Nephrology, Dialysis, Apheresis and Transplantation Department, Grenoble University Hospital, France.
Department of Medicine and Pharmacy, Grenoble Alpes University, Grenoble, France.
Transplantation. 2020 Jun;104(6):1263-1271. doi: 10.1097/TP.0000000000002920.
Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS).
We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate).
Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041).
C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.
他克莫司谷浓度（均值/变异性）和浓度-剂量比（C/D 比值）影响肾移植的结局。我们研究了 C/D 比值与受者死亡的肾移植物存活率（DCGS）之间的关系。
我们对 1029 例（2004-2016 年）接受他克莫司为基础的免疫抑制治疗、移植物存活时间超过 1 年、无初始使用依维莫司、且可获得抗人白细胞抗原抗体数据的肾移植患者进行了回顾性研究。我们分析了时间变化的 C/D 比值对 DCGS 的影响。定义快代谢者的 C/D 比值＜1.05。我们还研究了移植后第 3 至 6 个月（mo3 至 mo6）的早期 C/D 比值＜1.05 的影响。使用 Cox 生存分析进行调整潜在混杂因素（他克莫司谷浓度、他克莫司谷浓度的变异性、新生供体特异性抗体的发展、细胞色素 P450 3A5 基因型、移植前致敏、mo3 肾小球滤过率）。
在包含 1029 例患者的全分析集的单变量模型中，时间变化的 C/D 比值与 DCGS 显著相关（风险比[HR]，2.35；P＜0.001）。在基于 666 例有可获得细胞色素 P450 3A5 基因型的患者的多变量时间变化模型中，C/D 比值的影响仍然显著（HR，2.26；P=0.015）；即使在 mo3 时肾小球滤过率＜30 mL/min/1.73 m（HR，2.61；P=0.011）、新生供体特异性抗体的发展（HR，4.09；P＜0.001）和持续使用类固醇（HR=2.08，P=0.014）的情况下，考虑到其他混杂因素（包括他克莫司谷浓度）时，C/D 比值仍与 DCGS 显著相关。在同一多变量模型中，早期 C/D 比值（mo3 和 mo6 的中位数）与 DCGS 仍显著相关（HR，2.25；P=0.041）。
C/D 比值是 DCGS 的独立和早期预测因子。鉴定快代谢者可能是改善移植物存活率的一种策略，例如优化他克莫司的配方。需要进行机制研究以了解 C/D 比值的作用。
