Effect of 25-hydroxycholecalciferol on calcium absorption in chronic renal disease

Effect of 25-hydroxycholecalciferol on calcium absorption in chronic renal disease. Calcium absorption was measured in eight uremic patients before and after eight days of treatment with 100 or 500 μg of 25-hydroxycholecalciferol (25(OH)D3) per day. Fractional calcium absorption was estimated by administering47Ca i.v. and orally on separate days and counting forearm radioactivity four hours later. Calcium absorption in four patients with residual renal function rose from 16.3 ± 2.5 to 40.8 ± 5.5% after treatment. In order to determine if the increased calcium absorption was mediated by an increase in the production of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) by virtue of increased substrate delivery to the 25-hydroxycholecalciferol-1-hydroxylase system present in the residual renal tissue, identical studies were performed in four anephric patients. Calcium absorption in these patients averaged 15.7 ± 2.2% during the control period and rose to 46.0 ± 11.1% after treatment. Increments in serum calcium after treatment were similar in both groups of patients; the mean concentration rose from 9.6 ± 0.3 to 11.0 ± 0.6 mg/100 ml. The results indicate that 25(OH)D3 can improve calcium absorption in the absence of renal tissue suggesting that its conversion to 1,25(OH)2D3 may not be necessary for its effect on the gastrointestinal tract in the uremic patient.Effet du 25-hydroxycholécalciferol sur l'absorption du calcium au cours de l'insuffisance rénale chronique. L'absorption de calcium a été mesurée chez huit malades urémiques avant et après huit jours de traitement par 100 ou 500 μg de 25(OH)D3 par jour. L'absorption fractionnelle du calcium a été évaluée par l'administration de47Ca, intraveineuse et orale, à des jours différents, et par comptage de l'activité de l'avant-bras quatre heures après. L'absorption du calcium chez quatre malades ayant une fonction rénale résiduelle augmente de 16, 3 ± 2, 5 à 40, 8 ± 5, 5% après traitement. Des études semblables ont été réalisées chez quatre malades anéphriques de façon à apprécier le rôle éventuel, dans l'augmentation de l'absorption intestinale, d'une augmentation de la production de 1,25(OH)2D3 due à l'augmentation de l'apport de substrat à la 25-hydroxycholécalciferol-1-hydroxylase du tissu rénal. L'absorption du calcium chez ces malades est en moyenne de 15, 7 ± 2, 2% pendant la période contrôle et augmente après traitement à 46, 0 ± 11, 1%. Les augmentations du calcium sériques sont semblables dans les deux groupes de malades, la concentration moyenne passe de 9, 6 ± 3 à 11, 0 ± 0, 6 mg/100 ml. Les résultats indiquent que 25(OH)D3 peut améliorer l'absorption du calcium en l'absence de tissu rénal ce qui suggère que sa conversion en 1,25(OH)2D3 peut ne pas être nécessaire à son action sur le tractus gastro-intestinal du malade urémique

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

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 attribed 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 < 0.02. Decreased receptor content showed a negative correlation with serum N-terminal PTH (r= 0.71 and P < 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

Pathogenesis of secondary hyperparathyroidism

Pathogenesis of secondary hyperparathyroidism. Secondary hyperparathyroidism is a universal complication in patients with chronic renal failure. Hyperplasia of the parathyroid glands is typically seen in these patients. In early renal failure, alteration in vitamin metabolism, decreased levels of calcitriol and moderate decreases in ionized calcium may allow greater synthesis and secretion of PTH. As the disease progresses, there is a decrease in the number of vitamin D receptors (VDR) and calcium receptors (CaR). The decreased number of VDR and CaR makes the parathyroid glands more resistant to calcitriol and calcium. Phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol, and by a post-transcriptional mechanism increases PTH synthesis and secretion. Experimental work in uremic rats demonstrated that if the animals are fed a high-phosphorus diet, they not only developed secondary hyperparathyroidism but parathyroid cell hyperplasia. If the diet is then reduced in phosphorus, the levels of PTH return to normal. However, the parathyroid cell hyperplasia persists and no apoptosis is seen. Thus, the control of the three most important factors, calcium, calcitriol and phosphorus, is critical to prevent the development of secondary hyperparathyroidism and hyperplasia of the parathyroid glands