title: Metabolism, Protein Binding, and Renal Clearance of Microbiota-Derived p-Cresol in Patients with CKD.
abstract: Colonic microbial metabolism substantially contributes to uremic retention solutes in CKD. p-Cresyl sulfate is the main representative of this group of solutes, relating to adverse outcomes. Other than sulfate conjugation, p-cresol is subjected to endogenous glucuronide conjugation. Whether the balance between sulfate and glucuronide conjugation is relevant in CKD is unexplored.
  
  
  
  We prospectively followed 488 patients with CKD stages 1-5 (enrollment between November of 2005 and September of 2006; follow-up until December of 2010). Serum and urine levels of p-cresyl sulfate and p-cresyl glucuronide were measured using liquid chromatography-mass spectrometry. Total amount of microbial p-cresol was calculated by the sum of serum p-cresyl sulfate and p-cresyl glucuronide. Outcome analysis was performed for mortality and cardiovascular disease.
  
  
  
  Serum p-cresyl sulfate was a median of 193.0-fold (interquartile range, 121.1-296.6) higher than serum p-cresyl glucuronide, with a significant correlation between eGFR and proportion of serum p-cresyl sulfate to glucuronide (rho=0.23; P=0.001). There was also a significant correlation between eGFR and proportion of 24-hour urinary excretion of p-cresyl sulfate to glucuronide (rho=0.32; P<0.001). Higher serum p-cresol and lower proportion of serum p-cresyl sulfate to glucuronide were jointly and significantly associated with mortality (hazard ratio per SD higher, 1.58; 95% confidence interval, 1.10 to 2.29; P=0.01 and hazard ratio, 0.65; 95% confidence interval, 0.47 to 0.89; P<0.01, respectively) and cardiovascular disease (hazard ratio, 1.68; 95% confidence interval, 1.27 to 2.22; P<0.001 and hazard ratio, 0.55; 95% confidence interval, 0.42 to 0.72; P<0.001, respectively) after adjustment for eGFR, Framingham risk factors, mineral bone metabolism markers, C-reactive protein, and albumin.
  
  
  
  p-Cresol shows a preponderance of sulfate conjugation, although a relatively diminished sulfotransferase activity can be suggested in patients with advanced CKD. Along with total p-cresol burden, a relative shift from sulfate to glucuronide conjugation is independently associated with mortality and cardiovascular disease, warranting increased focus to the dynamic interplay between microbial and endogenous metabolism.
authors.affiliation: Department of Microbiology and Immunology, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium; and.
authors.forename: Ruben
authors.initials: R
authors.lastname: Poesen
authors.affiliation: Department of Microbiology and Immunology, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium; and.
authors.forename: Pieter
authors.initials: P
authors.lastname: Evenepoel
authors.affiliation: Department of Microbiology and Immunology, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium; and.
authors.forename: Henriette
authors.initials: H
authors.lastname: de Loor
authors.affiliation: Department of Microbiology and Immunology, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium; and.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuypers
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University of Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.affiliation: Department of Microbiology and Immunology, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium; and.
authors.forename: Björn
authors.initials: B
authors.lastname: Meijers
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000453:epidemiology; D003408:Cresols / Q000097:blood* / Q000652:urine*; D005260:Female; D000069196:Gastrointestinal Microbiome; D005919:Glomerular Filtration Rate; D020719:Glucuronides / Q000097:blood* / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011485:Protein Binding; D051436:Renal Insufficiency, Chronic / Q000401:mortality / Q000503:physiopathology*; D012307:Risk Factors; D013463:Sulfuric Acid Esters / Q000097:blood* / Q000652:urine*
chemical_list: C485699:4-cresylglucuronide; D003408:Cresols; D020719:Glucuronides; D013463:Sulfuric Acid Esters; C408690:4-cresol sulfate
keywords: Cresols; Follow-Up Studies; Humans; Microbiota; Protein Binding; Renal Insufficiency, Chronic; Sulfotransferases; chronic kidney disease; intestine; risk factors