肾移植术后常规免疫抑制方案下发生他克莫司肾毒性的影响因素

目的 探讨在常规免疫抑制方案下和正常血药浓度范围内肾移植受者发生他克莫司(Tac)肾毒性的影响因素及其对个体化治疗的指导意义。方法 回顾分析132例肾移植术后2年内按照Tac常规剂量(0.15～0.3 mg·kg-1·d-1)和血Tac浓度维持在8～11 μg/L，并坚持随访的首次肾移植受者的资料。Tac肾毒性经移植肾活检和临床实验室检测结果诊断。根据是否发生Tac肾毒性，分为肾毒性组和对照组。对可能的影响因素，包括受者的年龄、性别、是否发生过移植肾功能延迟恢复、药物暴露量、用药时间、肝功能异常、血清白蛋白水平、红细胞比容以及多药耐药基因(MDR1)和细胞色素P450酶3A5(CYP3A5)基因等共10项指标进行多因素回归分析。结果 在常规免疫抑制剂方案下和正常血药浓度范围内，Tac肾毒性发生率为18.9％(25/132)。经单因素和多因素分析，肝功能异常(RR=3.05，95％可信区间为0.879～11.533，P=0.024)、血清白蛋白水平(RR=0.966，95％可信区间为0.994～1.006，P=0.018)、红细胞比容(RR=0.999，95％可信区间为0.998～1.000，P= 0.032)、CYP3A5基因多态性（RR= 0.777，95％可信区间为0.023～6.798，P=0.032）及MDR1基因多态性(RR=0.654，95％可信区间为0.053～7.109，P=0.017)是导致Tac肾毒性的独立危险因素。结论 肾移植后在常规免疫抑制方案下及正常血药浓度内，肝功能异常是导致Tac肾毒性最主要的危险因素，白蛋白水平低下、红细胞比容降低也是导致Tac肾毒性的影响因素，此外还应考虑受者CYP3A5及MDR1的基因多态性，以实现个体化免疫抑制治疗。

Risk factors for standard Tac-related nephrotoxicity in renal transplant recipients

Objective To investigate the factors for standard TAC-related nephrotoxicity in renal transplant recipients. Methods Clinical data of 132 patients in TAC-based regiment with a dose of 0. 15-0.3 mg· kg-1 · day-1 and a trough level of 8-11 μg/L during first 2 years post renal transplantation, were retrospectively analyzed. TAC-related nephrotoxicity was diagnosed by renal biopsy and/or clinical criteria. All recipients were divided into 2 groups: TAC nephrotoxicity group (n = 25) and control group (n = 107). Logistic regression analysis was used to rank the relative risk of potential variables including age, gender, delayed graft function (DGF), drug exposure, duration of therapy,liver function, albumin level, hematocrit and gene polymorphism for CYP3A5 and MDR1.Results TAC-related nephrotoxicity was found in 25 (18. 9 ％ ) recipients. Univariate and Logistic regression analysis revealed that the influencing factors for TAC-related nephrotoxicity with a standard immunosuppressive regimen and a normal trough level range were identified as: abnormal liver function (RR = 3. 05,95 ％ CI 0. 879-11. 533, P = 0. 024), albumin level (RR = 0. 966,95 ％ CI 0. 994-1. 006, P = 0. 018 ), hematocrit ( RR = 0. 999, 95 ％ CI 0. 998-1. 000, P = 0. 032), CYP3A5 gene polymorphism (RR= 0. 777,95 ％ CI 0. 023-6. 798,P= 0. 032) ,and MDR1 gene polymorphism (RR=0. 654,95 ％ CI 0. 053-7. 109, P = 0. 017). Conclusion Liver function, albumin level, hematocrit, and gene polymorphism for CYP3A5 and MDR1 as well are influencing factors for TAC-related nephrotoxicity in renal transplant recipients with a standard immunosuppressive regimen and a normal trough level range,in which abnormal liver function is the most important adverse risk factor. These factors should be considered for better individual therapy in renal transplant recipients.