Anti-nephrin Autoantibodies Cause Minimal Change Disease

Background: Circulating autoantibodies against the podocyte slit diaphragm protein nephrin have recently been identified in patients with podocytopathies. However, whether these autoantibodies cause the observed minimal change disease phenotype with nephrotic syndrome is unknown. Methods: Using immunoprecipitation and subsequent Western blotting, we screened patient-derived anti-nephrin autoantibodies for reactivity with glomerular extracts from multiple species. Anti-nephrin autoantibody containing patient IgG (further referred to as anti-nephrin IgG) or control human IgG was then transferred to animals that were identified to react with anti-nephrin IgG. Upon IgG transfer, animals were monitored for proteinuria, serum anti-nephrin IgG, and morphological lesions. Results: The passive transfer of human anti-nephrin IgG resulted in substantial proteinuria and detectable anti-nephrin IgG in animal serum samples. Anti-nephrin IgG further induced podocyte foot process effacement in the absence of electron-dense deposits in electron microscopy, while Periodic-Acid-Schiff staining revealed no histological changes. Immunofluorescence analyses showed sparse positivity for human IgG at the glomerular filtration barrier, while it was absent in animals that received control IgG. Conclusion: Our study demonstrates for the first time the direct pathogenicity of patient-derived anti-nephrin autoantibodies in the development of a podocytopathy with minimal change lesions. Further studies are necessary to better understand the molecular mechanisms of anti-nephrin autoantibody action on podocytes. Funding: Government Support – Non-U.S.