Defined as a subacute reduction in GFR of >50%, with evidence of a proliferative GN; causes overlap with those of acute GN (Table 142-2). Broadly classified into three major subtypes on the basis of renal biopsy findings and pathophysiology: (1) immune complex-associated, e.g., in systemic lupus erythematosus (SLE); (2) “pauci-immune,” associated with antineutrophil cytoplasmic antibodies (ANCA); and (3) associated with anti-glomerular basement (anti-GBM) antibodies, e.g., in Goodpasture's syndrome. All three forms will typically have a proliferative, crescentic GN by light microscopy but differ in the results of the immunofluorescence and electron microscopy components of the renal biopsy.
Renal involvement is due to deposition of circulating immune complexes. Clinical features of SLE with or without renal involvement include arthralgias, “butterfly” skin rash, serositis, alopecia (hair loss), and central nervous system disease. Nephrotic syndrome with renal insufficiency is common. Renal biopsy reveals mesangial, focal, or diffuse GN and/or membranous nephropathy. Diffuse GN, the most common finding in renal biopsy series, is typically characterized by an active sediment, severe proteinuria, and progressive renal insufficiency and may have an ominous prognosis. Pts have a positive antinuclear antibody test, anti-dsDNA antibodies, and hypocomplementemia. Treatment includes glucocorticoids and cytotoxic agents. Oral or IV monthly cyclophosphamide is most commonly employed, typically for a period of 6 months; pts of childbearing age should first bank sperm and eggs. Mycophenolate mofetil is an alternative.
Antineutrophil Cytoplasmic Antibody (ANCA)-Associated, Pauci-Immune GN 
May be renal-limited (idiopathic pauci-immune GN) or associated with systemic vasculitis (granulomatosis with polyangiitis [GPA, formerly known as Wegener's] or microscopic polyarteritis nodosa). Defining characteristic is the presence of circulating ANCA. These are detected by immunofluorescence of alcohol-fixed neutrophils; a “perinuclear” pattern (pANCA) is usually due to antibodies against myeloperoxidase (MPO), whereas a “cytoplasmic” pattern (cANCA) is almost always due to reactivity against proteinase-3 (PR3). Confirmatory enzyme-linked immunosorbent assay testing against the MPO and PR3 antigens is mandatory, since the pANCA pattern can be caused by antibodies against other neutrophil components, e.g., lactoferrin; these do not have the same consistent relationship to vasculitis and pauci-immune GN. The anti-MPO or anti-PR3 titer does not always correlate with disease activity.
Pts typically have a prodromal, “flulike” syndrome, which may encompass myalgias, fever, arthralgias, anorexia, and weight loss. There may be associated cutaneous, pulmonary, upper respiratory (sinusitis), or neurologic (mononeuritis monoplex) complications of associated systemic vasculitis. In particular, pulmonary necrotizing capillaritis can lead to hemoptysis and pulmonary hemorrhage.
Standard initial therapy for ANCA-associated rapidly progressive GN includes methylprednisolone and cyclophosphamide; more specific depletion of B cells by anti-CD20 antibody therapy with rituximab is an alternative. Most centers will also utilize plasmapheresis in the initial management of pts with a severe pulmonary-renal syndrome or to stave off dialysis in pts with severe renal impairment. Steroids are quickly tapered soon after the acute inflammation subsides; cyclophosphamide is continued until a stable remission is achieved, typically within 3-6 months. Pts must receive prophylaxis for Pneumocystis carinii (jiroveci) pneumonia (PCP) with trimethoprim-sulfamethoxazole, atovaquone, or dapsone. Some form of maintenance immunosuppression is standard, typically for 12-18 months after achievement of a stable remission; drugs include methotrexate, mycophenolate mofetil, and azathioprine. Notably, however, pts treated with rituximab do not require maintenance oral immunosuppression, but may require maintenance with regular rituximab infusions or repeated rituximab therapy after a recurrence.
Anti-Glomerular Basement Membrane Disease
Caused by antibodies against the α3 NCI (noncollagenous) domain of type IV collagen; circulating anti-GBM antibody and linear immunofluorescence on renal biopsy establish the diagnosis. Pts may have isolated GN; Goodpasture's syndrome encompasses GN and lung hemorrhage. Plasma exchange may produce remission; renal prognosis is worse in those who require dialytic support, with >50% crescents on renal biopsy, or creatinine >5-6 mg/dL. Severe lung hemorrhage is treated with IV glucocorticoids (e.g., 1 g/d × 3 days). Approximately 10-15% will also have ANCA against MPO, some with evidence of vasculitis, e.g., leukocytoclastic vasculitis in the skin.
A generalized vasculitis causing IgA nephropathy, purpura, arthralgias, and abdominal pain; occurs mainly in children. Renal involvement is manifested by hematuria and proteinuria. Serum IgA is increased in half of pts. Renal biopsy is useful for prognosis. Treatment is symptomatic.
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