Nephrology and Transplant Laboratory, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.
Experimental Nephrology and Transplantation Laboratory, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain.
Front Immunol. 2022 Jun 27;13:869554. doi: 10.3389/fimmu.2022.869554. eCollection 2022.
Achieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants (/) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different and functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (<5 ng/ml). Multivariate Cox regression analyses revealed that CYP3A HM1 and IM pharmacogenetic phenotypes (hazard ratio (HR) 12.566, 95% CI 1.99-79.36, p = 0.007, and HR 4.532, 95% CI 1.10-18.60, p = 0.036, respectively), preformed DSTs (HR 3.482, 95% CI 1.99-6.08, p < 0.001), DSAs (HR 4.421, 95% CI 1.63-11.98, p = 0.003), and delayed graft function (DGF) (HR 2.023, 95% CI 1.22-3.36, p = 0.006) independently predicted BPAR. Notably, a significant interaction between T-cell depletion and TAC underexposure was observed, showing a reduction of the BPAR risk (HR 0.264, 95% CI 0.08-0.92, p = 0.037). Such variables except for DSAs displayed a higher predictive risk for the development of T cell-mediated rejection (TCMR). Refinement of pretransplant monitoring by incorporating TAC CYP3A SNPs with preformed DSAs as well as DSTs may improve current rejection-risk stratification and help induction treatment decision-making.
实现肾移植后快速的免疫抑制血药暴露是消除预先存在的和抗供体体液及细胞同种反应的关键。然而，虽然他克莫司（TAC）是抑制适应性同种免疫的基石免疫抑制剂，但它的血药暴露直接受到 CYP3A TAC 代谢酶中不同单核苷酸多态性（SNP）的影响。在这里，我们通过在接受 TAC 为基础的免疫抑制治疗的 447 例肾移植患者的大型欧洲队列中，调查了功能 TAC-CYP3A 遗传变异（/）如何影响活检证实的急性排斥（BPAR）的主要基线临床和免疫学危险因素，这些危险因素包括预先存在的供体特异性抗体（DSA）和供体特异性同种反应性 T 细胞（DST）。共有 70 例（15.7%）患者发生 BPAR。分别在 12 例（2.7%）和 227 例（50.8%）患者中观察到预先存在的 DSA 和 DST。根据不同的/和功能等位基因变异，我们发现 4 个新的不同簇影响移植后空腹 TAC 暴露；7 例（1.6%）为高代谢者 1（HM1），71 例（15.9%）为 HM2，324 例（72.5%）为中间代谢者（IM），45 例（10.1%）为差代谢者（PM1）。HM1/2 与 IM 和 PM 相比，TAC 谷浓度明显较低，剂量需求较高（p<0.001），且 TAC 暴露不足（<5ng/ml）的情况更为常见。多变量 Cox 回归分析显示，CYP3A HM1 和 IM 药物代谢表型（危险比（HR）12.566，95%置信区间（CI）1.99-79.36，p=0.007 和 HR 4.532，95%CI 1.10-18.60，p=0.036），预先存在的 DST（HR 3.482，95%CI 1.99-6.08，p<0.001），DSA（HR 4.421，95%CI 1.63-11.98，p=0.003）和延迟移植物功能（DGF）（HR 2.023，95%CI 1.22-3.36，p=0.006）独立预测 BPAR。值得注意的是，观察到 T 细胞耗竭与 TAC 暴露不足之间存在显著的相互作用，降低了 BPAR 风险（HR 0.264，95%CI 0.08-0.92，p=0.037）。除了 DSA 外，这些变量对 T 细胞介导的排斥（TCMR）的发展具有更高的预测风险。通过将 TAC CYP3A SNPs 与预先存在的 DSA 以及 DST 相结合，改进移植前监测，可能会改善当前的排斥风险分层，并有助于诱导治疗决策。
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