Protein-bound uremic toxins predict HF events and death in patients with chronic kidney disease

Protein-bound uremic toxins were independent predictors of hospitalisation and mortality related to heart failure (HF) in 526 patients with various stages of chronic kidney disease (CKD). The pathophysiological basis of this association still needs to be clarified.

The cardiovascular risk in patients with CKD is markedly higher than in the general population. Moreover, 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. Protein-bound uremic toxins (PBUTs), which accumulate in patients with CKD, are thought to contribute to the development and progression of cardiovascular disease. Indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), and hippuric acid (HA) are all PBUTs. They are metabolites of dietary proteins broken down by gut microbiota, which cannot be excreted effectively in patients with CKD. Their association with cardiovascular disease is well documented, but evidence of their relationship with HF is limited.

In a retrospective analysis including 526 patients in their sixties 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 PBUTs and the endpoint of a patient’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 patients (8.4%) reached the primary endpoint, of which 8 (18.6%) were fatal. After Cox regression analyses with adjustment for age, gender, body mass index, diabetes, and systolic blood pressure all 4 PBUTs (i.e. IxS, pCS, pCG and HA) remained independent predictors of new HF events. The results were highly statistically significant (all hazard ratios [HR] given /quartile change in uremic toxin plasma level): IxS HR 1.46 (P=0.019), pCS HR 1.75 (P=0.003), pCG HR 1.65 (P=0.004), and HA HR 1.43 (P=0.022). The most prevalent comorbidity in the study population was diabetes (33.5%), followed closely by coronary artery disease in 21.1% of the participants, and peripheral vascular disease in 17.5%.

Although the pathophysiological basis by which these toxins contribute to HF remains to be elucidated, free fractions of these PBUTs appear to be independent predictors of hospitalisation and mortality associated with HF in patients with CKD.

1. 1. Janowski J, et al, Cardiovascular disease in chronic kidney disease, 2021. Doi: 10.1161/CIRCULATIONAHA.120.050686.
   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 24 May, 2023