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Review
. 2021 May 14:12:686249.
doi: 10.3389/fphys.2021.686249. eCollection 2021.

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

Carlos Alexandre Falconi  1 , Carolina Victoria da Cruz Junho  1 , Fernanda Fogaça-Ruiz  1 , Imara Caridad Stable Vernier  1 , Regiane Stafim da Cunha  2 , Andréa Emilia Marques Stinghen  2 , Marcela Sorelli Carneiro-Ramos  1
Affiliations
Review

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

Carlos Alexandre Falconi et al. Front Physiol. .

Abstract

The kidneys and heart share functions with the common goal of maintaining homeostasis. When kidney injury occurs, many compounds, the so-called "uremic retention solutes" or "uremic toxins," accumulate in the circulation targeting other tissues. The accumulation of uremic toxins such as p-cresyl sulfate, indoxyl sulfate and inorganic phosphate leads to a loss of a substantial number of body functions. Although the concept of uremic toxins is dated to the 1960s, the molecular mechanisms capable of leading to renal and cardiovascular injuries are not yet known. Besides, the greatest toxic effects appear to be induced by compounds that are difficult to remove by dialysis. Considering the close relationship between renal and cardiovascular functions, an understanding of the mechanisms involved in the production, clearance and overall impact of uremic toxins is extremely relevant for the understanding of pathologies of the cardiovascular system. Thus, the present study has as main focus to present an extensive review on the impact of uremic toxins in the cardiovascular system, bringing the state of the art on the subject as well as clinical implications related to patient's therapy affected by chronic kidney disease, which represents high mortality of patients with cardiac comorbidities.

Keywords: cardiorenal syndrome; cardiovascular diseases; immune sustem; inflammation; renal diseases; uremic toxins.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Graphical representation of p-cresyl (PCS) and indoxyl sulfate (IS) formation inside the body. Both uremic toxins, p-cresyl sulfate and indoxyl sulfate are originate from the intestinal microbial metabolism of dietary amino acids. While the IS is delivered from the tryptophan, the PCS is delivered from tyrosine. After the chemical modifications occurred in the liver, both active metabolites reach the circulation and impact target organs.
FIGURE 2
FIGURE 2
Uremic toxicity is linked to endothelial dysfunction in CKD. Uremic toxins induce the expression of proinflammatory factors (e.g., MCP-1, E-selectin, ICAM-1, and VCAM-1), prothrombotic factors (e.g., TF), damage to the glycocalyx, the increase in permeability, the reduction of NO bioavailability and the formation of endothelial microparticles. As a result, endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis. ICAM-1, intercellular adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; NO, nitric oxide; TF, tissue factor; VCAM-1, vascular cell adhesion molecule-1.
FIGURE 3
FIGURE 3
The crosstalk between heart and kidney: contribution of uremic toxins. During the progression of renal lesion there is increase in the circulatory levels of uremic toxins accompanied by an increase on renin-angiotensin-aldosterone system (RAAS) activity and reactive oxygen species (ROS). On the other hand, the heart responds to kidney injury signaling a pro-oxidant, pro-inflammatory effects leading to mitochondrial damage, alterations in calcium loading, arrhythmias and cardiac remodeling. NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; ROS, reactive oxygen species; RAAS, renin-angiotensin-aldosterone system.
FIGURE 4
FIGURE 4
Schematic representation of chronic kidney disease (CKD)-associated immune dysfunctions. Chronic kidney disease leads to the accumulation of uremic toxins, which have an impact on innate and adaptive immune systems. The uremic toxins impair endothelial cells function and induce chronic low-grade activation of innate immune effectors (monocytes and neutrophils) through the participation of TLRs and inflammatory cytokines. These substances also affect the adaptive immune system causing a defective antigen presentation which brings with it a defective cellular and humoral response. DAMPS, damage-associated molecular patterns; ROS, reactive oxygen species; CAM, cellular adhesion molecules; DC, dendritic cells.
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