22-19: Membranous Nephropathy

GENERAL CONSIDERATIONS

Membranous nephropathy is the most common cause of primary nephrotic syndrome in adults, most often presenting in the fifth and sixth decades. Primary membranous nephropathy is an autoimmune disease with reactivity against several possible podocyte antigens. In 80% of cases, there are circulating antibodies against the phospholipase A₂ receptor (PLA₂R); roughly 10% involve reactivity against podocyte antigen thrombospondin type-1 domain-containing 7A (THSD7A). Secondary disease is associated with infections, such as hepatitis B and C, endocarditis, and syphilis; underlying carcinomas (some of these cases may also involve autoimmunity to THSD7A); autoimmune disease, such as SLE, mixed connective tissue disease, and thyroiditis; and certain drugs, such as NSAIDs and captopril. The course of primary disease is highly variable, with spontaneous remission in approximately 30% of patients and progression to ESKD over 3–10 years in 50%. Poorer outcome is associated with concomitant tubulointerstitial fibrosis, male sex, elevated serum creatinine on presentation, hypertension, and proteinuria greater than 10 g/day.

Patients with membranous nephropathy and nephrotic syndrome have a higher risk of hypercoagulable state with thrombosis than nephrosis from other etiologies, including a particular predisposition to renal vein thrombosis.

CLINICAL FINDINGS

A. Symptoms and Signs

Patients may be asymptomatic or may have edema or frothy urine. Symptomatic venous thrombosis may be an initial sign. There may be symptoms or signs of an underlying infection or neoplasm (especially lung, stomach, breast, and colon cancers) in secondary membranous nephropathy.

B. Laboratory Findings

Hypoalbuminemia and hyperlipidemia are characteristic laboratory findings in the nephrotic syndrome. Evaluation for secondary causes including serologic testing for SLE, syphilis, and viral hepatitides, and age- and risk-appropriate cancer screening should be performed. Elevated titer of circulating PLA₂R antibodies is now considered diagnostic for primary membranous nephropathy and may eliminate the need for kidney biopsy. PLA₂R antibody titers can be followed during treatment. Kidney biopsy findings in membranous nephropathy include increased capillary wall thickness without inflammatory changes or cellular proliferation (eFigure 22–15); when stained with silver methenamine, a “spike and dome” pattern results from projections of excess GBM between the subepithelial immune complex deposits (eFigure 22–16). Immunofluorescence shows IgG and C3 staining along capillary loops (eFigure 22–17). Electron microscopy shows a discontinuous pattern of dense deposits along the subepithelial surface of the basement membrane.