A molecular classifier for predicting future graft loss in late kidney transplant biopsies
A molecular classifier for predicting future graft loss in late kidney transplant biopsies
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DOI：
10.1172/jci41789
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Halloran, Philip F.
中科院分区：
文献类型：
--
作者：
Einecke, Gunilla;Reeve, Jeff;Halloran, Philip F.
肾移植受者在移植后一年或多年出现肾功能不全或蛋白尿的迹象，有相当大的风险进展为肾衰竭。为了评估肾脏在这个时候，一个“有因”活检进行，但这提供了一个小迹象，以表明哪些受体将继续器官衰竭。为了确定能够提供这些信息的分子，我们使用微阵列分析了移植后1年至31年之间采集的105例因活组织检查的基因表达。使用监督主成分分析，我们推导出一个分子分类器来预测移植物丢失。与移植失败相关的基因与组织损伤、上皮去分化、基质重塑和TGF-β效应有关，与排斥相关基因几乎没有重叠。我们为每例患者分配了一个预后分子风险评分，以确定移植物丢失的高风险或低风险。分子风险评分与间质纤维化、肾小管萎缩、肾小管炎、间质炎症、蛋白尿和肾小球滤过率相关。在多变量分析中，分子风险评分、肾小管周围毛细血管基底膜多层化、小动脉玻璃样变性和蛋白尿是移植物丢失的独立预测因子。在一个独立的验证集中，分子风险评分是移植物丢失的唯一预测因子。因此，分子风险评分反映了活动性损伤，在预测移植失败方面上级瘢痕形成或功能。
Kidney transplant recipients that develop signs of renal dysfunction or proteinuria one or more years after transplantation are at considerable risk for progression to renal failure. To assess the kidney at this time, a "for-cause" biopsy is performed, but this provides little indication as to which recipients will go on to organ failure. In an attempt to identify molecules that could provide this information, we used micorarrays to analyze gene expression in 105 for-cause biopsies taken between 1 and 31 years after transplantation. Using supervised principal components analysis, we derived a molecular classifier to predict graft loss. The genes associated with graft failure were related to tissue injury, epithelial dedifferentiation, matrix remodeling, and TGF-beta effects and showed little overlap with rejection-associated genes. We assigned a prognostic molecular risk score to each patient, identifying those at high or low risk for graft loss. The molecular risk score was correlated with interstitial fibrosis, tubular atrophy, tubulitis, interstitial inflammation, proteinuria, and glomerular filtration rate. In multivariate analysis, molecular risk score, peritubular capillary basement membrane multilayering, arteriolar hyalinosis, and proteinuria were independent predictors of graft loss. In an independent validation set, the molecular risk score was the only predictor of graft loss. Thus, the molecular risk score reflects active injury and is superior to either scarring or function in predicting graft failure.