Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease

Abstract

Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in secondary hyperparathyroidism (sHPT). These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and myocardium, ultimately associated with increased risk of mortality in patients with chronic kidney disease (CKD). sHPT may lead to cardiovascular calcifications by other mechanisms including an impaired effect of parathyroid hormone (PTH), and a decreased calcium-sensing receptor (CaR) expression on cardiovascular structures. PTH may play a direct role on vascular calcifications through activation of a receptor, the type-1 PTH/PTHrP receptor, normally attributed to PTH-related peptide (PTHrP). The CaR in vascular cells may also play a role on vascular mineralization as suggested by its extremely reduced expression in atherosclerotic calcified human arteries. Calcimimetic compounds increasing the CaR sensitivity to extracellular calcium efficiently reduce serum PTH, calcium, and phosphate in dialysis patients with sHPT. They upregulate the CaR in vascular cells and attenuate vascular mineralization in uremic states. In this article, the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT, the biology of the CaR in vascular structures and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications are reviewed.

The Calcimimetic Calindol Prevents High Phosphate-Induced Vascular Calcification by Upregulating Matrix GLA Protein

“…These results confirm that the activation of the CaSR at the vascular level may be important to prevent and reduce VC, by both an indirect effect on calcium and P levels and by a direct effect on CaSR activation [26,27]. …”

Impact of Aldosterone on Osteoinductive Signaling and Vascular Calcification

“…Elevated plasma phosphate levels are associated with a higher risk of death and conversely some studies documented an increased lifespan of CKD patients on phosphate binders [66,69]. Several mechanisms contribute to the phosphate-induced vascular changes [3,21,24,25,28,33] and hyperaldosteronism may be a further contributor to vascular calcification [29,52]. Hyperaldosteronism is frequently found in CKD patients [70,71] so that aldosterone might contribute to enhanced vascular osteoinduction in the vessels of such patients [6].…”

“…Vascular calcification [15] is not simply the result of passive precipitation of Ca 2+ and bivalent phosphate, but results from an active and regulated process involving inhibiting proteins, such as fetuin-A [16] and matrix Gla protein [17], apoptosis of vascular smooth muscle cells (VSMCs) [18,19] and triggering of an osteoinductive signaling cascade transforming VSMCs into osteo- and chondrogenic phenotypes [18,20,21,22,23,24,25,26,27,28,29]. …”

Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients

“…Low PTH concentrations as well as too high PTH concentrations in patients on dialysis (diabetics and non-diabetics) are associated with excess mortality [1]. PTH secretion is controlled by a variety of factors acting on the parathyroid gland, namely the chief cells of this gland: ionized calcium, 1,25 (OH)2 vitamin D and FGF23 are the so far known key factors controlling the synthesis and secretion of PTH by the chief cells of the parathyroid gland [1,2,3,4]. Since PTH concentrations are clearly associated with mortality in patients suffering from chronic renal failure and since the PTH concentrations are at least partially changeable in response to alterations of the key regulators or drugs that influence the key regulators, national as well as international academic nephrology societies have established guidelines for target PTH concentrations in order to keep the patient in the “valley of survival” within the U-shaped PTH mortality curve.…”

“…Moreover PTH is also a key hormone controlling bone metabolism [1,2,3,4]. The key role of PTH for the health of patients with advanced stages of renal failure such as end-stage renal failure with the need for renal replacement therapy (dialysis) is clearly reflected by the U-shaped relationship between all-cause mortality and PTH concentrations seen in large observational studies [1,2,3,4]. Low PTH concentrations as well as too high PTH concentrations in patients on dialysis (diabetics and non-diabetics) are associated with excess mortality [1].…”