PA21, a novel phosphate binder, improves renal osteodystrophy in rats with chronic renal failure

Abstract

The effects of PA21, a novel iron-based and non-calcium-based phosphate binder, on hyperphosphatemia and its accompanying bone abnormality in chronic kidney disease-mineral and bone disorder (CKD-MBD) were evaluated. Rats with adenine-induced chronic renal failure (CRF) were prepared by feeding them an adenine-containing diet for four weeks. They were also freely fed a diet that contained PA21 (0.5, 1.5, and 5%), sevelamer hydrochloride (0.6 and 2%) or lanthanum carbonate hydrate (0.6 and 2%) for four weeks. Blood biochemical parameters were measured and bone histomorphometry was performed for femurs, which were isolated after drug treatment. Serum phosphorus and parathyroid hormone (PTH) levels were higher in the CRF rats. Administration of phosphate binders for four weeks decreased serum phosphorus and PTH levels in a dose-dependent manner and there were significant decreases in the AUC0-28 day of these parameters in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups compared with that in the CRF control group. Moreover, osteoid volume improved significantly in 5% of the PA21 group, and fibrosis volume and cortical porosity were ameliorated in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups. These results suggest that PA21 is effective against hyperphosphatemia, secondary hyperparathyroidism, and bone abnormalities in CKD-MBD as sevelamer hydrochloride and lanthanum carbonate hydrate are, and that PA21 is a new potential alternative to phosphate binders.

Fig 1. The effects of (A) PA21, (B) sevelamer hydrochloride, and (C) lanthanum carbonate hydrate on serum creatinine level.

At day 29, administration of the investigated drugs was started. Each dot in the figures shows the mean value ± standard error of eight to 10 animals. SH, sevelamer hydrochloride; LC, lanthanum carbonate hydrate. ##P < 0.01, Aspin-Welch’s t-test between the normal and control groups.

Fig 2. The effects of (A) PA21, (B) sevelamer hydrochloride, and (C) lanthanum carbonate hydrate on serum phosphorus level.

At day 29, administration of the investigated drugs was started. Each dot in the figures shows the mean value ± standard error of eight to 10 animals. SH, sevelamer hydrochloride; LC, lanthanum carbonate hydrate. #P < 0.05 and ##P < 0.01, Student’s or Aspin-Welch’s t-test between the normal and control groups. *P < 0.05 and **P < 0.01, Dunnett’s or Steel’s multiple comparison tests between the control and the investigated drug administered groups.

Fig 3. The effects of (A) PA21, (B) sevelamer hydrochloride, and (C) lanthanum carbonate hydrate on serum calcium level.

At day 29, administration of the investigated drugs was started. Each dot in the figures shows the mean value ± standard error of eight to 10 animals. SH, sevelamer hydrochloride; LC, lanthanum carbonate hydrate. #P < 0.05 and ##P < 0.01, Student’s or Aspin-Welch’s t-test between the normal and control groups. *P < 0.05 and **P < 0.01, Dunnett’s or Steel’s multiple comparison tests between the control and the investigated drug administered groups.

Fig 4. The effects of (A) PA21, (B) sevelamer hydrochloride, and (C) lanthanum carbonate hydrate on serum PTH level.

Each dot in the figures shows the mean value ± standard error of eight to 10 animals. SH, sevelamer hydrochloride; LC, lanthanum carbonate hydrate. #P < 0.05 and ##P < 0.01, Aspin-Welch’s t-test between the normal and control groups. *P < 0.05 and **P < 0.01, Dunnett’s or Steel’s multiple comparison tests between the control and the investigated drug administered groups.

Fig 5. Representative images of the proximal femur of normal or CRF rats after four weeks of treatment with normal or 5% PA21 containing diet.

The sections (6 μm) were cut and stained with a Villanueva-Goldner stain for bright-field microscopy. Representative images (low and high magnification) from some groups are presented. (A) Normal group (low magnification), (B) normal group (high magnification), (C) control group (low magnification), (D) control group (high magnification), (E) 5% PA21 group (low magnification), and (F) 5% PA21 group (high magnification). These sections demonstrate mature bone (yellowish green), immature (red) and other bone structure.

Fig 6. Effects of PA21, sevelamer hydrochloride, and lanthanum carbonate hydrate on (A) OV, (B) Fb.V, and (C) Ct.Po.

Each column of the figures shows the mean value ± standard error of nine to 10 animals. SH, sevelamer hydrochloride; LC, lanthanum carbonate hydrate. #P < 0.05 and ##P < 0.01, Aspin-Welch’s t-test between the normal and control groups. *P < 0.05 and **P < 0.01, Aspin-Welch’s t-test between the control and the investigated drug administered groups.