Highly sensitized kidney transplant candidates: integrating acceptable mismatch, desensitization, imlifidase, and emerging immune-cell targeting strategies.

Highly sensitized kidney transplant candidates are difficult to transplant because anti-human leukocyte antigen (HLA) sensitization restricts access to immunologically compatible organs, as transplantation across donor-specific antibodies (DSA) increases the risk of antibody-mediated rejection (AMR) and premature graft loss. Management should therefore move beyond antibody characteristics alone and assess whether a compatible offer remains realistic for the individual patient within the relevant allocation system. This review proposes a sequential, compatibility-first access framework. Compatible transplantation should remain the preferred goal and may be achieved through kidney paired exchange, compatible living-donor pathways, sensitization-aware prioritization, and dedicated allocation programs. International experience shows that allocation design can mitigate access restrictions for moderately sensitized candidates, while highly sensitized candidates require more targeted prioritization. The Eurotransplant acceptable mismatch program exemplifies this principle by combining expert-defined acceptable antigens with allocation priority, thereby promoting compatible transplantation with excellent outcomes in a restricted highly sensitized cohort without therapeutic crossing of the immunological barrier. Compatible pathways should be tried and optimized before intervention-based strategies are considered. In candidates without a realistic compatible option within a reasonable timeframe, conventional desensitization, risk-adapted delisting of selected unacceptable antigens, or imlifidase-enabled transplantation may become justified, particularly when severe dialysis-related problems exist. Imlifidase can rapidly enable selected positive-crossmatch deceased-donor transplantation, but AMR remains frequent and strict governance, candidate selection, and posttransplant surveillance are mandatory. Novel AMR treatments, including CD38-directed therapies, may improve the long-term feasibility of barrier-crossing strategies. Emerging B-cell and plasma-cell targeting approaches, including interleukin-6-, CAR-T-cell-, and BCMA-directed strategies, remain investigational. Optimal care requires integrating immunologic precision, allocation design, intervention thresholds, and structured monitoring into an individualized compatibility-first strategy.