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

Abstract

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 ...

Cardiovascular Risk and Mineral Bone Disorder in Patients with Chronic Kidney Disease

“…Especially, sub- and supra-physiological levels of calcitriol have been associated with poor cardiovascular outcome and increased vascular calcification [112,113,114,115,116,117,118]. Although recent animal experiments using calcimimetics in 5/6-Nx rats reduced aortic calcification subsequent to high dose calcitriol and pointed even to a regression of vascular calcification, the available data from a large international placebo-controlled mulitcenter trial are less clear [119,120,121,122]. …”

Persistence of Vascular Calcification after Reversal of Uremia

“…There was no reversal of aortic calcification when uremic rats were switched from a high-phosphate diet to a low-phosphate diet for 28 days, although there may have been some reversal in rats treated with a calcimimetic. 35 In contrast, reversal of aortic valve calcification in uremic rats was shown after removal of adenine and supplemental phosphate from the diet. 36 The mechanism of the calcium resorption was not investigated.…”

The Calcimimetic Calindol Prevents High Phosphate-Induced Vascular Calcification by Upregulating Matrix GLA Protein

“…Several studies investigated the effects of calcimimetics in animal models with vascular calcification [22,23,24,25], including cinacalcet, the only calcimetic used in dialysis patients affected by secondary hyperparathyroidism, even if in vitro experimental data are missing. These results confirm that the activation of the CaSR at the vascular level may be important to prevent and reduce VC, by both an indirect effect on calcium and P levels and by a direct effect on CaSR activation [26,27].…”