Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis

Abstract

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have an estimated 700–800 and 523 million cases worldwide, respectively, with CVD being the leading cause of death in CKD patients. The pathophysiological interplay between the heart and kidneys is defined as the cardiorenal syndrome (CRS), in which worsening of kidney function is represented by increased plasma concentrations of uremic toxins (UTs), culminating in dialysis patients. As there is a high incidence of CVD in CKD patients, accompanied by arrhythmias and sudden cardiac death, knowledge on electrophysiological remodeling would be instrumental for understanding the CRS. While the interplay between both organs is clearly of importance in CRS, the involvement of UTs in pro‐arrhythmic remodeling is only poorly investigated, especially regarding the mechanistic background. Currently, the clinical approach against potential arrhythmic events is mainly restricted to symptom treatment, stressing the need for fundamental research on UT in relation to electrophysiology. This review addresses the existing knowledge of UTs and cardiac electrophysiology, and the experimental research gap between fundamental research and clinical research of the CRS. Clinically, mainly absorbents like ibuprofen and AST‐120 are studied, which show limited safe and efficient usability. Experimental research shows disturbances in cardiac electrical activation and conduction after inducing CKD or exposure to UTs, but are scarcely present or focus solely on already well‐investigated UTs. Based on UTs data derived from CKD patient cohort studies, a clinically relevant overview of physiological and pathological UTs concentrations is created. Using this, future experimental research is stimulated to involve electrophysiologically translatable animals, such as rabbits, or in vitro engineered heart tissues.

Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization

“…Previously, exposure to IS and another UT, p-cresyl sulfate, has been shown to decrease repolarization currents in H9c2 rat ventricular cardiomyocytes and computer simulations [ 22 , 23 ]. Additional studies, including in vivo studies, have shown pro-arrhythmic consequences but failed to delve into potential mechanisms of action [ 13 ]. With this current study, we have shown that UTs can additionally influence ion channel functionality, resulting in electrophysiological disturbances that might lead to increased susceptibility to arrhythmias in CKD patients.…”

“…All stock solutions were filtered and stored at −20 °C. Clinically relevant total UT concentrations were identified previously [ 13 ] and applied in all experiments. Albumin was present in all culture media to establish clinically relevant, free fraction concentrations of all UTs.…”

“…The high concentrations of UTs in ERSD, in association with the high SCD rates in these patients, suggests an important effect on cardiac electrophysiology that has been scarcely investigated in basic experimental studies [ 13 ]. Prolongation of the action potential duration (APD), as a trigger for increased susceptibility of early after depolarizations (EADs), is a known pro-arrhythmic parameter preceding SCD.…”

“…Studying deviations in cardiac repolarization could prove beneficial in identifying electrophysiologically dangerous UTs, laying the ground for a more specific approach to UT removal. While some experimental studies have shown systemic effects evoking altered calcium handling and sodium currents in models of CKD [ 14 , 15 , 16 ], the majority of data have predominately indicated effects on potassium currents, as recently reviewed by our group [ 13 ]. K V 11.1, or hERG, comprises one of the most important ion channels involved in repolarization of the action potential.…”

Glycated albumin and risk of cardiovascular diseases and mortality in patients with and without dialysis: A meta‐analysis

“…Among the main causes of human death, cardiovascular diseases (CVD) occupy first place 1 . In addition, deaths from diabetes mellitus (DM) 2 and chronic kidney disease (CKD) 3 are mainly because of CVD. In patients with diabetes, glycaemic control has a significant effect in preventing the development and progression of microvascular or CV complications 4–7 .…”