Extra-renal production of calcitriol in chronic renal failure

Renal 1-alpha-hydroxylase activity is tightly regulated in normal humans and intact animals. No significant changes in serum 1,25(OH)₂D levels occur in response to vitamin D challenge. However, conflicting reports have appeared in the literature with regard to stimulation of 1,25(OH)₂D production after 25(OH)D administration in uremia. To provide further insight into this issue, 25(OH)D at a dose of 100 μg every other day for two weeks followed by 50 μg every other day for the next two weeks was given orally to seven uremic mongrel dogs. After two weeks of 25(OH)D therapy, 1,25(OH)₂D levels increased from 16.4 ± 0.9 to 28.0 ± 1.9 pg/ml (P < 0.001) in parallel with a fourfold increase in 25(OH)D concentrations from a basal of 50.1 ± 6.5 to 203.2 ± 18.1 ng/ml. No significant changes in serum i-PTH, ICa or P were observed. Linear regression analysis of the relationship between serum concentrations of 1,25(OH)₂D versus 25(OH)D, for each dog during this period, showed highly significant correlation coefficients. To evaluate the possibility that extra-renal sites contribute to the described enhanced 1,25(OH)₂D net synthesis after 25(OH)D treatment, similar studies were performed in four anephric patients undergoing hemodialysis. Basal serum 1,25(OH)₂D levels were 5.5 ± 2.4 pg/ml and increased to 19.6 ± 5.0 pg/ml after 25(OH)D administration. A significant correlation was also found for the relationship between serum levels of 1,25(OH)₂D and 25(OH)D in anephrics (r = 0.72, P < 0.001). The same therapy in four normal volunteers showed no significant changes in serum 1,25(OH)₂D concentrations. Our results suggest that the effects of 25(OH)D administration on 1,25(OH)₂D levels are not exclusively a consequence of enhanced substrate availability to the renal 1-alpha-hydroxylase enzyme. Supraphysiological levels of 25(OH)D can augment circulating 1,25(OH)₂D concentrations in the absence of renal mass.