PREDICTIVE VALUE OF PROTEIN-BOUND UREMIC TOXINS FOR HEART FAILURE EVENTS IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract

Objective: Evaluate whether the plasma free fraction of four important protein-bound uremic toxins (PBUTs), indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG) and hippuric acid (HA), are independently associated with new heart failure (HF) events in patients with chronic kidney disease (CKD), not on dialysis. Design and method: Retrospective, single center analysis. 526 patients with CKD stages G1-G5 (not on dialysis), were included between January 2011 and January 2014. Outcome parameters were monitored until June 2017. Exclusion criteria were pregnancy, age <18 years, active infection, active malignancy, history of transplantation or a cardiovascular event within the past three months. Free fractions of uremic toxins were quantified by ultrahigh-performance liquid chromatography. Kaplan-Meier survival curves were constructed to investigate the univariate association between PBUTs and the composite endpoint of hospitalization or death due to HF. Multivariate Cox regression models were used to study the independent association of PBUTs with outcome. Results: The study population (57.8% male) had a median age of 66 years and varying degrees of CKD: stage G1 (12.2%), 2 (16.3%), 3A (21.1%), 3B (27.8%), 4 (19.2%) and 5 (3.4%). After a median follow up of 5.4 years 43 patients (8.4%) developed the primary endpoint, 18.6% (8/43) were fatal. In Cox regression analysis with adjustment for age, gender, body mass index, diabetes and systolic blood pressure, the free fractions of all four PBUTs remained independent predictors of new heart failure events [IxS: HR 1.46 (95% CI: 1.06 – 2.01; P = 0.019); pCS: HR 1.75 (95% CI: 1.21 - 2.54; P = 0.003); pCG: HR 1.65 (95% CI: 1.17 - 2.32; P = 0.004); HA: HR 1.43 (95% CI: 1.05 - 1.95; P = 0.022)]. Univariate survival analyses are shown in Figure 1. Conclusions: Free fraction of the PBUTs indoxyl sulfate, p-cresyl sulfate, p-cresyl glucuronide and hippuric acid were independently associated with hospitalization and mortality due to HF in patients with CKD. The pathophysiological pathways by which these toxins may contribute to heart failure remain to be elucidated.