PA21, a New Iron-Based Noncalcium Phosphate Binder, Prevents Vascular Calcification in Chronic Renal Failure Rats

Abstract

Chronic renal failure (CRF) is associated with the development of secondary hyperparathyroidism and vascular calcifications. We evaluated the efficacy of PA21, a new iron-based noncalcium phosphate binder, in controlling phosphocalcic disorders and preventing vascular calcifications in uremic rats. Rats with adeninediet-induced CRF were randomized to receive either PA21 0.5, 1.5, or 5% or CaCO 3 3% in the diet for 4 weeks, and were compared with uremic and nonuremic control groups. After 4 weeks of phosphate binder treatment, serum calcium, creatinine, and body weight were similar between all CRF groups. Serum phosphorus was reduced with CaCO 3 3% (2.06 mM; P # 0.001), PA21 1.5% (2.29 mM; P , 0.05), and PA21 5% (2.21 mM; P # 0.001) versus CRF controls (2.91 mM). Intact parathyroid hormone was strongly reduced in the PA21 5% and CaCO 3 3% CRF groups to a similar extent (1138 and 1299 pg/ml, respectively) versus CRF controls (3261 pg/ml; both P # 0.001). A lower serum fibroblast growth factor 23 concentration was observed in the PA21 5%, compared with CaCO 3 3% and CRF, control groups. PA21 5% CRF rats had a lower vascular calcification score compared with CaCO 3 3% CRF rats and CRF controls. In conclusion, PA21 was as effective as CaCO 3 at controlling phosphocalcic disorders but superior in preventing the development of vascular calcifications in uremic rats. Thus, PA21 represents a possible alternative to calciumbased phosphate binders in CRF patients.

Beraprost Sodium, a Stable Analogue of PGI2, Inhibits the Renin-Angiotensin System in the Renal Tissues of Rats with Chronic Renal Failure

“…Zou et al reported results that were in line with those reported in the current study, indicating that the levels of BUN and SCr were higher in patients with CRF [17]. Elevated serum phosphorus levels were observed among rats with CRF [18], and decreased calcium release was also detected in CRF patients [19]. BPS, a new, stable, orally active PGI2 analogue, possesses antiplatelet and vasodilating properties [20].…”

Novel iron-containing phosphate binders for treatment of hyperphosphatemia

“…Administration of SO up to 2 years was associated with only modest increases in tissue iron [28]. An adenine-diet-induced rat model of chronic renal failure assessed the effects of SO on vascular calcification [29]. Lowest vascular calcification scores and FGF-23 concentrations were reported in rats receiving PA21 5% in the diet.…”

The Role of Extracellular Phosphate Levels on Kidney Disease Progression in a Podocyte Injury Mouse Model

“…The amelioration of hyperphosphatemia and other complications by regulating Pi with Pi binders was demonstrated in several preclinical studies with rodent kidney disease models, such as the adenine model [8][9][10]. Moreover, studies in anti-GBM nephritis [11] or chronic antiThy1 nephritis rat models [12] show that lowering serum Pi with Pi binders or restricted Pi intake improves not only abnormal mineral metabolism but also the progression of kidney disease itself.…”

“…Although these studies showed the renoprotective effects of Pi regulation in glomerular injury models, little has been reported on the effect of Pi regulation in cases of direct tubular injury. The adenine model commonly used for rat and mouse studies primarily uses tubular injury to induce hyperphosphatemia [8][9][10], but this method is too artificial for evaluating the renoprotective effects of Pi regulation. Because there are only a few studies on hyperphosphatemia induced by glomerular injury, the renoprotective effect of Pi regulation in mice remains unexplored [13].…”