Discovery and validation of a molecular signature for the noninvasive diagnosis of human renal allograft fibrosis.
Discovery and validation of a molecular signature for the noninvasive diagnosis of human renal allograft fibrosis.
复制标题
DOI：
10.1097/tp.0b013e31824ef181
复制
发表时间：
2012-06-15
期刊：
影响因子：
6.2
通讯作者：
Suthanthiran M
中科院分区：
文献类型：
--
作者：
Anglicheau D;Muthukumar T;Hummel A;Ding R;Sharma VK;Dadhania D;Seshan SV;Schwartz JE;Suthanthiran M
肾小管间质纤维化（纤维化），一种与肾移植失败相关的组织学特征，使用侵入性移植物活检程序进行诊断。纤维化的非侵入性诊断测试可能有助于改善同种异体移植物的结果。我们从114名肾移植受者中获得了114份尿液标本，其中48份来自48名活检纤维化受者，66份来自66名活检正常受者。采用动态定量PCR方法检测尿细胞中mRNA水平，并与同种异体移植物诊断相关。使用76名受体的发现集（32名具有同种异体移植物纤维化，44名具有正常活检）来开发诊断特征，并且使用38名受体的独立验证集（16名具有同种异体移植物纤维化，22名具有正常活检）来验证特征。在发现集中，以下mRNA的尿细胞水平与同种异体移植物纤维化的存在显著相关：波形蛋白（P<0.0001，logistic回归模型），HGF（P<0.0001），α-SMA纤维连接蛋白1（FN 1）（P<0.0001），穿孔素PAI 1（P=0.0002）、TGFβ1（P = 0.0004）、TIMP 1（P = 0.0009）、颗粒酶B（P = 0.0009）、FSP 1（P=0.006）、CD 103（P=0.02）和胶原1A 1（P=0.04）。由波形蛋白、NKCC 2、E-cadherin和18 S rRNA的mRNA水平组成的4基因模型提供了最准确、最简约的同种异体移植物纤维化诊断模型，其灵敏度为93.8%，特异性为84.1%（P<0.0001）。在独立验证集中，该模型预测同种异体移植物纤维化的敏感性为77.3%，特异性为87.5%（P<0.0001）。尿细胞中mRNA的测量可能提供一种非侵入性的方法来诊断人肾移植物中的纤维化。
Tubulointerstitial fibrosis (fibrosis), a histological feature associated with the failing kidney allograft, is diagnosed using the invasive allograft biopsy procedure. A noninvasive diagnostic test for fibrosis may help improve allograft outcome. We obtained 114 urine specimens from 114 renal allograft recipients; 48 from 48 recipients with fibrosis in biopsies and 66 from 66 recipients with normal biopsies. Levels of mRNAs in urinary cells were measured using kinetic, quantitative PCR assays and the levels were related to allograft diagnosis. A discovery set of 76 recipients (32 with allograft fibrosis and 44 with normal biopsies) was used to develop a diagnostic signature and an independent validation set of 38 recipients (16 with allograft fibrosis and 22 with normal biopsies) was used to validate the signature. In the discovery set, urinary cell levels of the following mRNAs were significantly associated with the presence of allograft fibrosis: vimentin (P<0.0001, logistic regression model), HGF (P<0.0001), α-SMA (P<0.0001), fibronectin 1 (P<0.0001), perforin (P=0.0002), PAI1 (P=0.0002), TGFβ1 (P=0.0004), TIMP1 (P=0.0009), granzyme B (P=0.0009), FSP1 (P=0.006), CD103 (P=0.02), and collagen 1A1 (P=0.04). A 4-gene model comprised of levels of mRNA for vimentin, NKCC2, E-cadherin and 18S rRNA provided the most accurate, parsimonious, diagnostic model of allograft fibrosis with 93.8% sensitivity and 84.1% specificity (P<0.0001). In the independent validation set, this same model predicted the presence of allograft fibrosis with 77.3% sensitivity and 87.5% specificity (P<0.0001). Measurement of mRNAs in urinary cells may offer a noninvasive means of diagnosing fibrosis in human renal allografts.