Calcium-Sensing Receptor Expression and Parathyroid Hormone Secretion in Hyperplastic Parathyroid Glands from Humans

Cañadillas, Sagrario; Canalejo, Antonio; Santamaría, Rafael; Rodríguez, Marcela A.; Estepa, J. C.; Martín‐Malo, Alejandro; Bravo, Juan; Ramos, Blanca Patricia Lazalde; Aguilera–Tejero, Escolástico; Rodríguez, Mariano; Almadén, Yolanda

doi:10.1681/asn.2004080657

Cited by 53 publications

(30 citation statements)

References 28 publications

(22 reference statements)

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“…After treatment washout at the end of 52 weeks, PTH increased to levels higher than baseline in both arms, suggesting that underlying parathyroid disease severity may have worsened over time. Such a progression might be associated with a decrease in expression of the parathyroid calciumsensing and vitamin D receptors (21,22), potentially resulting in treatment resistance; if so, the relatively long treatment duration compared with other trials (1,13) may have made it less likely that either agent could demonstrate effectiveness.…”

Section: Discussionmentioning

confidence: 99%

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

Wetmore

Gurevich²,

Sprague

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Direct comparison of cinacalcet and vitamin D analogs as monotherapies to lower parathyroid hormone (PTH) levels has not been undertaken.Design, setting, participants, & measurements This was a prospective, multicenter, phase 4, randomized, openlabel study that enrolled participants from 2010 to 2012. Adult participants (n=312) on hemodialysis with PTH .450 pg/ml were randomized 1:1 to 12 months of treatment with either cinacalcet (n=155) or vitamin D analogs (n=157) to evaluate the mean percentage change in plasma PTH level (primary end point) and the proportion of participants achieving plasma PTH ,300 pg/ml or a $30% decrease in PTH (secondary end points). A preplanned analysis to determine whether there were important region-by-treatment interactions was also undertaken.Results Baseline mean PTH was 846 pg/ml (n=155) for cinacalcet and 816 pg/ml (n=157) for vitamin D analog therapy. The mean (95% confidence interval) percentage change from baseline in PTH was 212.1% (220.0% to 24.1%) in the cinacalcet arm and 27.0% (214.9% to 0.8%) in the vitamin D analog arm, a difference of 25.0% (215.4% to 5.4%) (P=0.35). Similarly, there was no difference in achievement of secondary efficacy end points between arms (19.4% and 15.3% of participants with PTH#300 pg/ml and 42.6% and 33.8% of participants had a PTH reduction .30% in the cinacalcet and vitamin D analog arms, respectively). A prespecified analysis revealed a large treatment-by-region interaction, with nominally greater response to cinacalcet compared with vitamin D analogs in non-United States participants (US versus non-US participants, P,0.001). Hypocalcemia was more common in the cinacalcet arm, whereas hypercalcemia and hyperphosphatemia occurred more often in the vitamin D analog arm.Conclusions Participants had similar modest reductions in PTH with either cinacalcet or vitamin D analog monotherapy over 52 weeks of treatment, but effects varied by region. Treatments differed with regard to effect on calcium and phosphorus levels.

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Section: Discussionmentioning

confidence: 99%

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

Wetmore

Gurevich²,

Sprague

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…Downregulation of parathyroid CaSR and VDR is a common feature of hyperplastic parathyroid glands. As a consequence, parathyroid cells become relatively insensitive to the inhibitory action of extracellular calcium and calcitriol (5).…”

Section: Discussionmentioning

confidence: 99%

Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats

Mendoza¹,

López²,

Canalejo³

et al. 2009

American Journal of Physiology-Renal Physiology

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Tejero E, Rodriguez M. Direct upregulation of parathyroid calciumsensing receptor and vitamin D receptor by calcimimetics in uremic rats. Am J Physiol Renal Physiol 296: F605-F613, 2009. First published December 17, 2008 doi:10.1152/ajprenal.90272.2008.-To investigate whether the effect of the calcimimetic AMG 641 and calcitriol on CaSR and VDR expression could be separated from their ability to reduce parathyroid cell proliferation, five-sixth nephrectomized (5/6 Nx) rats received vehicle, AMG 641, calcitriol, or AMG 641ϩcalcit-riol either daily for 13 days (long-term protocol) or in a single dose (short-term protocol). In the long-term protocol, AMG 641, calcitriol, and their combination significantly reduced the percentage of proliferating parathyroid cells. Proliferation was uncontrolled in the shortterm protocol. A significant increase in CaSR mRNA (% vs. ␤-actin) was detected in rats treated with both calcitriol (1.60 Ϯ 0.30) and AMG 641 (1.66 Ϯ 0.25) for 13 days (P ϭ 0.01 vs. 5/6 Nxϩvehicle, 0.89 Ϯ 0.09); and there was a further increase when both drugs were administered simultaneously (2.46 Ϯ 0.33). In the short-term protocol, only rats receiving AMG 641 alone (2.01 Ϯ 0.33, P Ͻ 0.001) showed increased expression of CaSR mRNA, whereas the combination (1.81 Ϯ 0.20) produced no additional benefit. AMG 641 also increased CaSR mRNA expression in vitro. Changes in VDR mRNA paralleled those of CaSR mRNA. In the long-term treatment, both AMG 641 (0.87 Ϯ 0.14) and calcitriol (0.99 Ϯ 0.12) increased VDR mRNA (P Ͻ 0.05 vs. 5/6 Nxϩvehicle, 0.49 Ϯ 0.10), and the increase was more accentuated when the drugs were combined (1.49 Ϯ 0.45). In the short-term protocol, only treatment with AMG 641, alone (1.52 Ϯ 0.41) or combined with calcitriol (1.86 Ϯ 0.24), increased VDR mRNA. In conclusion, our results demonstrate an acute increase in CaSR mRNA and VDR mRNA in the parathyroid glands of uremic rats treated with AMG 641, in which cell proliferation was uncontrolled, thus supporting a direct effect of calcimimetics on CaSR and VDR expression by hyperplastic parathyroid cells.hyperparathyroidism; PTH; hyperplasia; calcium and calcitriol REGULATION OF MINERAL METABOLISM involves the interaction of multiple organ systems, notably bone and kidneys, and multiple endocrine factors. One such factor is parathyroid hormone (PTH), which, when elevated, is the primary characteristic of secondary hyperparathyroidism (HPT). A predominant feature of secondary HPT is progressive parathyroid gland hyperplasia (12) with concomitantly decreased expression of the calciumsensing receptor (CaSR) (4, 18) and vitamin D receptor (VDR) (15,26). The downregulation of these receptors is an important pathogenic process in the progression of secondary HPT (5,15).

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“…The calcium-sensing receptor (CaSR), a G protein located on the parathyroid gland, is key in the regulation of PTH levels [3]. In hyperplastic parathyroid glands from patients with SHPT, CaSR downregulation has been demonstrated, particularly in glands with nodular hyperplasia, and has been shown to be an important pathogenic contributor to the progression of SHPT [4,5]. …”

Section: Introductionmentioning

confidence: 99%

Cinacalcet Upregulates Calcium-Sensing Receptors of Parathyroid Glands in Hemodialysis Patients

Sumida¹,

Nakamura

Ubara³

et al. 2013

Am J Nephrol

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Background: Cinacalcet hydrochloride (cinacalcet), a calcimimetic, has been shown to upregulate calcium-sensing receptor (CaSR) expression in parathyroid glands of rats with chronic renal insufficiency. However, the effect of cinacalcet on the reduced CaSR expression in human parathyroid glands remains to be elucidated. Methods: Four normal parathyroid glands and 71 hyperplastic parathyroid glands from 18 hemodialysis patients with refractory secondary hyperparathyroidism (SHPT) treated with (n = 10; cinacalcet group) or without (n = 8; conventional group) cinacalcet were examined immunohistochemically with a specific antibody against CaSR. The expression level of CaSR was analyzed semiquantitatively. Results: Compared with normal glands, the immunohistochemical expression of CaSR was decreased significantly in both the cinacalcet and conventional groups. In the cinacalcet group, the expression of CaSR was increased significantly compared with that in the conventional group (1.83 ± 0.14 vs. 0.87 ± 0.15, p < 0.001), even though the proportion of patients using vitamin D sterols and the mean administered dose of calcitriol equivalents were not significantly different between the two groups. The expression of CaSR was significantly decreased in the larger glands (>500 mg) compared with that in the smaller glands (<500 mg) in both groups; furthermore, it was markedly decreased in areas of nodular hyperplasia compared with diffuse hyperplasia in the cinacalcet group. Conclusions: Our results indicate that cinacalcet upregulates the depressed expression of CaSR in hemodialysis patients with SHPT, and that insufficient expression of CaSR, especially in larger glands with advanced nodular hyperplasia, underlies the pathogenesis of SHPT in patients who are resistant to cinacalcet.

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Calcium-Sensing Receptor Expression and Parathyroid Hormone Secretion in Hyperplastic Parathyroid Glands from Humans

Cited by 53 publications

References 28 publications

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM)

Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats

Cinacalcet Upregulates Calcium-Sensing Receptors of Parathyroid Glands in Hemodialysis Patients

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