Effect of a magnesium-based phosphate binder on medial calcification in a rat model of uremia

Abstract

Calcium-based phosphate binders are used to control hyperphosphatemia; however, they promote hypercalcemia and may accelerate aortic calcification. Here we compared the effect of a phosphate binder containing calcium acetate and magnesium carbonate (CaMg) to that of sevelamer carbonate on the development of medial calcification in rats with chronic renal failure induced by an adenine diet for 4 weeks. After 1 week, rats with chronic renal failure were treated with vehicle, 375 or 750 mg/kg CaMg, or 750 mg/kg sevelamer by daily gavage for 5 weeks. Renal function was significantly impaired in all groups. Vehicle-treated rats with chronic renal failure developed severe hyperphosphatemia, but this was controlled in treated groups, particularly by CaMg. Neither CaMg nor sevelamer increased serum calcium ion levels. Induction of chronic renal failure significantly increased serum PTH, dose-dependently prevented by CaMg but not sevelamer. The aortic calcium content was significantly reduced by CaMg but not by sevelamer. The percent calcified area of the aorta was significantly lower than vehicle-treated animals for all three groups. The presence of aortic calcification was associated with increased sox9, bmp-2, and matrix gla protein expression, but this did not differ in the treatment groups. Calcium content in the carotid artery was lower with sevelamer than with CaMg but that in the femoral artery did not differ between groups. Thus, treatment with either CaMg or sevelamer effectively controlled serum phosphate levels in CRF rats and reduced aortic calcification.

Figure 1

Study setup. CaMg, calcium acetate/magnesium carbonate; CaMg375, CaMg 375 mg/kg; CaMg750, CaMg 750 mg/kg; Sev750, 750 mg/kg sevelamer.

Figure 2

Mineral metabolism. (a) Serum phosphorus, (b) urinary phosphate, and (c) serum ionized calcium concentrations throughout the study. Data are expressed as mean±s.d. Statistical differences are indicated in Table 1.

Figure 3

Vascular calcification. (a) Calcium concentration in the aorta; (b) area percent von Kossa positivity (% aortic calcification) in CRF rats treated with vehicle (n=14), CaMg750 (n=14), CaMg375 (n=14), and Sev750 (n=14). CaMg, calcium acetate/magnesium carbonate; CaMg375, CaMg 375 mg/kg; CaMg750, CaMg 750 mg/kg; CRF, chronic renal failure; Sev, sevelamer; Sev750, sevelamer carbonate 750 mg/kg; Veh, vehicle. *Significant difference versus vehicle. Open symbols indicate the animals died before the day of killing.

Figure 4

Calcium X-ray fluorescence and X-ray diffraction patterns of the deposited mineral in the calcified aorta of a uremic rat treated with 375 mg/kg calcium acetate/magnesium carbonate (CaMg). All groups showed similar diffraction patterns.

Figure 5

mRNA expression of the different target genes relative to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the aorta of rats with chronic renal failure (CRF) compared with rats with normal renal function (NRF). The number of animals for each study group is indicated in the bars of Figure 1. Data are expressed as mean±s.d. bmp-2, bone morphogenic protein 2; CaMg, calcium acetate/magnesium carbonate; CaMg375, CaMg 375 mg/kg; CaMg750, CaMg 750 mg/kg; cbfa-1 core binding factor-α1; mgp, matrix gla protein; Osx, osterix; Sev, sevelamer; Sev750, sevelamer carbonate 750 mg/kg; sox9, sex determining region Y-box 9; TRPM7, transient receptor potential cation channel, subfamily M, member 7; VC, vascular calcification; VK, von Kossa positivity. *Significant difference versus NRF; °significant difference versus VC of the same group.