Abstract

Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD). Numerous CVD risk factors in CKD patients have been described, but these do not fully explain the high pervasiveness of CVD or increased mortality rates in CKD patients. In CKD the loss of urinary excretory function results in the retention of various substances referred to as “uremic retention solutes”. Many of these molecules have been found to exert toxicity on virtually all organ systems of the human body, leading to the clinical syndrome of uremia. In recent years, an increasing body of evidence has been accumulated that suggests that uremic toxins may contribute to an increased cardiovascular disease (CVD) burden associated with CKD. This review examined the evidence from several clinical and experimental studies showing an association between uremic toxins and CVD. Special emphasis is addressed on emerging data linking gut microbiota with the production of uremic toxins and the development of CKD and CVD. The biological toxicity of some uremic toxins on the myocardium and the vasculature and their possible contribution to cardiovascular injury in uremia are also discussed. Finally, various therapeutic interventions that have been applied to effectively reduce uremic toxins in patients with CKD, including dietary modifications, use of prebiotics and/or probiotics, an oral intestinal sorbent that adsorbs uremic toxins and precursors, and innovative dialysis therapies targeting the protein-bound uremic toxins are also highlighted. Future studies are needed to determine whether these novel therapies to reduce or remove uremic toxins will reduce CVD and related cardiovascular events in the long-term in patients with chronic renal failure.

Highlights

  • Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD) [1,2]

  • In a metagenome-wide association study in fecal samples of 405 Chinese subjects comprising of 218 individuals with atherosclerotic cardiovascular disease (ACVD) and 187 control subjects, Jie et al [47] reported that the gut microbiome of ACVD individuals differed from that of healthy controls by having an increased abundance of Enterobacteriaceae and Streptococcus spp

  • Samples compared to healthy controls. In another a study in Sweden, Karlsson et al [48], using shotgun sequencing of the gut metagenome, found that the genus Collinsella was enriched in patients with symptomatic atherosclerosis, whereas Roseburia and Eubacterium were enriched in healthy controls

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Summary

Introduction

Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD) [1,2]. Twenty-five of the 90 listed toxins (27.8%) are protein-bound, and 23 of them have an MW ≤ 500 D Among these uremic toxins, organic anions, such as IS, CMPF, PCS, indole-3-acetic acid (IAA), and hippuric acid (HA) are low-molecular-weight compounds. Organic anions, such as IS, CMPF, PCS, indole-3-acetic acid (IAA), and hippuric acid (HA) are low-molecular-weight compounds They should be classified as high-molecular-weight compounds in general circulation as they are firmly bound to plasma proteins, primarily albumin (molecular weight: 66 kDa). This set of toxins is difficult to be dialyzed with conventional hemodialysis despite having molecular sizes small enough to pass through the dialysis membrane. The concentrations for a broad range of uremic toxins correlate poorly with estimated glomerular filtration rate (eGFR) [10]

Origin and Metabolism of Uremic Toxins
Indole and Indole Components
Altered Gut Microbiota in Chronic Kidney Disease
Altered Gut Microbiota in Cardiovascular Disease
Gut microbiota and Uremic Toxins
Uremic Toxins and Cardiovascular Disease
Effects of Uremic Toxins on the Myocardium
Effects of Uremic Toxins on the Vasculature
Prebiotics
Probiotics
Synbiotics
Adsorbant AST-120
Genetically Engineered Bacteria
Dialysis Modalities
Peritoneal Dialysis
Findings
10. Summary and Conclusions
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