Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review.

Jana Holmar,Sofia De La Puente-Secades,Jürgen Floege,Setareh Orth-Alampour,Joachim Jankowski,Heidi Noels

doi:10.3390/cells9112428

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.

Highlights

13% of the population suffers from chronic kidney disease (CKD) globally, and about half of the patients with CKD stages 4-5 suffer and eventually die from cardiovascular disease (CVD) [1,2]
41 substances with increased plasma concentration in CKD patients were studied in the context of uremia and cardiovascular calcification
For the remaining 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. These included 15 low molecular weight uremic toxins (Table 1); 12 middle molecular weight uremic toxins (Table 2) as well as indoxyl sulphate and p-cresyl sulphate as protein-bound uremic toxins (Table 3)

Summary

Introduction

13% of the population suffers from chronic kidney disease (CKD) globally, and about half of the patients with CKD stages 4-5 suffer and eventually die from cardiovascular disease (CVD) [1,2]. Consequences of cardiovascular calcification include decreased arterial elasticity, an increase in pulse wave velocity, a decrease in coronary artery perfusion, aortic valve stenosis, progression of left ventricular hypertrophy as well as myocardial ischemia and failure [10,11]. These cardiovascular complications are among the main causes of death in CKD patients [2] and cardiovascular calcification heralds a poor prognosis in terms of cardiovascular morbidity in these patients [12,13]. KDIGO (Kidney Disease: Improving Global Outcomes) CKD guidelines suggest to consider patients with advanced CKD (stages 3–5) and cardiovascular calcifications at the highest cardiovascular risk [14]

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Results

Conclusion