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中华移植杂志(电子版) ›› 2022, Vol. 16 ›› Issue (02) : 65 -71. doi: 10.3877/cma.j.issn.1674-3903.2022.02.001

论著

他克莫司个体内高变异度与肝移植术后免疫介导移植物损伤的临床研究
田敏1, 王博1, 刘学民1, 张晓刚1, 郭坤1, 李宇1, 胡良硕1, 霍锦霞1, 吕毅1,†()   
  1. 1. 710061　西安交通大学第一附属医院肝胆外科
  • 收稿日期:2021-12-03 出版日期:2022-04-25
  • 通信作者: 吕毅
  • 基金资助:
    国家自然科学基金面上项目(81870445)

Relevant research between high intrapatient variability in tacrolimus and immune-mediated graft injury after liver transplantation

Min Tian1, Bo Wang1, Xuemin Liu1, Xiaogang Zhang1, Kun Guo1, Yu Li1, Liangshuo Hu1, Jinxia Huo1, Yi Lyu1,†()   

  1. 1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi′an Jiaotong University, Xi′an 710061, China
  • Received:2021-12-03 Published:2022-04-25
  • Corresponding author: Yi Lyu
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引用本文：

田敏, 王博, 刘学民, 张晓刚, 郭坤, 李宇, 胡良硕, 霍锦霞, 吕毅. 他克莫司个体内高变异度与肝移植术后免疫介导移植物损伤的临床研究[J]. 中华移植杂志(电子版), 2022, 16(02): 65-71.

Min Tian, Bo Wang, Xuemin Liu, Xiaogang Zhang, Kun Guo, Yu Li, Liangshuo Hu, Jinxia Huo, Yi Lyu. Relevant research between high intrapatient variability in tacrolimus and immune-mediated graft injury after liver transplantation[J]. Chinese Journal of Transplantation(Electronic Edition), 2022, 16(02): 65-71.

目的

探讨他克莫司个体内变异度(IPV)与肝移植术后免疫介导移植物损伤的关系。

方法

回顾性分析2015年1月至2019年12月在西安交通大学第一附属医院肝胆外科进行经典原位肝移植的288例受者资料。采用移植后2~6个月期间至少5个他克莫司血药浓度谷值(C0)计算得到他克莫司血药浓度变异系数(CV)。设定的复合终点包括：(1)肝移植术后6个月后免疫介导的移植物失功，包括慢性排斥反应、活检证实的晚期急性排斥反应；(2)肝移植术后6个月后免疫抑制剂毒性作用导致的肝功能损害；(3)肝移植术后6个月后出现的CMV血症。以CV均值为临界值将受者分为低CV组和高CV组，比较两组到达复合终点的受者比例，分析肝移植术后发生免疫介导移植物损伤的影响因素。正态分布计量资料以均数±标准差(±s)表示，采用独立样本t检验进行比较；非正态分布计量资料以中位数表示，采用Mann-Whitney U检验进行比较。计数资料以例数(%)表示，采用χ2检验进行比较。采用Kaplan-Meier法绘制生存曲线，使用log-rank检验进行比较。采用Cox比例风险模型分析肝移植术后免疫介导移植物损伤的危险因素，将单因素分析中P≤0.20的变量采用逐步后退法进行多因素分析。P<0.05为差异具有统计学意义。

结果

截至2021年6月30日，288例肝移植受者平均随访时间(37±16)个月(6~76个月)，共37例(12.85%)到达复合终点。肝移植术后2~6个月他克莫司血药浓度CV平均值为(28.11±10.72)%，以28.11%作为临界值将288例受者分为低CV组(CV<28.11%)和高CV组(CV≥28.11%)。两组供者年龄、性别，受者年龄、性别、体质指数、原发病性质、术前终末期肝病模型评分、术前Child-Pugh评分、术后免疫抑制方案、慢性排斥反应发生率以及术后2~6个月他克莫司C0、总胆红素和ALT水平差异均无统计学意义(P均>0.05)。高CV组受者急性排斥反应和CMV血症发生率高于低CV组受者(3.13%和0，5.47%和1.25%)，差异有统计学意义(P均<0.05)。高CV组到达复合终点的受者比例较低CV组高，分别为18.0%(23/128)和8.8%(14/160)，差异有统计学意义(χ2＝5.397，P<0.05)。高CV组受者较低CV组到达复合终点的受者时间更短，分别为(1764±72)d和(1909±51)d，差异有统计学意义(χ2＝6.367，P<0.05)。Cox比例风险模型分析结果显示，供者年龄、移植前受者Child-Pugh评分、移植后2~6个月总胆红素和他克莫司血药浓度CV是肝移植术后发生免疫介导移植物损伤的独立危险因素(HR＝1.033、2.353、1.011和0.450，P均<0.05)。

结论

肝移植术后2~6个月他克莫司高IPV(血药浓度CV≥28.11%)与免疫介导的移植物损伤存在显著相关性，可能导致急性排斥反应及CMV血症发生率增高。

关键词: 他克莫司, 个体内变异度, 变异系数, 肝移植, 急性排斥反应, 巨细胞病毒血症, 移植物损伤
Objective

To investigate whether intrapatient variability (IPV) of tacrolimus was closely related to immune-mediated graft injury in liver transplant recipients.

Methods

A retrospective cohort study was conducted in 288 patients who underwent classical orthotopic liver transplantation in the Liver Transplantation Center of the First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to December 2019. Tacrolimus IPV was calculated from at least 5 tacrolimus trough samples obtained between months 2 and 6 after liver transplantation and expressed as the coefficient of variation (CV). The composite endpoints included: ①Immune-mediated graft injury 6 months after liver transplantation, including chronic rejection and late acute rejection proven by biopsy; ②Liver function injury caused by the toxic effects of immunosuppressants 6 months after liver transplantation; ③Cytomegalovirus (CMV) viremia 6 months after liver transplantation. The recipients were divided into the low CV group and the high CV group with the mean value of CV as the critical value. The proportion of recipients reaching the composite endpoints were compared between the two groups, and the influencing factors of immune-mediated graft injury after liver transplantation were analyzed. Normal distribution measurement data shown in the form of (±s) were compared by independent sample t test. Nonnormally distributed measurement data shown in the form of median (full distance) were compared by Mann-Whitney U test. Count data shown in the form of percentage were compared with Chi-square test. The Kaplan-Meier method was used to plot the survival curve, and the log-rank test was used for comparison. Cox proportional hazard model was used to analyze the risk factors of immune-mediated graft injury after liver transplantation, and variables with P≤0.20 in univariate analysis were analyzed by step-back method for multivariate analysis. P<0.05 for difference was considered statistically significant.

Results

As of June 30, 2021, the 288 liver transplant recipients were included in the study, the follow-up ranged from 6 to 76 months, with an average of (37±16) months. And 37/288 (12.85%) patients reached the composite endpoint. The CV from 2 to 6 months after liver transplantation was normally distributed, and the average value of CV was (28.11±10.72)%. The average value of CV was used as the critical value to construct the low CV group (CV<28.11%) and high CV group (CV≥28.11%). No statistically significant differences in age and sex of donors, and age, sex, body mass index, primary disease, preoperative model score of end-stage liver disease, preoperative Child-Pugh score, postoperative immunosuppressive treatment protocol, incidence rate of chronic rejection of recipients, and tacrolimus C0, total bilirubin and ALT within 2 to 6 months after liver transplantation between the two groups (all P>0.05). However, the incidence rates of late acute rejection (3.13% vs. 0, P<0.05) and CMV viremia (5.47% vs. 1.25%, P<0.05) were higher in the high CV group than that in the low CV group; the proportion of liver transplant recipients reaching the composite endpoints was higher in the high CV group than that in the low CV group [18.0% (23/128) vs. 8.8% (14/160), χ2=5.397, P<0.05]. It showed that the time of liver transplant recipients reaching the composite endpoint in high CV group was less than that in low CV group [(1764±72) d vs. (1909±51) d, χ2=6.367, P<0.05)]. Cox proportional hazard model analysis showed that donor age, pre-transplant Child-Pugh score of recipients, total bilirubin and tacrolimus CV within 2 to 6 months after liver transplantation were independent risk factors for immune-mediated graft injury (HR=1.034, 2.353, 1.011 and 0.450, all P<0.05).

Conclusions

The high tacrolimus IPV (CV≥28.11%) within 2 to 6 months after liver transplantation was significantly associated with immune-mediated graft injury after liver transplantation. And, the high tacrolimus IPV exposure may lead to the increased incidence of late acute rejection and CMV viremia.

Key words: Tacrolimus, Intrapatient variability, Coefficient of variation, Liver transplant, Acute rejection, Cytomegalovirus viremia, Graft injury
表1 他克莫司血药浓度不同CV组肝移植受者临床资料比较
组别 例数 年龄(岁，±s) 男性[例(%)] 体质指数(kg/m2，±s) 恶性原发病[例(%)] 术前MELD评分(分，±s) 术前Child-Pugh评分(分，±s)
低CV组 160 46±10 121(75.6) 23±4 45(28.1) 19±9 10.0±2.0
高CV组 128 48± 9 97(75.8) 22±4 47(36.7) 18±9 10.1±1.9
t/χ2值 - 1.410 0.001 0.909 2.416 0.158 0.440
P值 - >0.05 >0.05 >0.05 >0.05 >0.05 >0.05
组别 例数 术后2~6个月 免疫抑制维持方案为他克莫司+MMF[例(%)] 急性排斥反应[例(%)] 慢性排斥反应[例(%)] CMV血症[例(%)]
他克莫司C0(ng/mL，±s) 总胆红素[μmol/L，M(min，max)] ALT(U/L，±s)
低CV组 160 6.8±1.0 16.7(1.8, 212.6) 42.5±31.2 147(91.9) 0 1(0.6) 2(1.2)
高CV组 128 6.9±1.2 18.3(4.2，311.0) 47.0±42.7 119(93.0) 4(3.1) 1(0.8) 7(5.5)
t/U/χ2值 - -1.027 9618 -0.992 0.120 5.070 0.025 4.181
P值 - >0.05 >0.05 >0.05 >0.05 <0.05 >0.05 <0.05
图1 他克莫司血药浓度不同CV组肝移植受者生存曲线注：他克莫司血药浓度CV<28.11%为低CV组，≥28.11%为高CV组；随访终点为受者发生免疫介导的移植物损伤复合终点
表2 肝移植受者术后免疫介导移植物损伤危险因素Cox比例风险模型分析
变量 单因素分析 多因素分析
HR值 95%可信区间 P值 HR值 95%可信区间 P值
供者年龄(岁) 1.034 1.004~1.064 <0.05 1.033 1.004~1.063 <0.05
受者年龄(岁) 1.000 0.962~1.039 >0.05 - - -
受者体质指数(kg/m2) 1.074 0.980~1.176 >0.05 1.072 0.980~1.171 >0.05
受者肝移植前MELD评分 1.014 0.962~1.068 >0.05 - - -
受者肝移植前Child-Pugh评分(分)            
  <10 1.000     1.000    
  ≥10 3.092 1.164~8.212 <0.05 2.353 1.169~4.739 <0.05
受者原发病性质            
  良性 1.000     1.000    
  恶性 2.127 0.933~4.848 >0.05 1.918 0.863~4.266 >0.05
肝移植术后2~6个月他克莫司血药浓度CV            
  ≥28.11% 1.000     1.000    
  <28.11% 0.422 0.210~0.845 <0.05 0.450 0.225~0.900 <0.05
肝移植术后2~6个月TBiL(μmol/L) 1.012 1.007~1.017 <0.05 1.011 1.007~1.016 <0.05
肝移植术后2~6个月ALT(U/L) 1.000 0.992~1.008 >0.05 - - -
1
Rayar M, Tron C, Jézéquel 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.
2
Ensor CR, Iasella CJ, Harrigan KM, et al. Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients[J]. Am J Transplant, 2018，18(6)：1527-1533.
3
Shuker N, Bouamar R, Hesselink DA, et al. Intrapatient variability in tacrolimus exposure does not predict the development of cardiac allograft vasculopathy after heart transplant[J]. Exp Clin Transplant, 2018，16(3)：326-332.
4
Schumacher L, Leino AD, Park JM. Tacrolimus intrapatient variability in solid organ transplantation: a multiorgan perspective[J]. Pharmacotherapy, 2021，41(1)：103-118.
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.
6
Kuypers DRJ. Intrapatient variability of tacrolimus exposure in solid organ transplantation: a novel marker for clinical outcome[J]. Clin Pharmacol Ther, 2020，107(2)：347-358.
7
Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation[J]. Clin Pharmacokinet, 2004，43(10)：623-653.
8
Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference[J]. Ther Drug Monit, 2009, 31(2)：139-152.
9
Ekberg H, Bernasconi C, Nöldeke J, et al. Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study[J]. Nephrol Dial Transplant, 2010，25(6)：2004-2010.
10
Bouamar R, Shuker N, Hesselink DA, et al. Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials[J]. Am J Transplant, 2013，13(5)：1253-1261.
11
Shuker N, Shuker L, van Rosmalen J, et al. A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation[J]. Transpl Int, 2016，29(11)：1158-1167.
12
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.
13
O′Regan JA, Canney M, Connaughton DM, et al. Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation[J]. J Nephrol, 2016，29(2)：269-276.
14
Rodrigo E, Segundo DS, Fernández-Fresnedo G, et al. Within-patient variability in tacrolimus blood levels predicts kidney graft loss and donor-specific antibody development[J]. Transplantation, 2016，100(11)：2479-2485.
15
Cheng EY. The role of humoral alloreactivity in liver transplantation: lessons learned and new perspectives[J]. J Immunol Res, 2017：3234906.
16
Neuberger JM, Bechstein WO, Kuypers DR, et al. Practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients: a guidance report and clinical checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) group[J]. Transplantation, 2017，101(4S Suppl 2)：S1-S56.
17
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.
18
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.
19
Pollock-Barziv SM, Finkelstein Y, Manlhiot C, et al. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children[J]. Pediatr Transplant, 2010，14(8)：968-975.
20
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.
21
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.
22
Barbier L, Garcia S, Cros J, et al. Assessment of chronic rejection in liver graft recipients receiving immunosuppression with low-dose calcineurin inhibitors[J]. J Hepatol, 2013，59(6)：1223-1230.
23
Terasaki PI. Tolerogenic mechanisms in liver transplantation[J]. SOJ Immunol, 2015, 3(4)：1-13.
24
Merli M, Di Menna S, Giusto M, et al. Conversion from twice-daily to once-daily tacrolimus administration in liver transplant patient[J]. Transplant Proc, 2010，42(4)：1322-1324.
25
Quintero J, Juampérez J, Ortega J, et al. Conversion from twice-daily to once-daily tacrolimus formulation in pediatric liver transplant recipients - a long-term prospective study[J]. Transpl Int, 2018，31(1)：38-44.
26
Dumortier J, Duvoux C, Dubel L, et al. A multicenter, prospective, observational study of conversion from twice-daily immediate-release to once-daily prolonged-release tacrolimus in liver transplant recipients in France: the COBALT study[J]. Ann Transplant, 2019，24：506-516.
27
Knops N, Levtchenko E, van den Heuvel B, et al. From gut to kidney: transporting and metabolizing calcineurin-inhibitors in solid organ transplantation[J]. Int J Pharm, 2013，452(1-2)：14-35.
28
Pashaee N, Bouamar R, Hesselink DA, et al. CYP3A5 genotype is not related to the intrapatient variability of tacrolimus clearance[J]. Ther Drug Monit, 2011，33(3)：369-371.
29
Spierings N, Holt DW, MacPhee IA. CYP3A5 genotype had no impact on intrapatient variability of tacrolimus clearance in renal transplant recipients[J]. Ther Drug Monit, 2013，35(3)：328-331.
30
Ro H, Min SI, Yang J, et al. Impact of tacrolimus intraindividual variability and CYP3A5 genetic polymorphism on acute rejection in kidney transplantation[J]. Ther Drug Monit, 2012，34(6)：680-685.
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[14] 王孟龙. 肿瘤生物学特征在肝癌肝移植治疗中的意义[J]. 中华肝脏外科手术学电子杂志, 2023, 12(05): 490-494.
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