Updates in tolerance: future directions to improve kidney allograft survival

Abstract

PURPOSE OF REVIEW: Long-term kidney allograft survival remains limited by chronic rejection and the toxicities of lifelong immunosuppression. Donor-specific tolerance, the acceptance of the graft without continuous pharmacological therapy, has long been considered the ultimate goal of transplantation. This review summarizes recent clinical advances in tolerance-inducing strategies and outlines future directions for clinical translation. RECENT FINDINGS: Clinical progress has accelerated in the past decade. Mixed hematopoietic chimerism protocols have matured from single-center feasibility studies to a recent phase 3 randomized trial in human leukocyte antigen (HLA)-identical recipients, achieving sustained immunosuppression-free survival with improved safety outcomes regulatory T cell therapies, tested across multiple early-phase trials, have consistently demonstrated safety, biological activity, and scalability in multicenter settings, with new approaches entering clinical development. SUMMARY: Tolerance in kidney transplantation is transitioning from conceptual aspiration to clinical feasibility. Landmark chimerism trials confirm that operational tolerance is possible in selected populations. Future priorities include refining conditioning regimens to reduce toxicity and extending eligibility to higher-risk recipients. Together, these developments suggest that tolerance-based strategies may ultimately transform kidney transplantation from chronic immunosuppression to durable immune re-education.