title: Renal systems biology of patients with systemic inflammatory response syndrome.
abstract: A 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.
authors.affiliation: Emergency Medicine Service, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.|Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Ephraim L
authors.initials: EL
authors.lastname: Tsalik
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospitals and Clinic, Kansas City, Missouri, USA.
authors.forename: Laurel K
authors.initials: LK
authors.lastname: Willig
authors.affiliation: National Center for Genome Resources, Santa Fe, New Mexico, USA.|Program of Biomedical Sciences and Engineering, University of California, Santa Cruz, Santa Cruz, California, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Rice
authors.affiliation: National Center for Genome Resources, Santa Fe, New Mexico, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: van Velkinburgh
authors.affiliation: Metabolon, Durham, North Carolina, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: Metabolon, Durham, North Carolina, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.affiliation: National Center for Genome Resources, Santa Fe, New Mexico, USA.|Department of Pediatrics, Center for Translational Sciences. University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Darrell L
authors.initials: DL
authors.lastname: Dinwiddie
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospitals and Clinic, Kansas City, Missouri, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Miller
authors.affiliation: Metabolon, Durham, North Carolina, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Mayer
authors.affiliation: Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Seth W
authors.initials: SW
authors.lastname: Glickman
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Jaehne
authors.affiliation: Department of Surgery, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Glew
authors.affiliation: Department of Respiratory Immunology, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Mohan L
authors.initials: ML
authors.lastname: Sopori
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan, USA.|Department of Emergency Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Ronny M
authors.initials: RM
authors.lastname: Otero
authors.affiliation: Department of Infectious Disease, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
authors.affiliation: Department of Emergency Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Cairns
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
authors.affiliation: Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Emanuel P
authors.initials: EP
authors.lastname: Rivers
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.|Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, North Carolina, USA.|Medicine Service, Durham Veterans Affairs Medical Center, Emergency Medicine, Durham, North Carolina, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Woods
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospitals and Clinic, Kansas City, Missouri, USA.|National Center for Genome Resources, Santa Fe, New Mexico, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.affiliation: National Center for Genome Resources, Santa Fe, New Mexico, USA.|Department of Respiratory Immunology, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood* / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism*; D016638:Critical Illness; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D040901:Proteomics; D012333:RNA, Messenger / Q000097:blood*; D006435:Renal Dialysis; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood* / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D049490:Systems Biology; D018511:Systems Integration; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D012333:RNA, Messenger