This action might not be possible to undo. Are you sure you want to continue?
syndrome is the clinical correlate of acute glomerular inflammation. In its most dramatic form, the acute nephritic syndrome is characterized by sudden onset (i.e., over days to weeks) of acute renal failure and oliguria (<400 mL of urine per day). Renal blood flow and glomerular filtration rate (GFR) fall as a result of obstruction of the glomerular capillary lumen by infiltrating inflammatory cells and proliferating resident glomerular cells. Renal blood flow and GFR are further compromised by intrarenal vasoconstriction and mesangial cell contraction that result from local imbalances of vasoconstrictor (e.g., leukotrienes, platelet-activating factor, thromboxanes, endothelins) and vasodilator substances (e.g., nitric oxide, prostacyclin) within the renal microcirculation. Extracellular fluid volume expansion, edema, and hypertension develop because of impaired GFR and enhanced tubular reabsorption of salt and water. As a result of injury to the glomerular capillary wall, urinalysis typically reveals red blood cell casts, dysmorphic red blood cells, leukocytes, and subnephrotic proteinuria of <3.5 g per 24 h ("nephritic urinary sediment"). Hematuria is often macroscopic. The classic pathologic correlate of the nephritic syndrome is proliferative glomerulonephritis. The proliferation of glomerular cells is due initially to infiltration of the glomerular tuft by neutrophils and monocytes and subsequently to proliferation of resident glomerular endothelial and mesangial cells (endocapillary proliferation). In its most severe form, the nephritic syndrome is associated with acute inflammation of most glomeruli, i.e., acute diffuse proliferative glomerulonephritis. When less vigorous, fewer than 50 percent of glomeruli may be involved, i.e., focal proliferative glomerulonephritis. In milder forms of nephritic injury, cellular proliferation may be confined to the mesangium, i.e., mesangioproliferative glomerulonephritis. RPGN is the clinical correlate of more subacute glomerular inflammation. Patients develop renal failure over weeks to months in association with a nephritic urinary sediment, subnephrotic proteinuria and variable oliguria, hypervolemia, edema, and hypertension. The classic pathologic correlate of RPGN is crescent formation involving most glomeruli (crescentic glomerulonephritis), crescents being half-moonshaped lesions in Bowman's space composed of proliferating parietal epithelial cells and infiltrating monocytes (extracapillary proliferation). In practice, the clinical term rapidly progressive glomerulonephritis and the pathologic term crescentic glomerulonephritis are often used interchangeably. In addition to classic crescentic glomerulonephritis, in which crescents dominate the glomerular pathology, crescents can also develop concomitantly with proliferative glomerulonephritis or as a complication of membranous glomerulopathy and other more indolent forms of glomerular inflammation. The acute nephritic syndrome and RPGN are part of a spectrum of presentations of immunologically mediated proliferative glomerulonephritis. Studies of experimental models suggest that nephritic syndrome and diffuse proliferative glomerulonephritis represent an acute immune response to a sudden large antigen load, whereas RPGN and crescentic glomerulonephritis represent a more subacute immune response to a smaller antigen load in presensitized individuals. At the other end of the spectrum, chronic low-grade immune injury presents with slowly progressive renal insufficiency or asymptomatic hematuria in association with focal proliferative or mesangioproliferative glomerulonephritis. These more indolent forms of immune-mediated glomerulonephritis are discussed later in this chapter.
ETIOLOGY AND DIFFERENTIAL DIAGNOSIS Acute nephritic syndrome and RPGN can result from renal-limited primary glomerulopathy or secondary glomerulopathy complicating systemic disease. Figure 274-1 highlights the histopathologic and serologic features that help distinguish among the major causes of nephritic syndrome and RPGN. In general, rapid diagnosis and prompt treatment are critical to avoid the development of irreversible renal failure. Renal biopsy remains the "gold standard" for diagnosis. Immunofluorescence microscopy is particularly helpful and identifies three major patterns of deposition of immunoglobulin that define three broad diagnostic categories: (1) granular deposits of immunoglobulin, a hallmark of immune-complex glomerulonephritis; (2) linear deposition of immunoglobulin along the glomerular basement membrane (GBM), characteristic of anti-GBM disease; and (3) paucity or absence of immunoglobulin, typical of pauci-immune glomerulonephritis (Fig. 274-2). Most patients (>70 percent) with full-blown acute nephritic syndrome have immune-complex glomerulonephritis. Pauci-immune glomerulonephritis is less common in this setting (<30 percent) and anti-GBM disease is rare (<1 percent). Among patients with RPGN, immune-complex glomerulonephritis and pauci-immune glomerulonephritis are equally prevalent (~45 percent each), whereas anti-GBM disease again accounts for a minority of cases (<10 percent). Three serologic markers often predict the immunofluorescence microscopy findings in nephritic syndrome and RPGN and may obviate the need for renal biopsy in classic cases. They are the serum C3 level and titers of anti-GBM antibody and antineutrophil cytoplasmic antibody (ANCA) (Fig. 274-1). As discussed in Chap. 273, the kidney is host to immune attack in immune-complex glomerulonephritis, most cases being initiated either by in situ formation of immune complexes or less commonly by glomerular trapping of circulating immune complexes. These patients typically have hypocomplementemia (low C3 and CH50 in 90 percent) and negative anti-GBM and ANCA serology. The glomerulus is the direct target of immune attack in anti-GBM disease, glomerular inflammation being initiated by an autoantibody directed at a 28-kDa autoantigen on the α3 chain of type IV collagen. Approximately 90 to 95 percent of patients with anti-GBM disease have circulating anti-GBM autoantibodies detectable by radioimmunoassay; serum complement levels are typically normal, and ANCA are usually not detected. The pathogenesis of pauci-immune glomerulonephritis is still being defined; however, most patients have circulating ANCA, implicating dysregulation of humoral immunity. The presence of mononuclear leukocytes in glomeruli and the paucity of glomerular immune deposits suggest that cellular mechanisms are also involved. Serum complement levels are typically normal, and anti-GBM titers are usually negative in ANCA-associated renal disease. IMMUNE-COMPLEX GLOMERULONEPHRITIS Immune-complex glomerulonephritis may (1) be idiopathic, (2) represent a response to a known antigenic stimulus (e.g., postinfectious glomerulonephritis), or (3) form part of a multisystem immune-complex disorder (e.g., lupus nephritis, Henoch-Schonlein purpura, cryoglobulinemia, bacterial endocarditis; Fig. 274-1). Here, we focus on postinfectious glomerulonephritis, the best characterized primary immunecomplex glomerulonephritis. The major secondary immune-complex glomerulonephritides are discussed in Chap. 275. Nephritic syndrome and RPGN occasionally complicate two other primary glomerulopathies, namely, membranoproliferative glomerulonephritis (MPGN) and IgA nephropathy when there is a florid proliferative component. Because nephrotic syndrome and asymptomatic hematuria are more common presentations of MPGN and IgA nephropathy, respectively, these glomerulopathies are discussed in later sections on nephrotic syndrome and asymptomatic urinary abnormalities.
POSTSTREPTOCOCCALGLOMERULONEPHRITIS This is the prototypical postinfectious glomerulonephritis and a leading cause of acute nephritic syndrome. Most cases are sporadic, though the disease can occur as an epidemic. Glomerulonephritis develops, on average, 10 days after pharyngitis or 2 weeks after a skin infection (impetigo) with a nephritogenic strain of group A beta-hemolytic streptococcus. The known nephritic strains include M types 1, 2, 4, 12, 18, 25, 49, 55, 57, and 60. Immunity to these strains is type-specific and long-lasting, and repeated infection and nephritis are rare. Epidemic poststreptococcal glomerulonephritis is most commonly encountered in children of 2 to 6 years of age with pharyngitis during the winter months. This entity appears to be decreasing in frequency, possibly due to more widespread and prompt use of antibiotics. Poststreptococcal glomerulonephritis in association with cutaneous infections usually occurs in a setting of poor personal hygiene or streptococcal superinfection of another skin disease. The classic clinical presentation of poststreptococcal glomerulonephritis is full-blown nephritic syndrome with oliguric acute renal failure; however, most patients have milder disease. Indeed, subclinical cases outnumber overt cases by four- to tenfold during epidemics. Patients with overt disease present with gross hematuria (red or "smoky" urine), headache, and generalized symptoms such as anorexia, nausea, vomiting, and malaise. Swelling of the renal capsule can cause flank or back pain. Physical examination reveals hypervolemia, edema, and hypertension. The urinary sediment is nephritic, with dysmorphic red blood cells, red cell casts, leukocytes, occasionally leukocyte casts, and proteinuria. Fewer than 5 percent of patients develop nephrotic-range proteinuria. The latter may only manifest as acute nephritis resolves and renal blood flow and GFR recover. Coexistent rheumatic fever is extremely rare. The serum creatinine is typically elevated at presentation [88 to 177 umol/L (1 to 2 mg/dL)]. Serum C3 levels and CH50 are depressed within 2 weeks in ~90 percent of cases. C4 levels are characteristically
normal, indicating activation of the alternate pathway of complement. Complement levels usually return to normal within 6 to 8 weeks. Persistently depressed levels after this period should suggest another cause, such as the presence of a C3 nephritic factor (see "Membranoproliferative Glomerulonephritis"). The majority of patients (>75 percent) have transient hypergammaglobulinemia and mixed cryoglobulinemia. The antecedent streptococcal infection may still be evident or may have resolved either spontaneously or in response to antibiotic therapy. Most patients (>90 percent) have circulating antibodies against streptococcal exoenzymes such as antistreptolysin O (ASO), anti-deoxyribonuclease B (anti-DNAse B), antistreptokinase (ASKase), anti-nicotinyl adenine dinucleotidase (anti-NADase), and antihyaluronidase (AHase). ASO, anti-DNAse B, anti-NAD, and AHase are most useful after pharyngeal infection, whereas anti-DNAse B and AHase are more sensitive indices of streptococcal skin infection. Antibody titers tend to rise after 7 days, peak after 1 month, and return to normal levels after 3 to 4 months. These tests are relatively specific, with a false-positive rate of <5 percent. Early antibiotic therapy may prevent the development of an antibody response. Acute poststreptococcal glomerulonephritis is usually diagnosed on clinical and serologic grounds, without resort to renal biopsy, especially in children with a typical antecedent history. The characteristic lesion on light microscopy is diffuse proliferative glomerulonephritis. Crescents are uncommon, and extraglomerular involvement is usually mild. Immunofluorescence microscopy reveals diffuse granular deposition of IgG and C3, giving rise to a "starry sky" appearance (Fig. 274-2). More
extensive immunoglobulin deposition throughout the glomerular capillary wall ("garland pattern") is associated with a worse prognosis. The characteristic finding on electron microscopy is the presence of large electron-dense immune deposits in the subendothelial, subepithelial, and mesangial areas. It is likely that the acute inflammatory reaction is initiated, in large part, by the subendothelial and mesangial deposits, which activate complement and trigger leukocyte recruitment and glomerular injury. Subepithelial deposits may be more prominent on electron microscopy, however, probably because the subendothelial and mesangial deposits are scavenged more efficiently by invading phagocytes. Extensive subepithelial immune deposits, or "humps," tend to be associated with worse proteinuria, being juxtaposed to the glomerular filtration barrier for protein. The pathogenesis of immune-complex glomerulonephritis is discussed extensively in Chap. 273. In addition to poststreptococcal glomerulonephritis, the nephritic syndrome and RPGN can complicate acute immune-complex glomerulonephritis due to other viral, bacterial, fungal, and parasitic infections. Several warrant specific mention. Diffuse proliferative immune-complex glomerulonephritis is a welldescribed complication of acute and subacute bacterial endocarditis and is usually associated with hypocomplementemia. The glomerular lesion typically resolves following eradication of the cardiac infection. Shunt nephritis is a syndrome characterized by immune-complex glomerulonephritis secondary to infection of ventriculoatrial shunts inserted for treatment of childhood hydrocephalus. The most common offending organism is coagulase-negative staphylococcus. Renal impairment is usually mild and associated with hypocomplementemia. Nephrotic syndrome complicates 30 percent of cases. Acute proliferative glomerulonephritis can also complicate chronic suppurative infections and visceral abscesses. Patients typically present with a fever of unknown origin and an active urine sediment. Although immune deposits containing IgG and C3 are detected on renal biopsy, serum complement levels are usually normal. TREATMENT Treatment of poststreptococcal glomerulonephritis focuses on eliminating the streptococcal infection with antibiotics and providing supportive therapy until spontaneous resolution of glomerular inflammation occurs. Patients are usually confined to bed during the acute inflammatory phase. Diuretics and antihypertensive agents are employed to control extracellular fluid volume and blood pressure. Dialysis is rarely needed to control hypervolemia or the uremic syndrome. Poststreptococcal glomerulonephritis carries an excellent prognosis and rarely causes ESRD. Microscopic hematuria may persist for as long as 1 year after the acute episode but eventually resolves. Whereas complete recovery is the rule in children, adults may occasionally be left with residual renal impairment. Antiglomerular Basement Membrane Disease Anti-GBM disease is an autoimmune disease in which autoantibodies directed against type IV collagen induce RPGN and crescentic glomerulonephritis. Acute nephritic syndrome is rare. Between 50 and 70 percent of patients have lung hemorrhage; the clinical complex of anti-GBM nephritis and lung hemorrhage is referred to as Goodpasture's syndrome. AntiGBM disease is a rare disorder of unknown etiology with an annual incidence of 0.5 per million. There is a bimodal peak in incidence. Patients with Goodpasture's syndrome are typically young males (5 to 40 years; male-female ratio of 6:1). In contrast, patients presenting during the second peak in the sixth decade rarely suffer lung hemorrhage and have an almost equal sex distribution. The target antigen is a component of the noncollagenous domain (NCI) of the α3 chain of type IV collagen, the α3 chain being preferentially expressed in glomerular and pulmonary alveolar basement membrane. The trigger(s) for loss of self-tolerance to this Goodpasture antigen has not been well defined. A genetic predisposition is
suggested by an association with HLA-DRw2 and occasional occurrence in identical twins. Patients with lung hemorrhage are more likely to be cigarette smokers and to have suffered a recent upper respiratory tract infection or exposure to volatile hydrocarbon solvents. These observations suggest that diverse insults to the alveolar basement membrane may render previously sequestered Goodpasture antigens available for interaction with circulating autoantibodies. It is not clear whether environmental factors also trigger the onset of nephritis. Binding of anti-GBM antibodies to the GBM induces activation of complement, leukocyte recruitment, necrotizing proliferative glomerulonephritis, disruption of the glomerular capillary wall, leakage of fibrin into Bowman's space, and crescent formation (see Chap. 273). A similar sequence of events in the lung leads to disruption of the alveolar capillary wall and pulmonary hemorrhage. Anti-GBM disease commonly presents with hematuria, nephritic urinary sediment, subnephrotic proteinuria, and rapidly progressive renal failure over weeks, with or without pulmonary hemorrhage. When pulmonary hemorrhage occurs, it usually predates nephritis by weeks or months. Hemoptysis can vary from fluffy pulmonary infiltrates on chest x-ray and mild dyspnea on exertion to life-threatening pulmonary hemorrhage. Hypertension is unusual and occurs in fewer than 20 percent of cases. The diagnostic serologic marker is circulating anti-GBM antibodies with a specificity for the NCI domain of the α3 chain of type IV collagen (Fig. 274-1). Anti-GBM antibodies are detected in the serum of >90 percent of patients with anti-GBM nephritis by specific radioimmunoassay. If radioimmunoassay is not available, circulating anti-GBM antibodies can be detected in 60 to 80 percent of patients by indirect immunofluorescence, i.e., by incubating the patient's serum with stored sections of normal human kidneys. Complement levels are normal. About 20 percent of patients have low titers of ANCA, usually a perinuclear ANCA (see Chap. 275), the pathophysiologic significance of which is unclear. Occasional patients have a positive cytoplasmic ANCA, which may signal the presence of coexistent extraglomerular renal vasculitis. Patients with lung involvement frequently have microcytic, hypochromic, iron-deficiency anemia from alveolar hemorrhage, and abnormal bilateral hilar and basilar interstitial shadowing on chest x-ray that may be difficult to distinguish from pulmonary edema or infection. The diffusion capacity for carbon dioxide is a useful tool for distinguishing among the latter diagnoses, being increased in patients with lung hemorrhage due to uptake of carbon monoxide by alveolar blood, and reduced in patients with infection or pulmonary edema. Renal biopsy is the gold standard for diagnosis of anti-GBM nephritis. The typical morphologic pattern on light microscopy is diffuse proliferative glomerulonephritis, with focal necrotizing lesions and crescents in >50 percent of glomeruli (crescentic glomerulonephritis). Immunofluorescence microscopy reveals linear ribbon-like deposition of IgG along the GBM (Fig. 274-2). C3 is present in the same distribution in 70 percent of patients. Prominent IgG deposition along the tubule basement membrane and tubulointerstitial inflammation is found occasionally. Electron microscopy reveals nonspecific inflammatory changes without immune deposits. Typical features on lung biopsy include alveolar hemorrhage, disruption of alveolar septa, hemosiderin-laden macrophages, and linear staining of IgG along the alveolar capillary basement membrane. It should be noted that Goodpasture's syndrome is not the only cause of the pulmonary-renal syndrome (i.e., renal failure and lung hemorrhage). Other important causes of this clinical complex include severe cardiac failure complicated by pulmonary edema (often blood-tinged) and prerenal azotemia; renal failure from any cause complicated by hypervolemia and pulmonary edema; immune-complex- mediated vasculitides such as systemic lupus erythematosus (SLE), Henoch-Schonlein purpura, and
cryoglobulinemia; pauci-immune vasculitides such as Wegener's granulomatosis and polyarteritis nodosa; infections such as Legionnaire's disease; and renal vein thrombosis with pulmonary embolism. In general, these disorders can be differentiated by astute analysis of the clinical, serologic, and histopathologic findings. TREATMENT Prior to the introduction of immunosuppressive therapy, greater than 80 percent of patients with antiGBM nephritis developed ESRD within 1 year, and many patients died from pulmonary hemorrhage or complications of uremia. With early and aggressive use of plasmapheresis, glucocorticoids, cyclophosphamide, and azathioprine, renal and patient survival have improved dramatically. In general, emergency plasmapheresis is performed daily or on alternate days until anti-GBM antibodies are not detected in the circulation (usually 1 to 2 weeks). Prednisone (1 mg/kg per day) is started simultaneously, in combination with either cyclophosphamide (2 to 3 mg/kg per day) or azathioprine (1 to 2 mg/kg per day) to suppress new synthesis of anti-GBM antibodies. The speed of initiation of therapy is a critical determinant of outcome. One-year renal survival approaches 90 percent if treatment is started before serum creatinine exceeds 442 umol/L (5 mg/dL) and falls to about 10 percent if renal failure is more advanced. Patients who require dialysis at presentation rarely recover renal function. Serial anti-GBM titers are monitored to gauge response to therapy. Relapses are not unusual and are often heralded by rising antibody titers. In patients with ESRD, renal transplantation is a viable treatment option. Recurrence of anti-GBM nephritis in the allograft is extremely unusual provided that anti-GBM antibody titers have been consistently negative for 2 to 3 months prior to transplantation. Pauci-Immune Glomerulonephritis The major pauci-immune glomerulonephritides are idiopathic renallimited crescentic glomerulonephritis, microscopic polyarteritis nodosa, and Wegener's granulomatosis (Fig. 274-1). RPGN is a more common clinical presentation than acute nephritic syndrome, and the usual pathology is necrotizing glomerulonephritis with crescents affecting >50 percent of glomeruli (crescentic glomerulonephritis). The marked overlap of clinical features and glomerular histopathology, and the presence of circulating ANCA in most patients, suggest that these entities are a spectrum of a single disease. Here, we focus on idiopathic renal-limited crescentic glomerulonephritis. The ANCAassociated glomerulopathies with extrarenal features, namely Wegener's granulomatosis and microscopic polyarteritis nodosa, are discussed in Chap. 275. Idiopathic Renal-Limited Crescentic Glomerulonephritis This is more common in middle-aged and older patients and shows a slight male preponderance. Patients typically present with RPGN, nephritic syndrome being rare. ANCA, usually a perinuclear ANCA IgG with specificity for myeloperoxidase (see Chap. 275), are detected in 70 to 90 percent of patients (Fig. 274-1). The erythrocyte sedimentation rate and C-reactive protein levels may be elevated; however, C3 levels are typically normal, and circulating immune complexes, cryoglobulins, and anti-GBM antibodies are not detected. Most patients have crescents on light microscopy, often associated with necrotizing glomerulonephritis. Immune deposits are scanty or absent. Immunofluorescence microscopy reveals abundant fibrin deposits within crescents (Fig. 274-2). Most cases are treated aggressively with glucocorticoids, with or without cyclophosphamide or azathioprine (see Chap. 275).