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Chapter: Essential Clinical Immunology: Immunological Aspects of Renal Disease

Rapidly Progressive Glomerulonephritis

RPGN, or crescentic glomerulonephritis, is a severe form of glomerulonephritis that leads to end-stage renal disease invariably in a matter of weeks.



RPGN, or crescentic glomerulonephritis, is a severe form of glomerulonephritis that leads to end-stage renal disease invariably in a matter of weeks. Patients present with acute nephritis picture associated with progressive loss of renal function. The his-tology on kidney biopsy shows extensive presence of circumferential crescents that tends to compress the glomerular tuft and occlusion of capillary lumens. Rents along the glomerular capillary wall allow inflammatory cells such as macrophages that release cytokines such as IL-1 and TNF. Also, movement of plasma products into the Bowman’s space induces fibrin for-mation. This process is usually followed by formation of fibrocellular crescents, which are not amenable to therapy. Prognosis is worse when about 80 percent of glomeruli are affected.


There are three types of RPGN, depend-ing on the mechanism of injury. RPGN type I or anti-GBM disease (Goodpas-ture’s syndrome) refers to the presence of circulating antibodies to an antigen in the GBM. The antigen has been identified to be the NC1 domain of the alpha-3 chain of type IV collagen. In addition to the role of B cells in producing this antibody, T cells isolated from affected patients also reacted to the same antigen. An anti-CD8 mono-clonal antibody appears to prevent anti-GBM disease in a rodent model (Reynolds et al. 2002). This finding suggests that T cells may enhance production of the anti-body to the alpha-3 chain of the GBM. In addition to renal failure, pulmonary hem-orrhage and hemoptysis can be seen in affected patients. The circulating antibody binds to the alveolar basement membrane, which contains the same alpha-3 chain and causes lung injury. Chest radiograph will show bilateral infiltrates because of pulmonary hemorrhage. The presence of pulmonary involvement is variable, which appears to reflect access of the cir-culating antibody to the alveolar basement membrane. Recent reports have indicated genetic susceptibility to this disease, which is supported by a murine model. In mice immunized with the alpha-3(IV) NC1, development of crescentic glomeru-lonephritis and lung hemorrhage appears in mice with MHC haplotypes H-2s, b and d. Laboratory diagnosis can be made by measurement of anti-GBM antibody titer. Indirect immunofluorescence is done by incubating the patient’s serum with nor-mal renal tissue. Fluorescein-labeled anti-human IgG is then added and checked if linear deposition of IgG can be seen. An ELISA test has been developed using native and recombinant alpha-3(IV) NCI. This test appears to be more accurate. If the tests described are negative, a kidney biopsy is performed. Immunofluorescence will show the characteristic linear deposi-tion of IgG along the glomerular capillar-ies and tubules. The main treatment for anti-GBM disease includes a combination of plasmapheresis, steroids, and cyclo-phosphamide. Plasmapheresis is designed to remove circulating antibodies. Ste-roids and cyclophosphamide will prevent further antibody production. About 40 percent of cases respond to this regimen. Early diagnosis is crucial because a serum creatinine of 5 mg/dl or greater suggests irreversible damage.


Type II RPGN is often considered an immune-complex RPGN. Immune com-plex deposits in the glomeruli suggest the presence of a systemic disease. Diseases associated with this type include PSGN, post-infectious glomerulonephritis, IgA nephropathy, lupus nephritis, and mixed cryoglobulinemia. Treatment of the under-lying disease may or may not improve the clinical picture, especially in advanced renal failure.


Type III RPGN, or pauci-immune glomerulonephritis, is a form of necrotiz-ing glomerulonephritis characterized by minimal or absence of immune depos-its on immunofluorescence or electron microscopy. In addition to renal failure, affected patients will exhibit systemic symptoms related to the respiratory tract, skin, nervous system, and musculoskeletal system. 

Most patients will have ANCA, an antibody that is invariably present in other form of vasculitides (Wegen-er’s granulomatosis, polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, and drug-induced vasculi-tis). Two target antigens have been identi-fied by ANCA – proteinase 3 (PR-3) and myeloperoxidase. Both can be found in the azurophilic granules of neutrophils and lysosomes of monocytes. When etha-nol-fixed neutrophils are incubated with serum from affected patients, two distinct immunofluorescent patterns can be identi-fied. The first is C-ANCA, which pertains to the diffuse staining of the cytoplasm, in contrast to clear nuclear staining. Antibodies against PR-3 antigen appear to exhibit this pattern. The majority of active Wegener’s granulomatosis will exhibit the C-ANCA pattern. P-ANCA refers to the perinuclear staining around the nucleus, which appears to be an artifact of etha-nol fixation. Antibodies to the myeloper-oxidase antigen are associated with this pattern. About 75–80 percent of pauci-immune glomerulonephritis cases exhibit the P-ANCA pattern. ANCA patterns for the other vasculitides are variable, mak-ing it a difficult marker for diagnostic use. Like anti-GBM disease, use of steroids, plasmapheresis, and cytotoxic agents can be attempted to treat this disease.


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