Renal systems biology of patients with systemic inflammatory response syndrome. Homo sapiens

A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on host response during critical illness. We examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Plasma metabolite values showed greater changes as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular weight proteins and acute phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among HD patients. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and n-acetylaspartate showed inverse correlations with the majority of significantly down-regulated genes. In conclusion, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness. These changes were not effectively mitigated by hemodialysis. These studies suggest several novel mechanisms whereby renal dysfunction contributes to critical illness. Overall design: We sequenced peripheral blood RNA of 133 representative subjects with systemic inflammatory response syndrome that had Acute Kidney Injury (AKI) or Hemodialysis (HD). No injury (AKI0; n= 58); AKI Stage 1 (AKI1; n= 36); AKI stage 2 and 3 (AKI23; n= 17); HD (N=22).

本研究采用系统生物学方法，全面考察了肾脏疾病与血液透析（Hemodialysis, HD）对重症患者宿主应答的影响。我们按肾功能分层，对150名重症患者的代谢组、蛋白质组及转录组展开了分析。
血浆代谢物水平随肾功能下降呈现更为显著的变化，其中接受慢性血液透析的患者代谢紊乱程度最为严重。具体而言，随着肾功能下降，6种尿毒症潴留分子、17种其他蛋白质分解代谢物、7种修饰核苷以及7种磷酸戊糖糖类水平均出现升高，这与氨基酸及核糖核苷酸排泄减少、分解代谢增强的变化趋势相符。
类似地，蛋白质组分析显示低分子量蛋白与急性期反应物水平均有所升高。
转录组分析则发现，接受血液透析的患者体内mRNA水平呈现广泛性降低。
系统整合分析揭示了血浆RNASE1与多种RNA分解代谢物及修饰核苷之间此前未被发现的关联。此外，尿囊素、N1-甲基-4-吡啶酮-3-甲酰胺以及N-乙酰天门冬氨酸与绝大多数显著下调基因呈负相关关系。
综上，重症期间肾功能状态对血浆代谢组、蛋白质组及外周血转录组均具有广泛影响，且此类变化未能通过血液透析得到有效缓解。本研究提示了肾功能异常参与重症疾病发生发展的若干新机制。
实验整体设计：本研究对133名符合代表性样本的全身性炎症反应综合征患者的外周血RNA进行了测序，这些患者均合并急性肾损伤（Acute Kidney Injury, AKI）或接受血液透析。具体分组如下：无肾损伤组（AKI0；n=58）、急性肾损伤1期组（AKI1；n=36）、急性肾损伤2-3期组（AKI23；n=17）以及血液透析组（n=22）。