Urinary-cell mRNA profile and acute cellular rejection in kidney allografts.
Urinary-cell mRNA profile and acute cellular rejection in kidney allografts.
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DOI：
10.1056/nejmoa1215555
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发表时间：
2013-07-04
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通讯作者：
Clinical Trials in Organ Transplantation 04 (CTOT-04) Study Investigators
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作者：
Suthanthiran M;Schwartz JE;Ding R;Abecassis M;Dadhania D;Samstein B;Knechtle SJ;Friedewald J;Becker YT;Sharma VK;Williams NM;Chang CS;Hoang C;Muthukumar T;August P;Keslar KS;Fairchild RL;Hricik DE;Heeger PS;Han L;Liu J;Riggs M;Ikle DN;Bridges ND;Shaked A;Clinical Trials in Organ Transplantation 04 (CTOT-04) Study Investigators
诊断肾移植急性排斥反应的标准检查是肾活检。无创检查更可取。从移植后第3天到第12个月，我们前瞻性地收集了485例肾移植受者的4300份尿液标本。信使RNA （mRNA）水平在尿细胞中测量，并与异体移植排斥状态使用逻辑回归相关。18S核糖体（rRNA）的三基因特征- CD3ε mRNA和干扰素诱导蛋白10 (IP-10) mRNA的归一化测量以及18S rRNA可区分出现急性细胞排斥反应和未出现排斥反应的活检标本（曲线下面积[AUC]， 0.85； 95%置信区间[CI]， 0.78至0.91；通过受体工作特征曲线分析，P<0.001）。自举重抽样的交叉验证估计AUC为0.83，Hosmer-Lemeshow检验显示拟合良好（P = 0.77）。在外部验证数据集中，AUC为0.74 (95% CI， 0.61至0.86；P<0.001)，与我们的主要数据集中的AUC没有显著差异（P = 0.13）。该特征将急性细胞排斥反应与急性抗体介导的排斥反应和临界排斥反应区分开来（AUC, 0.78; 95% CI， 0.68至0.89；P<0.001）。它还能区分接受抗白细胞介素-2受体抗体的患者和接受t细胞消耗抗体的患者（P<0.001），并在两组中诊断急性细胞排斥反应。尿路感染不影响特征（P = 0.69）。在无排斥反应的患者组中，重复尿液样本中特征的平均轨迹仍低于急性细胞排斥反应的诊断阈值，但在有排斥反应的患者组中，在活检显示排斥反应前几周内，特征的平均轨迹急剧上升（P<0.001）。尿细胞中CD3ε mRNA、IP-10 mRNA和18S rRNA水平的分子特征似乎可以诊断和预后同种异体肾移植急性细胞排斥反应。（由美国国立卫生研究院和其他机构资助。）
The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable. We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression. A three-gene signature of 18S ribosomal (rRNA)–normalized measures of CD3ε mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operating-characteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer–Lemeshow test indicated good fit (P = 0.77). In an external-validation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P = 0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti–interleukin-2 receptor antibodies from those who received T-cell–depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P = 0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001). A molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts. (Funded by the National Institutes of Health and others.)