Gut-derived uremic toxins and cardiovascular health in chronic kidney disease

Abstract

Uremic toxins (UTs) are bioactive compounds that accumulate in chronic kidney disease (CKD) due to impaired renal clearance, exacerbating disease progression and cardiovascular (CV) complications. These toxins originate from endogenous metabolism, gut microbiota, and dietary intake and include protein-bound UTs such as p-cresyl sulfate, indoxyl sulfate, and indole acetic acid, as well as small, water-soluble toxins such as trimethylamine-N-oxide and phenylacetylglutamine. Their accumulation promotes oxidative stress, inflammation, and endothelial dysfunction, contributing to vascular damage and associated with CV risk. Current management strategies focus on dietary interventions, prebiotics, probiotics, oral sorbents, emerging pharmacological approaches, and advanced dialysis techniques, but clinical outcomes remain inconsistent. Recent trials have demonstrated the potential of agents such as sevelamer, high-amylose-resistant starch, and AST-120 to reduce UT levels and improve certain vascular markers. However, more robust, long-term studies are necessary to fully establish the therapeutic efficacy and optimize treatment strategies to mitigate the impact of gut-derived UTs on CKD and CV health.

Keywords: Chronic kidney disease; Gut-derived uremic toxins; Indole acetic acid; Indoxyl sulfate; Phenylacetylglutamine; Trimethylamine-N-oxide; p-cresyl sulfate.

Figure 1

The metabolic pathways of gut-derived uremic toxins. Gut-derived uremic toxins are metabolic byproducts of dietary amino acids processed by intestinal microbiota. These microbial metabolites are then transported to the liver, where they undergo modifications, such as sulfation or conjugation, which increase their hydrophilicity and facilitate renal excretion. In cases of chronic kidney disease, however, impaired renal function reduces the clearance of these toxins, leading to their accumulation in the bloodstream and contributing to systemic toxicity. Created in BioRender.com

Figure 2

Gut-derived uremic toxins linked to cardiovascular health in chronic kidney disease. Protein-bound uremic toxins (PBUTs) are a group of toxins that are primarily produced in the gut and can build up in the body when kidney function is impaired, as in chronic kidney disease (CKD). Examples of these toxins include p-cresyl sulfate (pCS), indoxyl sulfate (IS), and indole acetic acid (IAA). These PBUTs bind to blood proteins, making them harder to remove during dialysis, leading to their accumulation in CKD patients. In addition to PBUTs, there are other types of uremic toxins (UTs), such as trimethylamine-N-oxide (TMAO) and phenylacetylglutamine (PAGln). Unlike PBUTs, these are small, water-soluble molecules easily absorbed into the bloodstream from the gut. However, in CKD, these water-soluble UTs are not efficiently filtered and eliminated by the kidneys, causing them to accumulate in the body. The accumulation of these UTs plays a significant role in the progression of cardiovascular disease and the development of arterial stiffness in patients with CKD. Among these UTs, research has mainly focused on pCS and IS, and these two UTs are known to contribute to endothelial dysfunction and peripheral artery occlusive disease (PAOD). However, less is understood about the clinical effects of other UTs like IAA, TMAO, and PAGln on endothelial dysfunction and PAOD in CKD, which are an area of interest for future research. Created in BioRender.com