Intestinal MDR1/ABCB1 level at surgery as a risk factor of acute cellular rejection in living-donor liver transplant patients
Intestinal MDR1/ABCB1 level at surgery as a risk factor of acute cellular rejection in living-donor liver transplant patients
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DOI：
10.1016/j.clpt.2005.09.013
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发表时间：
2006-01-01
影响因子：
6.7
通讯作者：
Inui, KI
中科院分区：
文献类型：
--
作者：
Masuda, S;Goto, M;Inui, KI
背景：尽管通过充分的免疫抑制来预防免疫反应可以延长移植物和患者的生存率，但他克莫司药代动力学的巨大个体间差异会干扰治疗。在这项研究中，我们研究了肠道MDR1 （ABCB1）是否是预测活体肝移植后急性细胞排斥反应发生的潜在生物标志物，以及预测他克莫司吸收的一个因素。方法：采用手术取肠黏膜组织标本164例，定量测定肠道MDR1和细胞色素P450 (CYP) 3A4 mRNA的表达。结果：术后前10天发生急性细胞排斥反应的概率与术后第2 ~ 4天他克莫司平均谷浓度显著相关（< 7 ng/mL组45.1%,< 7 ng/mL组22.9%,P = 0.0040）。高水平的MDR1与术后第10天发生急性细胞排斥反应相关（优势比为2.306[95%可信区间，1.058-5.028]），与术后第一年较差的生存率相关（优势比为7.413[95%可信区间，1.567-36.073]）。移植体重量比大于1.5 （r = -0.6798, P < 0.0001）和移植体重量比小于1.5 （r = -0.7180, P < 0.0001）的患者术后最初4天MDR1 mRNA表达水平与他克莫司浓度-口服剂量比呈负相关。结论：肠细胞MDR1 mRNA水平可能是术后急性细胞排斥反应和死亡的危险因素。因此，通过这种基于分子信息的初始剂量调整获得足够的他克莫司血药水平可能会减少肝移植后急性细胞排斥反应的发生。
Background: Although the prevention of immunologic reactions with sufficient inummosuppression prolongs graft and patient survival rates, the large interindividual variation in tacrolimus pharmacokinetics interferes with treatment. In this study we have examined whether intestinal MDR1 (ABCB1) is a potential biomarker predicting the occurrence of acute cellular rejection, as well as a factor to predict absorption of tacrolimus, after living-donor liver transplantation.Methods: By use of tissue specimens of intestinal mucosa (n = 164) obtained at surgery, the messenger ribonucleic acid (mRNA) expression of intestinal MDR1 and cytochrome P450 (CYP) 3A4 was quantified.Results: The probability of acute cellular rejection during the first 10 days after surgery was significantly associated with the average trough concentration of tacrolimus between postoperative days 2 and 4 (45.1% for < 7 ng/mL versus 22.9% for > 7 ng/mL,P = .0040). High levels of MDR1 were associated with an episode of acute cellular rejection before postoperative day 10 (odds ratio, 2.306 [95% confidence interval, 1.058-5.028]) and with a poor survival rate during the first postoperative year (odds ratio, 7.413 [95% confidence interval, 1.567-36.073]). The mRNA expression level of MDR1 was inversely correlated with the tacrolimus concentration-oral dose ratio during the initial 4 days after surgery in patients with a graft-to-recipient weight ratio greater than 1.5 (r = -0.6798, P < .0001) and those with a graft-to-recipient weight ratio of less than 1.5 (r = -0.7180, P < .0001).Conclusion: The enterocyte MDR1 mRNA level was suggested to be a risk factor for acute cellular rejection and death after surgery. Therefore obtaining a sufficient tacrolimus blood level via this molecular information- based initial dosage adjustment may enable the episode of acute cellular rejection after liver transplantation to be reduced.