Vitamin D retains an important role in the pathogenesis and management of secondary hyperparathyroidism in chronic renal failure

Chronic kidney disease (CKD) causes alterations in mineral metabolism inducing the development of secondary hyperparathyroidism (HPT) and renal osteodystrophy. Recently, it has been suggested that these alterations play an important role in determining extraskeletal calcification and thus cardiovascular morbidity and mortality among CKD patients. An impaired 1 α-hydroxylation of 25-hydroxycholecalciferol (25(OH)D₃) to 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) with decreased circulating 1,25(OH)₂D₃ levels is commonly observed in patients with creatinine clearance below 70 ml/min. The reduction in 1,25(OH)₂D₃ production triggers the up-regulation of parathyroid hormone (PTH) synthesis, through a decreased suppression on PTH gene transcription and a decreased intestinal calcium absorption. A reduced expression of vitamin D receptor (VDR) and a less efficient binding of the complex 1,25(OH)₂D₃-VDR to specific DNA segments account for the resistance to 1,25(OH)₂D₃ in target cells. Thus, absolute and relative 1,25(OH)₂D₃ deficiency is one of the causes of secondary HPT in patients with CKD, together with phosphate retention and skeletal resistance to PTH. Consistently with these pathophysiological mechanisms, the therapeutic use of 1,25(OH)₂D₃ still represents a milestone for the treatment of secondary HPT and renal osteodystrophy, even though hypercalcemia and hyperphosphatemia are common adverse events and may increase the risk of cardiovascular calcifications. To reduce the impact of such adverse effects while retaining anti-PTH activity, 1,25(OH)₂D₃ analogues with lower calcemic effects have been synthesized and are now available for clinical use.