Adequate phosphate binding with lanthanum carbonate attenuates arterial calcification in chronic renal failure rats

Abstract

Background. Hyperphosphataemia is a risk factor for arterial calcification contributing to the high cardiovascular mortality in patients with chronic kidney disease. Calciumbased phosphate binders can induce hypercalcaemia and are associated with progression of vascular calcification. Therefore, the effect of lanthanum carbonate, a non-calcium phosphate binder, on the development of vascular calcification was investigated in uraemic rats. Methods. Chronic renal failure (CRF) was induced by feeding rats an adenine-enriched diet for 4 weeks. After 2 weeks, 1% or 2% lanthanum carbonate was added to the diet for 6 weeks. Calcification in the aorta, carotid and femoral arteries was evaluated histomorphometrically, biochemically and by ex vivo micro-CT. Chondro-/osteogenic conversion of vascular smooth muscle cells was also analysed in the rat aorta. Results. Treatment with 1% lanthanum carbonate (1% La) did not reduce vascular calcification, but in the 2% lanthanum carbonate (2% La) group vascular calcium content and area% Von Kossa positivity were decreased compared with control CRF rats. The aortic calcified volume measured with ex vivo micro-CT was significantly reduced in rats treated with 2% La. Although calcification was inhibited by treatment with 2% La, the chondrocyte transcription factor sox-9 was abundantly expressed in the aorta. Conclusion. Treatment of CRF rats with 2% La reduces the development of vascular calcification by adequate phosphate binding resulting in a decreased supply of phosphate as a substrate for vascular calcification.

Longitudinal Relationships among Coronary Artery Calcification, Serum Phosphorus, and Kidney Function

“…Experimental models in both uremic and nonuremic animals support hyperphosphatemia as central to the process of vascular calcification. Irrespective of kidney function, mice or rats with higher serum phosphorus develop prominent aortic calcification that can be corrected by phosphate-binding drugs or dietary restriction (7)(8)(9)(10)20). A growing series of observations in humans are consistent with experimental models in that higher serum phosphorus has been reported to predict CAC and CVD events in people without clinically apparent kidney disease (11)(12)(13).…”

“…Uremic rodents are protected from developing aortic calcification and/or atherosclerotic lesions by treatment with noncalcemic phosphate binders (7,8). In gene knockout models for phosphorus-regulating factors, fibroblast growth factor 23, or Klotho, nonuremic mice develop elevated serum phosphorus levels and vascular calcification (9,10).…”

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…227), both of which have been suggested to impact on age-related changes across species. Relating to the role of P i in vascular calcification, studies in vitro and in animal models indicate that high P i levels (consistent with those present in hyperphosphatemic patients) directly promote the osteogenic conversion of smooth muscle cells and contribute to the formation of hydroxyapatite crystals (123,250,303,347).…”

Vascular Calcification in Chronic Renal Failure

“…In this context, it is worth mentioning that highturnover bone disease, as observed in most uremic patients, develops in subtotal nephrectomized apoE knockout mice, 94 remnant kidney rats on a high phosphorus diet, 68 and adenineinduced CRF rats. 95 Until now, the uremic LDLR knockout mouse is the only experimental model available for studies on the development of vascular calcification in the setting of low-turnover bone disease, 60 which is recognized with increasing frequency in CKD patients because of changed strategies to control secondary hyperparathyroidism. Criteria for vascular calcification (localization, extent, and consistency) in CRF animals depend largely on the aim of the study.…”