The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats

Henley, Charles M.; Davis, James; Miller, Gregory H.; Shatzen, Edward; Cattley, Russ; Li, Xiaodong; Martin, David P.; Yao, Wei; Lane, Nancy E.; Shalhoub, Victoria

doi:10.1016/j.ejphar.2009.05.013

Cited by 50 publications

(47 citation statements)

References 56 publications

(85 reference statements)

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“…[11][12][13] The mechanism by which VDRAs promote vascular calcification is unclear and has not been explained by increased circulating calcium or phosphate levels in many studies. [4][5][6]8 Vascular smooth muscle cells contain high-affinity binding sites for calcitriol, 14 suggesting a direct action and, consistent with this, calcitriol has been reported to increase calcification of smooth muscle cells in culture 15 and expression of bonerelated genes in aortas in vivo. 6 However, calcitriol does not induce calcification of intact aortas cultured under calcifying conditions, 16 suggesting that vascular VDRs may not be responsible for the promotion of vascular calcification by VDR agonists.…”

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confidence: 67%

“…An increase in circulating phosphate levels is not always observed with calcitriol 4,7,31,37 and does not correlate well with vascular calcification in animal models. [4][5][6][7][8]37 Further studies will be needed to determine whether medial vascular calcification is promoted by actions on systemic mineral metabolism or on other circulating factors. …”

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confidence: 99%

“…However, there is concern that they may contribute to the medial vascular calcification (also known as Monkeberg arteriosclerosis) that commonly occurs in these patients and is associated with poorer outcomes. [1][2][3] This concern stems from numerous studies showing that VDR agonists (VDRAs) increase vascular calcification in uremic animals [4][5][6][7][8][9] and even normal animals at high doses. 10 The possibility of accelerated vascular calcification has limited the use of VDRAs in chronic kidney disease, despite their potential benefits and the fact that VDRA use does not correlate with vascular calcification in cross-sectional studies of patients.…”

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confidence: 99%

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Role of Local Versus Systemic Vitamin D Receptors in Vascular Calcification

Lomashvili

Wang

O’Neill

2014

ATVB

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Objective-Calcitriol and various analogs are commonly used to suppress secondary hyperparathyroidism in chronic kidney disease but may also exacerbate vascular calcification. Although this could be because of increased intestinal calcium and phosphate absorption, direct effects through vitamin D receptors (VDRs) on vascular smooth muscle have also been proposed. Approach and Results-The role of these receptors was investigated by examining gene regulation in rat aortas treated with calcitriol ex vivo and in vivo and by transplanting aortas from VDR-null (VDR −/− ) mice into wild-type mice before induction of uremia and treatment with calcitriol. In cultured rat aortas, calcitriol increased the expression of mRNA for CYP24A1 but not mRNA for any bone-related or calcification-related genes. Gene expression in aortas in vivo was not altered by doses of calcitriol that promote calcification. Calcitriol markedly increased aortic calcification in uremic mice and this did not differ between VDR −/− aortic allografts and VDR +/+ recipient aortas. Conclusions-Calcitriol Lomashvili et al Calcitriol and Vascular Calcification 1476-fold increase in mRNA for CYP24A1, an enzyme that is induced by and metabolizes calcitriol 24 and used as a positive control. None of the genes, including CYP24A1, were upregulated in aortas from normal rats treated with calcitriol (100 ng/kg every 48 hours) in vivo ( Figure 1B). There was no aortic calcification. Although there was increased expression of some of these genes in uremic rats, there was no change with calcitriol treatment ( Figure 1C). The rats were fed a normal phosphate diet (to avoid any calcification that could have influenced the results) and received 4 injections of calcitriol 1, 3, 5, and 7 days before euthanization No aortic calcification occurred in vivo. Adenine-Induced Renal Failure in MiceInitial studies were performed to determine the optimal dosing of adenine, which differed with age. Mice were like rats in that weight loss is a reliable method to follow the degree of uremia. All animals have an initial weight loss as a result of decreased food intake, presumably because of palatability. Animals that do not become uremic regain this weight within 2 weeks, whereas subsequent weight loss is dependent on the degree of uremia. The adenine content is reduced as necessary to keep the weight >75% of baseline, the threshold for euthanasia required by the Institutional Animal Care and Use Committee. A dietary content of 0.75%, which is routinely used in rats, resulted in 100% mortality in mice within 2 weeks, regardless of age. A reduction to 0.6% still resulted in 100% mortality in the younger mice, whereas most of the older mice survived but required a dose reduction in >50%. At 0.45% adenine, 70% to 80% of the younger mice survived and only 20% required a dose reduction; older mice did not develop uremia. At contents of ≤0.3%, mice did not develop uremia and did not develop aortic calcification, despite a high-phosphorus diet (2%) and high doses of calcitriol (1000 ng/kg)....

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confidence: 67%

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confidence: 99%

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confidence: 99%

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Role of Local Versus Systemic Vitamin D Receptors in Vascular Calcification

Lomashvili

Wang

O’Neill

2014

ATVB

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“…With the severity of CKD produced in this model, vascular calcification is consistently generated without additional calcitriol (as in the 5/6Nx model) or a genetic predisposition to calcification (as in the mouse electrocautery model). However, in those studies which report weight loss, rats fed 0.75% adenine lost up to 50% of their initial weight within 5 weeks on the diet [36,37,38]. Whether the extensive medial calcification observed is due, in part, to weight loss and volume contraction or the adenine itself remains to be determined.…”

Section: Adenine Rat Modelmentioning

confidence: 98%

Vascular Calcification in Animal Models of CKD: A Review

Shobeiri¹,

Adams²,

2010

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Vascular calcification is a significant contributor to the cardiovascular mortality observed in chronic kidney disease (CKD). This review discusses the animal models (5/6 nephrectomy, mouse electrocautery model and dietary adenine) that have been employed in the study of vascular calcification outcomes in CKD. Rodent models of CKD generate a range of severity in the vascular calcification phenotype. Major limitations of the 5/6th nephrectomy model include the requirement for surgery and the need to use either excessive dietary phosphorus or vitamin D. Major limitations of the mouse electrocautery model include the requirement for surgery, the mortality rate when very advanced CKD develops, and resistance to vascular calcification without the use of transgenic animals. This is balanced against the major advantage of the ability to study transgenic animals to further understand the mechanisms associated with either the acceleration or inhibition of calcification. Dietary adenine generates severe CKD and does not require surgery. The major disadvantage is the weight loss that ensues when rats receive a diet containing 0.75% adenine. In summary, animal models are useful to study CKD-associated vascular calcification and the results obtained in these pre-clinical animal studies appear to translate to the evidence, however limited, which exists in humans with CKD.

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“…Although unlikely, due to the continued elevations in serum phosphate during the treatment period that indicated FGF23 activity was continuously inhibited, we cannot exclude the possibility that the high-dose FGF23-Ab elicited a compensatory response in FGF23 that may have had a direct impact on the vessel wall. Given data implicating elevated serum phosphate, potentiated by increased serum vitamin D, in promoting vascular calcification (42,43), sustained elevations of high serum phosphate in the presence of elevated vitamin D likely contributed directly to the vascular calcification observed in the high-dose group.…”

Section: Discussionmentioning

confidence: 99%

FGF23 neutralization improves chronic kidney disease–associated hyperparathyroidism yet increases mortality

Shalhoub¹,

Shatzen²,

Ward³

et al. 2012

J. Clin. Invest.

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361

252

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Chronic kidney disease-mineral and bone disorder (CKD-MBD) is associated with secondary hyperparathyroidism (HPT) and serum elevations in the phosphaturic hormone FGF23, which may be maladaptive and lead to increased morbidity and mortality. To determine the role of FGF23 in the pathogenesis of CKD-MBD and development of secondary HPT, we developed a monoclonal FGF23 antibody to evaluate the impact of chronic FGF23 neutralization on CKD-MBD, secondary HPT, and associated comorbidities in a rat model of CKD-MBD. CKD-MBD rats fed a high-phosphate diet were treated with low or high doses of FGF23-Ab or an isotype control antibody. Neutralization of FGF23 led to sustained reductions in secondary HPT, including decreased parathyroid hormone, increased vitamin D, increased serum calcium, and normalization of bone markers such as cancellous bone volume, trabecular number, osteoblast surface, osteoid surface, and bone-formation rate. In addition, we observed dose-dependent increases in serum phosphate and aortic calcification associated with increased risk of mortality in CKD-MBD rats treated with FGF23-Ab. Thus, mineral disturbances caused by neutralization of FGF23 limited the efficacy of FGF23-Ab and likely contributed to the increased mortality observed in this CKD-MBD rat model.

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The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats

Cited by 50 publications

References 56 publications

Role of Local Versus Systemic Vitamin D Receptors in Vascular Calcification

Role of Local Versus Systemic Vitamin D Receptors in Vascular Calcification

Vascular Calcification in Animal Models of CKD: A Review

FGF23 neutralization improves chronic kidney disease–associated hyperparathyroidism yet increases mortality

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