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NDT Advance Access published online on March 3, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp078
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Published by Oxford University Press on behalf of ERA-EDTA [2009]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


R-568 reduces ectopic calcification in a rat model of chronic kidney disease-mineral bone disorder (CKD-MBD)

Sharon M. Moe1,2, Mark F. Seifert1, Neal X. Chen1, Rachel M. Sinders1, Xianming Chen1, Dana Duan1, Charles Henley3, Dave Martin3 and Vincent H. Gattone, II1

1 Indiana University School of Medicine 2 Roudebush Veterans Affairs Medical Center, Indianapolis, IN 3 Amgen, Thousand Oaks, CA, USA

Correspondence and offprint requests to: Sharon M. Moe, Department of Medicine, Indiana University School of Medicine, 1001 W. 10th Street, OPW 526, Indianapolis, IN 46260, USA. Tel: +1-317-278-2868; Fax: +1-317-278-2860; E-mail: smoe{at}iupui.edu



  Abstract

Background. Chronic kidney disease-mineral bone disorder (CKD-MBD), a newly defined disorder in patients with CKD, describes the interacting triad of (1) biochemical abnormalities of calcium, phosphorus and parathyroid hormone (PTH), (2) extraskeletal calcification and (3) abnormal bone.

Methods. We studied the effects of the calcimimetic R-568, R-568 with calcium (R-568 + Ca) or calcium (Ca) alone compared with control CKD rats on this triad in the Cy/+ male rat, a model of progressive CKD that spontaneously develops CKD-MBD on a normal phosphorus diet. Animals were treated for either 14 or 18 weeks beginning at 20 weeks of age (34-week and 38-week animals, respectively).

Results. The results demonstrated similar efficacy of R-568, R-568 + Ca and Ca in lowering PTH levels. R-568 alone lowered plasma calcium compared to control over time, but increased phosphorus compared to control early in the course of the disease, but not at 38 weeks. Animals treated with Ca alone or R-568 + Ca had lower phosphorus levels; the Ca alone group had elevated Ca levels. Bone volume improved in the calcium-treated groups. In contrast, arterial and cardiac calcification worsened by most assessments in the R-568 + Ca and Ca alone treated animals compared with R-568 alone whereas R-568 alone treatment showed beneficial effects on most sites of extraskeletal calcification.

Conclusion. Thus, R-568, with or without Ca, improved the biochemical abnormalities of hyperparathyroidism but with higher and lower calcium levels, respectively, compared with controls. However, R-568 + Ca had more dramatic improvement in bone volume, but more extraskeletal calcification than R-568 alone. This complexity demonstrates that treatment of one component of CKD-MBD may lead to undesirable effects on other components.

Keywords: kidney; mineral bone disorder; parathyroid hormone; renal osteodystrophy; vascular calcification

Received for publication: 9. 9.08
Accepted in revised form: 9. 2.09


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