Chapter 48. The Kidney: II. Glomerular Diseases

This group of renal diseases is characterized by primary abnormalities of the glomerulus, both structural (inflammation, cellular proliferation, basement membrane thickening, fibrosis, epithelial cell changes) and functional (increased permeability causing pro-teinuria or hemorrhage of glomerular origin). Glomerular diseases may be congenital or acquired. Congenital glomerular diseases (the most common being Alport's syndrome, in which nephritis is associated with nerve deafness and cataract) are very rare. This chapter deals with acquired glomerular diseases.

The classification of glomerulonephritis uses a combination of clinical (congenital or acquired; acute or chronic), morphologic (proliferative, membranous, minimal change), and immunologic criteria (Table 48-1).

Pathologic Changes

Glomerular diseases may be focal, showing abnormality in some but not all the glomeruli; or diffuse, where all glomeruli are affected. In segmental glomerular involvement, only a portion of each individual glomerulus is affected, in contrast to a global change, which involves entire glomeruli. Combinations of these terms are commonly used; eg, in focal segmental involvement the abnormality is present in some but not all glomeruli and the affected glomeruli are only partially involved.

Identification of exact morphologic changes in the glomerulus in renal biopsy specimens is important in the differential diagnosis of glomerular diseases (Figure 48-1). Some knowledge of these changes is necessary because different glomerular diseases show varying combinations of these same basic features.

Proliferation of Cells in the Glomerulus

Any of the different cell types in the glomerulus may undergo proliferation in different diseases.

1. Mesangial cell proliferation is recognized by the presence of increased numbers of nuclei (in excess of three) in the central part of a glomerular lobule. Mesangial cells are part of the phagocytic mechanism of the glomerulus.

2. Endothelial cell proliferation causes obliteration of the capillary lumen.

3. Epithelial cell proliferation, when extensive, leads to formation of a crescent-shaped mass of cellular or collagenized tissue that obliterates Bowman's space. Epithelial cell proliferation is believed to be stimulated by fibrin deposition in Bowman's space.

Infiltration of the Glomerulus by Inflammatory Cells

Infiltration with neutrophils, lymphocytes, and macrophages is present in many cases of acute glomerulonephritis. Acute inflammation is accompanied by fluid exudation and swelling of the glomerulus (exudative glomerulonephritis).

Capillary Basement Membrane Thickening

Increased amounts of basement membrane material may be detected by light microscopy as a thickened capillary wall. The basement membrane can be specifically stained with silver stains and seen by electron microscopy. Basement membrane thickening is commonly associated with deposition of immune complexes, immunoglobulins, and complement. Such deposition may be subepithelial, intramembranous, or subendothelial and is seen only by immunofluorescence and electron microscopy. Regardless of its cause, basement membrane thickening typically causes increased glomerular capillary permeability to proteins, leading to nephrotic syndrome.

Increased Mesangial Matrix Material

This pathologic picture is commonly due to deposition of immunoglobulins and complement in the mesangium (positive staining on immunofluorescence and visible on electron microscopy).

Epithelial Foot Process Fusion

This feature can be seen only by electron microscopy. It is a nonspecific change that is believed to result whenever there is increased leakage of protein from the glomerular capillaries.

Fibrosis

Fibrosis (sclerosis) can affect part of the glomerulus (mesangium, Bowman's space) or may be global. Global sclerosis produces an obsolescent nonfunctional glomerulus and is followed by atrophy and fibrosis of the corresponding nephron (tubules). It may follow most of the changes described above or may be the primary abnormality (Figure 48-1).

Pathogenesis of Glomerular Disease

Most forms of primary glomerular disease are caused by two principal humoral immunologic mechanisms (Figure 48-2; Table 48-2). Evidence for cell-mediated reactions exists in minimal change glomerular disease.

Immune Complex Disease (Type III Hypersensitivity)

Immune complex disease is the most common cause of glomerular injury. Circulating immune complexes are deposited on the glomerular filtration membrane or in the mesangium (Figure 48-2); complement fixation and inflammation follow.

Immune complex deposition may produce most or all of the pathologic features described above, with one or the other predominating in different diseases (Table 48-2). Immunoglobulin and complement are demonstrable by immunofluorescence. The staining pattern on immunofluorescence is “lumpy-bumpy” (ie, granular), corresponding to irregular deposition of the immune complexes. Immune complexes are visible with the electron microscope as electron-dense deposits.

Antibody Reaction Against Antigens on the Glomerular Filtration Membrane

Anti-Glomerular Basement Membrane Antibody

Deposition of anti-glomerular basement membrane (GBM) antibodies directed against epitopes on the type IV collagen molecules of the basement membrane leads to complement fixation (Figure 48-2), with glomerular lesions that by light microscopy are identical to those seen in immune complex disease. Immunofluorescence, however, shows linear deposition of immunoglobulin and complement in the basement membrane. Linear deposition of antibody depends on the fact that the antigenic epitope is part of a repeating subunit uniformly expressed in the basement membrane.

Antibodies Against Non-GBM Antigens

The glomerular filtration membrane harbors other kinds of antigens against which antibodies may be directed. These non-GBM antigens are not uniformly distributed in the membrane, and antibody deposition may produce a granular rather than linear pattern on immunofluorescence, resembling immune complex injury. Two such antigen types are recognized: (1) An intrinsic antigen, which is a component of the endocytotic clathrin-coated pits of the epithelial cell is believed to be the antibody target in experimental Heymann's nephritis in rats. A similar antigen may be involved in human membranous glomerulonephritis; and (2) extrinsic antigens (derived from drugs, plant lectins, aggregated protein molecules, and products of infectious agents) may become planted on the filtration membrane and become the target for an antibody reaction.

In all these humoral immunologic reactions, complement activation occurs and represents the final common pathway for producing glomerular injury. In some cases, this is associated with inflammation and entry of neutrophils. In others, as in membranous glomerulonephritis, it leads to increased basement membrane permeability without inflammation.

Minimal change glomerular disease occurs most often in young children and is relatively uncommon in adults. It accounts for 80% of cases of nephrotic syndrome in children under 8 years of age.

Etiology & Pathogenesis

The basic change in minimal change disease appears to be related to loss of basement membrane polyanions (mainly heparan sulfate proteoglycan), which reduces the negative charge in the membrane. This decreases the filtration barrier to anionic molecules in the plasma—such as albumin—which are permitted to pass through, often in large amounts. Selective loss of albumin among all the plasma proteins is a typical feature of minimal change disease. The fusion of foot processes of the epithelial cell is believed to be a nonspecific reaction to increased protein filtration.

The cause of the chemical change in the basement membrane is unknown. An immunologic basis is strongly suggested by (1) its association with infections, immunizations, and atopic disorders such as hay fever and eczema; and (2) its excellent response to immunosuppressive drugs such as corticosteroids. Its association with Hodgkin's disease (where T lymphocyte abnormalities are common) and the finding that T lymphocytes of patients with minimal change disease produce lymphokines when cultured with renal tissue suggest that minimal change disease may be a cell-mediated immunologic disease.

Pathology

Light microscopy shows no abnormality (hence the term minimal change). Immunofluorescence shows absence of immunoglobulin or complement deposition. Electron microscopy shows fusion of the foot processes of the epithelial cells (epithelial cell disease) (Figure 48-3; see also Table 48-3). These changes disappear during remission.

Clinical Features

Minimal change disease causes nephrotic syndrome. The proteinuria is almost always highly selective, with loss of only low-molecular-weight anionic proteins. Selectivity of proteinuria is assessed by the ratio of transferrin (low-molecular weight (MW)) to IgG (high-MW) concentrations in urine. In highly selective proteinuria, the value is high; in nonselective proteinuria, it approaches 1. Hematuria, hypertension, and azotemia are absent.

Treatment & Prognosis

High-dosage corticosteroid therapy causes a dramatic decrease in proteinuria, with most patients showing complete remission within 8 weeks. After withdrawal of steroids, about 50% of patients relapse intermittently for up to 10 years. Those who undergo relapses are steroid-sensitive, that is, each relapse responds well to steroid therapy.

Resistance to steroids or development of renal failure is rare and should prompt a search for some other diagnosis, usually focal glomerulosclerosis or membranoproliferative glomerulonephritis. The prognosis for life and renal function for patients with minimal change glomerular disease is almost the same as that of the general population.

Acute poststreptococcal glomerulonephritis is one of the most common renal diseases in childhood. It is less common in adults. Occurrence is worldwide, at times in epidemic distribution.

Organisms other than beta-hemolytic streptococci may cause glomerulonephritis (nonstreptococcal acute glomerulonephritis). Convincing data exist to incriminate Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meningitidis, the plasmodia of malaria, Toxoplasma gondii, and some viruses.

Immune complexes formed between antigens in the organism and host antibody are deposited in the glomerular filtration membrane, fix complement, and lead to inflammation. The specific streptococcal antigen involved in forming circulating immune complexes is not known.

Pathology

Grossly, the kidneys are slightly enlarged and have a smooth surface. In severe cases there are scattered petechial hemorrhages. Light microscopic examination shows diffuse glomerulonephritis. The glomeruli are enlarged, edematous, and hypercellular (Figure 48-4; see also Table 48-3). The increased cellularity is due to proliferation of endothelial and mesangial cells plus infiltration with neutrophils and a few eosinophils. Epithelial proliferation producing crescents may be present in a few glomeruli. Rarely, crescent formation is extensive and results in rapidly progressive renal failure. Marked edema and endothelial swelling causes a narrowing of capillary lumens.

The immune complexes may be seen on light microscopy as characteristic humps, particularly in trichrome-stained sections. These correspond to large, dome-shaped electron-dense deposits on the epithelial side of the basement membrane (subepithelial humps) on electron microscopy (Figure 48-4). Deposits in other locations such as the mesangium and the subendothelial and intramembranous regions are frequently present.

Immunofluorescence shows a granular (lumpy-bumpy) deposition of IgG and C3 along the glomerular basement membrane and in the mesangium (Figure 48-4).

Clinical Features

Most patients with poststreptococcal glomerulonephritis present with an abrupt onset of the acute nephritic syndrome, characterized by mild periorbital edema, hypertension, and elevated serum urea and creatinine. A few patients present with nephrotic syndrome.

Throat and skin cultures are usually negative because the streptococcal infection has usually resolved. Serum levels of antistreptococcal antibodies such as antistreptolysin O and antihyaluronidase are often elevated. A transient reduction in serum C3 component of complement, with return to normal within 8 weeks, is common. Tests for circulating immune complexes are often positive.

Treatment & Prognosis

Treatment is supportive. The short-term prognosis is excellent, with 95% of patients making a clinical recovery within 6 weeks and returning to normal renal function within a year. Abnormalities in urinary sediment may persist for several years. A small number of patients progress rapidly to renal failure within 1–2 years. These cases are associated with the presence of numerous epithelial crescents (crescentic glomerulonephritis—see below).

The long-term prognosis is controversial. Most studies indicate that children with poststreptococcal glomerulonephritis do not suffer progressive renal disease; however, a few studies report an increased incidence of chronic renal failure after initial resolution.

The prognosis is much worse (1) in adults, in whom chronic disease occurs in 30–50% of cases; (2) in patients who have an atypical clinical presentation; and (3) in patients who have persistent heavy proteinuria.

Rapidly progressive glomerulonephritis is a rare disease defined by two criteria: (1) The presence of epithelial crescents in more than 70% of the glomeruli. An epithelial crescent is a proliferation of epithelial cells in Bowman's space (Figure 48-5). Crescents represent irreversible damage that always causes severe residual scarring of the affected glomerulus. Fibrin can be demonstrated in the crescent and is thought to induce its formation. (2) The occurrence of rapidly progressive renal failure, with end-stage disease occurring within months after onset.

Rapidly progressive glomerulonephritis is a heterogeneous condition that probably represents the end result of severe glomerular damage occurring in many diseases (Table 48-4). Poststreptococcal glomerulonephritis and Goodpasture's syndrome account for many of the cases.

After these known diseases have been ruled out, there remain a group of patients classified as having idiopathic rapidly progressive glomerulonephritis. In this group, approximately 20% have anti-glomerular basement membrane antibody in serum and a linear pattern on immunofluorescence (type I), and 30% have features of immune complex disease (type II). In the remaining 50%, immunofluorescence shows minimal activity (pauci-immune, or type III).

Pathology

Seventy percent of glomeruli must show crescent formation for this diagnosis to be made because scattered crescents are present in many glomerular diseases. Immunofluorescence studies show variable findings depending upon the cause. Electron microscopy shows varying destructive changes in the glomeruli.

Treatment & Prognosis

Treatment is unsatisfactory, and the prognosis is very poor without dialysis or transplantation. A few cases of occurrence of the disease in transplanted kidneys have been reported.

Goodpasture's syndrome is rare. It occurs in young adults, with males affected more frequently than females. Eighty percent of patients are positive for human leukocyte antigen (HLA)-DR2 antigen.

The serum contains anti-glomerular basement membrane antibodies of IgG type directed against glycoprotein antigens in noncollagenous domains on type IV collagen. These antibodies bind to both kidney and pulmonary alveolar basement membrane. Antibody binding to antigens on the glomerular basement membrane causes complement fixation (type II hypersensitivity) and a proliferative glomerulonephritis.

Pathology

Light microscopy initially shows a focal proliferative glomerulonephritis. In the later stages, diffuse glomerular involvement occurs. Proliferative changes are frequently associated with necrosis and epithelial crescent formation. Crescentic glomerulonephritis (Figure 48-5) is common. Sclerosis becomes prominent in the late stages.

Immunofluorescence shows IgG and C3 deposition in a characteristic diffuse linear pattern along the basement membrane (Figure 48-2). C3 deposition is important for the diagnosis because linear IgG deposition alone is a nonspecific change in many conditions, notably diabetes mellitus. Similar linear C3 and IgG deposition is present in basement membranes in the lung in patients with Goodpasture's syndrome.

Electron microscopy shows diffuse and irregular thickening of the glomerular basement membrane. The electron microscopic findings are nonspecific.

In most patients, the lungs show extensive alveolar damage and intra-alveolar hemorrhages with hemosiderin-laden macrophages present in large numbers in the alveoli (Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases).

Clinical Features

Goodpasture's syndrome commonly presents with proteinuria and hematuria followed by rapidly progressive glomerulonephritis (see above). Patients with pulmonary involvement have recurrent hemoptysis, with dyspnea, cough, and bilateral pulmonary infiltrates on x-ray. Some patients have only lung or only kidney involvement.

Chronic loss of blood in the urine and lungs may cause severe iron deficiency anemia.

Treatment & Prognosis

Treatment of Goodpasture's syndrome is unsatisfactory, and the prognosis is poor. Most cases progress to renal failure within 1 year after diagnosis.

Proliferation of mesangial cells as the only abnormality in a renal biopsy specimen is a nonspecific finding. Mesangial proliferative glomerulonephritis is best classified according to the predominant type of immunoglobulin present in the glomerulus.

With IgG in Mesangium

IgG deposition is common and may occur as an isolated finding or in the healing phase of postinfectious glomerulonephritis. The pathogenesis is unknown in most cases.

Light microscopy shows increased numbers of mesangial cells in the glomeruli (more than the normal three nuclei per lobule; see Figure 48-1). The mesangial matrix material is increased. Immunofluorescence shows the presence of IgG and C3 in the mesangium. Electron microscopy shows the presence of mesangial electron-dense deposits in some cases.

With IgA in Mesangium

IgA Nephropathy (Berger's Disease)

Berger's disease accounts for 10% of cases of nephrotic syndrome in both adults and children. It is most common in the age group from 10–30 years and has a male predominance. The etiology is unknown.

On light microscopy, there is mesangial hypercellularity and increased matrix material. Sclerosis is common with progressive disease. Immunofluorescence shows IgA deposits in the mesangium as confluent masses or discrete granules. C3 is frequently present. Electron microscopy shows mesangial hypercellularity, sclerosis, and electron-dense deposits.

Clinically, patients present with hematuria, often at the time of an upper respiratory infection. Hematuria is frequently recurrent. Proteinuria and microscopic hematuria commonly persist. Though progression of the disease is very slow, the ultimate prognosis is not good. Most patients progress to chronic renal failure after a mean interval of 6 years.

Henoch-Schönlein Purpura

Henoch-Schönlein purpura is a rare disease, mainly affecting children. It is characterized clinically by a systemic vasculitis affecting skin, joints, intestine, and kidneys. Renal involvement is common and may cause hematuria, proteinuria, acute renal failure, or nephrotic syndrome.

Light microscopy shows mesangial hypercellularity and epithelial crescents. Immunofluorescence shows the presence of IgA deposition in the mesangium. Electron microscopy shows mesangial deposits and hypercellularity.

Henoch-Schönlein purpura is a progressive disorder. About 20% of patients develop chronic renal disease.

Membranous glomerulonephritis is an important and common cause of nephrotic syndrome in adults (mean age 35 years). It is rare in children.

Eighty-five percent of cases of membranous glomerulonephritis are idiopathic. A few cases are associated with (1) systemic infections, including hepatitis B, malaria, schistosomiasis, syphilis, and leprosy; (2) drugs such as penicillamine, captopril, and heroin; (3) toxic metals such as gold and mercury; (4) neoplasms, including carcinomas, malignant lymphomas, and Hodgkin's lymphoma; (5) collagen diseases such as systemic lupus erythematosus, progressive systemic sclerosis, and mixed connective tissue disease; and (6) miscellaneous conditions including renal vein thrombosis and sickle cell disease.

Idiopathic membranous glomerulonephritis is characterized by the presence of IgG and complement as granular deposits in the subepithelial region indicative of a chronic antigen-antibody reaction. Circulating immune complexes are rarely present. It has been suggested that the mechanism of injury is via antibodies produced against non-GBM antigens in the basement membrane—either intrinsic (in the idiopathic form, which resembles Heymann's nephritis in experimental rats) or extrinsic planted antigens (in the secondary forms of the disease).

The mechanism whereby the antigen-antibody reaction causes injury is also unknown. Complement fixation occurs but does not cause inflammation. Rather, it increases membrane permeability, probably by action of the toxic C56789 complex, and stimulates synthesis of basement membrane material.

Pathology

Light and electron microscopy permit recognition of three stages of the disease (Figure 48-6; see also Table 48-3):

1. Stage I is characterized by the deposition of dome-shaped subepithelial electron-dense deposits. At this stage, the basement membrane is near normal, and a misdiagnosis of minimal change glomerular disease may be made on light microscopy. Protein leakage from the glomerulus leads to epithelial foot process fusion, but membranous glomerulonephritis can be distinguished from minimal change disease by the presence of electron-dense immune complex deposits.

2. Stage II is characterized by spikes of basement membrane material protruding outward toward the epithelial side between the deposits, which are now larger. These basement membrane spikes are seen on light microscopy with silver stains (deposits are not stained).

3. In stage III, the spikes enlarge and fuse on the epithelial side of the deposits; on silver stains, the basement membrane now appears to be split, connected by the spikes (giving an appearance on silver stain that has been likened to a chain with the unstained immune complex deposits appearing as bubbles or holes between the links of the chain). At this stage, basement membrane thickening can be detected on routine light microscopy (Figure 48-7).

There is no hypercellularity of the glomerulus in pure membranous glomerulonephritis. With progression, increasing thickness of the basement membrane converts the glomerulus into a hyaline mass. The changes of idiopathic membranous glomerulonephritis are identical to those of secondary disease.

Immunofluorescence shows granular deposits of IgG and C3 corresponding to the subepithelial deposits.

Clinically, patients with membranous glomerulonephritis present with either the nephrotic syndrome or asymptomatic proteinuria. The proteinuria is nonselective. Hematuria is absent in the early stage of the idiopathic disease.

Most patients have a slow progression to chronic renal failure. Recent evidence suggests that 70% of patients are alive at 10 years. The prognosis is better in females and much better in children.

Membranoproliferative glomerulonephritis is characterized by the presence of a combination of thickening of the capillary wall and proliferation of mesangial cells. Two distinct patterns are recognized (Figure 48-8).

Membranoproliferative Glomerulonephritis Type I (with Subendothelial Deposits)

Type I membranoproliferative glomerulonephritis accounts for 65% of cases. It is characterized by deposition of subendothelial immune complexes in the glomerular capillary. Most cases have no known cause.

Light microscopy shows diffuse thickening of capillary walls and proliferation of mesangial cells. The basement membrane appears to be split (double-contour, or tram-track, appearance). Immunofluorescence shows granular deposition of IgG and C3 in the capillary wall. Electron microscopy shows the diagnostic subendothelial deposits.

Clinically, type I is a disease of children and young adults who present with nephrotic syndrome or a mixed nephrotic-nephritic pattern. Serum C3 levels are decreased in the majority of cases. Progression is variable, but the overall prognosis is poor.

Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease)

Type II membranoproliferative glomerulonephritis accounts for the remaining 35% of cases. It is characterized by a dense intramembranous ribbon-like deposit on electron microscopy, leading to basement membrane thickening.

Light microscopy shows an eosinophilic, refractile, uniformly thickened basement membrane. Mesangial proliferation is less prominent than in type I. Immunofluorescence shows granular deposition of C3 in the capillary wall and mesangium. Immunoglobulins are not found.

Clinically, children and young adults tend to be affected most frequently. Presentation is identical to that of type I. Serum C3 levels are low, but C1q, C2, and C4 levels are normal, suggesting C3 activation by the alternative pathway. Almost all patients have C3 nephritogenic factor in the serum. C3 nephritogenic factor is an IgG autoantibody that binds to alternative pathway C3 convertase. The mechanism by which this is related to glomerular injury is unknown. The prognosis is poor.

Focal glomerulosclerosis is an uncommon disease that accounts for 10% of cases of nephrotic syndrome in children and young adults. The cause is unknown. In a few patients, focal glomerulosclerosis is associated with intravenous heroin abuse, and a few cases have been described in human immunodeficiency virus (HIV)-positive patients, in whom the virus is present in glomerular and tubular epithelial cells.

Pathology

Focal glomerulosclerosis is characterized by the presence of a focal segmental sclerotic area (pink hyaline material) in the peripheral part of the glomerulus, frequently near the hilum. Lipid droplets are often present as vacuoles in the sclerotic area. The glomeruli affected first are in the juxtamedullary (deep cortical) region, and a superficial renal biopsy may easily miss the involved glomeruli, leading to a diagnosis of minimal change glomerulonephritis. (Many cases of steroid-resistant minimal change glomerulonephritis prove to be focal glomerulosclerosis.)

Immunofluorescence shows granular IgM, C3, and sometimes IgA, and fibrinogen deposition in the affected glomeruli. Electron microscopy shows an increase in the amount of mesangial matrix and collapse of the glomerular capillaries in areas of glomerulosclerosis. Epithelial cell foot processes are fused. In some areas, there is a loss of epithelial cells. Epithelial cell damage is believed important in pathogenesis.

Clinical Features

Focal glomerulosclerosis is associated with nephrotic syndrome or asymptomatic proteinuria. The proteinuria is nonselective. Prognosis is poor, with slow progression to chronic renal failure. Focal glomerulosclerosis associated with HIV infection has a much worse prognosis, with renal failure developing 6–12 months from onset. There is no response to corticosteroid therapy. A few patients have disease recurring in the allografts after renal transplantation.

Glomerulonephritis is a common manifestation of numerous collagen disorders and systemic vasculitides. These diseases are described elsewhere (Chapter 68: Diseases of Joints & Connective Tissue), and only the renal manifestations are summarized here.

Systemic Lupus Erythematosus (SLE)

Renal involvement (lupus nephritis) is the most common cause of death in SLE and the presenting feature in 5% of patients with SLE. Clinical manifestations include proteinuria, microscopic hematuria, nephrotic syndrome, acute nephritic syndrome, and renal failure. During the phase of active disease, serum complement levels are decreased.

Light microscopy shows a variety of changes (Table 48-5). Focal and diffuse proliferation of capillary endothelial cells is the most serious microscopic abnormality. Mesangial hypercellularity is more common but less ominous. Diffuse or segmental basement membrane thickening produces the typical wire loop lesions (Figure 48-9) of SLE. Small, ill-defined basophilic bodies (hematoxyphil bodies) may rarely be found in areas of glomerular damage and are specific for SLE. Immunofluorescence shows lumpy IgG and C3 in the glomerular basement membrane and mesangium. Electron microscopy shows large immune complexes in the subendothelial, mesangial, and subepithelial regions. Wire loop lesions correspond with the presence of large subendothelial deposition of immune complexes and can be distinguished from membranous glomerulonephritis of SLE, in which there are subepithelial deposits.

The clinical features and prognosis depend on the histologic class of disease (Table 48-5). Eventually, many patients with SLE glomerular disease progress to chronic renal failure.

Polyarteritis Nodosa

Renal involvement is present in 80% of cases of polyarteritis nodosa. Thirty percent of patients with polyarteritis nodosa die of renal failure.

Grossly, the kidneys are reduced in size and show evidence of infarction and multiple hemorrhages. Light microscopy shows fibrinoid necrosis, inflammation, thrombosis, aneurysm formation, and rupture of the segmental and arcuate arteries. The chronic lesions in the vessels are dominated by fibrosis of the wall and are not specific for polyarteritis.

Microscopically, glomeruli show fibrinoid necrosis and proliferative changes with crescents. Immunofluorescence shows immunoglobulin (mainly IgG) and fibrin in areas of fibrinoid necrosis. The increased incidence of serum positivity for hepatitis B surface antigen suggests that renal lesions are mediated by immune complexes formed with this antigen in some patients with polyarteritis.

Clinically, renal involvement is usually manifested as hematuria, proteinuria, and hypertension. A minority of patients have antineutrophil cytoplasmic antibodies (ANCA) in the serum. Rapidly progressive renal failure is common.

Wegener's Granulomatosis

Renal involvement is one part of the classic triad of features of Wegener's granulomatosis—the others being upper respiratory tract and lung involvement. Antineutrophil cytoplasmic antibodies (ANCA) are present in 95% of patients. Renal disease occurs in 90% of cases and is characterized by proteinuria, hematuria, and rapidly progressive renal failure.

Light microscopy shows a necrotizing granulomatous arteritis involving small- and medium-sized arteries. The glomeruli show a focal segmental proliferative glomerulonephritis. Fibrinoid necrosis, capillary thrombosis, and epithelial crescent formation are common. Immunofluorescence shows granular deposits of IgA, C3, and fibrinogen in the glomerular capillary wall.

Chronic glomerulonephritis is a common pathologic lesion in the kidney that probably represents the end stage of many diseases affecting glomeruli (Figure 48-1). Most patients give a past history suggestive of glomerular disease. In 20% of patients, the first presentation is at the end stage with chronic renal failure.

Grossly, the kidneys are greatly reduced in size, and the cortex shows a finely irregular surface (granular contracted kidney; Figure 48-10). The cortex is narrowed, corticomedullary demarcation is obscured, and the arteries stand out because of thickened walls.

Microscopically, the narrowed cortex shows a great decrease in the number of nephrons. Glomeruli show diffuse sclerosis, with many converted to hyaline balls (Figure 48-11). There is atrophy of intervening tubules, and residual tubules often show dilation and are filled with pink proteinaceous material (thyroidization). Interstitial fibrosis is present and may be severe.

Immunofluorescence and electron microscopy show variable changes. Less fibrotic glomeruli may show evidence of electron-dense deposits containing IgG, IgA, and C3. These are important in distinguishing chronic glomerulonephritis from other conditions such as hypertensive nephrosclerosis and chronic pyelonephritis that may result in sclerosis of glomeruli, granular contraction of the kidneys, and chronic renal failure. Immunoglobulin and complement deposition are not present in chronic pyelonephritis and hypertensive nephrosclerosis.

Clinically, patients show chronic renal failure and hypertension and frequently have microscopic hematuria, proteinuria, and sometimes nephrotic syndrome.

Ten percent of patients with type II (adult-onset) diabetes mellitus die of chronic renal failure. The incidence of renal disease is still higher in type I (juvenile-onset) diabetes. With the high frequency of diabetes in the population, diabetic nephropathy is one of the more common renal diseases in adults.

Diabetic nephropathy is the result of diabetic microangiopathy (see Chapter 46: The Endocrine Pancreas (Islets of Langerhans)) and is almost invariably associated with diabetic retinopathy. There is controversy about whether strict control of diabetes mellitus prevents the occurrence of nephropathy.

Pathology

Grossly, the kidney shows little abnormality in all but the most severe cases, when the organ may be contracted and show fine scarring. Light microscopy shows several changes (Figure 48-12; see also Chapter 46: The Endocrine Pancreas (Islets of Langerhans)), the most common of which are capillary basement membrane thickening and focal and diffuse glomerulosclerosis. Electron microscopy of the focal nodular lesions shows them to be composed of increased mesangial matrix material. There are no discrete electron-dense deposits, and immunofluorescence is negative.

Clinical Features

Diabetic nephropathy presents with proteinuria, which may be sufficient to lead to nephrotic syndrome. Hypertension is commonly present. The renal lesion is progressive and causes progressive chronic renal failure. Diabetics also have an increased incidence of acute pyelonephritis.

Renal Amyloidosis

(See Chapter 2: Abnormalities of Interstitial Tissues)

The kidneys are almost always affected in secondary amyloidosis and in about 30% of cases of primary amyloidosis.

Amyloid deposition occurs mainly in the glomerular capillaries, where it appears as a homogeneous thickening of the basement membrane. In severe cases, the entire glomerulus is converted into a ball of amyloid (Figure 48-13). Amyloidosis can be diagnosed by the presence of apple-green birefringence when Congo red-stained sections are examined under polarized light. Electron microscopy shows the diagnostic amyloid fibrillar material.

Clinically, deposition of amyloid increases the permeability of the glomerular capillary, resulting in proteinuria and the nephrotic syndrome. Amyloidosis is a progressive disease that usually results in chronic renal failure, a common cause of death in patients with amyloidosis.

Many other diseases produce glomerular damage that may result in acute or chronic renal failure. Malignant hypertension is described elsewhere (see Chapter 20: The Blood Vessels). Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome produce coagulation in glomerular capillaries (see Chapter 27: Blood: IV. Bleeding Disorders). Subacute infective endocarditis leads to microemboli and immune complex-mediated glomerulonephritis (see Chapter 22: The Heart: II. Endocardium & Cardiac Valves). Preeclampsia-eclampsia of pregnancy produces swelling of glomerular cells with glomerular ischemia (see Chapter 55: Diseases of Pregnancy; Trophoblastic Neoplasms).