Membranous nephropathy (MN) has been recognized as a distinct morphological entity for over 50 years, but it is only recently that the underlying pathogenesis of the primary form of the disorder has been elucidated. This brief overview catalogues recent advances in understanding the pathogenesis of MN, focused mainly on its primary form. These studies have enumerated and identified several autologous podocyte antigens that serve as targets of autoantibody responses in primary MN. The dominant autoantigen is M-type phospholipase A2 receptor protein (PLA2R1) expressed on the surface of native glomerular podocytes. Autoantibodies to PLA2R1, usually of IgG4 subclass, are found in about 80% of patients with primary MN. These autoantibodies bind to genetically determined, conformational epitopes on PLA2R1, form immune complexes in situ and induce proteinuria, mostly likely via local activation of complement via the mannose-binding lectin pathway. The autoimmune response is modulated by genes at the HLA-DQA1 locus. The level of autoantibody to PLA2R correlates with the severity of the clinical disease and may predict recurrences in renal allografts, at least in some patients. Most forms of secondary MN appear to be due to distinctly different pathogenetic mechanisms.
Copyright © 2013 S. Karger AG, Basel.