Introduction: Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation leads to graft loss. The identity of the involved antibodies and specific immunogenic epitopes remains unclear.

Method: Pretransplant sera from patients with primary FSGS were profiled using high-density protein arrays using one hundred two unique kidney transplant patients enrolled from 5 different transplant programs in the US and Europe that included 64 patients with primary FSGS as cause of ESRD, and 38 demographically matched control patients with other causes of ESRD.

Results: High-density protein arrays identified antibodies against 789 antigens as significantly increased in patients at risk for rFSGS (p<0.05). Ten antibodies were selected for further validation based on the enrichment of their corresponding antigens in the kidney glomerulus (p<0.02) and were validated by ELISA in 141 sera. Anti-CD40 antibody levels had 78% prediction accuracy, while a panel of 7 out of 10 ELISA-validated antibodies that target glomerular antigens (antibodies to CD40, PTPRO, CGB-5, FAS, P2RY11, SNRPB2 and APOL2) increased accuracy to 92% for prediction of rFSGS.

By epitope mapping, increased immunogenicity was detected in the extracellular domain of the CD40 protein in rFSGS patients. Application of anti-CD40 antibodies purified from rFSGS patients induced podocyte injury, which was ameliorated by CD40 neutralization.

Conclusion: Our study identifies a pretransplant antibody panel that includes anti-CD40 antibodies for rFSGS risk stratification, and shows the podocytopathic effects of these antibodies.

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