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Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review.

ABSTRACT: Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

SUBMITTER: Harlacher E

PROVIDER: S-EPMC8745705 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Distal Colon Motor Dysfunction in Mice with Chronic Kidney Disease: Putative Role of Uremic Toxins.

Project description:Although gastrointestinal complications are a common feature of patients with chronic kidney disease (CKD), the impact of uremia on bowel motility remains poorly understood. The present study was, therefore, designed to investigate the impact of uremia on gut motility. Kidney failure was induced in mice by chemical nephrectomy using an adenine diet (0.25% w/w). Gastrointestinal transit time and colon motility were explored in vivo and ex vivo. Colons from control mice were incubated with uremic plasma or uremic toxins (urea, indoxyl-sulfate or p-cresyl-sulfate) at concentrations encountered in patients with end-stage renal disease. Mice fed an adenine diet for 3 weeks exhibited a 3-fold increase in plasma urea (p < 0.001) evidencing kidney failure. The median gastrointestinal transit time was doubled (1.8-fold, p < 0.001) while a reduction in colonic propulsive motility was observed in CKD mice (3-fold, p < 0.001). Colon from CKD mice exhibited an abnormal pattern of contraction associated with a blunted maximal force of contraction. Control colons incubated with plasma from hemodialysis patients exhibited a blunted level of maximal contraction (p < 0.01). Incubation with urea did not elicit any difference but incubation with indoxyl-sulfate or p-cresyl-sulfate decreased the maximal force of contraction (-66% and -55%, respectively. p < 0.01). Taken together, these data suggest that uremia impairs colon motility probably through the retention of uremic toxins. Colon dysmotility might contribute to the gastrointestinal symptoms often reported in patients with CKD.

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Association between Protein-Bound Uremic Toxins and Asymptomatic Cardiac Dysfunction in Patients with Chronic Kidney Disease.

Project description:Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2⁻5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPOmax), aerobic exercise capacity (VO2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPOmax and VO2max. IXS and PCS were independently associated with CPOmax and VO2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins.

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A metabolomics approach identified toxins associated with uremic symptoms in advanced chronic kidney disease.

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| S-EPMC8792216 | biostudies-literature

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Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets.

Project description:Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-?, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.

| S-EPMC7917723 | biostudies-literature

Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review.

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| S-EPMC7694747 | biostudies-literature

Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease.

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| S-EPMC4951226 | biostudies-literature

Ketoanalogs' Effects on Intestinal Microbiota Modulation and Uremic Toxins Serum Levels in Chronic Kidney Disease (Medika2 Study).

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| S-EPMC7922022 | biostudies-literature

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