The role of vitamin D in the pathogenesis and management of secondary hyperparathyroidism in chronic renal failure

Chronic renal failure (CRF) causes alterations in calcium-phosphate metabolism promoting the development of secondary hyperparathyroidism (HPT) and renal osteodystrophy. Recent data suggest that these alterations may play a crucial role in determining cardiovascular calcifications and, thus, cardiovascular mortality among CRF patients. An impaired 1α-hydroxylation of 25-hydroxycholecalciferol (25(OH)D) to 1,25-dihydroxycholecalciferol (1,25(OH)2D) with decreased circulating 1,25(OH)2D levels is commonly observed in patients with creatinine clearance below 70 ml/min. The reduction in 1,25(OH)2D production triggers the upregulation of PTH synthesis, through a decreased suppression on PTH gene transcription and a decreased intestinal calcium absorption. Low vitamin D stores often contribute to the decrease in production and tissue resistance to vitamin D worsens 1,25(OH)2D deficiency. A reduced expression of vitamin D receptor (VDR) and a less efficient binding of the complex 1,25(OH)2D-VDR to specific DNA segments account for the resistance to 1,25(OH)2D in target cells. Thus, absolute and relative 1,25(OH)2D deficiency is one of the causes of secondary HPT in patients with CRF, together with phosphate retention and skeletal resistance to PTH. Consistently with these pathophysiological mechanisms, the therapeutic use of 1,25(OH)2D still represents a milestone for the treatment of uremic secondary HPT and renal osteodystrophy, even though hypercalcemia and hyperphosphatemia are common adverse events and may increase the risk of cardiovascular calcifications. Furthermore, adynamic bone disease may develop after vitamin D therapy. Low levels of serum 25(OH)D are associated with more severe osteodystrophy and HPT, even among dialysis patients. To separate these adverse effects from anti-PTH activity, 1,25(OH)2D analogues with lower hypercalcemic effect have been synthesized and are now available for clinical use.