Autoantibodies Targeting Nephrin in Podocytopathies.
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Hengel Felicitas E, Dehde Silke, Lassé Moritz, Zahner Gunther, Seifert Larissa, Schnarre Annabel, Kretz Oliver, Demir Fatih, Pinnschmidt Hans O, Grahammer Florian, Lucas Renke, Mehner Lea Maxima, Zimmermann Tom, Billing Anja M, Oh Jun, Mitrotti Adele, Pontrelli Paola, Debiec Hanna, Dossier Claire, Colucci Manuela, Emma Francesco, Smoyer William E, Weins Astrid, Schaefer Franz, Alachkar Nada, Diemert Anke, Hogan Julien, Hoxha Elion, Wiech Thorsten, Rinschen Markus M, Ronco Pierre, Vivarelli Marina, Gesualdo Loreto, Tomas Nicola M, Huber Tobias B, International Society of Glomerular Disease
Аннотация
METHODS: We 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.
RESULTS: The 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.
CONCLUSIONS: In 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.).