Integrative Urinary Peptidomics in Renal Transplantation Identifies Biomarkers for Acute Rejection
Integrative Urinary Peptidomics in Renal Transplantation Identifies Biomarkers for Acute Rejection
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DOI：
10.1681/asn.2009080876
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发表时间：
2010-04-01
影响因子：
13.6
通讯作者：
Sarwal, Minnie M.
中科院分区：
文献类型：
--
作者：
Ling, Xuefeng B.;Sigdel, Tara K.;Sarwal, Minnie M.
无创性方法来诊断肾移植排斥反应是不可用的。质谱分析后的多反应监测提供了一种独特的方法来确定疾病特异性尿肽生物标志物。在这里，我们对来自50名肾移植患者和20名对照（n = 20）的70个独特样本进行了尿肽组分析，确定了急性排斥（AR）的40种肽的特定组。肽测序揭示了移植物损伤的提示机制，其中尿调蛋白（UMOD）和几种胶原蛋白（包括COL 1A 2和COL 3A 1）的蛋白水解降解起作用。40肽组区分训练（n = 46）和测试（n = 24）组中的AR（ROC曲线下面积>0.96）。对来自配对肾移植活检组织的转录信号进行综合分析，与尿液样本相匹配，发现除了AR中细胞外基质蛋白（MMP-7，SERPING 1和TIMP 1）的失调外，相应基因的协调转录变化。对34个移植活检组织进行定量PCR，证实了排斥组织中相应基因表达的协调变化。六基因生物标志物组（COL 1A 2、COL 3A 1、UMOD、MMP-7、SERPING 1、TIMP 1）以高特异性和灵敏度（ROC曲线下面积= 0.98）分类AR。这些数据表明，胶原蛋白重塑的变化是AR的特征，尿液中相应的蛋白水解降解产物的检测提供了一种非侵入性诊断方法。
Noninvasive methods to diagnose rejection of renal allografts are unavailable. Mass spectrometry followed by multiple-reaction monitoring provides a unique approach to identify disease-specific urine peptide biomarkers. Here, we performed urine peptidomic analysis of 70 unique samples from 50 renal transplant patients and 20 controls (n = 20), identifying a specific panel of 40 peptides for acute rejection (AR). Peptide sequencing revealed suggestive mechanisms of graft injury with roles for proteolytic degradation of uromodulin (UMOD) and several collagens, including COL1A2 and COL3A1. The 40-peptide panel discriminated AR in training (n = 46) and test (n = 24) sets (area under ROC curve >0.96). Integrative analysis of transcriptional signals from paired renal transplant biopsies, matched with the urine samples, revealed coordinated transcriptional changes for the corresponding genes in addition to dysregulation of extracellular matrix proteins in AR (MMP-7, SERPING1, and TIMP1). Quantitative PCR on an independent set of 34 transplant biopsies with and without AR validated coordinated changes in expression for the corresponding genes in rejection tissue. A six-gene biomarker panel (COL1A2, COL3A1, UMOD, MMP-7, SERPING1, TIMP1) classified AR with high specificity and sensitivity (area under ROC curve = 0.98). These data suggest that changes in collagen remodeling characterize AR and that detection of the corresponding proteolytic degradation products in urine provides a noninvasive diagnostic approach.