儿童肝移植中他克莫司浓度个体内变异

doi:10.16139/j.1007-9610.2022.02.012

摘要/Abstract

摘要：

目的： 研究儿童肝移植术后他克莫司浓度个体内变异（tacrolimus intra-patient variability,Tac-IPV）和对移植预后的影响。方法： 本单中心回顾性研究纳入392例儿童肝移植受者。所有患儿均在术后采用Tac为基础的免疫抑制方案。通过变异系数（coefficient of variation,CV）和Tac变异评分（Tac variability score,TVS）分别计算Tac-IPV。结合随访及穿刺结果,分析并发症发生组和正常恢复组IPV的差异。分析两种计算方法得到的IPV对移植术后相关并发症发生的影响。结果： 本研究共纳入男童175例,女童217例。移植时月龄为（24.73±36.58）个月。肝移植术后3年内的Tac-CV中位数分别为0.386 3、0.317 0、0.291 3,第4~5年的Tac-CV中位数为0.296 1。采用CV计算IPV,排斥反应、肝纤维化等并发症发生组与正常恢复组的IPV差异无统计学意义。采用TVS计算,术后肝纤维化组1~12个月IPV（P=0.011）和4~12个月IPV（P=0.001）与正常恢复组的差异有统计学意义。结论： 儿童肝移植术后前3年Tac-IPV逐年下降。Tac-IPV升高可能与肝纤维化等不良临床结局有关。

关键词: 他克莫司, 个体内变异度, 肝移植

Abstract:

Objective To study tacrolimus intra-patient variability (Tac-IPV) after liver transplantation in children and the influence on prognosis of transplantation. Methods A total of 392 pediatric liver transplant recipients were included in this single-center retrospective study. All children were treated with Tac-based immunosuppressive therapy postoperatively. Tac-IPV was calculated using both coefficient of variation (CV) and Tac variability score (TVS) methods. According to both follow-up and biopsy results, the difference in IPV was analyzed between complication group and normal recovery group. The influence of IPV on postoperative complications after transplantation were analyzed using two calculation methods. Results There were 175 males and 217 females with(24.73±36.58) months of age when transplantation included in this study. After pediatric liver transplantation, the median Tac-CV was 0.386 3, 0.317 0, and 0.291 3 in the first three years respectively, and 0.296 1 in 4-5 years. There was no significant difference in IPV calculated by CV between complication group and normal recovery group, such as rejection and liver fibrosis. However, the difference in IPV was significant statistically calculated by TVS within 1-12 months (P=0.011) and 4-12 months (P=0.001) between postoperative liver fibrosis group and normal recovery group. Conclusions After pediatric liver transplantation, Tac-IPV decreased in the first 3 years. Increase in Tac-IPV may be associated with poorer clinical outcomes such as liver fibrosis.

Key words: Tacrolimus, Intra-patient variability, Liver transplantation

中图分类号:

R657.3

吴浩翔, 吕子成, 侯宇宸, 张子杰, 乔子耘, 冯浩, 夏强. 儿童肝移植中他克莫司浓度个体内变异[J]. 外科理论与实践, 2022, 27(02): 145-151.

WU Haoxiang, LÜ Zicheng, HOU Yuchen, ZHANG Zijie, QIAO Ziyun, FENG Hao, XIA Qiang. Tacrolimus intra-patient variability in pediatric liver transplantation[J]. Journal of Surgery Concepts & Practice, 2022, 27(02): 145-151.

图/表 4

参考文献 30

[1]	Kwong A, Kim WR, Lake JR, et al. OPTN/SRTR 2018 annual data report: liver[J]. Am J Transplant, 2020,20 Suppl s1:193-299.
[2]	Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2018 annual data report: kidney[J]. Am J Transplant, 2020,20 Suppl s1:20-130.
[3]	Schutte-Nutgen K, Tholking G, Suwelack B, et al. Tacrolimus - pharmacokinetic considerations for clinicians[J]. Curr Drug Metab, 2018, 19(4):342-350. doi: 10.2174/1389200219666180101104159 pmid: 29298646
[4]	Brunet M, van Gelder T, Asberg A, et al. Therapeutic drug monitoring of tacrolimus-personalized therapy: se-cond consensus report[J]. Ther Drug Monit, 2019, 41(3):261-307. doi: 10.1097/FTD.0000000000000640 pmid: 31045868
[5]	Shuker N, van Gelder T, Hesselink DA. Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management[J]. Transplant Rev (Orlando), 2015, 29(2):78-84. doi: 10.1016/j.trre.2015.01.002 URL
[6]	Forbes A, Murrells T, Mulnier H, et al. Mean HbA1c, HbA1c variability, and mortality in people with diabetes aged 70 years and older: a retrospective cohort study[J]. Lancet Diabetes Endocrinol, 2018, 6(6):476-486. doi: 10.1016/S2213-8587(18)30048-2 URL
[7]	Yin S, Wang X, Huang Z, et al. Tacrolimus variability score outperforms coefficient of variation in predicting clinical outcomes of living kidney transplantation[J]. Br J Clin Pharmacol, 2022, 88(1):75-83. doi: 10.1111/bcp.14876 URL
[8]	中华医学会器官移植学分会肾移植学组. 他克莫司在临床肝移植中的应用指南[J]. 临床肝胆病杂志, 2015, 31(9):1372-1374.
[9]	Florescu DF. Solid organ transplantation: hypogammaglobulinaemia and infectious complications after solid organ transplantation[J]. Clin Exp Immunol, 2014, 178(Suppl 1):54-56. doi: 10.1111/cei.12510 URL
[10]	Gillis KA, Patel RK, Jardine AG. Cardiovascular complications after transplantation: treatment options in solid organ recipients[J]. Transplant Rev (Orlando), 2014, 28(2):47-55. doi: 10.1016/j.trre.2013.12.001 URL
[11]	Shah PB, Ennis JL, Cunningham PN, et al. The epide-miologic burden of tacrolimus variability among kidney transplant recipients in the united states[J]. Am J Nephrol, 2019, 50(5):370-374. doi: 10.1159/000503167 URL
[12]	Lieber SR, Volk ML. Non-adherence and graft failure in adult liver transplant recipients[J]. Dig Dis Sci, 2013, 58(3):824-834. doi: 10.1007/s10620-012-2412-0 URL
[13]	Christina S, Annunziato RA, Schiano TD, et al. Medication level variability index predicts rejection, possibly due to nonadherence, in adult liver transplant recipients[J]. Liver Transpl, 2014, 20(10):1168-1177. doi: 10.1002/lt.23930 URL
[14]	Del Bello A, Congy-Jolivet N, Danjoux M, et al. High tacrolimus intra-patient variability is associated with graft rejection, and de novo donor-specific antibodies occurrence after liver transplantation[J]. World J Gastroenterol, 2018, 24(16):1795-1802. doi: 10.3748/wjg.v24.i16.1795 URL
[15]	van der Veer MAA, Nangrahary N, Hesselink DA, et al. High intrapatient variability in tacrolimus exposure is not associated with immune-mediated graft injury after liver transplantation[J]. Transplantation, 2019, 103(11):2329-2337. doi: 10.1097/TP.0000000000002680 URL
[16]	Rayar M, Tron C, Jezequel C, et al. High intrapatient variability of tacrolimus exposure in the early period after liver transplantation is associated with poorer outcomes[J]. Transplantation, 2018, 102(3):e108-e114.
[17]	Di Maira T, Sapisochin G, Lilly L, et al. Posttransplant calcineurin inhibitors levels and intrapatient variability are not associated with long-term outcomes following liver transplantation[J]. Transplantation, 2020, 104(6):1201-1209. doi: 10.1097/TP.0000000000002987 URL
[18]	Venkat VL, Nick TG, Wang Y, et al. An objective measure to identify pediatric liver transplant recipients at risk for late allograft rejection related to non-adherence[J]. Pediatr Transplant, 2008, 12(1):67-72. doi: 10.1111/j.1399-3046.2007.00794.x pmid: 18186891
[19]	Shemesh E, Bucuvalas JC, Anand R, et al. The medication level variability index (MLVI) predicts poor liver transplant outcomes: a prospective multi-site study[J]. Am J Transplant, 2017, 17(10):2668-2678. doi: 10.1111/ajt.14276 pmid: 28321975
[20]	Shemesh E, Duncan S, Anand R, et al. Trajectory of adherence behavior in pediatric and adolescent liver transplant recipients: The medication adherence in children who had a liver transplant cohort[J]. Liver Transpl, 2018, 24(1):80-88. doi: 10.1002/lt.24837 URL
[21]	Kieling CO, da Silva AB, et al. Variabi-lity index of tacrolimus serum levels in pediatric liver transplant recipients younger than 12 years: non-adhe-rence or risk of non-adherence?[J]. Pediatr Transplant, 2017, 21(8).doi: 10.1111/petr.13058. doi: 10.1111/petr.13058
[22]	Riva N, Dip M, Halac E, et al. Survival time to biopsy-proven acute rejection and tacrolimus adverse drug reactions in pediatric liver transplantation[J]. Ther Drug Monit, 2018, 40(4):401-410. doi: 10.1097/FTD.0000000000000517 URL
[23]	Defrancq C, de Wilde N, Raes A, et al. Intra-patient variability in tacrolimus exposure in pediatric liver transplant recipients: evolution, risk factors, and impact on patient outcomes[J]. Pediatr Transplant, 2019, 23(3):e13388.
[24]	Rodrigo E, Segundo DS, Fernández-Fresnedo G, et al. Within-patient variability in tacrolimus blood levels predicts kidney graft loss and donor-specific antibody deve-lopment[J]. Transplantation, 2016, 100(11):2479-2485. pmid: 26703349
[25]	Whalen HR, Glen JA, Harkins V, et al. High intrapatient tacrolimus variability is associated with worse outcomes in renal transplantation using a low-dose tacrolimus immunosuppressive regime[J]. Transplantation, 2017, 101(2):430-436. doi: 10.1097/TP.0000000000001129 pmid: 26950724
[26]	Süsal C, Döhler B. Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: a collaborative transplant study report[J]. Am J Transplant, 2019, 19(10):2805-2813. doi: 10.1111/ajt.15346 URL
[27]	Vanhove T, Vermeulen T, Annaert P, et al. High intrapatient variability of tacrolimus concentrations predicts accelerated progression of chronic histologic lesions in renal recipients[J]. Am J Transplant, 2016, 16(10):2954-2963. doi: 10.1111/ajt.13803 pmid: 27013142
[28]	Rahamimov R, Tifti-Orbach H, Zingerman B, et al. Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation[J]. Eur J Clin Pharmacol, 2019, 75(7):951-958. doi: 10.1007/s00228-019-02643-y pmid: 30762079
[29]	Yin S, Song T, Jiang Y, et al. Tacrolimus trough level at the first month may predict renal transplantation outcomes among living chinese kidney transplant patients: a propensity score-matched analysis[J]. Ther Drug Monit, 2019, 41(3):308-316. doi: 10.1097/FTD.0000000000000593 URL
[30]	Benseler V, McCaughan GW, Schlitt HJ, et al. The liver: a special case in transplantation tolerance[J]. Semin Liver Dis, 2007, 27(2):194-213. pmid: 17520518

项目	类别	值
性别	男性	175（44.64）
	女性	217（55.36）
移植时月龄（月）	/	24.73±36.58
体重（kg）	/	10.57±7.89
诊断	胆道闭锁	325（82.91）
	代谢性疾病	23（5.87）
	肿瘤	2（0.51）
	其他	42（10.71）
手术类型	LDLT	288（73.47）
	DCD	104（26.53）
GRWR	/	3.31±1.15
免疫抑制方案	Tac	11（2.81）
	Tac+GC	95（24.23）
	Tac+MMF	15（3.83）
	Tac+GC+MMF	271（69.13）