Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients.
Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients.
复制标题
DOI：
10.5500/wjt.v4.i2.133
复制
发表时间：
2014-06-24
期刊：
影响因子：
--
通讯作者：
Salcedo, Magdalena
中科院分区：
文献类型：
--
作者：
Fernandez-Yunquera, Ainhoa;Ripoll, Cristina;Salcedo, Magdalena
目的：评价依维莫司单药治疗肝移植（LT）受者与抗钙调磷酸酶方案患者血清纤维化标志物的表达。方法：这项横断病例对照研究包括接受依维莫司单药治疗的LT患者（病例）（n = 30）和接受抗钙调神经磷酸酶方案（钙调神经磷酸酶抑制剂，CNI）的匹配对照，根据肝病病因和LT后时间配对（n = 30）。收集临床特征、血液检查和弹性图。采用酶联免疫吸附法测定血清转化生长因子- β (tgf - β)、血管生成素-1、肿瘤坏死因子（TNF）、血小板源性生长因子、III型前胶原氨基末端前肽（PIIINP）、透明质酸（HA）、VCM-1 （ng/mL）、白细胞介素(IL)-10、干扰素诱导蛋白10 （IP-10）、血管内皮生长因子和肝细胞生长因子（HGF） （pg/mL）水平。比较这些标记物在E和CNI之间的表达。根据可能影响肝纤维化的因素进行分层分析。变量用中位数（四分位数范围）或百分比来描述。结果：共纳入60例患者[年龄：59(49-64)，丙型肝炎病毒（HCV）： n = 21(35%)，从LT开始时间：73个月（16-105）]。患者使用依维莫司的中位时间为15个月。两组之间在炎症活性、APRI测试或肝脏弹性成像方面没有发现差异。各组间血清PIIINP、金属蛋白酶type = 1、血管生成素、HGF、IP-10、tnf - α、IL-10及血管细胞粘附分子水平均无显著差异。E组患者tgf - β表达[E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009]和HA表达[E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001]低于CNI组。在分层分析中，当受体年龄大于50岁时（tfg - bet1: P = 0.06; HA: P = 0.005），在无活动性肿瘤患者中（tfg - bet1, P = 0.009; HA: P = 0.01），根据术后时间（>大于5年，tfg - bet1: P = 0.001; HA: P = 0.002），与既往胆道并发症（HA: P = 0.01）和HCV复发（HA: P = 0.004）相关，这种差异保持不变。接受依维莫司单药治疗的肝移植受者血清中tgf - β - y HA的表达低于接受抗钙调磷酸酶治疗的患者。当根据供体年龄和自lt以来的时间对患者进行分类时，这种差异仍然存在。由于样本量小，当检查有胆道并发症或复发性HCV病史的患者时，差异不显著，但在依维莫司组中，tfg - β 1的表达倾向较低。哺乳动物雷帕霉素靶蛋白（mTOR）在静止的肝细胞星状细胞向活跃的促纤维化状态转化中发挥作用，实验模型已经证明抑制mTOR在减缓纤维化发生中的潜在活性。结论：本研究支持依维莫司在肝移植后肝纤维化调节中的可能作用，并提示有针对性的免疫抑制可以避免同种异体移植物的纤维化进展。
AIM: To evaluate the expression of serum fibrosis markers in liver transplantation (LT) recipients on everolimus monotherapy compared to patients on an anti-calcineurin regimen.METHODS: This cross-sectional case-control study included LT patients on everolimus monotherapy (cases) (E) (n = 30) and matched controls on an anti-calcineurin regimen (calcineurin inhibitors, CNI), paired by etiology of liver disease and time since LT (n = 30). Clinical characteristics, blood tests and elastography were collected. Serum levels of transforming growth factor-beta (TGF-beta), angiopoietin-1, tumor necrosis factor (TNF), platelet derived growth factor, amino-terminal propeptide of type III procollagen (PIIINP), hyaluronic acid (HA), VCM-1 (ng/mL), interleukin (IL)-10, interferon-inducible protein 10 (IP-10), vascular endothelial growth factor and hepatocyte growth factor (HGF) (pg/mL) were determined by enzyme-linked immunosorbent assay. Expression of these markers between E and CNI was compared. Stratified analysis was done according to factors that may influence liver fibrosis. Variables are described with medians (interquartillic range) or percentages.RESULTS: A total of 60 patients [age: 59 (49-64), hepatitis C virus (HCV): n = 21 (35%), time from LT: 73 mo (16-105)] were included. Patients had been on everolimus for a median of 15 mo. No differences in inflammatory activity, APRI test or liver elastography were found between the groups. No significant differences were observed between the groups in serum levels of PIIINP, metalloproteinase type = 1, angiopoietin, HGF, IP-10, TNF-alpha, IL-10 and vascular cell adhesion molecule. Patients on E had a lower expression of TGF-beta [E: 12.7 (3.7-133.6), CNI: 152.5 (14.4-333.2), P = 0.009] and HA [E: 702.89 (329.4-838.2), CNI: 1513.6 (691.9-1951.4), P = 0.001] than those on CNI. This difference was maintained in the stratified analysis when recipient age is more than 50 years (TFG-beta1: P = 0.06; HA: P = 0.005), in patients without active neoplasia (TFG-beta1, P = 0.009; HA: P = 0.01), according to time since LT (> than 5 years, TFG-beta1: P = 0.001; HA: P = 0.002), related to previous history of biliary complications (HA: P = 0.01) and HCV recurrence (HA: P = 0.004). Liver transplant recipients with everolimus monotherapy had less serum expression of TGF-beta y HA than matched patients with anti-calcineurins. This difference remains when classifying patients according to donor age and time since LT. Due to the small sample size, when examining patients with a prior history of biliary complications or recurrent HCV, the difference was non-significant but trends towards the lower expression of TFG-beta1 in the everolimus group. Mammalian target of rapamycin (mTOR) plays a role in the transformation of quiescent hepatocellular stellate cell to their active profibrotic state, and experimental models have demonstrated the potential activity of mTOR inhibition in attenuating fibrogenesis.CONCLUSION: This study supports a possible role of everolimus in liver fibrosis modulation after LT in a clinical setting and suggests that tailoring immunosuppression could avoid fibrosis progression in the allograft.