Antigen identification in membranous nephropathy moves toward targeted monitoring and new therapy

Membranous nephropathy, a disease characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane, is the most common cause of idiopathic nephrotic syndrome in Caucasian adults. In the rat model described by Heymann in 1959, the target antigen of antibodies is megalin, a multiligand receptor expressed in the rat glomerulus but absent from the human glomerulus. In the past few years, two major antigens have been identified in human membranous nephropathy. The first is neutral endopeptidase, the alloantigen involved in neonatal cases of membranous nephropathy that occur in newborns from neutral endopeptidase-deficient mothers. The second is the type-M phospholipase A2 receptor (PLA(2)R), the first autoantigen identified in idiopathic membranous nephropathy in the adult. Megalin, neutral endopeptidase, and PLA(2)R are all expressed on the podocyte surface where they serve as targets for circulating antibodies, which lead to in situ immune complex formation, complement activation, and proteinuria. The recent discovery of neutral endopeptidase and PLA(2)R provides new tools for monitoring human disease activity and should be of value in designing new antigen-driven therapeutic strategies.