Meta-Analysis of the Associations of p-Cresyl Sulfate (PCS) and Indoxyl Sulfate (IS) with Cardiovascular Events and All-Cause Mortality in Patients with Chronic Renal Failure.

Cheng-Jui Lin,Pei-Chen Wu,Chih-Jen Wu,Vincent Wu,Abelardo I Aguilera

doi:10.1371/journal.pone.0132589

Abstract

BackgroundIndoxyl sulfate (IS) and p-cresyl sulfate (PCS) are protein-bound uremic toxins that increase in the sera of patients with chronic kidney disease (CKD), and are not effectively removed by dialysis. The purpose of this meta-analysis was to investigate the relationships of PCS and IS with cardiovascular events and all-cause mortality in patients with CKD stage 3 and above.Methodology/Principle FindingsMedline, Cochrane, and EMBASE databases were searched until January 1, 2014 with combinations of the following keywords: chronic renal failure, end-stage kidney disease, uremic toxin, uremic retention, indoxyl sulfate, p-cresyl sulfate. Inclusion criteria were: 1) Patients with stage 1 to 5 CKD; 2) Prospective study; 3) Randomized controlled trial; 4) English language publication. The associations between serum levels of PCS and IS and the risks of all-cause mortality and cardiovascular events were the primary outcome measures. Of 155 articles initially identified, 10 prospective and one cross-sectional study with a total 1,572 patients were included. Free PCS was significantly associated with all-cause mortality among patients with chronic renal failure (pooled OR = 1.16, 95% CI = 1.03 to 1.30, P = 0.013). An elevated free IS level was also significantly associated with increased risk of all-cause mortality (pooled OR = 1.10, 95% CI = 1.03 to 1.17, P = 0.003). An elevated free PCS level was significantly associated with an increased risk of cardiovascular events among patients with chronic renal failure (pooled OR = 1.28, 95% CI = 1.10 to 1.50, P = 0.002), while free IS was not significantly associated with risk of cardiovascular events (pooled OR = 1.05, 95% CI = 0.98 to 1.13, P = 0.196).Conclusions/SignificanceElevated levels of PCS and IS are associated with increased mortality in patients with CKD, while PCS, but not IS, is associated with an increased risk of cardiovascular events.

Highlights

The prevalence of cardiovascular disease (CVD) is markedly higher in patients with chronic kidney disease (CKD) [1], and CVD disease is the primary cause of death in CKD patients, especially in those with end stage renal disease (ESRD) [2,3]
Cochrane, and EMBASE databases were searched until January 1, 2014 with combinations of the following keywords: chronic renal failure, end-stage kidney disease, uremic toxin, uremic retention, indoxyl sulfate, p-cresyl sulfate
Studies have shown that Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are associated with CVD, mortality, and deterioration of renal function in patients with CKD [15,16,17,18]

Summary

Introduction

The prevalence of cardiovascular disease (CVD) is markedly higher in patients with chronic kidney disease (CKD) [1], and CVD disease is the primary cause of death in CKD patients, especially in those with end stage renal disease (ESRD) [2,3]. Indoxyl sulfate (IS) is a protein-bound uremic solute resulting from bacterial metabolism of dietary tryptophan to indole [6,8,9] It is normally cleared by renal proximal tubular secretion; but in patients with CKD impaired renal function can lead to its accumulation [6,8,9]. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are protein-bound uremic toxins that increase in the sera of patients with chronic kidney disease (CKD), and are not effectively removed by dialysis The purpose of this meta-analysis was to investigate the relationships of PCS and IS with cardiovascular events and all-cause mortality in patients with CKD stage 3 and above

Methods

Results

Discussion

Conclusion