The 1,24,25(OH)₃D₃ metabolite in clinical and experimental CKD: Impact of calcitriol treatment

Calcitriol, and other vitamin D receptor activators, remain a primary treatment for elevated parathyroid hormone levels in patients with end stage kidney disease. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D₃ and 1,25(OH)₂D₃ in rats with experimental kidney disease treated with calcitriol and in a cross-sectional analysis of patients requiring hemodialysis. Methods: Animals were stratified by creatinine into a time control group or calcitriol (20 ng/kg/day) for 3 weeks following CKD induction using a dietary adenine model (0.25% adenine). Hemodialysis patients were recruited and demographic data including calcitriol prescription was obtained by chart review and participant interview. Vitamin D metabolites were assessed using LC-MS/MS. In the rat model, 1,25(OH)₂D₃ levels increased substantially in calcitriol-treated rats yet there was no increase in its primary metabolite: 1,24,25(OH)₂D₃. A lower ratio of 1,24,25(OH)₂D₃:1,25(OH)₂D₃ (1,25-VMR) was associated with increased calcium levels in calcitriol treated rats. In hemodialysis patients (N = 86), the level of 1,25(OH)₂D₃ was substantially higher in calcitriol-treated patients yet there was no difference between groups in 1,24,25(OH)₃D₃, resulting in a marked decrease in the 1,25-VMR in calcitriol treated patients. In hemodialysis patients treated with calcitriol, 1,25(OH)₂D₃ and a lower ratio between 1,24,25(OH)₃D₃ and 1,25(OH)₂D₃ were associated with higher serum calcium levels. Impaired metabolism of exogenous calcitriol may contribute to the adverse effects associated with this treatment. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies.