Abstract
Patients with chronic kidney disease (CKD) are at an increased risk of thromboembolic complications, including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. These complications lead to increased mortality. Evidence points to the key role of CKD-associated dysbiosis and its effect via the generation of gut microbial metabolites in inducing the prothrombotic phenotype. This phenomenon is known as thrombolome, a panel of intestinal bacteria-derived uremic toxins that enhance thrombosis via increased tissue factor expression, platelet hyperactivity, microparticles release, and endothelial dysfunction. This review discusses the role of uremic toxins derived from gut-microbiota metabolism of dietary tryptophan (indoxyl sulfate (IS), indole-3-acetic acid (IAA), kynurenine (KYN)), phenylalanine/tyrosine (p-cresol sulfate (PCS), p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln)) and choline/phosphatidylcholine (trimethylamine N-oxide (TMAO)) in spontaneously induced thrombosis. The increase in the generation of gut microbial uremic toxins, the activation of aryl hydrocarbon (AhRs) and platelet adrenergic (ARs) receptors, and the nuclear factor kappa B (NF-κB) signaling pathway can serve as potential targets during the prevention of thromboembolic events. They can also help create a new therapeutic approach in the CKD population.
Highlights
Despite the advances in the prevention and treatment of thromboembolic complications, patients with chronic kidney disease (CKD) are at an increased risk of a spontaneously induced thrombosis, paradoxically associated with bleeding complications [1,2]
This review summarizes the recent findings on the prothrombotic mechanisms activated by indoxyl sulfate (IS), indole-3-acetic acid (IAA), KYN, P-cresol sulfate (PCS), p-cresol glucuronide (PCG), PAGln and TMAO
As the gut–kidney–vascular axis has been recently highly researched as a factor contributing to the development of thrombotic events among CKD patients, this review summarizes the most recent developments in the field of gut microbiota-generated uremic toxins and their impact on thrombosis mechanisms in renal insufficiency
Summary
Despite the advances in the prevention and treatment of thromboembolic complications, patients with chronic kidney disease (CKD) are at an increased risk of a spontaneously induced thrombosis, paradoxically associated with bleeding complications [1,2]. Gut microbiotaderived uremic toxins linked in human and animal studies to thromboembolic complications associated with renal impairment mainly include metabolites of dietary tryptophan (TRP) (indoxyl sulfate (IS), indole-3-acetic acid (IAA) and kynurenine (KYN)), phenylalanine/tyrosine (p-cresol sulfate (PCS), p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln)), and choline/phosphatidylcholine (trimethylamine N-oxide (TMAO)). This group of inflicting thrombosis uremic solutes, generated by gut microbiota and retained with renal impairment, is named a “thrombolome”, which merges the words “thrombosis” and “metabolome” [7]. As the gut–kidney–vascular axis has been recently highly researched as a factor contributing to the development of thrombotic events among CKD patients, this review summarizes the most recent developments in the field of gut microbiota-generated uremic toxins and their impact on thrombosis mechanisms in renal insufficiency
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