Paolo Cravedi, Umberto Maggiore, Gabriele Mortari, Federico Alberici, Gaetano La Manna, Nelson Goes, Nicolas Bouvier, Giorgia Comai, Ali Poyan Mehr, Micaela Gentile, Alessandra Palmisano, Elisa Gessaroli, Simona Barbuto, Gianluca Caridi, Carolina Bigatti, Alberto Magnasco, Nicola Bossini, Xhuliana Kajana, Agnese Spennacchio, Lorenzo Gallon, Gian Marco Ghiggeri, F. Vincenti, Frank E. Hullekes, Rohan V. Mehta, Leonardo V. Riella, Enrico E. Verrina, Andrea Angeletti
Background: Focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation is a leading cause of allograft failure and remains difficult to treat. Standard therapies, including plasma exchange (PEX) and rituximab, are often ineffective and poorly tolerated. Growing evidence implicates immune-mediated circulating factors, such as IgG and IgM autoantibodies, in disease pathogenesis. Given the central role of memory B cells and plasma cells in antibody production, we tested the safety/efficacy profile of a combined B-cell and plasma cell-depleting approach with rituximab and daratumumab in patients with posttransplant FSGS recurrence. Methods: This is a retrospective analysis of a multicenter, international cohort of sixteen patients (median age 37 y) with biopsy-proven FSGS recurrence posttransplant who received anti-CD20 plus anti-CD38 monoclonal antibodies or anti-CD38 alone. The majority of patients were resistant to common therapies, including rituximab and PEX. Results: The treatment achieved complete or partial remission in 5 and 11 patients, respectively. Five experienced proteinuria relapse, and 4 responded to repeated daratumumab alone. At the last follow-up (median 11 [2-18] mo), 13 patients are still in remission and PEX was discontinued in all but 3 cases. Overall, kidney function improved after treatment, and no severe acute or chronic adverse events were reported. Serological analysis revealed a significant decline in IgM, but not in IgG, after treatment. Conclusions: Despite the retrospective, nonrandomized design, the temporal association between treatment and remission supports an effect of anti-CD38 monoclonal antibody alone or in combination with anti-CD20. Treatment is safe and may confer enhanced efficacy over standard approaches. Prospective, mechanistic studies are warranted to validate these findings and delineate the immunopathogenesis of FSGS recurrence.