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

Yaguchi, Atsushi; Tatemichi, Satoshi; Takeda, Hiroo; Kobayashi, Mamoru

doi:10.1371/journal.pone.0180430

Cited by 11 publications

(11 citation statements)

References 37 publications

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“…These findings were also reported by Yaguchi et al . [ 39 ], who demonstrated that PA21 treatment suppressed osteoid formation, fibrosis and porosity in rats with CKD. In the PA21-treated rats, the mineralization lag time and adjusted apposition rate did not substantially differ from those of the vehicle-treated group.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure

Neven

Corremans

Vervaet

et al. 2020

Nephrology Dialysis Transplantation

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Abstract Introduction Sucroferric oxyhydroxide (PA21) is an efficacious, well-tolerated iron-based phosphate binder and a promising alternative to existing compounds. We compared the effects of PA21 with those of a conventional phosphate binder on renal function, mineral homeostasis and vascular calcification in a chronic kidney disease–mineral and bone disorder (CKD-MBD) rat model. Methods To induce stable renal failure, rats were administered a 0.25% adenine diet for 8 weeks. Concomitantly, rats were treated with vehicle, 2.5 g/kg/day PA21, 5.0 g/kg/day PA21 or 3.0 g/kg/day calcium carbonate (CaCO3). Renal function and calcium/phosphorus/iron metabolism were evaluated during the study course. Renal fibrosis, inflammation, vascular calcifications and bone histomorphometry were quantified. Results Rats treated with 2.5 or 5.0 g/kg/day PA21 showed significantly lower serum creatinine and phosphorus and higher ionized calcium levels after 8 weeks of treatment compared with vehicle-treated rats. The better preserved renal function with PA21 went along with less severe anaemia, which was not observed with CaCO3. Both PA21 doses, in contrast to CaCO3, prevented a dramatic increase in fibroblast growth factor (FGF)-23 and significantly reduced the vascular calcium content while both compounds ameliorated CKD-related hyperparathyroid bone. Conclusions PA21 treatment prevented an increase in serum FGF-23 and had, aside from its phosphate-lowering capacity, a beneficial impact on renal function decline (as assessed by the renal creatinine clearance) and related disorders. The protective effect of this iron-based phosphate binder on the kidney in rats, together with its low pill burden in humans, led us to investigate its use in patients with impaired renal function not yet on dialysis.

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Section: Discussionmentioning

confidence: 99%

Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure

Neven

Corremans

Vervaet

et al. 2020

Nephrology Dialysis Transplantation

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“…A potential explanation could be the peculiar feature of the experimental model. Adenine can induce elevation of serum calcium, as described in other studies, because in addition to inducing CKD, it acts directly on osteoblasts compromising their mineralization capacity, inducing a severe bone disease with high remodeling rate [35][36][37] .…”

Section: Discussionmentioning

confidence: 72%

“…The absence of correlation between the trabecular volume and BD can be explained by the unique features of the adenine model. Adenine acts directly on osteoblasts compromising the cells capacity of mineralization and inducing a relative hypercalcemia and a high-turnover bone disease [35][36][37] . In our study, we found an increased osteoid surface evidencing compromised bone calcification; however, we also identified high bone reabsorption characterized by the increased osteoclast surface.…”

Section: Discussionmentioning

confidence: 99%

Digital radiography as an alternative method in the evaluation of bone density in uremic rats

et al. 2020

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Introduction: Digital radiography (DRx) may provide a suitable alternative to investigate mineral and bone disorder (MBD) and loss of bone density (BD) in rodent models of chronic kidney disease (CKD). The objective of this study was to use DRx to evaluate BD in CKD rats, and to evaluate the correlation between DRx findings and serum MBD markers and bone histomorphometry. Methods: Uremia was induced by feeding Wistar rats an adenine-enriched diet (0.75% for 4 weeks/0.10% for 3 weeks); outcomes were compared to a control group at experimental weeks 3, 4, and 7. The following biochemical markers were measured: creatinine clearance (CrC), phosphate (P), calcium (Ca), fractional excretion of P (FeP), alkaline phosphatase (ALP), fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). DRx imaging was performed and histomorphometry analysis was conducted using the left femur. Results: As expected, at week 7, uremic rats presented with reduced CrC and higher levels of P, FeP, and ALP compared to controls. DRx confirmed the lower BD in uremic animals (0.57±0.07 vs. 0.68 ± 0.06 a.u.; p = 0.016) compared to controls at the end of week 7, when MBD was more prominent. A severe form of high-turnover bone disease accompanied these biochemical changes. BD measured on DRx correlated to P (r=-0.81; p = 0.002), ALP (r = -0.69, p = 0.01), PTH (r = -0.83, p = 0.01), OS/BS (r = -0.70; p = 0.02), and ObS/BS (r = -0.70; p = 0.02). Conclusion: BD quantified by DRx was associated with the typical complications of MBD in CKD and showed to be viable in the evaluation of bone alterations in CKD.

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“…Since hyperphosphatemia restricts the use of VDRAs and is associated with mortality of patients with SHPT , the appropriate control of serum P is a foundation of treatment of SHPT. Studies of the effects of phosphate binders on the parathyroid gland in uremic rats have shown improvement of parathyroid gland enlargement with PTH suppression, and reduced parathyroid cell proliferation and bone abnormality by sevelamer hydrochloride ; suppression of PTH expression, inhibition of PTH gene stabilization, and an increase in sensitivity of CaSR to Ca by lanthanum carbonate ; PTH suppression and parathyroid cell proliferation by ferric citrate ; and suppression of PTH, FGF23, and bone disease by sucroferric oxyhydroxide . However, clinically, treatment of hyperphosphatemia using a Ca‐containing phosphate binder raises the risks of hypercalcemia and vascular calcification .…”

Section: Treatment Of Shptmentioning

confidence: 99%

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

2018

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The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade‐off hypothesis based on parathyroid hormone hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by parathyroid hormone through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca‐sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is, therefore, thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review.

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

Cited by 11 publications

References 37 publications

Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure

Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure

Digital radiography as an alternative method in the evaluation of bone density in uremic rats

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

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