Podocyte Antigens and Glomerular Disease

<i>Background:</i> Membranous nephropathy (MN), a major cause of nephrotic syndrome in the adult, is an immune-mediated disease characterized by the accumulation of subepithelial immune deposits leading to complement activation and podocyte injury. However, the target antigens of circulating antibodies are unknown. Current treatments for patients with MN are entirely empirical, and concept-driven therapies are dramatically lacking. <i>Methods:</i> Specificity of circulating antibodies and composition of glomerular deposits were analyzed in Heymann nephritis (HN), a faithful rat model of MN, and in a subset of patients with antenatal MN. <i>Results:</i> 20 years after the identification of megalin as the podocyte target antigen of nephritogenic antibodies in HN, we identified the human counterpart of megalin, the enzymatic podocyte antigen neutral endopeptidase (NEP). Antibodies to megalin or NEP induce formation of subepithelial immune deposits and of C5b-9, the membrane attack complex of complement. <i>Conclusion:</i> It is likely that antigens involved in idiopathic MN are expressed at the podocyte membrane. Their identification together with that of immunodominant epitopes may lead to specific antigen/ epitope-based immunotherapy aimed at inducing specific tolerance.