Protein-bound uremic toxins predict HF events and death in patients with CKD

The presence of protein-bound uremic toxins (PBUTs) may explain the high cardiovascular risk seen in patients with chronic kidney disease (CKD). According to a study, these toxins are independent predictors of new heart failure (HF) events.

Most patients with CKD die from cardiovascular events rather than end-stage renal failure [1]. This increased cardiovascular risk is only partially explained by traditional risk factors. PBUTs are metabolites of dietary proteins broken down by gut microbiota, which cannot be excreted effectively in patients with CKD. Examples include indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), and hippuric acid (HA). While their association with cardiovascular disease is well documented, evidence of their relationship with HF is limited.

In a retrospective analysis including 526 participants with a mean age of 66 years with varying stages of CKD (stages 1–5 but not on dialysis), free fractions of uremic toxins were quantified using ultra-high performance liquid chromatography over a 5-year follow-up [2]. Kaplan-Meier survival curves were used to investigate the univariate association between PBUT levels and the endpoint of a participant’s life due to HF (either hospitalisation or death).

Dr Bert Zwaenepoel (Ghent University Hospital, Belgium) found that after a median follow-up of 5.4 years, 43 participants (8.4%) reached the primary endpoint, of which 8 (18.6%) were fatal. After Cox regression analyses with adjustment for age, gender, BMI, diabetes, and systolic blood pressure, all 4 investigated PBUTs (i.e. IxS, pCS, pCG, and HA) remained significant and independent predictors of new HF events (see Table). The most prevalent comorbidity in the study population was diabetes (33.5%), closely followed by coronary artery disease in 21.1% of the participants, and peripheral artery disease in 17.5%.

Although the pathophysiological basis by which these toxins contribute to HF remains to be elucidated, their presence appears to be an independent predictor of hospitalisation and mortality associated with HF in patients with CKD.

Table: Hazard ratio per quartile change in uremic toxin plasma levels, adjusted for confounding factors in patients with varying stages of chronic kidney disease (CKD) [2].



HR = hazard ratio

1. Janowski J, et al. Circulation 2021;143:1157-72.
2. Zwaenepoel BAC, et al. Predictive value of protein-bound uremic toxins for heart failure events in patients with chronic kidney disease. Heart Failure 2023, 20–23 May, Prague, Czechia.

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Posted on 8 August 202317 May 2024