Mineral and bone disorders in chronic kidney disease and end-stage renal disease patients: new insights into vitamin D receptor activation

Progressive loss of kidney function leads to reduced production of calcitriol (1,25-dihydroxyvitamin D; active vitamin D) and an imbalance in serum calcium (Ca) and phosphorus (P) levels, which are associated with progression of renal failure as well as increased rates of cardiovascular (CV) events and mortality. In addition, multifactorial hypocalcemia and resistance to parathyroid hormone (PTH) can lead to prolonged and excessive synthesis and secretion of PTH, eventually leading to development of secondary hyperparathyroidism and renal osteodystrophy. These changes associated with chronic kidney disease (CKD), extending beyond bone and related biochemical abnormalities, have prompted the development of the term CKD–mineral and bone disorder to describe its systemic nature. Excessive P loading, among other factors, will promote vascular calcification (VC), and PTH production will affect bone remodeling. Although administration of calcitriol increases serum Ca levels and decreases PTH, it is also associated with elevated Ca × P product. Therefore, compounds that selectively activate vitamin D receptors (VDR activators), potentially reducing Ca–P toxicity and distinctly affecting pathogenic mechanisms of VC, might enhance CV and renal protection, increase the vitamin D therapeutic window, and thus provide a significant clinical benefit. Moreover, selective VDR activators have been associated with improvement in survival, at least among dialysis patients. Thus, selective VDR activators should be considered a novel and interesting approach to enhance the standard of care in CKD patients.