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Membranous Nephropathy

Membranous nephropathy is a distinct pathologic entity characterized by thickened basement membranes and monotonous granular deposits distributed in the epimembranous space of virtually all glomerular capillaries. Membranous nephropathy can be seen in association with various disorders. In several of these disorders, there is evidence that specific antigen-antibody systems account for the glomerular deposits. Examples include viral antigens in hepatitis, treponemal antigens in syphilis, tumor antigens in carcinoma of the lung and colon, and nuclear antigens in SLE. The specific antigens responsible for idiopathic membranous nephropathy have not been identified.

Clinical Features

Membranous nephropathy occurs most often in adults older than age 40. Children are rarely affected, although the disorder can occur in patients of any age. There is a male predominance of 2:1. Virtually all patients manifest proteinuria. Most patients present with a “pure” nephrotic syndrome in which proteinuria may be selective or nonselective and is often severe. Microscopic hematuria is present in 40% of patients, but red blood cell casts are rare. Hypertension and renal failure occur only late in the course. Laboratory findings include normal serum complement levels. Abnormalities in blood such as hepatitis B antigenemia, rheumatoid factors, and cryoglobulins may suggest an associated systemic disorder.

Causes

Membranous nephropathy is often seen in association with underlying malignancies, especially in older patients; 20% to 25% of patients older than age 60 have a coexisting malignancy. Membranous nephropathy is also seen in association with numerous infections such as hepatitis B and syphilis, with collagen vascular diseases such as SLE, and after therapy with organic gold salts or penicillamine (agents often used to treat patients with rheumatoid arthritis).

Pathology

In the early phases of membranous nephropathy, the light microscopic picture of glomeruli may be normal. With more advanced disease, there is thickening of the basement membranes best appreciated with periodic acid-Schiff stain . Silver methenamine stains may demonstrate darkly staining spikes protruding from the capillary basement membrane. The glomeruli may show normal cellularity or may have a modest increase in mesangial cells and matrix. Immunofluorescence staining reveals a granular pattern of IgG and usually C3 along the basement membrane of all glomerular capillary loops. IgA and IgM are less common, except in cases caused by SLE. Electron microscopy further delineates the light microscopic findings. In the early stages, numerous small electron-dense deposits are present in an epimembranous pattern (stage I). With progression, basement membrane material is interposed between the deposits (stage II). Later still, the membrane material extends outward surrounding the deposits (stage III). Finally (stage IV), the deposits become granular or lucent, leaving a thickened, scarred membrane. Deposits may also be present in the mesangium, especially in secondary forms of the disease.

Course

The clinical course of membranous nephropathy varies widely. Although membranous nephropathy is an uncommon cause of the nephrotic syndrome in children, the prognosis is relatively favorable, with a high rate of permanent remission and a 10-year mortality of only 10%. Adults may also have complete or partial remissions and sometimes have a course of repeated exacerbations and remissions. In about half of adult cases, however, proteinuria persists, and the condition progresses slowly to renal failure over 5 to 15 or more years. Male sex, older age at onset, severe proteinuria, and renal insufficiency all suggest a worse prognosis.