Anti-podocin and Anti-KIRREL1 Antibodies and Steroid Resistance, FSGS, and Disease Recurrence after Transplantation in Autoimmune Podocytopathies

BACKGROUND: Anti-nephrin, anti-podocin, and anti-KIRREL1 antibodies are increasingly recognized as causes of autoimmune podocytopathies, yet autoantibody-specific clinical phenotypes remain poorly defined. METHODS: We conducted a multicenter study integrating serology and super resolution microscopy in 471 samples, including 213 cases with 146 kidney biopsies (minimal changes n=63, focal segmental glomerulosclerosis [FSGS] n=83), and sera from 128 patients (minimal changes n=30, FSGS n=42, idiopathic nephrotic syndrome or isolated proteinuria n=56), including 61 paired specimens, plus 258 controls (75 kidney biopsies, 200 sera, including 17 paired specimens). Paired specimens were used to assess ELISA performance by comparing serum results with IgG colocalization of target proteins within the filtration slit using ROC curves. All assays showed high specificity but lower sensitivity than super resolution microscopy. Clinical features and long-term outcomes associated with individual autoantibodies and their combinations were also evaluated. RESULTS: Anti-slit diaphragm antibodies were detected in 67/213 patients: 63% had anti-nephrin, 9% anti-podocin, or 3% anti-KIRREL1 antibodies only, while 25% had multiple autoantibodies. Isolated anti-nephrin antibodies were associated with minimal changes (91%), steroid sensitivity (88%), and absence of chronic kidney disease (CKD) over 120 months. In contrast, anti-podocin and/or anti-KIRREL1 antibodies correlated with FSGS (84%), steroid resistance (58%), CKD progression (36%), and kidney failure (24%). Among 26 transplant recipients with FSGS, early post-transplant recurrence occurred in 83% of autoantibodies carriers and in 5% of the others. Recurrent patients showed anti-podocin/KIRREL1 antibodies, with or without anti-nephrin. CONCLUSIONS: These findings suggest that anti-podocin and anti-KIRREL1 antibodies associate with steroid resistance, FSGS and disease recurrence after transplantation in autoimmune podocytopathies.