Renal Failure.

Acute renal failure implies a rapid and frequently reversible deterioration of renal function. It is discussed in the section on “Acute Kidney Injury (Acute Tubular Necrosis),” because it commonly occurs in this disorder. Here, the discussion is limited to chronic renal failure, which is the end result of a variety of renal diseases and the major cause of death from renal disease.

Although exceptions abound, the evolution from normal renal function to symptomatic chronic renal failure broadly progresses through a series of four stages that merge into one another.

The details of the pathophysiology of chronic renal failure are beyond the scope of this book and are well covered in various nephrology texts. Table 20-1 lists the major systemic abnormalities in chronic kidney failure.

TABLE 20-1 Principal Systemic Manifestations of Chronic Kidney Disease and Uremia

Hypercellularity.

Some inflammatory diseases of the glomerulus are characterized by an increase in the number of cells in the glomerular tufts. This hypercellularity is characterized by one or more combinations of the following:

Basement Membrane Thickening.

By light microscopy, this change appears as thickening of the capillary walls, best seen in sections stained with periodic acid–Schiff (PAS). By electron microscopy such thickening takes one of two forms:

Hyalinosis and Sclerosis.

Hyalinosis, as applied to the glomerulus, denotes the accumulation of material that is homogeneous and eosinophilic by light microscopy. By electron microscopy the hyalin is extracellular and amorphous. It is made up of plasma proteins that have insudated from the circulation into glomerular structures. When extensive, this change contributes to obliteration of the capillary lumens of the glomerular tuft. Hyalinosis is usually a consequence of endothelial or capillary wall injury and typically the end result of various forms of glomerular damage. It is a common feature of focal segmental glomerulosclerosis.

Sclerosis is characterized by accumulations of extracellular collagenous matrix, either confined to mesangial areas as is often the case in diabetic glomerulosclerosis, or involving the capillary loops, or both. The sclerosing process may also result in obliteration of some or all of the capillary lumens in affected glomeruli, which in turn can result in formation of fibrous adhesions between the sclerotic portions of glomeruli and the nearby parietal epithelium and Bowman capsules.

Because many of the primary glomerulopathies are of unknown cause, they are often classified by their histology, as can be seen in Table 20-2. The histologic changes can be further subdivided by their distribution into diffuse, involving all glomeruli; global, involving the entire glomerulus; focal, involving only a proportion of the glomeruli; segmental, affecting a part of each glomerulus; and by either capillary loop or mesangial, affecting predominantly capillary or mesangial regions. These terms are sometimes appended to the histologic classifications.

Focal Segmental Glomerulosclerosis (FSGS).

Patients with this secondary change develop proteinuria, even if the primary disease was nonglomerular. The glomerulosclerosis seems to be initiated by the adaptive change that occurs in the relatively unaffected glomeruli of diseased kidneys.^19,21 Such a mechanism is suggested by experiments in rats subjected to ablation of renal mass by subtotal nephrectomy. Compensatory hypertrophy of the remaining glomeruli serves to maintain renal function in these animals, but proteinuria and segmental glomerulosclerosis soon develop, leading eventually to total glomerular sclerosis and uremia. The glomerular hypertrophy is associated with hemodynamic changes, including increases in glomerular blood flow, filtration, and transcapillary pressure (glomerular hypertension), and often with systemic hypertension. The sequence of events (Fig. 20-8) that is thought to lead to sclerosis in this setting entails endothelial and epithelial cell injury, increased glomerular permeability to proteins, and accumulation of proteins in the mesangial matrix. This is followed by proliferation of mesangial cells, infiltration by macrophages, increased accumulation of extracellular matrix (ECM), and segmental and eventually global sclerosis of glomeruli. This results in further reductions in nephron mass, ongoing activation of these compensatory changes, and a vicious circle of continuing glomerulosclerosis. Most of the mediators of chronic inflammation and fibrosis, particularly TGF-β, play a role in the induction of sclerosis. Currently, the most successful interventions to interrupt these mechanisms of progressive glomerulosclerosis involve treatment with inhibitors of the renin-angiotensin system, which not only reduce intraglomerular hypertension, but also have direct effects on each of the mechanisms identified above.²¹ Importantly, these agents have been shown to ameliorate progression of sclerosis in both animal and human studies.²⁰

FIGURE 20-8 Focal segmental glomerulosclerosis associated with loss of renal mass. The adaptive changes in glomeruli (hypertrophy and glomerular capillary hypertension), as well as systemic hypertension, cause epithelial and endothelial injury and resultant proteinuria. The mesangial response, involving mesangial cell proliferation and ECM production together with intraglomerular coagulation, causes the glomerulosclerosis. This results in further loss of functioning nephrons and a vicious circle of progressive glomerulosclerosis.

Contributing to the progressive injury of focal and segmental glomerulosclerosis is the inability of mature visceral epithelial cells (podocytes) to proliferate after injury. This can lead to a decrease in glomerular podocyte number after a severe injury resulting in loss of some of these cells, leading in turn to a process whereby remaining podocytes are either abnormally stretched to maintain an appropriate filtration barrier or unable to cover portions of the GBM, which become denuded of the overlying podocyte foot processes. These alterations lead to abnormal protein filtration as well as loss of structural support for the glomerular capillary walls. This latter alteration in turn may lead to segmental loop dilation because of now incompletely opposed intracapillary pressures, with subsequent formation of a fibrous attachment to Bowman capsule by the bulging capillary segment, and eventual sclerosis of this segment.²²

Tubulointerstitial Fibrosis.

Tubulointerstitial injury, manifested by tubular damage and interstitial inflammation, is a component of many acute and chronic glomerulonephritides. Tubulointerstitial fibrosis contributes to progression in both immune and nonimmune glomerular diseases, for example, diabetic nephropathy. Indeed, there is often a much better correlation of decline in renal function with the extent of tubulointerstitial damage than with the severity of glomerular injury.¹⁸ Many factors may lead to such tubulointerstitial injury, including ischemia of tubule segments downstream from sclerotic glomeruli, acute and chronic inflammation in the adjacent interstitium, and damage or loss of the peritubular capillary blood supply. Current work also points to the effects of proteinuria on tubular cell structure and function²³. On the basis of in vitro and animal studies, proteinuria is thought to cause direct injury to and activation of tubular cells. Activated tubular cells in turn express adhesion molecules and elaborate pro-inflammatory cytokines, chemokines, and growth factors that contribute to interstitial fibrosis. Filtered proteins that may produce these tubular effects include cytokines, complement products, the iron in transferrin, immunoglobulins, lipid moieties, and oxidatively modified plasma proteins.

Having discussed factors in the initiation and progression of glomerular injury, we now turn to a discussion of individual glomerular diseases. Table 20-5 summarizes the main clinical and pathologic features of the major forms of primary glomerulopathies.

TABLE 20-5 Summary of Major Primary Glomerulonephritides

Etiology and Pathogenesis.

Only certain strains of group A β-hemolytic streptococci are nephritogenic, more than 90% of cases being traced to types 12, 4, and 1, which can be identified by typing of M protein of the cell wall.

Poststreptococcal glomerulonephritis is an immunologically mediated disease. The latent period between infection and onset of nephritis is compatible with the time required for the production of antibodies and the formation of immune complexes. Elevated titers of antibodies against one or more streptococcal antigens are present in a great majority of patients. Serum complement levels are low, compatible with activation of the complement system and consumption of complement components. There are granular immune deposits in the glomeruli, supporting an immune complex–mediated mechanism. The streptococcal antigenic com-ponent responsible for the immune reaction has eluded identification for years. Several cationic antigens, including a nephritis-associated streptococcal plasmin receptor (NAPlr), unique to nephritogenic strains of streptococci, can be found in affected glomeruli. Other evidence suggests that streptococcal pyogenic exotoxin B (SpeB) and its zymogen precursor (zSpeB), another protein that functions as a plasmin receptor, are the principal antigenic determinants in most cases of poststreptococcal glomerulonephritis.²⁵ It is not known if these represent antigens planted in the GBM, or parts of circulating immune complexes, or both. GBM proteins altered by streptococcal enzymes have also been implicated as antigens.

Morphology. The classic diagnostic picture is one of enlarged, hypercellular glomeruli (Fig. 20-9). The hypercellularity is caused by (1) infiltration by leukocytes, both neutrophils and monocytes; (2) proliferation of endothelial and mesangial cells; and (3) in severe cases by crescent formation. The proliferation and leukocyte infiltration are diffuse, that is, involving all lobules of all glomeruli. There is also swelling of endothelial cells, and the combination of proliferation, swelling, and leukocyte infiltration obliterates the capillary lumens. There may be interstitial edema and inflammation, and the tubules often contain red cell casts.

FIGURE 20-9 Acute proliferative glomerulonephritis. A, Normal glomerulus. B, Glomerular hypercellularity is due to intracapillary leukocytes and proliferation of intrinsic glomerular cells. C, Typical electron-dense subepithelial “hump” and a neutrophil in the lumen. D, Immunofluorescent stain demonstrates discrete, coarsly granular deposits of complement protein C3, corresponding to “humps” illustrated in part C.

(A–C, courtesy of Dr. H. Rennke, Brigham and Women’s Hospital, Boston, MA. D, courtesy of D. J. Kowaleska, University of Washington, Seattle, WA.)

By immunofluorescence microscopy, there are granular deposits of IgG, IgM, and C3 in the mesangium and along the GBM (Fig. 20-9D). Although immune complex deposits are almost universally present, they are often focal and sparse. The characteristic electron microscopic findings are discrete, amorphous, electron-dense deposits on the epithelial side of the membrane, often having the appearance of “humps” (Fig. 20-9C), presumably representing the antigen-antibody complexes at the epithelial cell surface. Subendothelial and intramembranous deposits are also commonly seen, and mesangial deposits may be present.

Clinical Course.

In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cola-colored urine) 1 to 2 weeks after recovery from a sore throat. The patients have red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension. In adults the onset is more likely to be atypical, such as the sudden appearance of hypertension or edema, frequently with elevation of BUN. During epidemics caused by nephritogenic streptococcal infections, glomerulonephritis may be asymptomatic, discovered only on screening for microscopic hematuria. Important laboratory findings include elevations of antistreptococcal antibody titers and a decline in the serum concentration of C3 and other components of the complement cascade.

More than 95% of affected children eventually recover totally with conservative therapy aimed at maintaining sodium and water balance. A small minority of children (perhaps fewer than 1%) do not improve, become severely oliguric, and develop a rapidly progressive form of glomerulonephritis (described later). Some of the remaining patients may undergo slow progression to chronic glomerulonephritis with or without recurrence of an active nephritic picture. Prolonged and persistent heavy proteinuria and abnormal GFR mark patients with an unfavorable prognosis.

In adults the disease is less benign. Although the overall prognosis in epidemics is good, in only about 60% of sporadic cases do the patients recover promptly. In the remainder the glomerular lesions fail to resolve quickly, as manifested by persistent proteinuria, hematuria, and hypertension. In some of these patients, the lesions eventually clear totally, but others develop chronic glomerulonephritis. Some patients will develop a syndrome of rapidly progressive glomerulonephritis.

Classification and Pathogenesis.

RPGN may be caused by a number of different diseases, some restricted to the kidney and others systemic. Although no single mechanism can explain all cases, there is little doubt that in most cases the glomerular injury is immunologically mediated. A practical classification divides RPGN into three groups on the basis of immunological findings (Table 20-6). In each group the disease may be associated with a known disorder, or it may be idiopathic.

TABLE 20-6 Rapidly Progressive Glomerulonephritides

ANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane.

The first type of RPGN is anti-GBM antibody–induced disease, characterized by linear deposits of IgG and, in many cases, C3 in the GBM that are visualized by immunofluorescence.²⁶ In some of these patients, the anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated with renal failure (Goodpasture syndrome). Plasmapheresis to remove the pathogenic circulating antibodies is usually part of the treatment, which also includes therapy to suppress the underlying immune response.

The Goodpasture antigen is a peptide within the noncollagenous portion of the α₃ chain of collagen type IV.⁵ What triggers the formation of these antibodies is unclear in most patients. Exposure to viruses or hydrocarbon solvents (found in paints and dyes) has been implicated in some patients, as have various drugs and cancers. There is a high prevalence of certain HLA subtypes and haplotypes (e.g., HLA-DRB1) in affected patients, a finding consistent with the genetic predisposition to autoimmunity.²⁷

The second type of RPGN is the result of immune complex deposition. It can be a complication of any of the immune complex nephritides, including postinfectious glomerulonephritis, lupus nephritis, IgA nephropathy, and HenochSchönlein purpura. In all these cases, immunofluorescence studies reveal the granular pattern of staining characteristic of immune complex deposition. This type of RPGN frequently demonstrates cellular proliferation within the glomerular tuft, in addition to crescent formation. These patients cannot usually be helped by plasmapheresis, and they require treatment for the underlying disease.

The third type of RPGN, also called pauci-immune type, is defined by the lack of anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy. Most patients with this type of RPGN have circulating antineutrophil cytoplasmic antibodies (ANCAs) that produce cytoplasmic (c) or perinuclear (p) staining patterns and, as we have seen (Chapter 11), play a role in some vasculitides. Hence, in some cases this type of RPGN is a component of a systemic vasculitis such as Wegener granulomatosis or microscopic polyangiitis. In many cases, however, pauci-immune crescentic glomerulonephritis is isolated and hence idiopathic. More than 90% of such idiopathic cases have c-ANCAs or p-ANCAs in the sera.²⁶ The presence of circulating ANCAs in both idiopathic crescentic glomerulonephritis and cases of crescentic glomerulonephritis that occur as a component of systemic vasculitis, and the similar pathologic features in either setting, have led to the idea that these disorders are pathogenetically related. According to this concept, all cases of crescentic glomerulonephritis of the pauci-immune type are manifestations of small-vessel vasculitis or polyangiitis, which is limited to glomerular and perhaps peritubular capillaries in cases of idiopathic crescentic glomerulonephritis. The clinical distinction between systemic vasculitis with pauci-immune renal involvement and idiopathic crescentic glomerulonephritis accordingly has become de-emphasized, since these entities are viewed as part of a spectrum of vasculitic disease. ANCAs have proved to be invaluable as a highly sensitive diagnostic marker for pauci-immune crescentic glomerulonephritis, but proof of their role as a direct cause of this glomerulonephritis has been elusive. Recent strong evidence of their pathogenic potential has been obtained by studies in mice showing that transferring antibodies against myeloperoxidase (the target antigen of most p-ANCAs) induces a form of RPGN.²⁸

To summarize, all three types of RPGN may be associated with a well-defined renal or extrarenal disease, but in many cases (∼50%), the disorder is idiopathic. Of the patients with this syndrome, about one fifth have anti–GBM antibody–mediated glomerulonephritis without lung involvement; another one fourth have immune complex–mediated crescentic glomerulonephritis; and the remainder are of the pauci-immune type. The common denominator in all types of RPGN is severe glomerular injury.

Morphology. The kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces. Depending on the underlying cause, the glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation. The histologic picture, however, is dominated by distinctive crescents (Fig. 20-10). Crescents are formed by proliferation of parietal cells and by migration of monocytes and macrophages into the urinary space. Neutrophils and lymphocytes may be present. The crescents eventually obliterate Bowman space and compress the glomerular tuft. Fibrin strands are frequently prominent between the cellular layers in the crescents; indeed, as discussed earlier, the escape of fibrinogen into Bowman space and its conversion to fibrin are an important contributor to crescent formation. By immunofluorescence microscopy, immune complex–mediated cases show granular immune deposits; Goodpasture syndrome cases show linear GBM fluorescence for Ig and complement, and pauci-immune cases have little or no deposition of immune reactants. Electron microscopy discloses deposits in those cases due to immune complex deposition (type II). Regardless of type, electron microscopy may show distinct ruptures in the GBM, the severe injury that allows leukocytes, proteins, and inflammatory mediators to reach the urinary space, where they trigger the crescent formation (Fig. 20-11). In time, most crescents undergo sclerosis, but restoration of normal glomerular architecture may be achieved with early aggressive therapy.

FIGURE 20-10 Crescentic glomerulonephritis (PAS stain). Note the collapsed glomerular tufts and the crescent-shaped mass of proliferating parietal epithelial cells and leukocytes internal to Bowman capsule.

(Courtesy of Dr. M.A. Venkatachalam, University of Texas Health Sciences Center, San Antonio, TX.)

FIGURE 20-11 Crescentic glomerulonephritis. Electron micrograph showing characteristic wrinkling of GBM with focal disruptions (arrows).

Clinical Course.

The renal manifestations of all forms of crescentic glomerulonephritis include hematuria with red blood cell casts in the urine, moderate proteinuria occasionally reaching the nephrotic range, and variable hypertension and edema. In Goodpasture syndrome the course may be dominated by recurrent hemoptysis or even life-threatening pulmonary hemorrhage. Serum analyses for anti-GBM antibodies, antinuclear antibodies, and ANCAs are helpful in the diagnosis of specific subtypes. Although milder forms of glomerular injury may subside, the renal involvement is usually progressive over a matter of weeks and culminates in severe oliguria. Recovery of renal function may follow early intensive plasmapheresis (plasma exchange) combined with steroids and cytotoxic agents in Goodpasture syndrome. This therapy can reverse both pulmonary hemorrhage and renal failure. Other forms of RPGN also respond well to steroids and cytotoxic agents. However, despite therapy, some patients may eventually require chronic dialysis or transplantation, particularly if the disease is discovered at a late stage.

Pathophysiology.

The manifestations of the nephrotic syndrome include:

The various components of nephrotic syndrome bear a logical relationship to one another. The initial event is a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. The glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells, acts as a size and charge barrier through which the plasma filtrate passes. Increased permeability resulting from either structural or physicochemical alterations allows protein to escape from the plasma into the urinary space. Massive proteinuria results.

The heavy proteinuria depletes serum albumin levels at a rate beyond the compensatory synthetic capacity of the liver, resulting in hypoalbuminemia and a reversed albumin-to-globulin ratio. Increased renal catabolism of filtered albumin also contributes to the hypoalbuminemia. The generalized edema is, in turn, the consequence of decreased colloid osmotic pressure of the blood with subsequent accumulation of fluid in the interstitial tissues. There is also sodium and water retention, which aggravates the edema (Chapter 4). This seems to be due to several factors, including compensatory secretion of aldosterone, mediated by the hypovolemia-enhanced renin secretion; stimulation of the sympathetic system; and a reduction in the secretion of natriuretic factors such as atrial peptides. Edema is characteristically soft and pitting, most marked in the periorbital regions and dependent portions of the body. It may be massive, with pleural effusions and ascites.

The largest proportion of protein lost in the urine is albumin, but globulins are also excreted in some diseases. The ratio of low- to high-molecular-weight proteins in the urine in various cases of nephrotic syndrome is a manifestation of the selectivity of proteinuria. A highly selective proteinuria consists mostly of low-molecular-weight proteins (albumin, 70 kD; transferrin, 76 kD molecular weight), whereas a poorly selective proteinuria consists of higher molecular-weight globulins in addition to albumin.

The genesis of the hyperlipidemia is complex. Most patients with nephritic syndrome have increased blood levels of cholesterol, triglyceride, very-low-density lipoprotein, low-density lipoprotein, Lp(a) lipoprotein, and apoprotein, and there is a decrease in high-density lipoprotein concentration in some patients. These defects seem to be due in part to increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased catabolism. Lipiduria follows the hyperlipidemia, because lipoproteins also leak across the glomerular capillary wall. The lipid appears in the urine either as free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cells and then shed along with the degenerated cells.

Nephrotic patients are particularly vulnerable to infection, especially staphylococcal and pneumococcal, probably related to loss of immunoglobulins in the urine. Thrombotic and thromboembolic complications are also common in nephrotic syndrome, due in part to loss of endogenous anticoagulants (e.g., antithrombin III) and antiplasmins in the urine. Renal vein thrombosis, once thought to be a cause of nephrotic syndrome, is most often a consequence of this hypercoagulable state, particularly in patients with membranous nephropathy (see below).

Causes.

The relative frequencies of the several causes of the nephrotic syndrome vary according to age and geography. In children younger than 17 years in North America, for example, the nephrotic syndrome is almost always caused by a lesion primary to the kidney; among adults, in contrast, it may often be associated with a systemic disease. Table 20-7 represents a composite derived from several studies of the causes of the nephrotic syndrome and is therefore only approximate. The most frequent systemic causes of the nephrotic syndrome are diabetes, amyloidosis, and SLE. The most important of the primary glomerular lesions are minimal-change disease, membranous glomerulopathy, and focal segmental glomerulosclerosis. The first is most common in children in North America, the second is most common in older adults, and focal segmental glomerulosclerosis occurs at all ages.²⁹ These three lesions are discussed individually in the following sections. Other primary causes, the various proliferative glomerulonephritides including MPGN, frequently present as a mixed syndrome with nephrotic and nephritic features.

TABLE 20-7 Cause of Nephrotic Syndrome

* Approximate prevalence of primary disease = 95% of nephrotic syndrome in children, 60% in adults. Approximate prevalence of systemic disease = 5% in children, 40% in adults.

† Membranoproliferative and other proliferative glomerulonephritides may have mixed nephrotic/nephritic syndromes.

Pathogenesis.

Membranous glomerulopathy is a form of chronic immune complex–mediated disease. In secondary membranous glomerulopathy, the inciting antigens can sometimes be identified in the immune complexes. For example, membranous glomerulopathy in SLE is associated with deposition of autoantigen-antibody complexes. Antigens that have been identified in the deposits in some patients include exogenous antigens (e.g., hepatitis B, Treponema), endogenous nonrenal antigens (e.g., thyroglobulin), and endogenous renal antigens (e.g., the membrane protein neutral endopeptidase recognized by placental transfer of maternal antibodies in cases of neonatal membranous nephropathy and possibly the phospholipase A₂ receptor in adult cases).¹²

The lesions bear a striking resemblance to those of experimental Heymann nephritis, which, as you might recall, is induced by antibodies to a megalin antigenic complex. It is still not known if a similar antigen is present in most cases of idiopathic membranous glomerulopathy in humans. Susceptibility to Heymann nephritis in rats and membranous glomerulopathy in humans is linked to the major histocompatibility complex locus, which can influence the ability to produce antibodies to the nephritogenic antigen. Thus, idiopathic membranous glomerulopathy, like Heymann nephritis, is considered an autoimmune disease linked to susceptibility genes and caused most likely by antibodies to a renal autoantigen.

How does the glomerular capillary wall become leaky in membranous glomerulopathy? There is a paucity of neutrophils, monocytes, or platelets in glomeruli. The virtually uniform presence of complement and corroborating experimental work suggest a direct action of C5b-C9, the pathway leading to the formation of the membrane attack complex. It is postulated that C5b-C9 activates glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage.³²

Morphology. By light microscopy the glomeruli either appear normal in the early stages of the disease or exhibit uniform, diffuse thickening of the glomerular capillary wall (Fig. 20-12A). By electron microscopy the thickening is seen to be caused by irregular dense deposits of immune complexes between the basement membrane and the overlying epithelial cells, the latter having effaced foot processes (Fig. 20-12B and D). Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM. These spikes are best seen by silver stains, which color the basement membrane, but not the deposits, black. In time, these spikes thicken to produce domelike protrusions and eventually close over the immune deposits, burying them within a markedly thickened, irregular membrane. Immunofluorescence microscopy demonstrates that the granular deposits contain both immunoglobulins and complement (see Fig. 20-12C). As the disease advances sclerosis may occur; in the course of time glomeruli may become totally sclerosed. The epithelial cells of the proximal tubules contain protein reabsorption droplets, and there may be considerable interstitial mononuclear cell inflammation.

FIGURE 20-12 Membranous nephropathy. A, Silver methenamine stain. Note the marked diffuse thickening of the capillary walls without an increase in the number of cells. There are prominent “spikes” of silver-staining matrix (arrow) projecting from the basement membrane lamina densa toward the urinary space, which separate and surround deposited immune complexes that lack affinity for the silver stain. B, Electron micrograph showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note the effacement of foot processes overlying deposits. CL, capillary lumen; End, endothelium; Ep, epithelium. C, Characteristic granular immunofluorescent deposits of IgG along GBM. D, Diagrammatic representation of membranous nephropathy.

(A, Courtesy of Dr. Charles Lassman, UCLA School of Medicine, Los Angeles, CA.)

Clinical Features.

In a previously healthy individual, this disorder usually begins with the insidious onset of the nephrotic syndrome or, in 15% of patients, with non-nephrotic proteinuria. Hematuria and mild hypertension are present in 15% to 35% of cases. It is necessary in any patient to first rule out the secondary causes described earlier, since treatment of the underlying condition (malignant neoplasm, infection, or SLE) or discontinuance of the offending drug can reverse the injury.

The course of the disease is variable but generally indolent. In contrast to minimal-change disease, described later, the proteinuria is nonselective and usually does not respond well to corticosteroid therapy. Progression is associated with increasing sclerosis of glomeruli, rising serum creatinine reflecting renal insufficiency, and development of hypertension. Although proteinuria persists in more than 60% of patients, only about 10% die or progress to renal failure within 10 years, and no more than 40% eventually develop renal insufficiency. Concurrent sclerosis of glomeruli in the renal biopsy at the time of diagnosis is a predictor of poor prognosis. Spontaneous remissions and a relatively benign outcome occur more commonly in women and in those with proteinuria in the non-nephrotic range. Because of the variable course of the disease, it has been difficult to evaluate the overall effectiveness of corticosteroids or other immunosuppressive therapy in controlling the proteinuria or progression.

Etiology and Pathogenesis.

Although the absence of immune deposits in the glomerulus excludes classic immune complex mechanisms, several features of the disease point to an immunological basis,³⁴ including (1) the clinical association with respiratory infections and prophylactic immunization; (2) the response to corticosteroids and/or other immunosuppressive therapy; (3) the association with other atopic disorders (e.g., eczema, rhinitis); (4) the increased prevalence of certain HLA haplotypes in patients with minimal-change disease associated with atopy (suggesting a genetic predisposition); (5) the increased incidence of minimal-change disease in patients with Hodgkin lymphoma, in whom defects in T cell–mediated immunity are well recognized; and (6) reports of proteinuria-inducing factors in the plasma or lymphocyte supernatants of patients with minimal-change disease.

The current leading hypothesis is that minimal-change disease involves some immune dysfunction, eventually resulting in the elaboration of a cytokine that damages visceral epithelial cells and causes proteinuria. The ultrastructural changes point to a primary visceral epithelial cell injury, and studies in animal models suggest the loss of glomerular polyanions. Thus, defects in the charge barrier may contribute to the proteinuria. The actual route by which protein traverses the epithelial cell portion of the capillary wall remains an enigma. Possibilities include transcellular passage through the epithelial cells, passage through residual spaces between remaining but damaged foot processes or through abnormal spaces developing underneath the portion of the foot process that directly abuts the basement membrane, or leakage through foci in which the epithelial cells have become detached from the basement membrane.

Additional insight into mechanisms by which epithelial cell injury results in proteinuria in minimal-change disease, focal segmental glomerulosclerosis, and related entities comes from the discovery of mutations in several podocyte proteins, including nephrin and podocin, discussed in the section on focal glomerulosclerosis below. These structural proteins are localized to the slit diaphragm, and nephrotic syndrome resulting from mutations in these proteins illustrates that structural defects of the podocyte are sufficient to cause marked proteinuria in the absence of an immune injury. A mutation in the nephrin gene causes a hereditary form of congenital nephrotic syndrome (Finnish type) with minimal-change glomerular morphology.⁸

Clinical Features.

Despite massive proteinuria, renal function remains good, and there is commonly no hypertension or hematuria. The proteinuria usually is highly selective, most of the protein being albumin. Most children (>90%) with minimal-change disease respond rapidly to corticosteroid therapy. However, proteinuria may recur, and some patients may become steroid-dependent or resistant. Nevertheless, the long-term prognosis for patients is excellent, and even steroid-dependent disease resolves when children reach puberty. Although adults are slower to respond, their long-term prognosis is also excellent.

As has been noted, minimal-change disease in adults can be associated with Hodgkin lymphoma and, less frequently, other lymphomas and leukemias. In addition, secondary minimal-change disease may follow NSAID therapy, usually in association with acute interstitial nephritis, to be described later in this chapter.

Classification and Types.

Focal segmental glomerulosclerosis (FSGS) occurs in the following settings³⁵:

Idiopathic focal segmental glomerulosclerosis accounts for as many as 10% and 35% of cases of nephrotic syndrome in children and adults in many series, respectively. FSGS (both primary and secondary forms) has increased in incidence and is now the most common cause of nephrotic syndrome in adults in the United States,²⁹ particularly in Hispanic and African-American patients. The clinical signs differ from those of minimal-change disease in the following respects: (1) there is a higher incidence of hematuria, reduced GFR, and hypertension; (2) proteinuria is more often nonselective; (3) there is poor response to corticosteroid therapy; and (4) there is progression to chronic kidney disease, with at least 50% developing end-stage renal disease within 10 years.

Pathogenesis.

Whether idiopathic FSGS represents a distinct disease or is simply a phase in the evolution of a subset of patients with minimal-change disease remains unresolved. The characteristic degeneration and focal disruption of visceral epithelial cells are thought to represent an accentuation of the diffuse epithelial cell change typical of minimal-change disease. It is this epithelial damage that is the hallmark of FSGS. Multiple different mechanisms can cause this epithelial damage, including circulating cytokines and genetically determined defects affecting components of the slit diaphragm complex. The hyalinosis and sclerosis stem from entrapment of plasma proteins in extremely hyperpermeable foci and increased ECM deposition. The recurrence of proteinuria, sometimes within 24 hours after transplantation, with subsequent progression to overt lesions of FSGS, suggests that a circulating factor, perhaps a cytokine, may be the cause of the epithelial damage in some patients. An approximately 50-kD non-Ig factor causing proteinuria has been isolated from sera of such patients, but more precise characterization of this factor has not been achieved.³⁶

Morphology. By light microscopy the focal and segmental lesions may involve only a minority of the glomeruli and may be missed if the biopsy specimen contains an insufficient number of glomeruli (Fig. 20-14A). The lesions initially tend to involve the juxtamedullary glomeruli, although they subsequently become more generalized. In the sclerotic segments there is collapse of capillary loops, increase in matrix, and segmental deposition of plasma proteins along the capillary wall (hyalinosis), which may become so pronounced as to occlude capillary lumens. Lipid droplets and foam cells are often present (Fig. 20-14B). Glomeruli that do not show segmental lesions usually appear normal on light microscopy but may show increased mesangial matrix. On electron microscopy both sclerotic and nonsclerotic areas show diffuse effacement of foot processes, and there may also be focal detachment of the epithelial cells and denudation of the underlying GBM. By immunofluorescence microscopy IgM and C3 may be present in the sclerotic areas and/or in the mesangium. In addition to the focal sclerosis, there may be pronounced hyalinosis and thickening of afferent arterioles. With the progression of the disease, increased numbers of glomeruli become involved and sclerosis spreads within each glomerulus. In time, this leads to total (i.e., global) sclerosis of glomeruli, with pronounced tubular atrophy and interstitial fibrosis.

FIGURE 20-14 Focal segmental glomerulosclerosis, PAS stain. A, Low-power view showing segmental sclerosis in one of three glomeruli (at 3 o’clock). B, High-power view showing hyaline insudation and lipid (small vacuoles) in sclerotic area.

A morphologic variant of FSGS, called collapsing glomerulopathy, is characterized by retraction and/or collapse of the entire glomerular tuft, with or without additional FSGS lesions of the type described above (Fig. 20-15). A characteristic feature is proliferation and hypertrophy of glomerular visceral epithelial cells. This lesion may be idiopathic, but it is the most characteristic lesion of HIV-associated nephropathy. In both cases there is associated prominent tubular injury with formation of microcysts. It has a particularly poor prognosis.^37,38

FIGURE 20-15 Collapsing glomerulopathy. Visible are retraction of the glomerular tuft, narrowing of capillary lumens, proliferation and swelling of visceral epithelial cells, and prominent accumulation of intracellular protein absorption droplets in the visceral epithelial cells. The appearance is identical in cases wherein the etiology is idiopathic to cases associated with HIV infection. Silver methenamine stain.

(Courtesy of Dr. Jolanta Kowalewska, University of Washington, Seattle, WA.)

The discovery of a genetic basis for some cases of FSGS and other causes of the nephrotic syndrome has improved the understanding of the pathogenesis of proteinuria in the nephrotic syndrome and has provided new methods for diagnosis and prognosis of affected patients. The first relevant gene to be identified, NPHS1, maps to chromosome 19q13 and encodes the protein nephrin.⁸ Nephrin is a key component of the slit diaphragm (see Fig. 20-3), the zipper-like structure between podocyte foot processes that might control glomerular permeability. Several mutations of the NPHS1 gene have been identified that give rise to congenital nephrotic syndrome of the Finnish type, producing a minimal-change disease–like glomerulopathy with extensive foot process effacement. Prenatal diagnosis of congenital nephrotic syndrome is possible by analysis of the NPHS1 gene.

A distinctive pattern of autosomal recessive FSGS results from mutations in the NPHS2 gene, which maps to chromosome 1q25–q31 and encodes the protein product podocin. Podocin has also been localized to the slit diaphragm. Mutations in NPHS2 result in a syndrome of steroid-resistant nephrotic syndrome of childhood onset. Affected children usually show pathologic features of FSGS. Podocin mutations may account for as many as 30% of cases of steroid-resistant nephrotic syndrome in children.^8,39 A third set of mutations in the gene encoding the podocyte actin-binding protein α-actinin 4 underlies some cases of autosomal dominant FSGS, which can be insidious in onset but has a high rate of progression to renal insufficiency.³⁹

A fourth type of mutation was found in some kindreds with adult-onset FSGS, in the gene encoding TRPC6. This protein is widely expressed, including in podocytes, and the pathogenic mutations may perturb podocyte function by increasing calcium flux in these cells.

What these proteins have in common is their localization to the slit diaphragm and to adjacent podocyte cytoskeletal structures. Their specific functions and interactions are incompletely understood, but it is clear that the integrity of each is necessary to maintain the normal glomerular filtration barrier. Additional components of the podocyte/slit diaphragm apparatus, such as CD2-associated protein (CD2AP), have been identified that may also contribute to proteinuria, as has been suggested in studies of knockout mice (but only rarely demonstrated in humans).⁶ While identification of these genetic defects has clarified the pathogenesis of some cases of the so-called idiopathic nephrotic syndrome, many other factors contribute to permeability defects. These include cell-cell and cell-matrix interactions, particularly those mediated by α₃β₁ integrins, dystroglycans, and laminins. Defects in these interactions may also cause a loss of podocyte adhesion to the GBM.

Renal ablation FSGS, a secondary form of FSGS, occurs as a complication of glomerular and nonglomerular diseases causing reduction in functioning renal tissue, particularly reflux nephropathy and unilateral agenesis. These may lead to progressive glomerulosclerosis and renal failure. The pathogenesis of FSGS in this setting has been described earlier in this chapter.

Clinical Course.

There is little tendency for spontaneous remission in idiopathic FSGS, and responses to corticosteroid therapy are variable. In general, children have a better prognosis than adults do. Progression of renal failure occurs at variable rates. About 20% of patients follow an unusually rapid course, with intractable massive proteinuria ending in renal failure within 2 years. Recurrences are seen in 25% to 50% of patients receiving allografts.

Pathogenesis.

In most cases of type I MPGN there is evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways.⁴² The antigens involved in idiopathic MPGN are unknown. In many cases they are believed to be proteins derived from infectious agents such as hepatitis C and B viruses, which presumably behave either as “planted” antigens after first binding to or becoming trapped within glomerular structures or are contained in preformed immune complexes deposited from the circulation.

Most patients with dense-deposit disease (type II MPGN) have abnormalities that suggest activation of the alternative complement pathway.⁴³ These patients have a consistently decreased serum C3 but normal C1 and C4, the immune complex–activated early components of complement. They also have diminished serum levels of factor B and properdin, components of the alternative complement pathway. In the glomeruli, C3 and properdin are deposited, but IgG is not. Recall that in the alternative complement pathway, C3 is directly cleaved to C3b (Fig. 20-16; see also Chapter 2, Fig. 2-14). The reaction depends on the initial interaction of C3 with such substances as bacterial polysaccharides, endotoxin, and aggregates of IgA in the presence of factors B and D. This leads to the generation of C3bBb, the alternative pathway C3 convertase. This C3 convertase is labile, being degraded by factors I and H, but it can be stabilized by properdin. More than 70% of patients with dense-deposit disease have a circulating antibody termed C3 nephritic factor (C3NeF), which is an autoantibody that binds to the alternative pathway C3 convertase (see Fig. 20-16). Binding of the antibody stabilizes the convertase, protecting it from enzymatic degradation and thus favoring persistent C3 activation and hypocomplementemia. There is also decreased C3 synthesis by the liver, further contributing to the profound hypocomplementemia. Precisely how C3NeF is related to glomerular injury and the nature of the dense deposits is unknown. C3NeF activity also occurs in some patients with a genetically determined disease, partial lipodystrophy, some of whom develop dense-deposit disease (type II MPGN).

Morphology. By light microscopy both types of MPGN are similar. The glomeruli are large and hypercellular. The hypercellularity is produced both by proliferation of cells in the mesangium and so-called endocapillary proliferation involving capillary endothelium and infiltrating leukocytes. Crescents are present in many cases. The glomeruli have an accentuated “lobular” appearance due to the proliferating mesangial cells and increased mesangial matrix (Fig. 20-17). The GBM is thickened, often segmentally; this is most evident in the peripheral capillary loops. The glomerular capillary wall often shows a “double-contour” or “tram-track” appearance, especially evident in silver or PAS stains. This is caused by “duplication” of the basement membrane (also commonly referred to as splitting), usually as the result of new basement membrane synthesis in response to the subendothelial deposits of immune complexes. Within the duplicated basement membranes there is inclusion or interposition of cellular elements, which can be of mesangial, endothelial, or leukocytic origin. Such interposition also gives rise to the appearance of “split” basement membranes (Fig. 20-18A).

FIGURE 20-17 Membranoproliferative glomerulonephritis, showing mesangial cell proliferation, increased mesangial matrix (staining black with silver stain), basement membrane thickening with segmental splitting, accentuation of lobular architecture, swelling of cells lining peripheral capillaries, and influx of leukocytes (endocapillary proliferation).

FIGURE 20-18 A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions (M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope. C, Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope.

(A, Courtesy of Dr. Jolanta Kowalewska, University of Washington, Seattle, WA.)

Types I and II MPGN differ in their ultrastructural and immunofluorescent features (Fig. 20-18).

Type I MPGN (the great majority of cases) is characterized by the presence of discrete subendothelial electron-dense deposits. Mesangial and occasional subepithelial deposits may also be present (see Fig. 20-18A). By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present, suggesting an immune complex pathogenesis.

In dense-deposit disease (type II MPGN) (Fig. 20-18B), a relatively rare entity, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure due to the deposition of dense material of unknown composition in the GBM proper. C3 is present in irregular granular or linear foci in the basement membranes on either side but not within the dense deposits. C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). IgG is usually absent, as are the early-acting complement components (C1q and C4).

Clinical Features.

Most patients present in adolescence or as young adults with nephrotic syndrome and a nephritic component manifested by hematuria or, more insidiously, as mild proteinuria. Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course. Some patients develop numerous crescents and a clinical picture of RPGN. About 50% develop chronic renal failure within 10 years. Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective. There is a high incidence of recurrence in transplant recipients, particularly in dense-deposit disease; dense deposits may recur in 90% of such patients, although renal failure in the allograft is much less common.

Pathogenesis.

IgA, the main Ig in mucosal secretions, is present in plasma at low concentrations, mostly in monomeric form, the polymeric forms being catabolized in the liver. In patients with IgA nephropathy, plasma polymeric IgA is increased, and circulating IgA-containing immune complexes are present in some patients. However, it is clear that increased production of IgA cannot itself cause this disease. Although there are two subclasses of IgA molecules in humans (IgA1 and IgA2), only IgA1 forms the nephritogenic deposits of IgA nephropathy. The prominent mesangial deposition of IgA suggests entrapment of IgA immune complexes in the mesangium, and the presence of C3 combined with the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway. A genetic influence is suggested by the occurrence of this condition in families and in HLA-identical brothers and the increased frequency of certain HLA and complement genotypes in some populations.

Taken together, these clues suggest a genetic or acquired abnormality of immune regulation leading to increased IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents (e.g., viruses, bacteria, food proteins). IgA1 and IgA1-containing immune complexes are then trapped in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury. In support of this scenario, IgA nephropathy occurs with increased frequency in individuals with gluten enteropathy (celiac disease), in whom intestinal mucosal defects are well defined, and in liver disease, in which there is defective hepatobiliary clearance of IgA complexes (secondary IgA nephropathy).

The nature of the initiating antigens is unknown, and several infectious agents and food products have been implicated. The deposited IgA appears to be polyclonal, and it may be that a variety of antigens are involved in the course of the disease. Alternatively, there is evidence for qualitative alterations in the IgA1 molecule itself, specifically a defect in normal galactosylation that makes it immunogenic, giving rise to autoantibodies against the IgA1 that form immune complexes that deposit in the mesangium.⁴⁵

Clinical Features.

The disease affects people of any age, but older children and young adults are most commonly affected. Many patients present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract; 30% to 40% have only microscopic hematuria, with or without proteinuria; and 5% to 10% develop a typical acute nephritic syndrome. The hematuria typically lasts for several days and then subsides, only to return every few months. The subsequent course is highly variable. Many patients maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years. Onset in old age, heavy proteinuria, hypertension, and the extent of glomerulosclerosis on biopsy are clues to an increased risk of progression. Recurrence of IgA deposits in transplanted kidneys is frequent. In approximately 15% of those with recurrent IgA deposits, there is resulting clinical disease, which most frequently runs the same slowly progressive course as that of the primary IgA nephropathy.

Pathogenesis.

The disease manifestations are due to abnormal α₃ (COL4A3), α₄ (COL4A4), or α₅ (COL4A5) chain of type IV collagen. This is due to mutation of COL4A5 in the classic X-linked form and COL4A3 or COL4A4 in the autosomal forms. In all cases, the result is defective assembly of type IV collagen, which is crucial for function of the GBM, the lens of the eye, and the cochlea. Because the GBM consists of networks of trimeric collagen molecules composed of α₃, α₄, and α₅ chains, mutations in COL4A5 also result in defective assembly of the collagen network.⁴⁶ The α₃ chain includes the Goodpasture antigen, and glomeruli from patients with Alport syndrome who lack the α₃ chain fail to react with anti-GBM antibodies from patients with Goodpasture syndrome.

Morphology. On histologic examination the glomeruli are always involved. The early lesion is detectable only by electron microscopy and consists of diffuse GBM thinning. Interstitial foam cells stuffed with neutral fats and mucopolysaccharides are a nonspecific finding consequent to proteinuria that for unknown reasons can be unusually prominent in this disorder. As the disease progresses there is development of focal segmental and global glomerulosclerosis and other changes of progressive renal injury, including vascular sclerosis, tubular atrophy, and interstitial fibrosis.

The characteristic electron microscopic findings of fully developed disease are found in most individuals with hereditary nephritis. The GBM shows irregular foci of thickening alternating with attenuation (thinning), and pronounced splitting and lamination of the lamina densa, often producing a distinctive basket-weave appearance (Fig. 20-20). Similar alterations can be found in the tubular basement membranes.

FIGURE 20-20 Hereditary nephritis (Alport syndrome). Electron micrograph of glomerulus with irregular thickening of the basement membrane, lamination of the lamina densa, and foci of rarefaction. Such changes may be present in other diseases but are most pronounced and widespread in hereditary nephritis. CL, capillary lumen; Ep, epithelium.

Immunohistochemistry can be helpful in cases with absent or borderline basement membrane lesions, because antibodies to α₃, α₄, and α₅ collagen fail to stain both glomerular and tubular basement membranes in the classic X-linked form. There is also absence of α₅ staining in skin biopsy specimens from these patients.

Clinical Features.

The most common presenting sign is gross or microscopic hematuria, frequently accompanied by red cell casts. Proteinuria may develop later, and rarely, the nephrotic syndrome develops. Symptoms appear at ages 5 to 20 years, and the onset of overt renal failure is between ages 20 and 50 years in men. The auditory defects may be subtle, requiring sensitive testing.

Clinical Course.

In most individuals, chronic glomerulonephritis develops insidiously and slowly progresses to renal insufficiency or death from uremia during a span of years or possibly decades (see the discussion of chronic renal failure). Not infrequently, patients present with such nonspecific complaints as loss of appetite, anemia, vomiting, or weakness. In some, the renal disease is suspected with the discovery of proteinuria, hypertension, or azotemia on routine medical examination. In others, the underlying renal disorder is discovered in the course of investigation of edema. Most patients are hypertensive, and sometimes the dominant clinical manifestations are cerebral or cardiovascular. In all, the disease is relentlessly progressive, though at widely varying rates. In nephrotic patients, as glomeruli become obliterated and therefore the GFR decreases, the protein loss in the urine diminishes. If patients with chronic glomerulonephritis do not recieve dialysis or if they do not receive a renal transplant, they invariably succumb to their disease.

Pathogenesis.

The pathogenesis of diabetic glomerulosclerosis is intimately linked with that of generalized diabetic microangiopathy, discussed in Chapter 24. The principal points are as follows⁵³:

To sum up, two processes seem to play a role in the fully developed diabetic glomerular lesions: a metabolic defect, probably linked to advanced glycosylation end products, that accounts for the thickened GBM and increased mesangial matrix that occur in patients; and hemodynamic effects, associated with glomerular hypertrophy, which also contribute to the development of glomerulosclerosis. Both of these processes contribute also to the loss of podocytes, which may undergo apoptosis in response to the metabolic abnormalities and exposure to reactive oxygen species, or become detached from the basement membranes as a consequence of these metabolic changes and/or stretching induced by hemodynamic perturbations.⁵⁶ The morphologic alterations and clinical features of diabetic nephropathy are described in Chapter 24.