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.
Subject(s)
Calcimimetic Agents/therapeutic use , Calcinosis/etiology , Cardiovascular Diseases/etiology , Hyperparathyroidism, Secondary/etiology , Kidney Diseases/complications , Kidney , Receptors, Calcium-Sensing/agonists , Animals , Calcinosis/metabolism , Calcinosis/physiopathology , Calcium/metabolism , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Chronic Disease , Humans , Hyperparathyroidism, Secondary/metabolism , Hyperparathyroidism, Secondary/physiopathology , Hyperparathyroidism, Secondary/therapy , Kidney/drug effects , Kidney/metabolism , Kidney/physiopathology , Kidney Diseases/metabolism , Kidney Diseases/physiopathology , Kidney Diseases/therapy , Parathyroid Hormone/metabolism , Phosphates/metabolism , Receptors, Calcium-Sensing/metabolism , Risk Factors , Vascular Calcification/etiology , Vascular Calcification/metabolism , Vascular Calcification/physiopathologyABSTRACT
Parathyroid hormone (PTH) and vitamin D were considered the major factors regulating phosphate homeostasis. Now, with the identification of fibroblast growth factor 23 (FGF23), a phosphaturic molecule inhibiting calcitriol and PTH, they need to be integrated into three feedback loops involving parathyroid, bone, and kidney. PTH and calcitriol are required for the appropriate synthesis of FGF23 by bone cells. PTH also regulates klotho expression in the kidney and thereby the phosphaturic action of FGF23.
