Autoantibodies against nephrin and podocin are associated with disease severity and steroid dependence in adult-onset nephrotic syndrome

Abstract Nephrotic syndrome is a glomerular disorder characterized by heavy proteinuria and hypoalbuminemia. Autoantibodies against slit diaphragm proteins such as nephrin and podocin have been identified in subsets of patients, but their prevalence and clinical significance in adult-onset disease are not fully understood. We retrospectively studied 114 adults with biopsy-proven nephrotic syndrome, including minimal change nephrotic syndrome, focal segmental glomerulosclerosis, and phospholipase A2 receptor- and neural epidermal growth factor-like 1-associated membranous nephropathy. Serum anti-nephrin and anti-podocin autoantibodies were quantified using enzyme-linked immunosorbent assays. Anti-nephrin autoantibodies were detected predominantly in minimal change nephrotic syndrome (38.2%) and less frequently in focal segmental glomerulosclerosis (14.3%), but were rare in membranous nephropathy. In contrast, anti-podocin autoantibodies were observed across disease types and were most frequent in neural epidermal growth factor-like 1-associated membranous nephropathy (30.8%). Autoantibody-positive patients presented with more severe nephrotic syndrome, and antibody positivity was associated with a higher incidence of steroid-dependent nephrotic syndrome in exploratory multivariable analyses. In patients with paired samples, autoantibody titers decreased or disappeared in remission. Notably, anti-nephrin antibodies were preferentially associated with MCNS, whereas anti-podocin antibodies were detected across disease entities and may reflect the extent of podocyte injury rather than disease specificity. Moreover, combined assessment of anti-nephrin and anti-podocin antibody status provided improved stratification of baseline disease severity and relapse-prone disease compared with anti-nephrin antibody status alone.