One tool, multiple gains: anti-CD38 therapy in antibody-mediated rejection

Antibody-mediated rejection (AMR) remains a challenge in kidney transplantation, responsible for ≈20% of allograft loss. Given the limited efficiency of conventional therapies, there has been growing interest in new strategies targeting plasma cells. These include anti-CD38 monoclonal antibodies such as daratumumab, felzartamab and isatuximab. These agents, originally developed for haematologic malignancies, offer a novel strategy to target antibody secreting cells and natural killer cells, with the potential to reduce donor-specific antibodies and microvascular inflammation. Emerging clinical data suggest promising efficacy with an acceptable safety profile, sparking growing interest in their use within the transplant community. However, these effects appear transient, with a high interindividual variability, likely influenced by the heterogeneity of B cell populations after establishment of an allo-immune response. Of note, these therapeutics also affect B and T regulatory cells, raising important questions about immune balance with the risk of T cell-mediated rejection. This review synthesizes the current understanding of AMR, presents the Banff 2022 diagnostic frameworks updates and critically appraises the exciting potential and limitations of anti-CD38 therapies in AMR. As the transplant community shifts toward precision immunotherapy, anti-CD38 agents may help reshape future treatment paradigms in kidney transplantation-provided their use is guided by mechanistic insights and rigorous clinical evaluation.