Thrombolome and Its Emerging Role in Chronic Kidney Diseases

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.

Secondary Immunodeficiency Related to Kidney Disease (SIDKD)—Definition, Unmet Need, and Mechanisms

“…Beyond their important role in homeostasis, platelets are important cellular contributors to host defense 99 and essential for sufficient neutrophil activation and recruitment into peripheral organs under different inflammatory conditions. However, gut microbial uremic toxins, which accumulate during CKD, 100 and altered HDL levels contribute to altered homeostasis and immune effector functions in SIDKD (Figure 3). 101 This dichotomy may be explained by the fact that critical factors determining the effective formation of platelet-leukocyte aggregates, e.g.…”

Tissue Factor, Thrombosis, and Chronic Kidney Disease

“…Accumulated uremic toxins are involved in CKD progression and complications, including cardiac dysfunction, sarcopenia, and cognitive function [ 19 , 40 , 41 ]. Notably, the relationship between the hemostasis system and uremic toxins in CKD pathogenesis has recently received considerable attention [ 17 , 18 , 19 , 20 ] ( Figure 1 ).…”

“…The Kyn pathway, another route of tryptophan metabolism, is catalyzed by the enzymes tryptophan dioxygenase (TDO) in the liver and indoleamine 2,3-dioxygenases (IDOs), which are inducible enzymes under pathological conditions, such as inflammation [ 58 ]. Kyn and its degradation products accumulate as a result of impaired renal function and play crucial roles in thrombotic activity during CKD pathogenesis [ 17 , 18 , 59 ]. In a previous study, it was demonstrated that the levels of plasma TF and other pro-coagulant markers were correlated with metabolites related to the Kyn pathway in patients undergoing dialysis or conservative treatment [ 60 , 61 ].…”

“…TF dysregulation is linked to abnormal hemostasis and increases the risk of thrombotic events [ 16 ]. Typically, inflammatory mediators, such as cytokines, oxidative stress, and oxidized low-density lipoprotein, elevate TF levels, but recent studies have revealed the relationship between CKD-specific pathogenesis, including uremic toxins, and regulation of TF activity [ 17 , 18 , 19 , 20 ]. Therefore, new mechanisms underlying thrombosis development in patients with CKD are attracting increasing attention.…”

Proteomics: A Tool to Study Platelet Function

“…Recently, the gut microbiota as a source of uremic toxins has shown to be a risk factor for thromboembolic complications [ 175 ]. These include metabolites of dietary tryptophan (indoxyl sulfate (IS), indole-3-acetic acid and kynurenine (KYN)), phenylalanine/tyrosine (p-cresol sulfate (PCS), p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln)), and choline/phosphatidylcholine (trimethylamine N-oxide (TMAO)) [ 176 ]. Uremic toxins have been shown to effect endothelial cells, vascular smooth muscle cells, macrophages and platelets, leading to increased inflammation, platelet activation and aggregation [ 177 ], e.g., via the release of endothelial microparticles [ 178 ], production of reactive oxygen species (ROS) [ 178 ], or decreased production of nitric oxide [ 179 ].…”