#369 Anti-nephrin antibodies identify patients with steroid-resistant nephrotic syndrome responsive to immunosuppressants

Abstract Background and Aims The presence of circulating anti-nephrin antibodies has been recently reported in some patients with nephrotic syndrome (NS) and minimal change lesions, implying an autoimmune podocytopathy subset. We hypothesized that the presence of anti-nephrin antibodies would identify a subset of patients with steroid resistant NS (SRNS) and explain their response to second-line immunosuppressant therapy before and after kidney transplantation. Method We evaluated 31 patients with available kidney biopsy samples of our previously described prospective cohort of SRNS patients, genetically tested with whole exome sequencing at Meyer University Hospital IRCCS. By using high-resolution confocal microscopy, we assessed the co-localization between IgG and nephrin staining on kidney biopsy. To unequivocally establish anti-nephrin specificity of the deposited IgG, we performed super-resolution STimulated Emission Depletion (STED) microscopy. Results We observed anti-nephrin antibodies in 35.5% of patients with SRNS irrespective of podocytopathy lesion pattern. Antibody-positive (Antibody+) patients had a more severe NS at onset and better response to immunosuppression therapy compared to antibody-negative (Antibody-) patients. Only 1/11 Antibody+ patient developed chronic kidney disease compared to 9/20 Antibody- patients over a 10-year period. The single multidrug-resistant Antibody+ patient reached kidney failure had a pathogenic variant in the autosomal dominant-transmitted LMX1B. The patient experienced recurrence of NS after kidney transplantation with a positive response to plasmapheresis and rituximab. The allograft biopsy confirmed the presence of anti-nephrin antibodies. Conclusion The observed variability in patients with SRNS, influenced by a combination of genetic factors and nephrin autoimmunity, likely contributes to the diverse long-term outcomes and variations in responses to second-line immunosuppressant therapy.