Metabolism, Protein Binding, and Renal Clearance of Microbiota-Derived p-Cresol in Patients with CKD.

Abstract

BACKGROUND AND OBJECTIVES:

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.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:

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.

RESULTS:

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.

CONCLUSIONS:

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: Ruben Poesen, Pieter Evenepoel, Henriette de Loor, Dirk Kuypers, Patrick Augustijns, Björn Meijers
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 11 Issue 7 Pg. 1136-1144 (07 07 2016) ISSN: 1555-905X [Electronic] United States
• PMID: 27084876 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by the American Society of Nephrology.

Chemical References

• 4-cresylglucuronide
• Cresols
• Glucuronides
• Sulfuric Acid Esters
• 4-cresol sulfate

Topics

• Adult
• Cardiovascular Diseases (epidemiology)
• Cresols (blood, urine)
• Female
• Gastrointestinal Microbiome
• Glomerular Filtration Rate
• Glucuronides (blood, urine)
• Humans
• Male
• Middle Aged
• Prospective Studies
• Protein Binding
• Renal Insufficiency, Chronic (mortality, physiopathology)
• Risk Factors
• Sulfuric Acid Esters (blood, urine)