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

<div><p>Background</p><p>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.</p><p>Methodology/Principle Findings</p><p>Medline, 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, <i>P</i> = 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, <i>P</i> = 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, <i>P</i> = 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, <i>P</i> = 0.196).</p><p>Conclusions/Significance</p><p>Elevated 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.</p></div

Forest plots of the associations between serum levels of renal biomarkers and the risk of cardiovascular events among patients with chronic renal failure: (A) free PCS, (B) free IS, (C) albumin, (D) creatinine, (E) PTH.

<p>Forest plots of the associations between serum levels of renal biomarkers and the risk of cardiovascular events among patients with chronic renal failure: (A) free PCS, (B) free IS, (C) albumin, (D) creatinine, (E) PTH.</p

Funnel plot for evaluating publication bias regarding the association between free PCS and (A) mortality risk and (B) the risk of cardiovascular events.

<p>White circles represent observed studies, and black circles represent possibly missed studies imputed using Duval and Tweedie’s trim-and-fill method. White and black rhombuses represent observed and theoretical combined effect size, respectively.</p

Forest plots of the associations between serum levels of renal biomarkers and the risk of all-cause mortality among patients with chronic renal failure: (A) free PCS, (B) free IS, (C) albumin, (D) creatinine, (E) PTH.

<p>Forest plots of the associations between serum levels of renal biomarkers and the risk of all-cause mortality among patients with chronic renal failure: (A) free PCS, (B) free IS, (C) albumin, (D) creatinine, (E) PTH.</p

Sensitivity analysis performed by leave-one-out approach: (A) association between serum level of free PCS and the risk of mortality, (B) association between serum level of free PCS and the risk of cardiovascular events, (C) association between serum level of free IS and the risk of mortality, (D) association between serum level of free IS and the risk of cardiovascular events.

<p>Sensitivity analysis performed by leave-one-out approach: (A) association between serum level of free PCS and the risk of mortality, (B) association between serum level of free PCS and the risk of cardiovascular events, (C) association between serum level of free IS and the risk of mortality, (D) association between serum level of free IS and the risk of cardiovascular events.</p

Characteristics of studies included in the meta-analysis.

<p>Data are reported as mean ± standard deviation unless otherwise indicated.</p><p>ESRD, end stage renal disease; CKD, chronic kidney disease; IS, indoxyl sulfate; PCS, p-cresyl sulfate; NR, not reported.</p><p>^† Mean ± SEM.</p><p>^‡ Median (range).</p><p>Characteristics of studies included in the meta-analysis.</p

Flow chart of study selection.

<p>Flow chart of study selection.</p

The number of eyes and participants that met the criteria for inclusion or exclusion.

<p>The number of eyes and participants that met the criteria for inclusion or exclusion.</p

Variations in RNFL thickness of different segments with axial length.

<p>Variations in RNFL thickness of different segments with axial length.</p

The inverse correlation between RNFL thickness and axial length.

<p>The inverse correlation between RNFL thickness and axial length.</p