title: Cardiovascular disease relates to intestinal uptake of p-cresol in patients with chronic kidney disease.
abstract: BACKGROUND
  Serum p-cresyl sulfate (PCS) associates with cardiovascular disease in patients with chronic kidney disease. PCS concentrations are determined by intestinal uptake of p-cresol, human metabolism to PCS and renal clearance. Whether intestinal uptake of p-cresol itself is directly associated with cardiovascular disease in patients with renal dysfunction has not been studied to date.
  
  
  METHODS
  We performed a prospective study in patients with chronic kidney disease stage 1 - 5 (NCT00441623). Intestinal uptake of p-cresol, under steady state conditions, was estimated from 24 h urinary excretion of PCS. Primary endpoint was time to first cardiovascular event, i.e., cardiac death, myocardial infarction/ischemia, ventricular arrhythmia, cardiovascular surgery, ischemic stroke or symptomatic peripheral arterial disease. Statistical analysis was done using Kaplan-Meier estimates and Cox proportional hazard analyses.
  
  
  RESULTS
  In a cohort of 200 patients, median 24 h urinary excretion of PCS amounted to 457.47 μmol (IQR 252.68 - 697.17). After a median follow-up of 52 months, 25 patients reached the primary endpoint (tertile 1/2/3: 5/6/14 events, log rank P 0.037). Higher urinary excretion of PCS was directly associated with cardiovascular events (univariate hazard ratio per 100 μmol increase: 1.112, P 0.002). In multivariate analysis, urinary excretion of PCS remained a predictor of cardiovascular events, independent of eGFR (hazard ratio 1.120, P 0.002).
  
  
  CONCLUSIONS
  In patients with chronic kidney disease, intestinal uptake of p-cresol associates with cardiovascular disease independent of renal function. The intestinal generation and absorption of p-cresol may be therapeutic targets to reduce cardiovascular disease risk in patients with renal dysfunction.
authors.forename: Ruben
authors.initials: R
authors.lastname: Poesen
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Viaene
authors.forename: Kristin
authors.initials: K
authors.lastname: Verbeke
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Bert
authors.initials: B
authors.lastname: Bammens
authors.forename: Kathleen
authors.initials: K
authors.lastname: Claes
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuypers
authors.forename: Pieter
authors.initials: P
authors.lastname: Evenepoel
authors.affiliation: Department of Microbiology and Immunology, Division of Nephrology, University Hospitals Leuven, B-3000, Leuven, Belgium. bjorn.meijers@uzleuven.be.
authors.forename: Björn
authors.initials: B
authors.lastname: Meijers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001530:Belgium / Q000453:epidemiology; D015415:Biomarkers / Q000652:urine; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000453:epidemiology* / Q000652:urine*; D015897:Comorbidity; D003408:Cresols / Q000493:pharmacokinetics* / Q000652:urine*; D005260:Female; D006801:Humans; D015994:Incidence; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000453:epidemiology* / Q000652:urine*; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D003408:Cresols; C032538:4-cresol