p-Cresol and Cardiovascular Risk in Mild-to-Moderate Kidney Disease

Background and objectives: Cardiovascular disease is highly prevalent in chronic kidney disease. Traditional risk factors are insufficient to explain the high cardiovascular disease prevalence. Free p-cresol serum concentrations, mainly circulating as its derivative p-cresyl sulfate, are associated with cardiovascular disease in hemodialysis patients. It is not known if p-cresol is associated with cardiovascular disease in patients with chronic kidney disease not yet on dialysis. Design, setting, participants, & measurements: In a prospective observational study in 499 patients with mild-to-moderate kidney disease, we examined the multivariate association between p-cresol free serum concentrations and cardiovascular events. Results: After a mean follow-up of 33 mo, 62 patients reached the primary end point of fatal or nonfatal cardiovascular events. Higher baseline concentrations of free p-cresol were directly associated with cardiovascular events (univariate hazard ratio [FIR] 1.79, P < 0.0001). In multivariate analysis, p-cresol remained a predictor of cardiovascular events, independent of GFR and independent of Framingham risk factors (full model, HR 1.39, P = 0.04). Conclusions: These findings suggest that p-cresol measurements may help to predict cardiovascular disease risk in renal patients over a wide range of residual renal function, beyond traditional markers of glomerular filtration. Whether p-cresol is a modifiable cardiovascular risk factor in CKD patients remains to be proven. Clin J Am Soc Nephrol 5: 1182-1189, 2010. doi: 10.2215/CJN.07971109