Abstract <p>Circulating anti-nephrin antibodies have recently been identified as mediators in many cases of childhood nephrotic syndrome. After binding of the antibody to nephrin, a key component of the slit diaphragm, different intracellular signaling mechanisms lead to foot process effacement. These new insights into the pathophysiology of nephrotic syndrome may have the potential to influence clinical treatment strategies. First, the measurement provides a pathomechanism-specific serological biomarker of a previously clinically diagnosed renal disease. Second, it may have additional value for diagnosis and prognostication, as anti-nephrin antibodies are more common in steroid-sensitive forms and less frequently associated with multidrug-resistant forms. Furthermore, anti-nephrin autoantibodies have the potential to be used as biomarkers for disease activity and to estimate the risk of relapse before kidney transplantation, after conduction of appropriate clinical trials. Additionally, the detection of autoantibodies strengthens the role of B-cell targeting therapies and provides a potential rationale for further multicenter, prospective, randomized clinical trials using B-cell depletion to potentially reduce corticosteroid use and relapse rates in children. In the future, more targeted therapies such as the interference with downstream effects of antibody binding or the depletion of autoantigen-specific antibody producing cells might become possible. Finally, the detection of anti-nephrin autoantibodies provides an explanation for patients and their families with a previously elusive “idiopathic” disease in antibody positive patients. In summary, the identification of anti-nephrin antibodies in nephrotic syndrome now opens up new questions and paves the way for further experimental and clinical studies to improve diagnostic and therapeutic approaches.</p> Graphical abstract <p></p>