• Felicitas E Hengel, Silke Dehde, Moritz Lassé, Gunther Zahner, Larissa Seifert, Annabel Schnarre, Oliver Kretz, Fatih Demir, Hans O Pinnschmidt, Florian Grahammer, Renke Lucas, Lea Maxima Mehner, Tom Zimmermann, Anja M Billing, Jun Oh, Adele Mitrotti, Paola Pontrelli, Hanna Debiec, Claire Dossier, Manuela Colucci, Francesco Emma, William E Smoyer, Astrid Weins, Franz Schaefer, Nada Alachkar, Anke Diemert, Julien Hogan, Elion Hoxha, Thorsten Wiech, Markus M Rinschen, Pierre Ronco, Marina Vivarelli, Loreto Gesualdo, Nicola M Tomas, Tobias B Huber, and International Society of Glomerular Disease.
• From the III. Department of Medicine (F.E.H., S.D., M.L., G.Z., L.S., A.S., O.K., F.G., R.L., L.M.M., E.H., M.M.R., N.M.T., T.B.H.) and the Departments of Medical Biometry and Epidemiology (H.O.P.), Pathology (T.Z., T.W.), Pediatric Nephrology (J.O.), and Obstetrics and Fetal Medicine (A.D.), Hamburg Center for Kidney Health (F.E.H., S.D., M.L., G.Z., L.S., A.S., O.K., F.G., R.L., L.M.M., J.O., E.H., M.M.R., N.M.T., T.B.H.), and the Hamburg Center for Translational Immunology (N.M.T., T.B.H.), University Medical Center Hamburg-Eppendorf, Hamburg, and the Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg (F.S.) - all in Germany; the Department of Biomedicine, Aarhus University, Aarhus, Denmark (F.D., A.M.B., M.M.R.); the Department of Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis, and Transplantation Unit, University of Bari Aldo Moro, Bari (A.M., P.P., L.G.), and the Division of Nephrology, Bambino Gesù Children's Hospital, IRCCS, Rome (M.C., F.E., M.V.) - both in Italy; INSERM, Unité Mixte de Recherche S 1155, Sorbonne Université (H.D., P.R.), and the Pediatric Nephrology Department, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris (C.D., J.H.), Paris, and the Division of Nephrology, Centre Hospitalier du Mans, Le Mans (P.R.) - all in France; the Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, and the Department of Pediatrics, Ohio State University College of Medicine - both in Columbus (W.E.S.); the Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School - both in Boston (A.W.); and the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (N.A.).
• N. Engl. J. Med. 2024 Aug 1; 391 (5): 422433422-433.

BackgroundMinimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear.MethodsWe conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin.ResultsThe study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice.ConclusionsIn this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).Copyright © 2024 Massachusetts Medical Society.

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