Tsalik, Ephraim LWillig, Laurel KRice, Brandon Jvan Velkinburgh, Jennifer CMohney, Robert PMcDunn, Jonathan EDinwiddie, Darrell LMiller, Neil AMayer, Eric SGlickman, Seth WJaehne, Anja KGlew, Robert HSopori, Mohan LOtero, Ronny MHarrod, Kevin SCairns, Charles BFowler, Vance GRivers, Emanuel PWoods, Christopher WKingsmore, Stephen FLangley, Raymond J2017-01-012015-10https://hdl.handle.net/10161/13306A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this, we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change 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 patients on HD. 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 were inversely correlated with the majority of significantly downregulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes were not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness.Acute Kidney InjuryAdultAgedAged, 80 and overBiomarkersBlood ProteinsCritical IllnessFemaleGene Expression ProfilingGene Expression RegulationHumansKidneyKidney Function TestsMaleMetabolomicsMiddle AgedProteomicsRNA, MessengerRenal DialysisSystemic Inflammatory Response SyndromeSystems BiologySystems IntegrationTime FactorsTreatment OutcomeUnited StatesJournal article1523-1755