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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/F1376    most recent 90737.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lopez, I. Articles by Rodriguez, M. PubMed PubMed Citation Articles by Lopez, I. Articles by Rodriguez, M.

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

¹Departmento de Medicina y Cirugia Animal, Universidad de Cordoba, and ²Unidad de Investigacion y Servicio de Nefrología, Hospital Universitario Reina Sofia, Cordoba, Spain; and ³Department of Metabolic Disorders, Amgen, Incorporated, Thousand Oaks, California

Submitted 10 December 2008 ; accepted in final form 17 March 2009

The 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 = 20), calcitriol [80 ng/kg ip/48 h (n = 20)], or the calcimimetic AMG 641 [1.5 mg/kg sc/48 h (n = 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 ± 26.4 mg/g) than in rats receiving vehicle (178.3 ± 38.6 mg/g). An infiltrate of phagocytic cells expressing the calcium-sensing 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 ± 0.6 vs. 3.1 ± 0.5 mg/day, vehicle) (P < 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