Molecular Correlates of Renal Function in Kidney Transplant Biopsies
Molecular Correlates of Renal Function in Kidney Transplant Biopsies
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DOI：
10.1681/asn.2008080863
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发表时间：
2009-05-01
影响因子：
13.6
通讯作者：
Halloran, Philip F.
中科院分区：
文献类型：
--
作者：
Bunnag, Sakarn;Einecket, Gunilla;Halloran, Philip F.
反映肾移植功能障碍的实质中的分子变化尚不清楚。我们研究了146例临床指征的人肾移植活检的组织病理学、基因表达和肾功能之间的关系。肾功能受损(估计的GFR)与肾小管萎缩和纤维化有关，但与炎症或排斥反应无关。活检前的功能恶化与炎症和小管炎有关，在发生排斥反应的情况下更严重。微阵列分析显示，肾功能受损与与组织损伤一致的转录组表达变化之间存在相关性，但与细胞毒性T细胞渗透或干扰素-伽马效应无关。对临床变量、组织学损害和转录集的多变量分析证实，损伤相关转录集的表达与肾功能独立相关。对单个基因的分析证实，与肾功能有最大正或负相关性的转录本是那些提示对损伤和实质去分化的反应的转录本，而不是炎症。我们根据与肾功能相关的单个转录本定义了新的基因集，这些基因与先前形成的损伤集以及萎缩和纤维化高度相关。因此，在因临床原因而进行的活检中，功能障碍反映在转录组的变化上，代表组织损伤和去分化，而不是炎症负担。
The molecular changes in the parenchyma that reflect disturbances in the function of kidney transplants are unknown. We studied the relationships among histopathology, gene expression, and renal function in 146 human kidney transplant biopsies performed for clinical indications. Impaired function (estimated GFR) correlated with tubular atrophy and fibrosis but not with inflammation or rejection. Functional deterioration before biopsy correlated with inflammation and tubulitis and was greater in cases of rejection. Microarray analysis revealed a correlation between impaired renal function and altered expression of sets of transcripts consistent with tissue injury but not with those consistent with cytotoxic T cell infiltration or IFN-gamma effects. Multivariate analysis of clinical variables, histologic lesions, and transcript sets confirmed that expression of injury-related transcript sets independently correlated with renal function. Analysis of individual genes confirmed that the transcripts with the greatest positive or negative correlations with renal function were those suggestive of response to injury and parenchymal dedifferentiation not inflammation. We defined new sets of genes based on individual transcripts that correlated with renal function, and these highly correlated with the previously developed injury sets and with atrophy and fibrosis. Thus, in biopsies performed for clinical reasons, functional disturbances are reflected in transcriptome changes representing tissue injury and dedifferentiation but not the inflammatory burden.