Molecular Mechanisms Underlying the Cardiovascular Toxicity of Specific Uremic Solutes

Abstract

Mounting evidence strongly suggests a causal link between chronic kidney disease (CKD) and cardiovascular disease (CVD). Compared with non-CKD patients, patients with CKD suffer disproportionately from CVD and derive suboptimal benefits from interventions targeting conventional CVD risk factors. Uremic toxins (UTs), whose plasma levels rapidly rise as CKD progresses, represent a unique risk factor in CKD, which has protean manifestations on CVD. Among the known UTs, tryptophan metabolites and trimethylamine N-oxide are well-established cardiovascular toxins. Their molecular mechanisms of effect warrant special consideration to draw translational value. This review surveys current knowledge on the effects of specific UTs on different pathways and cell functions that influence the integrity of cardiovascular health, with implication for CVD progression. The effect of UTs on cardiovascular health is an example of a paradigm in which a cascade of molecular and metabolic events induced by pathology in one organ in turn induces dysfunction in another organ. Deciphering the molecular mechanisms underlying such cross-organ pathologies will help uncover therapeutic targets to improve the management of CVD in patients with CKD.

Cardiovascular Risk Comparison between Expanded Hemodialysis Using Theranova and Online Hemodiafiltration (CARTOON): A Multicenter Randomized Controlled Trial

“…In addition to traditional cardiovascular risk factors, nontraditional factors, including uremic toxins, electrolyte and fluid imbalance, anemia, and inflammation, contribute to worsening cardiovascular outcomes in ESRD 2 – 5 . In particular, uremic toxins induce oxidative stress and vascular inflammation and remodeling 6 – 9 . Furthermore, uremic conditions induce platelet activation and aggregation, which leads to thrombus formation 7 , 8 .…”

Toxin Removal and Inflammatory State Modulation during Online Hemodiafiltration Using Two Different Dialyzers (TRIAD2 Study)

“…According to the last United States Renal Data System (USRDS) report, in 2018, the prevalence of cardiovascular disease (CVD) in the United States, adjusted for age, sex, and race, was 37.5% of subjects without chronic kidney disease (CKD) vs. 63.4% of patients with stages 1–2 of CKD, 66.6% of patients with stage 3 CKD, and 75.3% of patients with stages 4–5 of CKD [ 3 ]. In the natural history of nephropathy, besides the traditional cardiovascular risk factors, an increasingly important role is played by the nontraditional factors, such as renal failure per se, uremic toxin retention, anemia, hyperhomocysteinemia, malnutrition, hyperparathyroidism, electrolyte imbalance, abnormal calcium–phosphate metabolism, chronic inflammation, and oxidative stress [ 4 , 5 , 6 , 7 ].…”

Proteomics: A Tool to Study Platelet Function

“…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 ]. Unraveling contributing factors of platelet dysfunction by mass spectrometry-based proteomics for diagnostic and prognostic purposes would greatly contribute to identification of risk factors and treatment options due to its multifactorial composition and disease stage-associated and interpatient variability.…”