Combined Anti-CD20 and/or Anti-CD38 Therapy in Recurrent FSGS: Results Before Reasons

Recurrent focal segmental glomerulosclerosis (rFSGS) is a major complication after kidney transplantation, affecting about one-third of patients with primary FSGS and significantly increasing the risk of graft loss. Although circulating pathogenic factors are strongly implicated, their exact identity remains unknown. Increasing evidence suggests that humoral immune mechanisms, including antibodies against nephrin and other podocyte-associated targets, may contribute to disease recurrence, providing a rationale for therapies targeting both B cells and plasma cells. The commentary discusses growing evidence supporting combined anti-CD20 (e.g., rituximab) and anti-CD38 (e.g., daratumumab) therapy for refractory rFSGS. It highlights a multicenter French study of 17 kidney transplant recipients in which 65% of patients achieved complete or partial remission, allowing responders to discontinue plasma exchange. Some patients who relapsed responded successfully to retreatment with daratumumab, suggesting repeated plasma-cell depletion may remain effective. Despite these promising clinical outcomes, the mechanisms underlying treatment efficacy remain unclear. The authors propose that benefits may extend beyond antibody depletion, potentially involving IgM-mediated complement activation and broader immune modulation. They advocate introducing combined therapy earlier in the disease course, before irreversible podocyte damage develops. However, they acknowledge that current evidence is based on retrospective studies with heterogeneous protocols, underscoring the need for prospective trials to optimize treatment timing, identify predictive biomarkers, and better define safety and patient selection.