Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Alberta, Canada.
J Clin Invest. 2010 Jun;120(6):1862-72. doi: 10.1172/JCI41789. Epub 2010 May 24.
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 microarrays 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.
移植后 1 年或更长时间出现肾功能障碍或蛋白尿迹象的肾移植受者，发生肾衰竭的风险相当高。为了在此时评估肾脏，进行了“有因”活检，但这几乎不能提示哪些受者会发生器官衰竭。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 105 例移植后 1 至 31 年内进行的“有因”活检中的基因表达。通过有监督的主成分分析，我们得出了一个分子分类器来预测移植物丢失。与移植物衰竭相关的基因与组织损伤、上皮去分化、基质重塑和 TGF-β作用有关，与排斥相关基因几乎没有重叠。我们为每个患者分配了一个预后分子风险评分，确定了高风险或低风险的移植物丢失。分子风险评分与间质纤维化、肾小管萎缩、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、肾小管毛细血管基底膜分层、血管玻璃样变和蛋白尿是移植物丢失的独立预测因子。在独立验证组中，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跃的损伤，在预测移植物衰竭方面优于瘢痕形成或功能。
