Abstract
BackgroundUremic toxins are emerging as important, non-traditional cardiovascular risk factors in chronic kidney disease (CKD). P-cresol has been defined as a prototype protein-bound uremic toxin. Conjugation of p-cresol creates p-cresylsulfate (PCS) as the main metabolite and p-cresylglucuronide (PCG), at a markedly lower concentration. The objective of the present study was to evaluate serum PCG levels, determine the latter’s association with mortality and establish whether the various protein-bound uremic toxins (i.e. PCS, PCG and indoxylsulfate (IS)) differed in their ability to predict mortality.Methodology/Principal FindingsWe studied 139 patients (mean ± SD age: 67±12; males: 60%) at different CKD stages (34.5% at CKD stages 2–3, 33.5% at stage 4–5 and 32% at stage 5D). A recently developed high-performance liquid chromatography method was used to assay PCG concentrations. Total and free PCG levels increased with the severity of CKD. During the study period (mean duration: 779±185 days), 38 patients died. High free and total PCG levels were correlated with overall and cardiovascular mortality independently of well-known predictors of survival, such as age, vascular calcification, anemia, inflammation and (in predialysis patients) the estimated glomerular filtration rate. In the same cohort, free PCS levels and free IS levels were both correlated with mortality. Furthermore, the respective predictive powers of three Cox multivariate models (free PCS+other risk factors, free IS+other risk factors and free PCS+other risk factors) were quite similar - suggesting that an elevated PCG concentration has much the same impact on mortality as other uremic toxins (such as PCS or IS) do.ConclusionsAlthough PCG is the minor metabolite of p-cresol, our study is the first to reveal its association with mortality. Furthermore, the free fraction of PCG appears to have much the same predictive power for mortality as PCS and IS do.
Highlights
Kidney failure is characterized by the gradual accumulation of several uremic retention compounds, some of which result from the degradation of proteins and amino acids [1,2,3,4]
We recently studied indoxylsulfate (IS, a protein-bound uremic toxin that results from the metabolism of dietary tryptophan) and found that it may be involved in the high incidence of vascular disease and mortality observed in chronic kidney disease (CKD) patients [16]
Included patients had to be over the age of 40, with a confirmed diagnosis of CKD (defined as being on hemodialysis or having two previous, estimated creatinine clearances,90 ml/min/1.73 m2, with an interval of 3 to 6 months)
Summary
Kidney failure is characterized by the gradual accumulation of several uremic retention compounds, some of which result from the degradation of proteins and amino acids [1,2,3,4]. When these compounds interact with biological functions, they are referred to as uremic toxins. Conjugation of p-cresol creates p-cresylsulfate (PCS) as the main metabolite and p-cresylglucuronide (PCG), at a markedly lower concentration. The objective of the present study was to evaluate serum PCG levels, determine the latter’s association with mortality and establish whether the various protein-bound uremic toxins (i.e. PCS, PCG and indoxylsulfate (IS)) differed in their ability to predict mortality
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