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We have previously demonstrated that while both normal humans and dogs tightly control serum calcitriol levels after 25(OH)D administration, anephric humans and 5/6 nephrectomized dogs significantly increase circulating 1,25(OH)2D when supraphysiological concentrations of 25(OH)D are reached in serum. Plasma 1,25(OH)2D level is determined not only by its rate of production but also by its rate of degradation. To further characterize the mechanisms involved in the responses to 25(OH)D therapy in normal circumstances and in chronic uremia, we measured metabolic clearance rate (MCR) and production rate (PR) of 1,25(OH)2D in normal dogs and in dogs with moderate and severe renal failure, at normal and supraphysiological serum concentrations of 25(OH)D. Basal MCR in uremic dogs, either with moderate or with severe renal failure, did not differ significantly from normals (6.7 +/- 0.7, 6.8 +/- 0.4 and 6.8 +/- 0.3 ml/min, respectively). Oral 25(OH)D administration for two weeks did not affect MCR either in normal animals or in both groups of uremic dogs. 25(OH)D treatment did not affect production rates in normal dogs and in animals with moderate renal failure (with normal basal values of 1,25(OH)2D), but significantly increased 1,25(OH)2D production from 0.13 +/- 0.01 to 0.25 +/- 0.04 micrograms/day (P less than 0.05) in dogs with severe renal insufficiency. These data suggest that it is the basal level of 1,25(OH)2D which regulates the synthesis of 1,25(OH)2D in response to 25(OH)D administration in normal and uremic animals.

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 micrograms every other day for two weeks followed by 50 micrograms 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 less than 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 less than 0.001). The same therapy in four normal volunteers showed no significant changes in serum 1,25(OH)2D concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

1,25-(OH)2D has been shown to suppress the synthesis and secretion of parathyroid hormone in vivo and in dispersed parathyroid cell cultures. Control of transcription by 1,25-(OH)2D is believed to be mediated by interaction of this hormone with a specific receptor within target cells. We have examined the 1,25-(OH)2D receptor in parathyroid glands from normal dogs and chronic renal failure dogs. The levels of receptor were fourfold lower in parathyroid extracts from these uremic dogs than in those from normal dogs (109 +/- 11 vs. 446 +/- 61 fmol/mg protein). No differences were observed in the binding affinity for 1,25-(OH)2D or in the sedimentation in sucrose density gradients. Since this receptor has been shown to be upregulated by 1,25-(OH)2D, our findings of lower levels of receptor could be attributed to decreased serum concentrations of 1,25-(OH)2D in chronically uremic animals. Regression analysis of log serum 1,25-(OH)2D versus log receptor content yielded a correlation coefficient of 0.62 with P less than 0.02. Decreased receptor content showed a negative correlation with serum N-terminal PTH (r = 0.71 and P less than 0.01). It is likely that this reduced 1,25-(OH)2D receptor number in the parathyroid glands of chronically uremic animals renders the glands less responsive to the inhibitory action of 1,25-(OH)2D on the synthesis and secretion of PTH, and may contribute to the hyperparathyroidism associated with chronic renal failure.