Reduced Binding of [<sup>3</sup>H]l,25-Dihydroxyvitamin D<sub>3</sub>in the Parathyroid Glands of Patients with Renal Failure

Korkor, Adel B.

doi:10.1056/nejm198706183162504

Cited by 273 publications

(88 citation statements)

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“…After reverse transcription, VDR mRNA was quantified by using real-time PCR and was standardized to ␤-actin mRNA. The mean Ϯ SEM (n ϭ 10) is expressed as relative mRNA with a maximal value of 1. thyroid gland VDR (14,17). Because serum calcium levels are inversely proportional to serum PTH, we hypothesized that PTH may suppress VDR expression in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Reduced dietary calcium also has been associated with diminished VDR mRNA in avian and rat parathyroid gland (11,12). If left untreated, renal failure with subsequent vitamin D deficiency and hypocalcemia will lead to a decrease in parathyroid gland VDR content and the development of vitamin D resistance (17,18). The molecular trigger responsible for the hypocalcemia-mediated decline in renal and parathyroid gland VDR content is heretofore unknown.…”

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confidence: 99%

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Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Healy

Vanhooke²,

Prahl³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The vitamin D receptor (VDR) is a nuclear transcription factor responsible for mediating the biological activities of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Renal and parathyroid gland VDR content is an important factor in calcium homeostasis, vitamin D metabolism, and the treatment of secondary hyperparathyroidism and renal osteodystrophy. In these tissues, VDR expression is highly regulated by the calcium and vitamin D status. Although 1,25(OH)2D3 up-regulates VDR expression, hypocalcemia and vitamin D deficiency result in drastically reduced expression of the receptor. The generation of 25-hydroxyvitamin D3-1␣-hydroxylase-null mice, which are incapable of endogenously producing 1,25(OH)2D3, has allowed us to investigate the influence of parathyroid hormone (PTH) on VDR expression independent of PTHmediated increases in 1,25(OH)2D3. Administration of human PTH (1-34) (110 g͞kg per day) for 48 h reduced renal VDR levels from 515 to 435 fmol͞mg protein (15%, P < 0.03) in wild-type mice. In the 25-hydroxyvitamin D3-1␣-hydroxylase-null mice, PTH administration strongly reduced renal VDR levels, from 555 to 394 fmol͞mg protein (29%, P < 0.001). These results demonstrate that PTH is a potent down-regulator of VDR expression in vivo. The biological response to 1,25(OH) 2 D 3 is directly related to the VDR content of target tissues (6, 7). Thus, the regulation of receptor expression is a critical determinant of hormone activity. The VDR has been shown to be developmentally regulated, expressed in a tissue-specific manner, and regulated by a variety of physiological factors and hormones (8). It is well established that 1,25(OH) 2 D 3 can stimulate receptor expression in the kidney and parathyroid gland while having minimal influence on intestinal VDR expression (9-13). Several studies also have noted a positive correlation between calcium and VDR expression. Hypocalcemia induced by dietary calcium restriction dramatically reduces renal VDR levels and prevents 1,25(OH) 2 D 3 from increasing VDR expression (14-16). Reduced dietary calcium also has been associated with diminished VDR mRNA in avian and rat parathyroid gland (11,12). If left untreated, renal failure with subsequent vitamin D deficiency and hypocalcemia will lead to a decrease in parathyroid gland VDR content and the development of vitamin D resistance (17, 18). The molecular trigger responsible for the hypocalcemia-mediated decline in renal and parathyroid gland VDR content is heretofore unknown.PTH expression is inversely related to serum calcium values (19). Because hypocalcemic animals have high circulating levels of PTH and reduced renal and parathyroid gland VDR expression, we hypothesized that PTH may down-regulate VDR expression. Previous investigations into PTH-mediated regulation of VDR expression yielded mixed results. A PTH-mediated increase of VDR and VDR mRNA was reported in osteoblastlike UMR-106 cells (20, 21), whereas a PTH-mediated decrease in VDR and its transcript was reported in ROS 17͞2.8 osteoblast cells (22). In vivo, osmotic PTH adm...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Healy

Vanhooke²,

Prahl³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, phosphate retention will directly decrease serum 1,25(OH) 2 (99,(102)(103)(104)(105). In addition, during renal failure, there is decreased binding of 1,25(OH) 2 D 3 to the parathyroid cells (106). Thus, during renal failure, the combination of lower levels of 1,25(OH) 2 D 3 and decreased binding of the available 1,25(OH) 2 D 3 to the parathyroid cells results in a marked increase in secretion of PTH at all levels of [Ca ion ].…”

Section: Ckd In Patients Who Are Not On Dialysismentioning

confidence: 99%

Contribution of Intestine, Bone, Kidney, and Dialysis to Extracellular Fluid Calcium Content

Bushinsky

2010

Clinical Journal of the American Society of Nephrology

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Calcium (Ca) balance is the net of Ca intake and output from the body over a period of time. The concept of Ca balance does not consider the redistribution of Ca that often occurs in patients with chronic kidney disease (CKD), especially those who are on dialysis, which is often in the form of soft tissue and/or vascular calcification. In this article, we consider movement of Ca with respect to the extracellular fluid (ECF) and develop a mathematical formulation for Ca homeostasis with respect to the ECF that includes input and output from the diet, the bone, the kidney, and dialysis. We consider calcium homeostasis in healthy individuals and in patients with excess parathyroid hormone, excess 1,25-dihydroxyvitamin D 3 , and metabolic acidosis; patients who have CKD and are not on dialysis; and, finally, patients who have CKD and are on dialysis. On the basis of a number of assumptions, dialysis patients with a daily intake of >37.5 mmol of elemental Ca (1.5 g) have movement of Ca into the ECF even without supplemental activated vitamin D. Addition of activated vitamin D, which increases intestinal Ca absorption and can increase resorption of Ca from bone, leads to the movement of Ca into the ECF at virtually all levels of intake; however, there are numerous unanswered questions regarding Ca homeostasis in patients with CKD, including how much of the Ca, administered as a phosphate binder, is absorbed and what is the fate of this absorbed Ca. Until these pressing questions are answered with well-designed experiments, we do not know whether we are doing more harm than good for our dialysis patients by administering additional Ca as a phosphate binder, especially when they also receive activated vitamin D.

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“…6 Decreased production of calcitriol also impairs intestinal absorption of calcium and further contributes to hypocalcemia and stimulation of PTH secretion by the parathyroid glands (PTG). In addition, the uremic state is associated with impaired negative feedback of calcitriol on the PTG as a result of decreased numbers of vitamin D receptors (VDR) [7][8][9] and impaired binding of the calcitriol-VDR complex with vitamin D response elements in genomic DNA of PTG cells. 10 Phosphorus retention also increases PTH synthesis and secretion by stabilizing PTH mRNA, and retained phosphorus may stimulate parathyroid cell growth.…”

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confidence: 99%

Comparison of the Effects of Daily and Intermittent‐Dose Calcitriol on Serum Parathyroid Hormone and Ionized Calcium Concentrations in Normal Cats and Cats with Chronic Renal Failure

Hostutler

DiBartola

Chew

et al. 2006

Veterinary Internal Medicne

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Background: Chronic renal failure is complicated by secondary hyperparathyroidism, which traditionally has been controlled by dietary restriction of phosphorus and administration of phosphorus binders. Early treatment of patients with chronic renal failure with calcitriol may be indicated because once established, parathyroid gland hyperplasia does not readily resolve with therapy.Hypothesis: Daily and intermittent dosing of calcitriol will decrease plasma parathyroid hormone concentration in normal cats and cats with chronic renal failure without causing ionized hypercalcemia.Animals: Ten normal cats; 10 cats with chronic renal failure. Methods: Phase 1 was daily calcitriol administration (2.5 ng/kg PO q24h) for 14 days. Phase 2 was intermittent calcitriol administration (8.75 ng/kg PO q84h) for 14 days. A 7-day washout period separated phases 1 and 2. Before each phase, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured. On days 1, 2, and 3 of both phases, serum ionized calcium concentrations were measured. On the last day of both phases, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured 0, 2, 4, and 6 hours after calcitriol administration.Results: Overall, serum parathyroid hormone concentrations were significantly higher in cats with chronic renal failure than in normal cats (P 5 .022), but serum parathyroid hormone concentrations for both normal cats and cats with chronic renal failure were not significantly different before and after 14 days of treatment with calcitriol, regardless of whether calcitriol was administered daily or intermittently. Adverse effects of calcitriol administration (specifically ionized hypercalcemia) were not seen in either feline group during either phase of the study over the 3-day evaluation after calcitriol administration was initiated.Conclusions and Clinical Importance: At the dosages used, calcitriol treatment did not result in significant differences in serum parathyroid hormone concentrations before and after treatment in both normal cats and cats with chronic renal failure. With these dosages, adverse affects of calcitriol administration were not seen. Potential reasons for lack of apparent effect include small sample size, insufficient duration of study, insufficient dosage of calcitriol, problems with formulation or administration of calcitriol, and variable gastrointestinal absorption of calcitriol.

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Reduced Binding of [³H]l,25-Dihydroxyvitamin D₃in the Parathyroid Glands of Patients with Renal Failure

Cited by 273 publications

References 35 publications

Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Contribution of Intestine, Bone, Kidney, and Dialysis to Extracellular Fluid Calcium Content

Comparison of the Effects of Daily and Intermittent‐Dose Calcitriol on Serum Parathyroid Hormone and Ionized Calcium Concentrations in Normal Cats and Cats with Chronic Renal Failure

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Reduced Binding of [3H]l,25-Dihydroxyvitamin D3in the Parathyroid Glands of Patients with Renal Failure

Cited by 273 publications

References 35 publications

Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Parathyroid hormone decreases renal vitamin D receptor expressionin vivo

Contribution of Intestine, Bone, Kidney, and Dialysis to Extracellular Fluid Calcium Content

Comparison of the Effects of Daily and Intermittent‐Dose Calcitriol on Serum Parathyroid Hormone and Ionized Calcium Concentrations in Normal Cats and Cats with Chronic Renal Failure

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Reduced Binding of [³H]l,25-Dihydroxyvitamin D₃in the Parathyroid Glands of Patients with Renal Failure