Kidney Transplant Rejection Treatments Reviewed as Phase 3 Trials Offer New Hope

Antibody-mediated rejection remains the leading cause of kidney transplant failure more than 25 years after it was first formally recognized. A US cohort study of 3,131 recipients found that the 194 patients who developed AMR faced a 10-fold higher hazard of death-censored graft failure compared with those who did not. A separate analysis of 5,679 AMR patients showed nearly triple the risk of graft failure and death within two years, with annual healthcare costs four times higher — approximately $35,750 per patient — underscoring the enormous clinical and economic burden. Despite this urgency, not a single therapy has achieved regulatory approval.

This 2025 treatment standard review, published in Nephrology Dialysis Transplantation, was authored by seven leading European transplantologists who conducted a comprehensive re-evaluation of all prospective interventional trial data. The Banff classification diagnoses AMR based on donor-specific antibodies (DSA) and/or capillary C4d deposition combined with microvascular inflammation, with morphological subtypes of active, chronic-active, and chronic (inactive) AMR. Incidence ranges from 3–12% for acute AMR and 7.5–20.1% over 10 years for chronic forms. Early AMR is often driven by preformed DSA and causes acute dysfunction, while de novo DSA-driven rejection progresses insidiously over years.

The authors systematically dismantled the evidence for previously used therapies. Steroids, rituximab, bortezomib, and IL-6 antagonists all lack sufficiently robust evidence. The RITUX-ERAH phase 3 trial of rituximab showed no effect on graft loss or renal function. The TRITON and RituxiCAN-C4 trials similarly found no benefit on biopsy results or clinical outcomes. The IMAGINE phase 3 trial of clazakizumab (anti-IL-6) was terminated early for lack of efficacy on eGFR decline. Imlifidase, a novel IgG-cleaving enzyme that markedly reduces DSA levels transiently, likewise showed no effect on AMR morphology or graft survival in a phase 2 trial. Complement inhibition with eculizumab, C1 esterase inhibitors, and sutimlimab also failed to demonstrate convincing benefit in controlled settings, though case series suggest potential utility in severe early complement-driven AMR.

For current practice, the authors recommend apheresis — either plasmapheresis or immunoadsorption — as the mainstay of treatment for early AMR, based on the rationale of rapidly depleting circulating DSA. The prematurely terminated AKARIS immunoadsorption trial did show fewer graft failures in the treatment arm. High-dose IVIG may be added at the end of apheresis sessions as an option, though its supporting evidence remains limited. Critically, the review emphasizes that optimization of existing immunosuppression is important but unlikely to significantly lower already-formed antibody levels.

The most promising emerging data concern CD38 antibodies, particularly felzartamab, which target natural killer (NK) cells expressing CD38 — a key effector population in Fc gamma receptor-mediated endothelial injury. Phase 2 trial results demonstrated reversal of AMR activity, a mechanistic finding the authors describe as a rational strategy targeting downstream pathobiology rather than upstream antibody production alone. A phase 3 trial of felzartamab (TAR:GET-1) is currently recruiting. A phase 3 trial of tocilizumab (anti-IL-6 receptor; INTERCEPT trial) is also underway. Additionally, phase 2 trials are investigating the FcRn blocker efgartigimod (SHAMROCK; NCT06503731), the SYK/tyrosine kinase inhibitor fostamatinib (FOSTAMR), and the complement inhibitor BIVV020. The authors strongly encourage enrollment of patients in these trials as the only path to generating sufficient evidence to change the treatment landscape.