A calcimimetic (R-568), but not calcitriol, prevents vascular remodeling in uremia

Koleganova, Nadezda; Piecha, Grzegorz; Ritz, Eberhard; Schmitt, Claus Peter; Gross, Marie–Luise

doi:10.1038/ki.2008.490

Cited by 80 publications

(78 citation statements)

References 44 publications

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“…Follow-up of 10 weeks of nephrectomized rats fed a standard rodent diet (0.8% P and 1.1% Ca) reveals that no calcification develops in the aorta, 69 except for the aortic arch 70 which is the site most prone for the onset of calcification. Increasing the dietary phosphorus concentration to 0.9% P in 5/6th nephrectomized rats did not induce medial calcifications after a short-term follow-up of 6 to 8 weeks.…”

Section: Remnant Kidney Ratmentioning

confidence: 98%

“…In accordance with medial calcification in human vessels, 101,102 no local vascular inflammation is detected, the media thickness is increased and osteochondrogenic cells around calcified foci are observed in uremic rat models. 70,77,102 Experiments aiming to investigate the efficiency of therapies on medial calcification should optimally use rodent models that develop consistent, robust medial calcification in all animals within a relative short time period as seen in the adenine-induced CRF rat model either on a low protein diet or treated with low dose vitamin D 3 , or 5/6th nephrectomized rats administered high doses of vitamin D 3 . Alternatively, experimental models showing a high biological variability with respect to the severity of arterial calcification might be applied to define and analyze determinants of vascular calcification and to get a better insight into the molecular evolution of the calcification process.…”

Section: The Adenine-induced Chronic Renal Failure Ratmentioning

confidence: 99%

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Vascular Calcification in Chronic Renal Failure

Neven

D’Haese

2011

Circulation Research

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Accelerated atherosclerotic plaque calcification and extensive medial calcifications are common and highly detrimental complications of chronic kidney disease. Valid murine models have been developed to investigate both pathologically distinguishable complications, which allow for better insight into the cellular mechanisms underlying these vascular pathologies and evaluation of compounds that might prevent or retard the onset or progression of vascular calcification. This review describes various experimental models that have been used for the study of arterial intimal and/or medial calcification and discusses the extent to which this experimental research has contributed to our current understanding of vascular calcification, particularly in the setting of chronic renal failure. (Circ Res. 2011;108:249-264.) Key Words: animal models Ⅲ vascular calcification Ⅲ chronic renal failure C ardiovascular disease is the main cause of morbidity and mortality in patients with chronic kidney disease (CKD), accounting for approximately 50% of all deaths in patients on dialysis and in recipients of renal transplants. 1 A large-scale prospective population-based study showed that renal function was inversely associated with cardiovascular and allcause mortality. 2 Vascular calcification is the major cause of cardiovascular disease in patients with CKD as it contributes to myocardial ischemia, impaired myocardial function, valvular insufficiency, arrhythmias and stroke and is shown to be a strong independent predictor of mortality in the general 3,4 as well as in the dialysis population. [5][6][7] In patients with endstage renal disease, the risk of death increases with the number of vascular sites affected by calcification in the aorta and the carotid and femoral arteries. 5 The high prevalence of vascular calcification is already reported in early stages of CKD 8,9 and in young dialysis patients. 10,11 Atherosclerotic plaque burden in the intimal layer is higher and these lesions are also more heavily calcified in CKD patients compared to the normal population. 12-14 Although intimal calcification is associated with cardiovascular mortality, 6 it remains controversial whether calcification of advanced atherosclerotic lesions stabilizes plaque vulnerability [15][16][17] or rather contributes to rupture of the fibrous cap, 18,19 leading to thrombotic events and myocardial infarction. Interestingly, Ehara et al 20 nicely showed that the pattern of calcification in the intimal plaque is of importance: small, frequent, spotty calcifications are more often found in patients with an acute myocardial infarction or with unstable angina pectoris, whereas the presence of extensive calcifications was highest in those with stable angina pectoris. Recent investigations add new insights to this observation and indicate that, in contrast to spacious calcified areas, sparse microcalcifications produce local stress, 21 activate macrophages to secrete inflammatory mediators 22 and induce apoptosis of vascular smooth muscle cells, 23...

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Section: Remnant Kidney Ratmentioning

confidence: 98%

Section: The Adenine-induced Chronic Renal Failure Ratmentioning

confidence: 99%

Vascular Calcification in Chronic Renal Failure

Neven

D’Haese

2011

Circulation Research

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“…In addition, calcimimetic-induced upregulation of the calcium-sensing receptor in vascular smooth muscle and endothelial cells may attenuate the progression of vascular calcification (8)(9)(10). In patients receiving hemodialysis, cinacalcet may slow the progression of vascular and cardiac-valve calcification (11).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis

Parfrey¹,

Drüeke²,

Correa‐Rotter³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

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“…However, in phosphate-restricted rats, administration of AMG 641 further reduces extraosseous calcification. This suggests that, as advanced in other publications (1,17,20), calcimimetics may also have a direct effect (possibly mediated by CaSR activation) on the vascular wall that helps to reduce calcification. Although the regression of vascular calcification obtained with the calcimimetic may appear to be relatively small, compared with what is accomplished by phosphorus restriction, we believe that it is significant because in the clinical setting it is very difficult to achieve adequate phosphorus control and thus any additional measures are relevant.…”

Section: Discussionmentioning

confidence: 52%

“…Our results clearly demonstrate that these cells express CaSR, thus providing a possible mechanism for an effect of calcimimetics on cells that eliminate mineral deposits. Calcimimetics have already been shown to increase CaSR expression in the arterial wall (20), to prevent vascular remodeling in uremia (20), and to retard uremia-associated VC (17); however, further studies will be necessary to demonstrate a CaSR-mediated stimulatory effect of calcimimetics on the phagocytic cells that appear in calcified arteries.…”

Section: Discussionmentioning

confidence: 99%

The calcimimetic AMG 641 accelerates regression of extraosseous calcification in uremic rats

López¹,

Mendoza²,

Guerrero³

et al. 2009

American Journal of Physiology-Renal Physiology

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M. The calcimimetic AMG 641 accelerates regression of extraosseous calcifications in uremic rats. Am J Physiol Renal Physiol 296: F1376 -F1385, 2009. First published March 25, 2009 doi:10.1152/ajprenal.90737.2008The purpose of the present study was to test the hypothesis that extraskeletal calcification regresses in uremic rats after reduction in phosphorus intake and treatment with calcimimetics. Extraosseous calcification was induced in five to six nephrectomized rats fed a high-phosphorus (1.2%) diet who received calcitriol (80 ng/kg ip) every other day for a period of 14 days. Next, dietary phosphorus was reduced to 0.6%, and rats were treated with vehicle (n ϭ 20), calcitriol [80 ng/kg ip/48 h (n ϭ 20)], or the calcimimetic AMG 641 [1.5 mg/kg sc/48 h (n ϭ 20)]. Aortic and soft-tissue calcium and phosphorus content was evaluated after 14 and 28 days. At 28 days, reduction of phosphorus intake resulted in a significant decrease in tissue mineral content in vehicle-and AMG 641-treated rats but not in rats receiving calcitriol. Aortic calcium and phosphorus was lower in rats treated with AMG 641 (96.7 Ϯ 26.4 mg/g) than in rats receiving vehicle (178.3 Ϯ 38.6 mg/g). An infiltrate of phagocytic cells expressing the calciumsensing receptor was identified in areas surrounding foci of calcification. Additional studies in parathyroidectomized rats demonstrated that AMG 641 increased the urinary excretion of calcium (6.2 Ϯ 0.6 vs. 3.1 Ϯ 0.5 mg/day, vehicle) (P Ͻ 0.001). In conclusion, experimentally induced extraosseous calcification in uremic rats can be partially resolved by reducing phosphorus intake; the addition of calcimimetics may accelerate the regression process through mechanisms potentially involving a direct stimulatory effect on mineral phagocytic cells plus an increase in urinary calcium excretion.calcitriol; hyperparathyroidism; vascular calcification ELEVATIONS OF PLASMA calcium, phosphorus, and Ca ϫ P product observed in chronic kidney disease (CKD) patients with secondary hyperparathyroidism (HPT) are associated with vascular calcification (VC) and increased risk of cardiovascular morbidity and mortality (14, 34). In the clinical setting, the development of extraosseous calcification in uremic patients is largely related to abnormalities in mineral metabolism and to management of secondary HPT (4,5,14,27,34,38,39). Current strategies to control secondary HPT, including the use of vitamin D sterols, phosphate binders, and calcimimetics (23), have differing effects on these minerals. Calcitriol, while effective in controlling parathyroid hormone (PTH) levels, has been shown to induce VC in vivo and in vitro (16,25).Calcimimetics suppress PTH synthesis and secretion and, in contrast to most vitamin D sterols, do not induce hypercalcemia (6, 21). Moreover, it has been demonstrated that calcimimetics prevent the development of extraosseous calcification in uremic rats (24,25). Clinical studies in uremic patients (4) and experimental work (19) have shown that high extracellular phosphorus levels is a key ...

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A calcimimetic (R-568), but not calcitriol, prevents vascular remodeling in uremia

Cited by 80 publications

References 44 publications

Vascular Calcification in Chronic Renal Failure

Vascular Calcification in Chronic Renal Failure

The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis

The calcimimetic AMG 641 accelerates regression of extraosseous calcification in uremic rats

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