Membranous Nephropathy: Recent Travels and New Roads Ahead

Insights from experimental studies have been recently translated into substantial advances in understanding the pathogenesis of human membranous nephropathy (MN). These include identification of neutral endopeptidase (NEP) as the target antigen in alloimmune MN resulting from fetomaternal immunization in NEP-deficient mothers, and our demonstration that a high proportion of patients with idiopathic MN (IMN) have circulating antibodies to the M-type phospholipase A2 receptor (PLA2R), a transmembrane protein located on podocytes. Here we highlight the studies that led to these discoveries and our current knowledge about the possible role of anti-PLA2R autoantibodies in the pathogenesis of IMN. Given that the sensitivity and specificity of anti-PLA2R for IMN are >75 and 100%, respectively, we foresee that a widely available assay for anti-PLA2R will prove to be valuable for diagnosing IMN, distinguishing it from secondary MN, and evaluating response to therapy. We suggest reasons why 25% of patients with IMN have tested negative for anti-PLA2R, and propose possible explanations for the presence of complement deposits in IMN despite the fact that immunoglobulin G4 (IgG4), the predominant anti-PLA2R IgG subclass, is incapable of activating the classical complement pathway. Finally, we point out avenues to be explored, including the events that induce production of anti-PLA2R, their ability to cause podocyte injury, the role of complement, and the nature of the antibodies in secondary forms of MN.