Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.

BeCAT BCRT and Department of Nephrology and Intensive Care Charité Universitätsmedizin Berlin Berlin Institute of Health Berlin Germany

CHU Nantes Laboratoire d'immunologie CIMNA Nantes France

Department of Hepatobiliary and Transplant Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Nephrology Hospital Universitario Marqués de Valdecilla Instituto de Investigación Marqués de Valdecilla (IDIVAL Santander Spain

Department of Nephrology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Nephrology University Medical Center Regensburg Regensburg Germany

HLA Laboratory Charité Universitätsmedizin Berlin Berlin Germany

Immunology Department University Hospital Marqués de Valdecilla IDIVAL Santander Spain

Institute of Liver Studies MRC Centre for Transplantation Department of Inflammation Biology Faculty of Sciences and Medicine King's College London London UK

Kidney Transplant Unit Nephrology department Bellvitge University Hospital IDIBELL Barcelona University Barcelona Spain

Nantes Université Inserm CHU Nantes Centre de Recherche en Transplantation et Immunologie UMR1064 ITUN Nantes France

Nephrology and Transplantation Laboratory IDIBELL Barcelona University Barcelona Spain

Renal Transplant Unit Department of Internal Medicine Amsterdam University Medical Centers Academic Medical Center University of Amsterdam Amsterdam the Netherlands

Transplant Laboratory Institute for Clinical and Experimental Medicine Prague Czech Republic

Transplantation Research and Immunology Group Nuffield Department of Surgical Sciences University of Oxford Oxford UK

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