Baghai Arassi Maral, Fisch Nora, Feißt Manuel, Krupka Kai, Höcker Britta, Fichtner Alexander, Kanzelmeyer Nele, König Jens, Melk Anette, Oh Jun, Pape Lars, Weber Lutz T, Weitz Marcus, Tönshoff Burkhard
Department of Pediatrics I, Medical Faculty, University Children's Hospital, Heidelberg University, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
Molecular Systems Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Pediatr Nephrol. 2025 Jul 21. doi: 10.1007/s00467-025-06872-5.
Data on the relevance of tacrolimus intrapatient variability (TacIPV) and concentration-to-dose ratio (C/D ratio) as an approximation of tacrolimus metabolism for predicting outcomes in pediatric kidney transplant (pKTx) recipients are scarce.
We conducted a multicenter retrospective study of 255 pKTx recipients from the CERTAIN registry. TacIPV was quantified as the coefficient of variation (CV%) during months 6-12 post-transplant. In addition, the C/D ratio, corrected for body surface area, was calculated for the first 6 months post-transplant. Cutoffs were determined by minimization of log-rank P values: 23% for TacIPV and 1.0 for C/D ratio. Rejection episodes were classified according to the Banff criteria in the period following marker quantification.
A total of 13,159 tacrolimus trough blood levels were analyzed, with a median of 52 (IQR, 41-63) measurements per patient. High TacIPV (> 23%) during months 6-12 post-transplant was associated with an increased risk of rejection beyond 12 months post-transplant (hazard ratio (HR) 1.04, 95% CI 1.01-1.06, P = 0.002; Kaplan-Meier analysis P = 0.002). Similarly, a low C/D ratio (< 1.0), i.e., rapid tacrolimus metabolism, during the first 6 months was associated with a higher risk of rejection between months 6 and 12 (inverse HR 3.13, 95% CI 1.01-9.09, P = 0.04; Kaplan-Meier analysis P = 0.011).
This largest to date multicenter study determines pediatric-specific cutoff values for TacIPV and tacrolimus C/D ratio as a predictive marker for graft rejection. Patients with these risk factors should be closely monitored and their immunosuppressive therapy adjusted accordingly.
关于他克莫司患者内变异性（TacIPV）和浓度-剂量比（C/D比）作为他克莫司代谢近似值对预测小儿肾移植（pKTx）受者结局的相关性的数据很少。
我们对CERTAIN登记处的255名pKTx受者进行了一项多中心回顾性研究。TacIPV被量化为移植后6至12个月期间的变异系数（CV%）。此外，计算了移植后前6个月校正体表面积后的C/D比。通过最小化对数秩P值确定临界值：TacIPV为23%，C/D比为1.0。在标志物量化后的时期内，根据Banff标准对排斥反应发作进行分类。
共分析了13159次他克莫司血药谷浓度，每位患者的测量中位数为52次（四分位间距，41 - 63次）。移植后6至12个月期间高TacIPV（>23%）与移植后12个月后排斥反应风险增加相关（风险比（HR）1.04，95%置信区间1.01 - 1.06，P = 0.002；Kaplan - Meier分析P = 0.002）。同样，在最初6个月期间低C/D比（<1.0），即他克莫司代谢快，与6至12个月期间排斥反应风险较高相关（反向HR 3.13，95%置信区间1.01 - 9.09，P = 0.04；Kaplan - Meier分析P = 0.011）。
这项迄今为止最大的多中心研究确定了TacIPV和他克莫司C/D比的小儿特异性临界值，作为移植排斥反应的预测标志物。具有这些危险因素的患者应密切监测，并相应调整其免疫抑制治疗。
