Anti-nephrin autoantibodies in podocytopathies: pathogenicity, assay discordance, and translation

Experimental targeting of nephrin causes proteinuria and podocyte injury, and human studies identify anti-nephrin autoantibodies in a subset of podocytopathies. Serum and tissue recognition, associations with disease activity, and transfer of patient total immunoglobulin G support an autoimmune endotype. The pathogenic contribution of the naturally occurring nephrin-specific fraction has not been fully resolved. This narrative review examines target recognition, pathogenic effects, clinical validity, and the benefit of acting on a test result as separate questions. We focus on adult minimal change disease and primary focal segmental glomerulosclerosis, with childhood nephrotic syndrome and transplant recurrence providing complementary evidence. Experimental studies explain how nephrin targeting alters slit diaphragm organization and signaling. Comparisons of original studies identify glycan and tag interference, platform-dependent detection, and differences in treatment exposure and antibody class. Low detection with human-cell antigens also supports considering genuine variation in the frequency of this endotype. Observational studies show serologic changes with disease activity and signals preceding relapse or transplant recurrence. These findings motivate investigational applications in disease characterization, monitoring, and risk assessment. Assays remain unstandardized, and autoantibody-guided management has not been shown to improve outcomes over standard care. Prospective studies and decision-focused trials should determine when these signals add useful information and improve treatment.