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Cardiovascular disease is highly prevalent in patients with chronic kidney disease. Hyperphosphatemia is associated with subclinical atheromatosis in chronic kidney disease. Phosphate-induced endothelial dysfunction and vascular calcification are thought to be key inducers of atherosclerosis in this condition. Zhou et al. now demonstrate that phosphate promotes de novo cholesterol synthesis in vascular smooth muscle and macrophages through increased 3-hydroxy-3-methylglutaryl coenzyme A reductase activation. This observation may change current concepts of atherosclerosis development and management in chronic kidney disease., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

In chronic kidney disease (CKD), the progressive decrease in renal function leads to disturbances of mineral metabolism that generally cause secondary hyperparathyroidism. The increase in serum parathyroid hormone is associated with reduced serum calcium and calcitriol levels and/or increased serum fibroblast growth factor-23 and phosphate levels. The resulting CKD-associated disorder of mineral and bone metabolism is associated with various other metabolic dysregulations such as acidosis, malnutrition, inflammation, and accumulation of uremic toxins. It favors the occurrence of vascular calcification, which results from an imbalance between numerous inhibitors and promoters of soft-tissue mineralization. This review provides an overview of the most recent state of knowledge concerning the mechanisms that lead to the development of vascular calcification in the CKD setting. It further proposes directions for potential new therapeutic targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vascular calcification (VC) is associated with elevated cardiovascular mortality rates in patients with CKD. Recent clinical studies of patients with advanced CKD have observed an association between low serum magnesium (Mg) levels on one hand and elevated VC and cardiovascular mortality on the other. These findings have stimulated interest in understanding Mg's impact on CKD in general and the associated VC in particular. In vitro and preclinical in vivo data indicate that Mg has the potential to protect vascular smooth muscle cells against calcification via several different molecular mechanisms. Accordingly, data from pilot interventional studies in the clinic suggest that oral Mg supplementation reduces VC in patients with CKD. The present review provides an overview of our current understanding of the impact of Mg on the development of VC in patients with CKD., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Cardiac valve calcification and vascular calcification (VC) are associated with cardiovascular mortality in the general population and in patients with chronic kidney disease (CKD). CKD, diabetes mellitus, and atherosclerosis are among the causes of systemic inflammation that are associated with VC., Areas Covered: This review collates clinical and experimental evidence that inflammation accelerates VC progression. Specifically, we review the actions of key pro-inflammatory cytokines and inflammation-related transcription factors on VC, and the role played by senescence. Inflammatory cytokines, such as the TNF superfamily and IL-6 superfamily, and inflammation-related transcription factor NF-κB promote calcification in cultured vascular smooth muscle cells, valvular interstitial cells, or experimental animal models through direct effects, but also indirectly by decreasing circulating Fetuin A or Klotho levels., Expert Opinion: Experimental evidence suggests a causal link between inflammation and VC that would change the clinical approach to prevention and treatment of VC. However, the molecular basis remains unclear and little is known about VC in humans treated with drugs targeting inflammatory cytokines. The effect of biologicals targeting TNF-α, RANKL, IL-6, and other inflammatory mediators on VC, in addition to the impact of dietary phosphate in patients with chronic systemic inflammation, requires study.

Vascular calcification (VC) is a degenerative pathology of the vessel wall. In the general population, VC appearance is associated with aging, but this pathology can also develop as a consequence of atherosclerosis, diabetes, inflammatory and chronic kidney disease. VC is strongly associated with increased risk of mortality and cardiovascular disease. Although VC has long been considered as the result of a passive precipitation of mineral, it is now well established that this pathology results from an active and highly regulated cellular process, which shares similarities with bone formation. This review summarizes our current knowledge on VC formation, and details the modalities of action of the main actors known to modulate this process.

Aims: Vascular calcification (VC) contributes to morbidity and mortality in patients with chronic kidney disease (CKD). Allosteric modulators of the calcium (Ca)-sensing receptor (CaSR) may slow the progression of VC in CKD patients either by reducing serum parathyroid hormone (PTH), Ca, and phosphate levels or by a direct effect on the vessel wall. The aim of this study was to examine the effects of calcimimetics on CaSR expression, cell phenotype, and mineral deposition in human vascular smooth muscle cells (h-VSMCs)., Methods and Results: Primary h-VSMCs were exposed for 14 days to increasing concentrations of Ca(2+) (from 1.8 to 5 mmol/L) in the presence or absence of calcimimetics R-568 or AMG 641 (0.1 μmol/L). Mineralization was detected by Alizarin red staining, and the cell phenotype was assessed using immunocytochemistry and qRT-PCR. CaSR expression was evaluated using flow cytometry. Short- and long-term exposure (1 day to 14 days) of h-VSMCs to calcimimetics promoted CaSR protein transport from the endoplasmic reticulum to the plasma membrane with enhanced CaSR expression on the cell surface, together with an increase in total cell CaSR expression due to enhanced biosynthesis. In pro-mineralizing conditions, exposure to calcimimetics counteracted the Ca(2+)-dependent reduction of CaSR expression, decreased matrix collagen secretion, and mineral deposition by ~90%. These effects involved CaSR activation since it could be inhibited by CaSR siRNA, but not scrambled siRNA., Conclusions: The calcimimetic-dependent increase in biosynthesis and activation of the CaSR in h-VSMCs probably play a key role in the protection against calcium-induced VC.