Predictive value of protein-bound uremic toxins for heart failure in patients with chronic kidney disease

Abstract

Aims: This retrospective cohort study aimed to be the first to evaluate the association between plasma protein-bound uremic toxins (PBUTs) concentrations, echocardiographic parameters of heart failure (HF), and incident HF events in patients with chronic kidney disease (CKD) not on dialysis.

Methods and results: Retrospective, single-centre, cohort study at the Ghent University Hospital, Belgium. Adults with CKD stages G1-G5, not on dialysis, could be included. Exclusion criteria were ongoing pregnancy, age <18 years, active acute infection, active malignancy, history of transplantation, or a cardiovascular event within 3 months prior to inclusion. Free and total concentrations of five PBUTs were quantified at baseline: indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), indole-3 acetic acid (IAA), and hippuric acid (HA). Patients were grouped into three echocardiographic categories: normal left ventricular ejection fraction (LVEF) and normal left ventricular end-diastolic pressure (LVEDP), normal LVEF and increased LVEDP, and reduced LVEF, based on available echocardiographic data in a time interval of ±6 months around the plasma sample collection. A total of 523 patients were included between January 2011 and January 2014. Echocardiographic data within the predefined timeframe were available for 210 patients (40% of patients). Levels of pCG and pCS were significantly higher in patients with reduced (<50%) versus normal LVEF (P < 0.05). After a median follow-up 5.5 years, 43 (8.4%) patients reached the composite endpoint of hospitalization or mortality due to HF. Free fractions of IxS, pCS, and pCG showed the strongest association with clinical outcome: free IxS: HR 1.71 (95% CI 1.11-2.63; P = 0.015), free pCS: HR 1.82 (95% CI 1.11-3.01; P = 0.019), and free pCG: HR 1.67 (95% CI 1.08-2.58; P = 0.020), and these results were independent of age, gender, body mass index, diabetes, and systolic blood pressure. In models that were also adjusted for serum creatinine, the free fractions of these PBUTs remained significant.

Conclusions: Elevated free concentrations of IxS, pCG, and pCS were independently associated with an increased risk of HF events in non-dialysed CKD patients. Further research is necessary to confirm these findings and investigate the potential impact of PBUT-lowering interventions on HF events in this patient group.

Keywords: Biomarkers; Chronic kidney disease; Heart failure; Uremic toxins.