Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

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.

Extracellular Vesicles and Their Relationship with the Heart–Kidney Axis, Uremia and Peritoneal Dialysis

“…UT accumulation can be observed in all types of CRS [3,12,31,32]. Following renal injury, the structural damage in the kidney compromises renal function resulting in a reduction in GFR and/or subsequent increased proteinuria [2], this can cause an increase in UT accumulation in the blood further compounding the functional and structural deterioration of the kidneys and other organs [3].…”

“…Following renal injury, the structural damage in the kidney compromises renal function resulting in a reduction in GFR and/or subsequent increased proteinuria [2], this can cause an increase in UT accumulation in the blood further compounding the functional and structural deterioration of the kidneys and other organs [3]. Although it has been pointed out that this accumulation of toxins causes a primary injury to the kidney, some studies have suggest (i.e., Di Lullo et al) that it could be considered a type 5 CRS since the uremic compounds can also directly cause damage to the cardiac tissue, featuring a systemic disease [3,12].…”

“…Extracellular vesicles (EVs) have been widely investigated for their role in intercellular communication and as potential biomarkers, particularly in inflammatory pathological conditions. Cardiorenal syndrome results from interrelated heart and kidney injuries, which leads to an accumulation of uremic toxins in the body, especially with the progression of chronic kidney disease (CKD) [1][2][3]. However, the participation of EVs in CRS has not been fully elucidated.…”

Carbamylated Proteins in Renal Disease: Aggravating Factors or Just Biomarkers?

“…The retention of such compounds leads to uremic syndrome, which is characterized by the loss of biological functions, contributing to disease progression. A wide number of uremic toxins have been identified in CKD patients, among which is urea [ 4 , 5 , 6 ]. While direct urea toxicity has been controversial—described as well tolerated or, conversely, harmful [ 7 ]—it is established that urea promotes indirect adverse effects through carbamylation [ 8 ].…”

“…However, the mechanisms involved in carbamylation-induced urea toxicity in renal patients lack clarity, unlike other uremic toxins. Indeed, AGEs and hippuric acid are involved in cardiovascular complications, whereas indoxyl sulfate and p-cresyl sulfate are responsible for inflammation and fibrosis in renal tubular cells [ 5 , 6 , 22 ]. Thus, the cause–consequence link between these uremic toxins and kidney disease progression is well established.…”