Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches

Abstract

Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Both conditions are rising in incidence as well as prevalence, creating poor outcomes for patients and high healthcare costs. Recent data suggests CKD to be an independent risk factor for CVD. Accumulation of uremic toxins, chronic inflammation, and oxidative stress have been identified to act as CKD-specific alterations that increase cardiovascular risk. The association between CKD and cardiovascular mortality is markedly influenced through vascular alterations, in particular atherosclerosis and vascular calcification (VC). While numerous risk factors promote atherosclerosis by inducing endothelial dysfunction and its progress to vascular structural damage, CKD affects the medial layer of blood vessels primarily through VC. Ongoing research has identified VC to be a multifactorial, cell-mediated process in which numerous abnormalities like mineral dysregulation and especially hyperphosphatemia induce a phenotype switch of vascular smooth muscle cells to osteoblast-like cells. A combination of pro-calcifying stimuli and an impairment of inhibiting mechanisms like fetuin A and vitamin K-dependent proteins like matrix Gla protein and Gla-rich protein leads to mineralization of the extracellular matrix. In view of recent studies, intercellular communication pathways via extracellular vesicles and microRNAs represent key mechanisms in VC and thereby a promising field to a deeper understanding of the involved pathomechanisms. In this review, we provide an overview about pathophysiological mechanisms connecting CKD and CVD. Special emphasis is laid on vascular alterations and more recently discovered molecular pathways which present possible new therapeutic targets.

Keywords: Atherosclerosis; Chronic kidney disease; Coronary artery disease; Vascular calcification.

Fig. 1

Intimal and medial calcification in CKD. CKD-specific risk factors are adding up to traditional cardiovascular risk factors and result in endothelial dysfunction and intimal calcification. A phenotype switch of vascular smooth muscle cells to osteoblast-like cells with a loss of smooth muscle cell markers like SM22a and expression of osteochondrogenic markers like Runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP) represents a crucial event in medial calcification. In this process, levels of miRs are altered which act as regulators of calcification in CKD. MGP matrix Gla protein, GRP Gla-rich protein, EV extracellular vesicles, CV cardiovascular, miR microRNA, CCP calciprotein particle