Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

Abstract

Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

“…The relationship of Pi with CVDs, such as ventricular hypertrophy, coronary disease and heart failure, increases the mortality rate, placing this compound among the uremic toxins with the greatest deleterious effect on the cardiovascular system (Tonelli et al, 2005;Dhingra et al, 2010;Barreto et al, 2014). Pi has been pointed out in several studies as a uremic toxin which causes cardiovascular calcification (Holmar et al, 2020).…”

“…In addition, the IS concentration in free or protein-bound form is approximately 1-9, which provides a circulating IS reservoir even after dialysis in uremic patients. The IS retained in CKD is also associated with several harmful effects on other organs, such as changes in thyroid function, endothelial dysfunction, hyperplasia of smooth muscle cells, vascular calcification and increase in atherosclerosis in men (Gao and Liu, 2017;Holmar et al, 2020).…”

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

“…Uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (pCS) have been associated with an increased risk of cardiovascular events and cardiovascular mortality in CKD patients. Mechanistically, many of these uremic toxins have been linked to inflammation and oxidative stress [ 25 , 26 ], but also to arterial stiffness and endothelial dysfunction in vitro [ 27 ]. Given the central role of the endothelium in preserving vascular health and counteracting atherosclerosis and cardiovascular risk, this manuscript systematically reviewed uremic toxin-induced EC dysfunction and its implications for cardiovascular disease specifically in the context of CKD.…”

Bacterial metabolites and cardiovascular risk in children with chronic kidney disease

“…The accumulation of uremic toxins in adult CKD patients has been repeatedly described and is associated with the progression of kidney disease and its comorbidities, first and foremost CVD [141][142][143]. Subsequently, pediatric nephrologists started to pay attention to these gut-derived uremic toxins and their impact on CKDassociated comorbidities.…”