Blydt-Hansen T D, Sharma A, Gibson I W, Mandal R, Wishart D S
Department of Pediatrics and Child Health (Nephrology), University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, MB, Canada.
Am J Transplant. 2014 Oct;14(10):2339-49. doi: 10.1111/ajt.12837. Epub 2014 Aug 19.
The goal of this study was to evaluate the utility of urinary metabolomics for noninvasive diagnosis of T cell-mediated rejection (TCMR) in pediatric kidney transplant recipients. Urine samples (n = 277) from 57 patients with surveillance or indication kidney biopsies were assayed for 134 unique metabolites by quantitative mass spectrometry. Samples without TCMR (n = 183) were compared to borderline tubulitis (n = 54) and TCMR (n = 30). Partial least squares discriminant analysis identified distinct classifiers for TCMR (area under receiver operating characteristic curve [AUC] = 0.892; 95% confidence interval [CI] 0.827-0.957) and borderline tubulitis (AUC = 0.836; 95% CI 0.781-0.892), respectively. Application of the TCMR classifier to borderline tubulitis samples yielded a discriminant score (-0.47 ± 0.33) mid-way between TCMR (-0.20 ± 0.34) and No TCMR (-0.80 ± 0.32) (p < 0.001 for all comparisons). Discriminant scoring for combined borderline/TCMR versus No TCMR (AUC = 0.900; 95% CI 0.859-0.940) applied to a validation cohort robustly distinguished between samples with (-0.08 ± 0.52) and without (-0.65 ± 0.54, p < 0.001) borderline/TCMR (p < 0.001). The TCMR discriminant score was driven by histological t-score, ct-score, donor-specific antibody and biopsy indication, and was unaffected by renal function, interstitial or microcirculatory inflammation, interstitial fibrosis or pyuria. These preliminary findings suggest that urinary metabolomics is a sensitive, specific and noninvasive tool for TCMR identification that is superior to serum creatinine, with minimal confounding by other allograft injury processes.
本研究的目的是评估尿代谢组学在小儿肾移植受者中对T细胞介导的排斥反应（TCMR）进行无创诊断的效用。对57例接受监测或因适应证进行肾活检的患者的尿液样本（n = 277），通过定量质谱法检测了134种独特的代谢物。将无TCMR的样本（n = 183）与临界性肾小管炎样本（n = 54）和TCMR样本（n = 30）进行比较。偏最小二乘判别分析分别确定了TCMR（受试者工作特征曲线下面积[AUC]=0.892；95%置信区间[CI]0.827 - 0.957）和临界性肾小管炎（AUC = 0.836；95%CI 0.781 - 0.892）的不同分类器。将TCMR分类器应用于临界性肾小管炎样本，得到的判别分数（-0.47±0.33）介于TCMR（-0.20±0.34）和无TCMR（-0.80±0.32）之间（所有比较p<0.001）。将临界性/TCMR合并组与无TCMR组的判别评分（AUC = 0.900；95%CI 0.859 - 0.940）应用于验证队列，能可靠地区分有临界性/TCMR（-0.08±0.52）和无临界性/TCMR（-0.65±0.54，p<0.001）的样本（p<0.001）。TCMR判别分数受组织学t评分、ct评分、供者特异性抗体和活检适应证的驱动，不受肾功能、间质或微循环炎症、间质纤维化或脓尿的影响。这些初步研究结果表明，尿代谢组学是一种用于识别TCMR的敏感、特异且无创的工具，优于血清肌酐，且受其他移植肾损伤过程的干扰最小。
