Project Summary/Abstract Minimal change disease and primary focal and segmental glomerulosclerosis are morphologic expressions of a diffuse podocytopathy of to date unknown cause, and all present with acute onset Nephrotic Syndrome. Although the majority of patients achieve clinical remission, relapse and treatment failure is common, and when progressing to end stage kidney disease, the disease frequently and vigorously recurs in the allograft. We recently published a groundbreaking study that identified circulating autoantibodies against the extracellular domain of nephrin in a subset of adults and children with non-genetic Minimal Change Disease and in a single patient with recurrent disease in the allograft, which correlate with disease activity. Our findings underpin the paradigm-shifting hypothesis that at least a subset of these diseases are mediated by an organ- specific, antibody-mediated autoimmune disease of B cell origin which causes an acquired diffuse podocytopathy by means of direct action of the autoantibodies on the podocyte, an essential component of the kidney filter. The current proposal now aims at proving this concept by 1) establishing pathogenic autoimmunity in anti-nephrin mediated podocytopathy by means of analyzing immunophenotypes and immunological signatures, and by 2) identifying direct downstream pathomechanistic effects by nephrin autoantibodies that cause changes in podocyte structure and function. Altogether, results from these studies will serve as critical basis for the development of novel, personalized and targeted treatment strategies for our patients with minimal change disease, primary focal and segmental glomerulosclerosis as well as those patients with recurrent disease in the transplant.