Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.

Fukuda, Naoko; Tanaka, Hideaki; Tominaga, Yoshihiro; Fukagawa, Masafumi; Kurokawa, Kiyoshi; Seino, Yoshiki

doi:10.1172/jci116720

Cited by 563 publications

(296 citation statements)

References 29 publications

(17 reference statements)

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“…In that study, rats were fed a low-Ca diet and may have had parathyroid gland hyperplasia that could affect both Ca receptor and VDR content (17,18). Our results showing an effect of Ca on VDR are in agreement with Brown et al (9).…”

Section: Discussionsupporting

confidence: 89%

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Regulation of Parathyroid Vitamin D Receptor Expression by Extracellular Calcium

Garfia¹,

Cañadillas²,

Canalejo

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Low extracellular calcium (Ca) stimulates parathyroid hormone (PTH) secretion and also increases the renal synthesis of calcitriol (CTR), which is known to decrease PTH production. This study began with the hypothesis that the parathyroid cell response to CTR may be modulated by extracellular Ca concentration through an effect on parathyroid cell vitamin D receptor (VDR). In the present study, rat parathyroid glands were incubated in low (0.6 mM) and high (1.5 mM) Ca concentration. The parathyroid VDRmRNA was higher in 1.5 than 0.6 mM Ca. Furthermore, this effect was not observed in incubated slices of kidney cortex and medulla, tissues which also possess both Ca and vitamin D receptors. Experiments were also performed to evaluate the effect of Ca on VDR expression in vivo. Male Wistar rats received intraperitoneal injections of CaCl 2 or a single intramuscular injection of EDTA to obtain 6 h of hypercalcemic (ionized Ca, 1.4 to 1.6 mM) or hypocalcemic (ionized Ca, 0.85 to 0.95 mM) clamp; a third group of rats was used as control. A small dose of CTR was administered to hypercalcemic rats to match the serum CTR levels of hypocalcemic rats. Parathyroid gland VDRm-RNA and VDR protein were increased in hypercalcemic rats as compared with hypocalcemic rats. Increasing doses of CTR upregulated VDRmRNA and VDR only in hypercalcemic rats. Additional experiments showed that the decrease in VDR in hypocalcemic rats prevented the inhibitory effect of CTR on PTHmRNA. In conclusion, our study shows that extracellular Ca regulates VDR expression by parathyroid cells independently of CTR and that by this mechanism hypocalcemia may prevent the feedback of CTR on the parathyroids.The parathyroid cell increases parathyroid hormone (PTH) secretion in response to a decrease in the extracellular calcium (Ca) concentration. A cell membrane Ca sensor receptor enables these cells to respond to small changes in serum Ca concentration (1). PTH acts on its target organs, mainly kidney and bone, to increase the serum Ca to its normal level. Calcitriol (CTR), the production of which is stimulated by hypocalcemia and also by PTH, is another hormone that contributes to restoration of normocalcemia by stimulating intestinal absorption of Ca (2). Thus there are two different hormones, PTH and CTR, with a calcemic effect, and both share the commitment of preserving normocalcemia. The elevation of serum Ca feeds back on the parathyroid cell, inhibiting PTH secretion and synthesis (2); in addition, high CTR also inhibits PTH synthesis by acting on specific vitamin D receptors (VDR) (3). The inhibitory effect of CTR on parathyroid cells has been widely demonstrated to the point that CTR is used to reduce PTH levels in uremic patients with advanced hyperparathyroidism (4). However, it would not seem appropriate that CTR should inhibit PTH synthesis if hypocalcemia persists; such inhibition would counteract the function of the parathyroid cell, which is to restore normocalcemia. Furthermore, it would seem paradoxical that the parathyroid c...

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Section: Discussionsupporting

confidence: 89%

“…ferent. Russell et al (7) used vitamin D-depleted chickens, thus serum CTR and Ca levels were low and this would result in parathyroid hyperplasia, which may affect both Ca-sensing receptor (17) and VDR content (18). In our study, rats were not vitamin D-depleted.…”

Section: Discussionmentioning

confidence: 77%

Regulation of Parathyroid Vitamin D Receptor Expression by Extracellular Calcium

Garfia¹,

Cañadillas²,

Canalejo

et al. 2002

Journal of the American Society of Nephrology

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“…Considering that all 14 patients in this study had a long history of hemodialysis, the majority of the parathyroidal lesions were naturally recognized as the N-type. N-type hyperplasia is usually present in patients with higher concentrations of intact PTH and the more severe bone symptoms [2]. Fukuda et al [2] reported that the clinically severe N-type parathyroid hyperplasia was associated with a reduced number of vitamin D receptors per unit of gland section compared with the mild D-type gland hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

“…N-type hyperplasia is usually present in patients with higher concentrations of intact PTH and the more severe bone symptoms [2]. Fukuda et al [2] reported that the clinically severe N-type parathyroid hyperplasia was associated with a reduced number of vitamin D receptors per unit of gland section compared with the mild D-type gland hyperplasia. Because the density of calcium sensing receptors is lower in the N-type glands, it is apparent that vitamin D receptor abnormalities in the parathyroid glands of patients with uremia play a role in the abnormal set point for calcium-regulated PTH secretion.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Histological Findings and Parathyroid Scintigraphy in Hemodialysis Patients with Secondary Hyperparathyroid Glands

et al. 2005

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Abstract. To determine the usefulness of parathyroid scintigraphy in histological estimation for secondary hyperparathyroidism (2HPT) using Tc-99m sestamibi or Tc-99m tetrofosmin. Tc-99m sestamibi (MIBI) and Tc-99m tetrofosmin (Tetro) parathyroid imaging following double-phase study, magnetic resonance imaging (MRI), and ultrasound were performed on 14 patients with 2HPT. All patients underwent parathyroidectomy. The uptake of two tracers in parathyroid areas was compared with the histopathologic findings. Forty-nine parathyroid glands were surgically explored and histologically proven to be hyperplastic. Of these, 42 were diagnosed with nodular type (N-type) hyperplasia, and 7 with diffuse type (D-type) hyperplasia. MIBI and Tetro parathyroid imagings detected 34 and 35 parathyroid glands, respectively. The sensitivity of MIBI was determined to be 76.2% (32/42) for N-type, and 28.6% (2/7) for D-type. The sensitivity of Tetro was determined to be 78.6% (33/42) for N-type and 28.6% (2/7) for D-type. The sensitivity of both MIBI and Tetro was significantly higher for N-type than for D-type, 76.2% (32/42) vs. 28.6% (2/7) in MIBI, P = 0.022; 78.6% (33/42) vs. 28.6% (2/7) in Tetro, P = 0.015. The sensitivity of MRI was determined to be 76.2% (32/42) for N-type and 42.9% (3/7) for D-type, and the sensitivity of ultrasound was 71.4% (30/42) for N-type and 71.4% (5/7) for D-type. There was no significant difference in the sensitivity of MRI or ultrasound between N-type and D-type. The uptake ratios of MIBI and Tetro were also greater for N-type than for D-type. The detectability of both MIBI and Tetro was greater for N-type than for D-type. Tc-99m MIBI or Tc-99m Tetro parathyroid scintigraphy therefore may be used clinically to distinguish N-type from D-type parathyroid gland hyperplasia.

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“…Additionally, elevated FGF23 activates the enzyme 24‐hydroxylase (CYP24), hydroxylating both 25(OH)D and 1,25(OH) 2 D. 24‐hydroxylase limits the amount of 1,25(OH) 2 D in target tissues both by producing 24,25(OH) 2 D (thus decreasing the availability of 25(OH)D for 1 hydroxylation) or by accelerating the catabolism of 1,25(OH) 2 D to 1,24,25(OH) 3 D resulting in calcitroic acid, which is biologically inactive 76, 77. CKD is also considered as a state of vitamin D resistance, because VDR expression in bone cells and in nodular parathyroid glands is reduced 78. Low 1,25(OH) 2 D levels also impair its binding to the VDR‐RXR complex 79, 80.…”

Section: Vitamin D Metabolism In Chronic Kidney Diseasementioning

confidence: 99%

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

Molina

Carrero

Bover

et al. 2017

J cachexia sarcopenia muscle

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The spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non‐genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25‐hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.

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Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.

Cited by 563 publications

References 29 publications

Regulation of Parathyroid Vitamin D Receptor Expression by Extracellular Calcium

Regulation of Parathyroid Vitamin D Receptor Expression by Extracellular Calcium

Comparison of Histological Findings and Parathyroid Scintigraphy in Hemodialysis Patients with Secondary Hyperparathyroid Glands

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

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