Prusinskas Benas, Ohlsson Sinja, Kathemann Simone, Pilic Denisa, Kampmann Kristina, Büscher Rainer, Paul Andreas, Pape Lars, Hoyer Peter F, Lainka Elke
Department of Pediatrics II, Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children's Hospital, Essen, Germany.
Department of Pediatrics II, Pediatric Nephrology and Kidney Transplantation, University Children's Hospital Essen, Essen, Germany.
Front Pediatr. 2021 Jun 2;9:659608. doi: 10.3389/fped.2021.659608. eCollection 2021.
The calcineurin inhibitor (CNI) tacrolimus (TAC) is a cornerstone agent in immunosuppressive therapy in pediatric liver transplantation (LTX). Adverse effects limit the use of CNI. In adults, calculating the individual TAC metabolism rate allows to estimate the transplant recipient's risk for therapy-associated complications. A retrospective, descriptive data analysis was performed in children who had undergone LTX in 2009-2017 and had received TAC twice daily in the first year after LTX. A weight-adjusted concentration/dose ratio (C/D ratio) was calculated [TAC trough level/(daily TAC dose/body weight)] every 3 months after LTX to estimate the average individual TAC metabolism rate. Depending on the C/D ratio, all patients were divided into two groups: fast metabolizers (FM) and slow metabolizers (SM). Clinical and laboratory parameters were analyzed as risk factors in both groups. A total of 78 children (w 34, m 44, median age at LTX 2.4; 0.4-17.0 years) were enrolled in the study. FM (SM) had a mean C/D ratio of <51.83 (≥51.83) ng/ml/(mg/kg). FM were younger at the time of LTX (median age 1.7; 0.4-15.8 years) than SM (5.1, 0.4-17.0), = 0.008. FM were more likely to have biliary atresia (20/39, 51%) compared to SM (11/39, 28%), = 0.038, whereas SM were more likely to have progressive familial intrahepatic cholestasis (9/39, 23%) vs. in FM (1/39, 3%), = 0.014. Epstein-Barr virus (EBV) infection occurred more frequently in FM (27/39, 69%) than SM (13/39, 33%), = 0.002. Three FM developed post-transplant lymphoproliferative disorder. The annual change of renal function did not differ in both groups (slope FM 1.2 ± 0.6; SM 1.4 ± 0.8 ml/min/1.73 m per year, and = 0.841). Calculation of individual, weight-adjusted TAC C/D ratio is a simple, effective, and cost-efficient tool for physicians to estimate the risk of therapy-associated complications and to initiate individual preventive adjustments after pediatric LTX. Lower TAC levels are tolerable in FM, especially in the presence of EBV infection, reduced renal function, or when receiving a liver transplant in the first 2 years of life.
钙调神经磷酸酶抑制剂（CNI）他克莫司（TAC）是小儿肝移植（LTX）免疫抑制治疗的基石药物。不良反应限制了CNI的使用。在成人中，计算个体TAC代谢率有助于评估移植受者发生治疗相关并发症的风险。对2009年至2017年接受LTX且在LTX后第一年每天接受两次TAC治疗的儿童进行了一项回顾性描述性数据分析。在LTX后每3个月计算一次体重调整后的浓度/剂量比（C/D比）[TAC谷浓度/（每日TAC剂量/体重）]，以估计个体平均TAC代谢率。根据C/D比，将所有患者分为两组：快代谢者（FM）和慢代谢者（SM）。分析两组的临床和实验室参数作为危险因素。共有78名儿童（女34名，男44名，LTX时的中位年龄为2.4岁；0.4至17.0岁）纳入研究。FM（SM）的平均C/D比<51.83（≥51.83）ng/ml/（mg/kg）。FM在LTX时比SM年轻（中位年龄1.7岁；0.4至15.8岁），而SM为5.1岁（0.4至17.0岁），P = 0.008。与SM（11/39，28%）相比，FM更易患胆道闭锁（20/39，51%），P = 0.038，而SM更易患进行性家族性肝内胆汁淤积症（9/39，23%），而FM为（1/39，3%），P = 0.014。FM中爱泼斯坦-巴尔病毒（EBV）感染比SM更常见（27/39，69%）（13/39，33%），P = 0.002。3名FM发生了移植后淋巴细胞增生性疾病。两组肾功能的年度变化无差异（FM斜率为1.2±0.6；SM为1.4±0.8 ml/min/1.73 m每年，P = 0.841）。计算个体体重调整后的TAC C/D比是医生评估小儿LTX后治疗相关并发症风险并启动个体预防性调整的一种简单、有效且经济高效的工具。在FM中，尤其是存在EBV感染、肾功能减退或在生命的前2年接受肝移植时，较低的TAC水平是可以耐受的。
