他克莫司个体内高变异度与肝移植术后免疫介导移植物损伤的临床研究  

Relevant research between high intrapatient variability in tacrolimus and immune-mediated graft injury after liver transplantation

作　　者：田敏[1] 王博[1] 刘学民[1] 张晓刚[1] 郭坤[1] 李宇[1] 胡良硕[1] 霍锦霞[1] 吕毅[1] Min Tian;Bo Wang;Xuemin Liu;Xiaogang Zhang;Kun Guo;Yu Li;Liangshuo Hu;Jinxia Huo;Yi Lyu(Department of Hepatobiliary Surgery,The First Affiliated Hospital of Xi′an Jiaotong University,Xi′an 710061,China)

机构地区：[1]西安交通大学第一附属医院肝胆外科,710061

出　　处：《中华移植杂志（电子版）》2022年第2期65-71,共7页Chinese Journal of Transplantation(Electronic Edition)

基　　金：国家自然科学基金面上项目(81870445)。

摘　　要：目的探讨他克莫司个体内变异度(IPV)与肝移植术后免疫介导移植物损伤的关系。方法回顾性分析2015年1月至2019年12月在西安交通大学第一附属医院肝胆外科进行经典原位肝移植的288例受者资料。采用移植后2~6个月期间至少5个他克莫司血药浓度谷值(C0)计算得到他克莫司血药浓度变异系数(CV)。设定的复合终点包括:(1)肝移植术后6个月后免疫介导的移植物失功,包括慢性排斥反应、活检证实的晚期急性排斥反应;(2)肝移植术后6个月后免疫抑制剂毒性作用导致的肝功能损害;(3)肝移植术后6个月后出现的CMV血症。以CV均值为临界值将受者分为低CV组和高CV组,比较两组到达复合终点的受者比例,分析肝移植术后发生免疫介导移植物损伤的影响因素。正态分布计量资料以均数±标准差(±s)表示,采用独立样本t检验进行比较;非正态分布计量资料以中位数表示,采用Mann-Whitney U检验进行比较。计数资料以例数(%)表示,采用χ^(2)检验进行比较。采用Kaplan-Meier法绘制生存曲线,使用log-rank检验进行比较。采用Cox比例风险模型分析肝移植术后免疫介导移植物损伤的危险因素,将单因素分析中P≤0.20的变量采用逐步后退法进行多因素分析。P<0.05为差异具有统计学意义。结果截至2021年6月30日,288例肝移植受者平均随访时间(37±16)个月(6~76个月),共37例(12.85%)到达复合终点。肝移植术后2~6个月他克莫司血药浓度CV平均值为(28.11±10.72)%,以28.11%作为临界值将288例受者分为低CV组(CV<28.11%)和高CV组(CV≥28.11%)。两组供者年龄、性别,受者年龄、性别、体质指数、原发病性质、术前终末期肝病模型评分、术前Child-Pugh评分、术后免疫抑制方案、慢性排斥反应发生率以及术后2~6个月他克莫司C0、总胆红素和ALT水平差异均无统计学意义(P均>0.05)。高CV组受者急性排斥反应和CMV血症发生率高于低CV组受Objective To investigate whether intrapatient variability(IPV)of tacrolimus was closely related to immune-mediated graft injury in liver transplant recipients.Methods A retrospective cohort study was conducted in 288 patients who underwent classical orthotopic liver transplantation in the Liver Transplantation Center of the First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to December 2019.Tacrolimus IPV was calculated from at least 5 tacrolimus trough samples obtained between months 2 and 6 after liver transplantation and expressed as the coefficient of variation(CV).The composite endpoints included:①Immune-mediated graft injury 6 months after liver transplantation,including chronic rejection and late acute rejection proven by biopsy;②Liver function injury caused by the toxic effects of immunosuppressants 6 months after liver transplantation;③Cytomegalovirus(CMV)viremia 6 months after liver transplantation.The recipients were divided into the low CV group and the high CV group with the mean value of CV as the critical value.The proportion of recipients reaching the composite endpoints were compared between the two groups,and the influencing factors of immune-mediated graft injury after liver transplantation were analyzed.Normal distribution measurement data shown in the form of(±s)were compared by independent sample t test.Nonnormally distributed measurement data shown in the form of median(full distance)were compared by Mann-Whitney U test.Count data shown in the form of percentage were compared with Chi-square test.The Kaplan-Meier method was used to plot the survival curve,and the log-rank test was used for comparison.Cox proportional hazard model was used to analyze the risk factors of immune-mediated graft injury after liver transplantation,and variables with P≤0.20 in univariate analysis were analyzed by step-back method for multivariate analysis.P<0.05 for difference was considered statistically significant.Results As of June 30,2021,the 288 liver transplant recipients were

关 键 词：他克莫司 个体内变异度 变异系数 肝移植 急性排斥反应 巨细胞病毒血症 移植物损伤 

分 类 号：R657.3[医药卫生—外科学]