Treatment standard - the highly sensitized kidney transplant candidate

Highly sensitized kidney transplant candidates are exposed to prolonged dialysis time and limited access to transplantation despite significant advances in allocation. Conventional desensitization therapies have shown limited efficacy in reducing circulating HLA antibodies, most often being incomplete or transient, reflecting the persistence of humoral alloimmune memory. Long-lived plasma cells, memory B cells and their supporting T-cell networks represent key cellular reservoirs sustaining or rapidly restoring HLA antibodies. A deeper understanding of these cellular reservoirs is now driving a shift in desensitization strategies. Rather than relying solely on antibody removal or depletion of a single cell population, emerging approaches seek to disrupt humoral immunity at multiple, complementary levels. Rapid IgG degradation with imlifidase can overcome immediate antibody barriers, while CD38-targeted therapies and rational combinations targeting both peripheral memory B cells and bone marrow-resident long-lived plasma cells (LLPC) with distinct targeted therapies aim to remodel the underlying antibody-producing compartment. At the same time, immune-engineering approaches, including chimeric antigen receptor (CAR)-T cells and bispecific T cell engagers, are opening new possibilities for profound depletion of B-cell and plasma-cell populations. More radical strategies, such as nonmyeloablative autologous hematopoietic stem cell transplantation, seek to reset rather than simply suppress the immune repertoire, while emerging HLA-directed platforms may ultimately enable selective targeting of alloimmune memory. Together, these developments mark a shift from transient antibody reduction towards deeper and potentially durable remodeling of humoral alloimmune memory. The ultimate challenge is to achieve sufficient HLA-specific immune control to enable transplantation while minimizing the consequences of broad immune depletion.