Open Access Highly Accessed Research article

Cardiovascular disease relates to intestinal uptake of p-cresol in patients with chronic kidney disease

Ruben Poesen1, Liesbeth Viaene1, Kristin Verbeke2, Patrick Augustijns3, Bert Bammens1, Kathleen Claes1, Dirk Kuypers1, Pieter Evenepoel1 and Björn Meijers14*

Author Affiliations

1 Department of Microbiology and Immunology, Division of Nephrology, University Hospitals Leuven, B-3000, Leuven, Belgium

2 Translational Research for Gastrointestinal Disorders (Targid) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University of Leuven, B-3000 Leuven, Belgium

3 Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, University of Leuven, B-3000 Leuven, Belgium

4 Division of Internal Medicine, Department of Nephrology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium

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BMC Nephrology 2014, 15:87  doi:10.1186/1471-2369-15-87

Published: 9 June 2014

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.

Keywords:
Cardiovascular disease; Gut; P-cresyl sulfate