Electron microscopy of biopsy specimens from patients with membranous nephropathy demonstrate subepithelial deposits, leading to the hypothesis that immune complexes form in situ against antigens that are present on the podocyte foot process plasma membrane.
Perhaps the strongest evidence in support for this mechanism comes from the relatively recent (Debiec et al, Lancet 2004) discovery that neonatal membranous nephropathy can result from antibodies against a podocyte protein, neutral endopeptidase (NEP).
NEP typically functions to cleave biologically active peptides and is present on the podocyte membrane. Interestingly, there are women with truncating mutations in NEP who do not express any NEP. After multiple pregnancies, they develop anti-NEP antibodies, which are able to cross the placenta and cause significant nephrotic syndrome, including substantial subepithelial deposits, in the developing fetus. The nephrotic syndrome fortunately subsides with disappearance of the maternal anti-NEP antibody from the circulation, and the membranous phenotype can be successfully transmitted to rabbits following injection of maternal serum.
While certainly interesting and suggestive of a common mechanism in membranous-induced nephrotic syndrome, neutral endopeptidase is probably not the crucial antigen in most cases of membranous nephropathy.