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.

Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme

“…Increased arterial stiffness is a typical vasculopathy in CKD patients [ 6 ]. Besides this, CKD patients suffer from endothelial dysfunction (i.e., impaired nitric oxide regulation) favoring the calcification process in the arteries [ 7 , 8 ]. Furthermore, calcification inhibitors such as fetuin A, pyrophosphate (PPi) and Matrix gla protein (MGP) are produced in an attempt to restrict excessive calcification or mineralization.…”

Lanthionine, a Novel Uremic Toxin, in the Vascular Calcification of Chronic Kidney Disease: The Role of Proinflammatory Cytokines

“…Cardiovascular disease is the most common cause of death in patients with chronic kidney disease (CKD) at all stages of the disease. The high cardiovascular risk may be due in part to excess vascular calcification (VC) [1][2][3][4][5][6][7][8]. The following factors have been associated with medial and/or intimal VC and are disproportionately represented among CKD patients: increasing age and dialysis vintage, hyperphosphatemia and hypercalcemia, oral calcium intake, secondary hyperparathyroidism and adynamic bone disease, and excessive vitamin D administration [9][10][11][12][13][14][15].…”

The Emerging Role of Nutraceuticals in Cardiovascular Calcification: Evidence from Preclinical and Clinical Studies

“…The transdifferentiation of VSMCs can be promoted by several different factors, including oxidative stress, an imbalance between calcification promoters and inhibitors, cellular senescence, and hyperphosphatemia [ 14 ]. Once VSMCs are differentiated, they secrete calcifying extracellular vesicles rich in calcium-phosphate crystals, promoting further mineralization in the ECM [ 15 ]. In addition, osteoblast-like VSMCs can release apoptotic bodies, which act as scaffolds for ECM mineralization [ 16 ].…”