Kidney

Deposition of Circulating Immune Complexes

It has long been known that GN may be caused by deposition of preformed immune complexes. Because fluid from the blood passes through the GBM at high pressure (to produce urine) and the GBM is a continuous barrier, it is a common site of deposition of circulating immune complexes. Hence, the kidneys are often involved in systemic immune complex diseases (type III hypersensitivity). Examples include systemic lupus erythematosus, in which the antigens are endogenous nucleoproteins, or the GN that follows certain bacterial (streptococcal), viral (hepatitis B), parasitic ( Plasmodium falciparum malaria), and other infections, in which the antigens are exogenous. Often the inciting antigen is unknown.

The hallmark of immune complex-mediated GN is the appearance of deposits of immunoglobulins and complement, which can be demonstrated by immunofluorescence and electron microscopy. By immunofluorescence microscopy, these deposits appear granular, to which some pathologists give the rather picturesque description of “lumpy-bumpy” ( Fig. 12.3A ). Electron microscopy reveals electron-dense immune deposits in the GBM; these may be subendothelial, subepithelial, or in the mesangium.

Formation of Immune Complexes In Situ

Binding of antibodies to extrinsic molecules planted in the GBM or intrinsic glomerular antigens in a patchy distribution produces the appearance of in situ immune complex formation. In both cases the bound antibodies appear granular by immunofluorescence microscopy. Membranous nephropathy is the classic example of glomerular disease resulting from local formation of immune complexes containing antibodies reactive with endogenous antigens. In this disorder, complexes formed in the subepithelial portion of the GBM cause profound loss of glomerular permeability, resulting in the nephrotic syndrome, with little or no inflammation.

Deposition of Antiglomerular Basement Membrane Antibody

Antibody-mediated GN results from the glomerular deposition of autoantibodies directed against protein components of the GBM. The best-characterized disease in this group is anti-GBM antibody–mediated GN, also known as Goodpasture disease. In this type of injury, antibodies are directed against intrinsic GBM antigens. The distribution of these antigens is continuous, creating a linear pattern of staining when visualized with immunofluorescence microscopy ( Fig. 12.3B ). This form of GN is an example of type II hypersensitivity ( Chapter 5 ).

Other Mechanisms of Glomerular Injury

Several other mechanisms may cause glomerular injury.

• Unregulated activation of complement may be triggered by autoantibodies against complement components or inherited abnormalities of complement regulatory proteins. The ensuing complement-mediated injury may affect several tissues, including the kidney. Two forms of GN (dense deposit disease and C3 GN) and one form of a systemic disease with significant renal manifestations (complement-mediated thrombotic microangiopathy, also known as atypical hemolytic uremic syndrome) belong to this category.

• Other recruited or intrinsic cells may contribute to glomerular injury. Resident glomerular cells, especially mesangial cells, may be stimulated by antibodies and immune complexes to secrete cytokines and other mediators that can contribute to glomerular inflammation. Activated T lymphocytes have also been implicated in experimental models of glomerular injury, but there is little evidence for this in human diseases. Platelets may aggregate and release mediators, including prostaglandins, growth factors, and TGF-β, which may stimulate collagen deposition (glomerulosclerosis).

• Podocyte injury . Because of the role of podocytes in maintaining the permeability barrier of the GBM, injury to these cells is an important cause of glomerular disease. Podocyte injury can be induced by antibodies to podocyte antigens; by toxins; possibly by certain cytokines; or by still poorly characterized circulating factors, as in some cases of focal segmental glomerulosclerosis (discussed later). Podocyte injury produces morphologic changes including effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and the resulting disruption of normal slit diaphragms often results in proteinuria. Inherited mutations in the structural components of slit diaphragms, such as nephrin and podocin, are also associated with functional alterations that lead to rare hereditary forms of nephritis.

• Loss of nephrons itself exacerbates glomerular injury. Once renal disease, glomerular or otherwise, destroys sufficient nephrons to reduce the GFR to 30% to 50% of normal, the remaining glomeruli undergo progressive scarring, called glomerulosclerosis, leading eventually to end-stage renal disease. The loss of nephrons triggers adaptive changes to maintain renal function, including glomerular enlargement, and increased blood flow and transcapillary pressure (capillary hypertension). These alterations are ultimately maladaptive, resulting in endothelial and podocyte injury, increased glomerular permeability to proteins (even in the absence of primary glomerular disease), and accumulation of proteins and lipids in the mesangial matrix. Subsequently, there may be capillary obliteration and finally segmental (affecting a portion of a glomerulus) or global (affecting the entire glomerulus) sclerosis of glomeruli. The latter results in further reduction of nephron mass, initiating a cycle of progressive scarring and loss of function.

We now turn to a consideration of specific types of GN and the syndromes they produce ( Table 12.2 ). We divide these diseases into those that primarily cause the nephrotic syndrome and those associated with manifestations of the nephritic syndrome; some diseases do not fit into either category. The diagnosis and classification of glomerular diseases are based largely on morphology, so renal biopsy is a mainstay of the diagnosis and management of these disorders.

Pathogenesis

The leading hypothesis for the pathogenesis of minimal change disease is that circulating molecules injure podocytes and cause proteinuria secondary to foot process effacement. Since foot process effacement is common to many causes of nephrotic syndrome, it is not entirely clear whether it is the primary lesion or is secondary to proteinuria. An immune mechanism is suspected mainly because of the clinical response to steroids. Although there are reports of “permeability factors” secreted by patients' lymphocytes and other cells, none has been characterized biochemically or established as being causative. Recent work points to a potential pathogenic role for antibodies against slit diaphragm proteins, but this also remains to be proven. Thus, the pathogenesis of the disease remains unknown.

Morphology

The glomeruli are histologically normal (accounting for the name of the disease), and no deposits of antibody or complement are seen by immunofluorescence ( Fig. 12.4A ). The cells of the proximal convoluted tubules often are heavily laden with protein droplets and lipids due to tubular reabsorption of the molecules that have leaked through the diseased glomeruli. The only morphologic glomerular abnormality is the diffuse effacement of podocyte foot processes, visible by electron microscopy ( Fig. 12.4B ). Other ultrastructural changes in podocytes include vacuolization, microvillus formation, and occasional focal detachments, suggesting some form of podocyte injury. Steroid therapy reverses these podocyte alterations, and proteinuria remits concomitantly.

Clinical Features

The disease typically manifests with abrupt development of the nephrotic syndrome in an otherwise healthy child. Renal function is usually preserved. The protein loss affects mainly smaller plasma proteins, chiefly albumin (selective proteinuria). The prognosis for children with this disorder is favorable. More than 90% of children respond to a short course of corticosteroid therapy; however, proteinuria recurs in more than two-thirds of the initial responders, and some of these individuals become steroid dependent. Less than 5% develop chronic kidney disease over time, most often focal segmental glomerulosclerosis (FSGS), suggesting that minimal change disease and FSGS are stages in a continuum of progressive glomerular disease. Because of its responsiveness to therapy in children, minimal change disease must be differentiated from other causes of the nephrotic syndrome. Adults with this disease also respond to steroid therapy, but the response is slower than in children and relapses are more common.

Pathogenesis

Injury to podocytes is the likely initiating event of primary FSGS. Injury may manifest initially as foot process fusion, associated with increased glomerular permeability, and may progress to loss of podocytes and slit diaphragms. The source of the injury remains unknown. As with minimal change disease, permeability-inducing factors produced by lymphocytes have been proposed, but they remain undefined. The recurrence of proteinuria in some patients following renal transplantation for FSGS, sometimes within a day or less, supports the idea that a circulating mediator leads to podocyte damage. Entrapment of plasma proteins and lipids and ECM deposition in glomeruli lead to obliteration of the capillaries and consequent glomerulosclerosis.

Morphology

Primary FSGS initially affects the juxtamedullary glomeruli, but with progression, most glomeruli may be affected. The lesions involve some tufts within a glomerulus while sparing others ( Fig. 12.5 ). The affected glomerular segments exhibit obliterated capillary lumina, increased mesangial matrix, deposition of hyaline material, and foamy (lipid-laden) macrophages. Immunofluorescence microscopy often reveals nonspecific trapping of immunoglobulins, usually IgM, and complement in the areas of sclerosis. On electron microscopy, the podocytes exhibit effacement of foot processes. With time, progression leads to global sclerosis of the glomeruli, pronounced tubular atrophy, and interstitial fibrosis, which, in advanced disease, is difficult to differentiate from other forms of chronic glomerular disease.

A morphologic variant called collapsing glomerulopathy is characterized by collapse of the glomerular tuft and epithelial cell hyperplasia. This is a more severe manifestation of FSGS that carries a particularly poor prognosis.

Clinical Features

FSGS must be distinguished from minimal change disease because the clinical course and response to therapy are markedly different. Both are associated with the nephrotic syndrome, but the incidence of hematuria and hypertension is higher in individuals with FSGS. Also, unlike minimal change disease, FSGS-associated proteinuria is nonselective, and in general the response to corticosteroid therapy is poor. At least 50% of patients with FSGS develop end-stage renal disease within 10 years of diagnosis.

Pathogenesis

Primary membranous nephropathy is an autoimmune disease in which autoantibodies form in situ immune complexes usually with endogenous glomerular antigens. Circulating autoantibodies against the podocyte antigen phospholipase A ₂ receptor (PLA2R) are present in 70% to 80% of patients, and in the rest, antibodies against several other glomerular antigens have been detected, but it is not established if any of these are causative. Complement proteins are also detected; however, the mechanism for complement activation is unclear since the most common autoantibody is of the IgG4 isotype, which is a poor activator of the classical complement pathway.

Morphology

The main histologic feature of membranous nephropathy is diffuse thickening of the capillary wall ( Fig. 12.6A ). Immunofluorescence microscopy shows granular deposits of immunoglobulins and complement along the GBM ( Fig. 12.6B ). By electron microscopy, the thickening is seen to be caused by subepithelial deposits between the GBM and epithelial cells; the intervening small protrusions of GBM matrix produce a spike and dome pattern (see Fig. 12.6B ). As the disease progresses, the spikes enclose the deposits, which become incorporated into the GBM. In addition, as in other causes of nephrotic syndrome, the podocytes show effacement of foot processes. With further progression, glomeruli may become sclerosed.

Clinical Features

Most cases of membranous nephropathy present as nephrotic syndrome, usually without antecedent illness. In contrast to minimal change disease, the proteinuria is nonselective and usually fails to respond to corticosteroid therapy. Serologic detection of anti-PLA2R is helpful in making a diagnosis and the titer is useful in monitoring response to therapy. Membranous nephropathy follows a notoriously variable and often indolent course. Overall, although proteinuria persists in greater than 60% of patients, only about 40% progress to renal failure over a period of 2 to 20 years. An additional 10% to 30% of cases have a more benign course with partial or complete remission of proteinuria.

Pathogenesis

Type I MPGN may be caused by deposition of circulating immune complexes or by in situ immune complex formation with a planted antigen with activation of both classical and alternative complement pathways. In many cases, an underlying disorder can be identified, such as infection (e.g., hepatitis B and C), autoimmune disease (e.g., SLE), or monoclonal gammopathy. The disease is idiopathic in a minority of patients.

Morphology

By light microscopy the glomeruli are large and show hypercellularity caused by proliferation of mesangial cells and capillary endothelial cells and by infiltrating leukocytes; these changes often accentuate the glomerular lobules ( Fig. 12.7A ). The GBM is thickened, and the glomerular capillary wall often shows a double contour, or “tram track,” appearance. This “splitting” of the GBM is due to its disruption by interposed mesangial and inflammatory cells and the deposition of mesangial matrix and immune complexes. By immunofluorescence microscopy, granular deposits of IgG and complement proteins are often present ( Fig. 12.7B ). By electron microscopy, discrete deposits are seen in the GBM and occasionally in the mesangium ( Fig. 12.7C ).

Clinical Features

Most patients with primary MPGN present as adolescents or young adults with hematuria and varying degrees of proteinuria. The disease usually follows a slowly progressive, unremitting course. Treatment with steroids, immunosuppressive agents, and antiplatelet drugs has not proven to be of any benefit. MPGN may also occur in association with other disorders (secondary MPGN), such as systemic lupus erythematosus, hepatitis B and C, chronic liver disease, and chronic bacterial infections. Indeed, many so-called “idiopathic” cases are believed to be associated with hepatitis C and related cryoglobulinemia. These secondary cases of MPGN are more common in adults; treatment of the underlying disease may resolve the kidney lesions.

Pathogenesis

Complement dysregulation due to acquired or hereditary abnormalities of the alternative pathway of complement activation is the underlying cause of dense deposit disease and C3 GN. Some patients have an activating autoantibody against C3 convertase, called C3 nephritic factor (C3NeF), that causes uncontrolled cleavage of C3 by the alternative complement pathway. In other patients, autoantibodies to or mutations in various complement regulatory proteins, such as Factor H, Factor I, and membrane cofactor protein (MCP) are the cause of unregulated activation of the alternative pathway of complement.

Morphology

Although glomerular changes in dense deposit disease and C3 GN vary from relatively subtle to severe, the classic light microscopic presentation is similar to that seen in MPGN type I. The glomeruli are hypercellular, the capillary walls show duplicated basement membranes, and the mesangial matrix is increased ( Fig. 12.8A ). By immunofluorescence microscopy, in both dense deposit disease and C3 GN there is mesangial and glomerular capillary wall staining for C3 ( Fig. 12.8B ). IgG and the early components of the classical complement pathway (C1q and C4) are usually absent in both conditions. By electron microscopy, in C3 GN there are mesangial and subendothelial electron-dense “waxy” deposits ( Fig. 12.8C ). By contrast, in the aptly named dense deposit disease, the GBM is transformed into an irregular, ribbonlike, electron-dense structure, resulting from the deposition of C3-containing material ( Fig. 12.8D ).

Clinical Features

Dense deposit disease is usually seen in children and young adults, whereas C3 GN is more common in adults. In both diseases, patients present with variable proteinuria or hematuria and usually mild azotemia. Serum C3 levels are typically reduced. Both diseases carry a poor prognosis and almost one-third of patients progress to end-stage renal failure. The diseases tend to recur in up to 85% of patients after renal transplantation.

Pathogenesis

Postinfectious GN is caused by glomerular deposition of immune complexes consisting of microbial antigens and specific antibodies, resulting in complement activation by the classical pathway and subsequent inflammation. In children, it most often follows infection by certain “nephritogenic” strains of β-hemolytic streptococci. Streptococcal antigens implicated in the formation of the complexes include streptococcal exotoxin B, a highly immunogenic protein that has been detected in the GBM deposits. In older adults, GN may develop following and even concurrent with active staphylococcal infection. Typical features of immune complex disease, such as hypocomplementemia and granular deposits of IgG and complement on the GBM, are seen. The immune complexes may be preformed circulating complexes of streptococcal antigens and antibodies that deposit in the GBM or may be formed in situ by antibody binding to streptococcal antigens deposited in the GBM.

Morphology

By light microscopy, the most characteristic change in postinfectious GN is increased cellularity of the glomerular tufts that affects nearly all glomeruli—hence the term diffuse GN ( Fig. 12.9A ). The increased cellularity is caused by proliferation of endothelial and mesangial cells and by infiltrating neutrophils and monocytes. Sometimes there is necrosis of the capillary walls. In a few cases, crescents (discussed later) may be observed within the urinary space, formed in response to the severe injury. Immunofluorescence studies reveal granular deposits of IgG and complement within the capillary walls and some mesangial areas ( Fig. 12.9B ). Electron microscopy shows subendothelial, intramembranous, or, most often, subepithelial deposits nestled against the GBM forming “humps” ( Fig. 12.9C ). These deposits are usually cleared over a period of about 2 months after resolution of the infection.

Clinical Features

Poststreptococcal GN is a representative example of postinfectious GN. The typical case develops in a child 1 to 4 weeks after recovery from a group A streptococcal infection, but in rare instances the disease develops during the infection. In most cases, the initiating infection is localized to the pharynx or skin. The clinical presentation varies from asymptomatic to mild hematuria to acute nephritic syndrome with edema, hypertension, and mild to moderate azotemia. Some degree of proteinuria is often present, and it is occasionally severe enough to produce the nephrotic syndrome. Serum complement levels are low during the active phase of the disease, and serum anti–streptolysin O antibody titers are elevated in poststreptococcal cases.

More than 95% of affected children eventually recover renal function, but some develop rapidly progressive GN owing to severe injury with crescent formation (see later), or chronic renal disease from secondary scarring. In adults, the prognosis is more guarded, with 15% to 50% of affected individuals developing chronic renal disease over a few years or 1 to 2 decades, depending on the clinical and histologic severity.

Pathogenesis

In most cases, the glomerular injury of RPGN is immunologically mediated. Three forms are recognized:

• Anti-GBM antibody–mediated crescentic GN (Goodpasture disease) is characterized by linear deposits of IgG and, in many cases, C3, in the GBM (type II hypersensitivity, Chapter 5 ). In some patients, the anti-GBM antibodies also bind to pulmonary alveolar capillary basement membranes and lead to pulmonary hemorrhages, which, when associated with renal failure, is known as Goodpasture syndrome ( Chapter 11 ).

• Immune complex–mediated crescentic GN may complicate any of the immune complex nephritides, including postinfectious GN, systemic lupus erythematosus, IgA nephropathy, and Henoch-Schönlein purpura. In other cases, immune complexes are demonstrated but the underlying cause is undetermined. This type of RPGN frequently shows cellular proliferation and influx of leukocytes within the glomerular tuft (proliferative GN), in addition to crescent formation. A consistent finding is the characteristic granular pattern of staining of the GBM and/or mesangium for immunoglobulin and/or complement on immunofluorescence studies.

• Pauci-immune crescentic GN is defined by the lack of detectable anti-GBM antibody or immune complex deposition. The presence of circulating antineutrophil cytoplasmic antibodies (PR3-ANCA) in some cases of crescentic GN suggests that these are a component of a systemic vasculitis ( Chapter 8 ). In many cases, however, pauci-immune crescentic GN is idiopathic.

Morphology

The light microscopic changes are similar in various forms of crescentic GN. The glomeruli show cellular proliferation outside the capillary loops, sometimes in association with segmental capillary necrosis, breaks in the GBM, and deposition of fibrin in Bowman’s space. The distinctive lesions outside the capillary loops are called crescents owing to their shape as they fill Bowman’s space. Crescents are formed both by proliferation of parietal epithelial cells and by migration of monocytes and other leukocytes ( Fig. 12.10A ). In addition to crescents, cellular proliferation is seen within the capillary loops and/or in the mesangial areas in cases with immune complex-mediated pathogenesis. Immunofluorescence studies reveal the characteristic strong linear staining with IgG and C3 along the GBM in anti-GBM antibody-mediated disease (see Fig. 12.3B ), a granular pattern of glomerular staining in immune complex-mediated GN, and no staining in pauci-immune GN. Electron microscopy shows electron-dense immune complex deposits within the glomeruli in immune complex–mediated GN. Electron microscopy may show ruptures in the GBM, signifying severe glomerular injury ( Fig. 12.10B ). The crescents eventually obliterate Bowman’s space and over time may undergo scarring, resulting in progressive glomerulosclerosis.

Clinical Features

The onset of RPGN resembles other causes of the nephritic syndrome, but oliguria and azotemia are more pronounced. Proteinuria sometimes approaching the nephrotic range may occur. Some affected individuals become anuric and require long-term dialysis or transplantation. If untreated, RPGN can lead to renal failure within a period of weeks to months. The prognosis is roughly correlated to the fraction of involved glomeruli (patients in whom crescents are present in less than 80% of the glomeruli have a more favorable prognosis), and the severity of renal failure at diagnosis. All forms are treated with immunosuppressive agents; plasmapheresis may also benefit those with anti-GBM antibody GN and ANCA-related pauci-immune crescentic GN.

Clinical Features

SLE has protean clinical manifestations ( Chapter 5 ). The renal manifestations usually present as a mixed nephrotic/nephritic picture. Patients may develop hematuria with red cell casts and proteinuria that is severe enough to produce full-blown nephrotic syndrome. Kidney involvement portends a poor prognosis, and renal failure is a frequent cause of death.