Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure
Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure
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DOI：
10.1038/ki.2013.465
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发表时间：
2014-06-01
影响因子：
19.6
通讯作者：
Kim, S. Joseph
中科院分区：
文献类型：
--
作者：
Sapir-Pichhadze, Ruth;Wang, Yao;Kim, S. Joseph
他克莫司水平的广泛变化已被确定为肾移植存活率低下的风险因素，但过去的研究没有正确解释药物暴露随时间的动态性质。在此，我们在一项对接受他克莫司为基础的免疫抑制的成人肾移植受者进行的回顾性队列研究中，评估了他克莫司随时间变化的暴露是否会增加长期不良结局的风险。采用时间依赖性考克斯比例风险模型来检查移植后1年开始的他克莫司水平标准差（TacSD）与晚期同种异体移植物排斥反应、移植肾小球病或移植物完全丧失（包括死亡）的复合终点之间的相关性。在356例患者中，TacSD每增加1个单位，复合终点的校正风险显著增加27%（风险比1.27（95%置信区间1.03，1.56））。根据TacSD阈值，复合终点的相对风险也有分级增加（TacSD 1.5、2、2.5和3的风险比分别为1.33、1.50、1.84和2.56）。移植物总损失和不包括死亡的复合终点的结果相似。因此，时间依赖性TacSD增加可能是肾移植不良结果的一个独立风险因素。TacSD可以作为一种监测工具，以识别高风险患者。减少TacSD的干预措施是否会改善结果需要进一步研究。
Wide variations in tacrolimus levels have been identified as a risk factor for inferior kidney allograft survival but past studies have not properly accounted for the dynamic nature of drug exposure over time. Here we evaluated whether time-varying exposure to tacrolimus increases the risk of long-term adverse outcomes in a retrospective cohort study in adult kidney transplant recipients on tacrolimus-based immunosuppression. Time-dependent Cox proportional hazards models were used to examine the association between the standard deviation of tacrolimus levels (TacSD) starting at 1-year post-transplant and the composite end point of late allograft rejection, transplant glomerulopathy, or total graft loss (including death). Among 356 patients, there was a significant 27% increase in the adjusted hazard of the composite end point for every 1-unit increase in TacSD (hazard ratio 1.27 (95% confidence interval 1.03, 1.56)). There was also a graded increase in the relative hazard for the composite end point by TacSD threshold (hazard ratios 1.33, 1.50, 1.84, and 2.56 for TacSD 1.5, 2, 2.5, and 3, respectively). The results were similar for total graft loss and the composite end point excluding death. Thus, increased time-dependent TacSD may be an independent risk factor for adverse kidney transplant outcomes. TacSD may serve as a monitoring tool to identify high-risk patients. Whether interventions to decrease TacSD will improve outcomes requires further study.