Alternative Viewpoint on Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

G. Thölking, S. Reuter
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引用次数: 1

Abstract

Bartlett et al. reported in a large US-based single-center study that the tacrolimus metabolism rate, defined as the concentration-to-dose ratio (CDR), does not have an impact on biopsy-proven acute rejection as previously shown in kidney transplant recipients. In contrast to our results, they observed a higher mortality rate in nonrapid metabolizers (NRM) compared to rapid metabolizers (RM). Although estimated glomerular filtration rate values were lower at several time points in RMs compared to NRM, they vote against CDR-based tailoring of the tacrolimus therapy. First, Bartlett et al. defined RM and NRM differently compared to previous studies. Their CDR cut-off for RM/NRM was 2.04 (ng/ml)*1/ mg that is considerably higher compared to previous definitions [< 1.05 (ng/ml)*1/mg] 4 and < 0.67 (ng/ml)*1/mg. In accordance, they identified 74.3% RM compared to 39.1% and 25.2% RM. Hence, a substantial number of their RM would have been classified as NRM in the other studies. Notably, as kidney transplant recipients with a CDR between 1.05 and 1.54 (ng/ml)*1/ mg (intermediate group) showed comparable results to patients with a CDR ≥ 1.55 (ng/ml)*1/ mg we have even chosen to combine both groups in later analyses. Second, in contrast to European studies, Bartlett et al.’s study included 40% African Americans; ethnicity has a known impact. 7 Third, the low rejection rate (e.g., in contrast to Egeland et al.), might have masked differences as already stated by the authors. Different induction therapies and missing protocol biopsies, frequently detecting rejection in stable grafts, might be responsible. 8 Fourth, Bartlett et al. use a lower tacrolimus trough level compared with our data. 4 Lower troughs might mitigate tacrolimus adverse effects. 9 Fifth, the authors speculate that NRM have a higher exposure to tacrolimus over time, leading to increased toxicity, which is not supported by data. In fact, others showed comparable area under the receiver operating characteristic curve between RM and NRM. 11 A reanalysis of the study data using different CDR cut-offs would be interesting.
肾移植受者他克莫司浓度剂量比及其与临床结果关系的另一种观点
Bartlett等人在一项美国大型单中心研究中报道,他克莫司代谢率(定义为浓度剂量比(CDR))对肾移植受者活检证实的急性排斥反应没有影响。与我们的结果相反,他们观察到非快速代谢者(NRM)的死亡率高于快速代谢者(RM)。尽管与NRM相比,RMs在几个时间点的肾小球滤过率估计值更低,但他们反对基于cdr的他克莫司治疗。首先,Bartlett等人对RM和NRM的定义与以往的研究不同。他们对RM/NRM的CDR截止值为2.04 (ng/ml)*1/mg,与之前的定义[< 1.05 (ng/ml)*1/mg] 4和< 0.67 (ng/ml)*1/mg]相比,有很大的提高。因此,他们确定了74.3%的RM,而RM为39.1%和25.2%。因此,在其他研究中,他们的大量RM将被归类为NRM。值得注意的是,由于CDR在1.05至1.54 (ng/ml)*1/ mg(中间组)之间的肾移植受者与CDR≥1.55 (ng/ml)*1/ mg的患者的结果相当,我们甚至在后来的分析中选择将两组合并。其次,与欧洲研究相反,Bartlett等人的研究包括40%的非裔美国人;种族的影响是众所周知的。第三,低拒绝率(例如,与Egeland等人相比)可能掩盖了作者已经陈述的差异。不同的诱导疗法和缺少活检方案,在稳定的移植物中经常发现排斥反应,可能是原因。8第四,与我们的数据相比,Bartlett等人使用了较低的他克莫司谷水平。4较低的波谷可能减轻他克莫司的不良反应。第五,作者推测NRM随着时间的推移与他克莫司的接触增加,导致毒性增加,这没有数据支持。事实上,其他人在RM和NRM之间的接收者工作特征曲线下显示出相当的面积。使用不同的CDR截断值重新分析研究数据将是有趣的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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