Strehler Yara, Lachmann Nils, Niemann Matthias, Halleck Fabian, Budde Klemens, Pruß Axel
Institute of Transfusion Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
PIRCHE AG, Berlin, Germany.
Transfus Med Hemother. 2024 Feb 28;51(3):140-151. doi: 10.1159/000536533. eCollection 2024 Jun.
Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation.
This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0-5%; PRA-0) and intermediately sensitized (PRA 6-84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System.
Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup.
The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.
欧洲移植组织设立了可接受错配（AM）项目，以促进高致敏患者及时进行肾移植，但关于总体移植物存活和新生供者特异性抗体（dnDSA）形成的长期详细临床和免疫结果仍在深入研究中。对于免疫风险不同的患者，诱导治疗的正确选择尚未最终确定，人类白细胞抗原（HLA）表位匹配对dnDSA形成的影响也未明确。
这项单中心回顾性研究分析了2000年至2019年期间在AM项目中接受移植的94例患者，并与通过欧洲移植肾脏分配系统移植的非致敏（群体反应性抗体[PRA]0 - 5%；PRA-0）和中度致敏（PRA 6 - 84%；PRA-6/84）患者的病例对照匹配队列进行比较。
PRA-0组和AM队列之间估计的10年总体移植物存活率相似，而PRA-6/84组与PRA-0组相比明显不利。与AM组和PRA-6/84组相比，PRA-0组中估计的10年抗体介导排斥反应发生率显著更低。与AM组相比，PRA-0患者中新生供者特异性抗体（dnDSA）的估计发生率显著更低，AM组和PRA-6/84队列之间无差异。PRA-6/84队列是唯一与耗竭性诱导（抗胸腺细胞球蛋白[ATG]或OKT3）相比，白细胞介素-2受体拮抗剂（IL2RA）诱导与更长的总体移植物存活、患者存活和移植物存活相关的亚组。由Eplets和PIRCHE-II确定的广泛HLA-A、-B、-DR错配（mmABDR）和HLA表位错配可预测整个队列以及AM亚组中的dnDSA形成。
为AM患者付出的巨大努力是合理的，以便在可接受的风险状况和非劣效结果下及时进行器官移植。与ATG/OKT3诱导相比，中度致敏患者中IL2RA诱导与更好的总体移植物存活、患者存活和移植物存活相关，对排斥反应发作或dnDSA形成没有负面影响。计算机模拟表位匹配可能进一步有助于减少dnDSA形成，特别是在高风险AM患者中。
