Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

Abstract

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dL), a two-fold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98–1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06–1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.

Microbiome and Cardiovascular Disease in CKD

“…However, not all studies agree with these findings. In a large cohort of 1273 patients on dialysis, indoxyl sulfate and p-cresol were not associated with cardiovascular events (18). Only in a subcohort of patients on dialysis with low serum albumin was p-cresyl significantly associated with cardiovascular events (18), suggesting that other factors may modify this relationship.…”

Hemodialysis‐induced cardiovascular disease

“…In both dialysis and nondialysis patients, free p‐creosol sulfate concentrations are associated with CVD and mortality. In analysis of HEMO study participants, there was no correlation between p‐cresol sulfate and indoxyl sulfate and cardiovascular outcomes; however, among patients with low albumin levels, there was such an association . AST‐120 is an orally administered binder that can adsorb small molecule uremic toxins and is used internationally to slow the progression of renal disease and improve uremic symptoms .…”

Effect of Ionic Strength, pH and Chemical Displacers on the Percentage Protein Binding of Protein-Bound Uremic Toxins

“…For example, PCS and IS have repeatedly been associated with overall mortality, cardiovascular disease and progression of CKD [3][4][5]. Notwithstanding Shafi et al [20] failed to confirm an association between total PCS and IS and cardiovascular outcomes in prevalent HD patients in a latest post hoc analysis on the HEMO trial, a commentary in the same issue suggested that analytical issues and case-mix may explain the discrepant findings [21]. Serum 3-IAA concentration has been reported to be an independent predictor of mortality and cardiovascular events in patients with CKD [6].…”