Parathyroid hormone suppression by intravenous 1,25-dihydroxyvitamin D. A role for increased sensitivity to calcium.

Numerous in vitro studies in experimental animals have demonstrated a direct suppressive effect of 1,25-dihydroxyvitamin D (1,25(OH)2D) on parathyroid hormone (PTH) synthesis. We therefore sought to determine whether such an effect could be demonstrated in uremic patients undergoing maneuvers designed to avoid changes in serum calcium concentrations. In addition, the response of the parathyroid gland in patients undergoing hypercalcemic suppression (protocol I) and hypocalcemic stimulation (protocol II) before and after 2 wk of intravenous 1,25(OH)2D was evaluated. In those enlisted in protocol I, PTH values fell from 375 +/- 66 to 294 +/- 50 pg (P less than 0.01) after 1,25(OH)2D administration. During hypercalcemic suppression, the "set point" (PTH max + PTH min/2) for PTH suppression by calcium fell from 5.24 +/- 0.14 to 5.06 +/- 0.15 mg/dl (P less than 0.05) with 1,25(OH)2D. A similar decline in PTH levels after giving intravenous 1,25(OH)2D was noted in protocol II patients. During hypocalcemic stimulation, the parathyroid response was attenuated by 1,25(OH)2D. We conclude that intravenous 1,25(OH)2D directly suppresses PTH secretion in uremic patients. This suppression, in part, appears to be due to increased sensitivity of the gland to ambient calcium levels.

1,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs.

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.

Metabolic clearance rate and production rate of calcitriol in uremia.

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.