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. 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
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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