Millán Olga, Budde Klemens, Sommerer Claudia, Aliart Irene, Rissling Olesja, Bardaji Beatriz, Matz Maaren, Zeier Martin, Silva Irene, Guirado Lluis, Brunet Mercè
Pharmacology and Toxicology Laboratory, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain.
Medizinische Klinik mit Schwerpunkt Nephrologie, Charité Universitätsmedizin Berlin, Berlin, Germany.
Br J Clin Pharmacol. 2017 Dec;83(12):2636-2650. doi: 10.1111/bcp.13399. Epub 2017 Sep 21.
MicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients.
Eighty de novo kidney transplant recipients were recruited from four European centres. All patients received tacrolimus, mycophenolate mofetil, and methylprednisolone. Urinary pellet expression of miR-142-3p, miR-210-3p and miR-155-5p was assessed by quantitative real-time polymerase chain reaction and urinary CXCL10 levels by enzyme-linked immunosorbent assay at the 1 week and the 1 , 2 , 3 and 6 months post-transplantation.
Eight patients experienced AR. Before and during AR, patients showed a significant increase of urinary miR-142-3p, miR-155-5p and CXCL10 levels and a decrease of miR-210-3p levels. Receiver operating characteristic curve analysis showed that miR-155-5p (area under the curve = 0.875; P = 0.046) and CXCL10 (area under the curve = 0.865; P = 0.029) had excellent capacity to discriminate between rejectors and nonrejectors. The optimal cut-off values for the prognosis of AR were 0.51, with 85% sensitivity and 86% specificity for miR-155-5p and 84.73 pg ml , with 84% sensitivity and 80% specificity for CXCL10. miR-155-5p and CXCL10 levels correlated with glomerular filtration rate. Levels of both biomarkers normalized after recovery of graft function.
The regular early post-transplantation monitoring of urinary miR-155-5p and CXCL10 can help in the prognosis of AR and graft dysfunction. Large prospective randomized multicentre trials are warranted to refine our cut-off values and validate the clinical usefulness of these biomarkers.
微小RNA（miRNA）可能是肾移植排斥反应和移植肾预后的有用生物标志物。尿CXCL10水平升高与急性排斥反应（AR）相关，且可能预测移植肾失功。我们研究了肾移植受者中miRNA、CXCL10水平及免疫抑制药物暴露与AR和移植肾功能的相关性。
从四个欧洲中心招募了80例初发肾移植受者。所有患者均接受他克莫司、霉酚酸酯和甲泼尼龙治疗。在移植后1周、1、2、3和6个月，通过定量实时聚合酶链反应评估尿沉渣中miR-142-3p、miR-210-3p和miR-155-5p的表达，通过酶联免疫吸附测定评估尿CXCL10水平。
8例患者发生AR。在AR发生前及发生期间，患者尿miR-142-3p、miR-155-5p和CXCL10水平显著升高，miR-210-3p水平降低。受试者工作特征曲线分析显示，miR-155-5p（曲线下面积=0.875；P=0.046）和CXCL10（曲线下面积=0.865；P=0.029）具有区分排斥者和非排斥者的良好能力。AR预后的最佳截断值，miR-155-5p为0.51，敏感性为85%，特异性为86%；CXCL10为84.73 pg/ml，敏感性为84%，特异性为80%。miR-155-5p和CXCL10水平与肾小球滤过率相关。移植肾功能恢复后，两种生物标志物水平均恢复正常。
移植后早期定期监测尿miR-155-5p和CXCL10有助于AR和移植肾功能障碍的预后评估。有必要进行大型前瞻性随机多中心试验以优化我们的截断值并验证这些生物标志物的临床实用性。
