium. In in individuals with celiac disease, in whom intestinal mucosal contrast with IgA nephropathy, which is purely a renal defects are seen, and in liver disease, in which there is defec- disorder, Henoch-Schönlein purpura is a systemic syn- tive hepatobiliary clearance of IgA complexes (secondary drome involving the skin (purpuric rash), gastrointestinal IgA nephropathy). tract (abdominal pain), joints (arthritis), and kidneys. M O R P H O LO G Y PATHOGENESIS Histologically, the lesions in IgA nephropathy vary consider- Accumulating evidence suggests that IgA nephropathy is ably. The glomeruli may be normal or may show mesangial associated with an abnormality in IgA production and clear- widening and segmental inflammation confined to some ance, as well as antibodies against abnormally glycosylated glomeruli (focal proliferative GN); diffuse mesangial prolifera- IgA. IgA, the main immunoglobulin in mucosal secretions, is tion (mesangioproliferative GN); or (rarely) overt crescentic increased in 50% of patients with IgA nephropathy owing to GN. The characteristic immunofluorescence picture is of increased production of the IgA1 subtype by plasma cells in mesangial deposition of IgA, often with C3 and proper- the bone marrow. In addition, circulating IgA-containing din and smaller amounts of IgG or IgM (Fig. 13–11). Early immune complexes are present in some cases. A genetic components of the classical complement pathway usually are influence is suggested by the occurrence of this condition in absent. Electron microscopy confirms the presence of families and in HLA–identical siblings, and by the increased electron-dense deposits in the mesangium. The deposits may frequency of certain HLA and complement genotypes in extend to the subendothelial area of adjacent capillary walls some populations. Studies also suggest an abnormality in in a minority of cases, usually those with focal proliferation. glycosylation of the IgA1 immunoglobulin that reduces plasma Biopsy findings may help predict whether progression or clearance and favors deposition in the mesangium. This response to intervention is likely.  Glomerular Diseases 531 fats and mucopolysaccharides (foam cells) as a reaction to marked proteinuria. With progression, increasing glomerulo- sclerosis, vascular sclerosis, tubular atrophy, and interstitial fibrosis are typical changes. Under the electron microscope, the basement membrane of glomeruli is thin and attenuated early in the course. Late in the course, the GBM develops irregular foci of thickening or attenuation with pro- nounced splitting and lamination of the lamina densa, yielding a “basketweave” appearance. Clinical Course The inheritance is heterogeneous, being most commonly X-linked as a result of mutation of the gene encoding α5 type IV collagen. Males therefore tend to be affected more Figure 13–11 IgA nephropathy. Characteristic immunofluorescence frequently and more severely than females and are more deposition of IgA, principally in mesangial regions, is evident. IgA, immu- likely to develop renal failure. Rarely, inheritance is auto- noglobulin A. somal recessive or dominant, linked to defects in the genes that encode α3 or α4 type IV collagen. Persons with heredi- Clinical Course tary nephritis present at age 5 to 20 years with gross or The disease most often affects children and young adults. microscopic hematuria and proteinuria, and overt renal More than half of those with IgA nephropathy present with failure occurs between 20 and 50 years of age. gross hematuria after an infection of the respiratory or, less Female carriers of X-linked Alport syndrome or carriers commonly, gastrointestinal or urinary tract; 30% to 40% of either gender of the autosomal forms usually present have only microscopic hematuria, with or without protein- with persistent hematuria, which most often is asymptom- uria, and 5% to 10% develop a typical acute nephritic syn- atic and is associated with a benign clinical course. In drome. The hematuria typically lasts for several days and these patients, biopsy specimens show only thinning of then subsides, only to return every few months. The sub- the GBM. sequent course is highly variable. Many patients maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 25% to 50% of cases over a S U M M A RY period of 20 years. Renal biopsy findings may help identify The Nephritic Syndrome those with worse prognosis, as indicated by diffuse mesan- gial proliferation, segmental sclerosis, endocapillary prolif- The nephritic syndrome is characterized by hematuria, eration, or tubulointerstitial fibrosis. oliguria with azotemia, proteinuria, and hypertension. The most common cause is immunologically mediated Hereditary Nephritis glomerular injury; lesions are characterized by prolifera- Hereditary nephritis refers to a group of hereditary glo- tive changes and leukocyte infiltration. merular diseases caused by mutations in genes encoding Acute