title: Protein-bound uremic toxins, inflammation and oxidative stress: a cross-sectional study in stage 3-4 chronic kidney disease.
abstract: OBJECTIVE
  Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are nephro- and cardiovascular toxins, produced solely by the gut microbiota, which have pro-inflammatory and pro-oxidative properties in vitro. We undertook this study to investigate the associations between IS and PCS and both inflammation and oxidative stress in the chronic kidney disease (CKD) population.
  
  
  METHODS
  In this cross-sectional observational cohort study, participants with stage 3-4 CKD who enrolled in a randomized controlled trial of cardiovascular risk modification underwent baseline measurements of serum total and free IS and PCS (measured by ultraperformance liquid chromotography), inflammatory markers (interferon gamma [IFN-γ], interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]), antioxidant and oxidative stress markers (plasma glutathione peroxidase [GPx] activity, total antioxidant capacity [TAC] and F2-isoprostanes) and pulse wave velocity (PWV), a marker of arterial stiffness.
  
  
  RESULTS
  There were 149 CKD patients (59% male; age 60 ± 10 years; 44% diabetic) with a mean eGFR of 40 ± 9 mL/min/1.73 m(2) (range 25-59). Serum free and total IS were independently associated with serum IL-6, TNF-α and IFN-γ, whereas serum free and total PCS were independently associated with serum IL-6 and PWV. Free IS and PCS were additionally independently associated with serum GPx but not with TAC or F2-isoprostanes.
  
  
  CONCLUSIONS
  IS and PCS were associated with elevated levels of selected inflammatory markers and an antioxidant in CKD patients. PCS was also associated with increased arterial stiffness. Inflammation and oxidative stress may contribute to the nephro- and cardiovascular toxicities of IS and PCS. Intervention studies targeting production of IS and PCS by dietary manipulation and the subsequent effect on cardiovascular-related outcomes are warranted in the CKD population.
authors.affiliation: School of Medicine, University of Queensland, Queensland, Australia; Translational Research Institute, Queensland, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia. Electronic address: megan.rossi@health.qld.gov.au.
authors.forename: Megan
authors.initials: M
authors.lastname: Rossi
authors.affiliation: School of Medicine, University of Queensland, Queensland, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Campbell
authors.affiliation: School of Medicine, University of Queensland, Queensland, Australia; Translational Research Institute, Queensland, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.affiliation: School of Medicine, University of Queensland, Queensland, Australia; Department of Cardiology, Princess Alexandra Hospital, Queensland, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Stanton
authors.affiliation: School of Medicine, University of Queensland, Queensland, Australia; Translational Research Institute, Queensland, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Vesey
authors.affiliation: Human Movement Studies, University of Queensland, Queensland, Australia.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Coombes
authors.affiliation: Human Movement Studies, University of Queensland, Queensland, Australia.
authors.forename: Kassia S
authors.initials: KS
authors.lastname: Weston
authors.affiliation: School of Medicine, University of Queensland, Queensland, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Hawley
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Queensland, Australia.
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Queensland, Australia.
authors.forename: Jacobus P J
authors.initials: JP
authors.lastname: Ungerer
authors.affiliation: School of Medicine, University of Queensland, Queensland, Australia; Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Isbel
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000276:immunology / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000276:immunology* / Q000378:metabolism*; D003408:Cresols / Q000276:immunology / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007200:Indican / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000276:immunology*; D051436:Renal Insufficiency, Chronic / Q000276:immunology* / Q000378:metabolism*; D040242:Risk Reduction Behavior; D013463:Sulfuric Acid Esters / Q000276:immunology / Q000378:metabolism; D014118:Toxins, Biological / Q000276:immunology / Q000378:metabolism; D014511:Uremia / Q000276:immunology / Q000378:metabolism; D059289:Vascular Stiffness / Q000276:immunology
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D001798:Blood Proteins; D003408:Cresols; D015850:Interleukin-6; D013463:Sulfuric Acid Esters; D014118:Toxins, Biological; C408690:4-cresol sulfate; D007200:Indican
keywords: Indoxyl sulfate; Inflammation; Oxidative stress; P-cresyl sulfate; Uremic toxins