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Peritoneal Delivery of Sodium Pyrophosphate Blocks the Progression of Pre-existing Vascular Calcification in Uremic Apolipoprotein-E Knockout Mice

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Abstract

Chronic kidney disease (CKD) is generally associated with disturbances of mineral and bone metabolism. They contribute to the development of vascular calcification (VC), a strong, independent predictor of cardiovascular risk. Pyrophosphate (PPi), an endogenous inhibitor of hydroxyapatite formation, has been shown to slow the progression of VC in uremic animals. Since in patients with CKD treatment is usually initiated for already existing calcifications, we aimed to compare the efficacy of PPi therapy with that of the phosphate binder sevelamer, using a uremic apolipoprotein-E knockout mouse model with advanced VCs. After CKD creation or sham surgery, 12-week-old female mice were randomized to one sham group and four CKD groups (n = 18–19/group). Treatment was initiated 8 weeks after left nephrectomy allowing prior VC development. Uremic groups received either intraperitoneal PPi (high dose, 1.65 mg/kg or low dose, 0.33 mg/kg per day), oral sevelamer (3 % in diet), or placebo treatment for 8 weeks. Both intima and media calcifications worsened with time in placebo-treated CKD mice, based on both quantitative image analysis and biochemical measurements. Progression of calcification between 8 and 16 weeks was entirely halted by PPi treatment, as it was by sevelamer treatment. PPi did not induce consistent bone histomorphometry changes. Finally, the beneficial vascular action of PPi probably involved mechanisms different from that of sevelamer. Further studies are needed to gain more precise insight into underlying mechanisms and to see whether PPi administration may also be useful in patients with CKD and VC.

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Acknowledgments

The study was supported by a grant from Baxter. We are grateful to Picardie Regional Council and Jules Verne University of Picardie for awarding postdoctoral grants to Fellype C. Barreto and Rodrigo Bueno de Oliveira (who also received a postdoctoral grant from CNPq, Brazil). The authors thank Charlotte Paquet, Jules Verne University of Picardie, for valuable technical help. We also wish to thank Arpita Das, Lianmei Feng, Ahmed Fariyal and Paul Zieski, Baxter Healthcare, for the preparation of the peritoneal dialysis solutions.

Conflict of interest

Tilman B. Drüeke declares having received honoraria as a consultant and/or speaker from Shire, Genzyme and Amgen. Ziad A. Massy declares having received honoraria as speaker from FMC, Genzyme and Amgen. Vanda Jorgetti declares having received speaker honoraria, consulting fees and/or research funding from Amgen, Abbott and Genzyme. At the time of the study, Bruce L. Riser was an employee of Baxter Healthcare, a company with potential commercial interest in this research. Other authors at Inserm Unit-1088, UFR de Médicine/Pharmacie, Amiens and the Division of Nephrology, Amiens University Hospital and Jules Verne University of Picardy, Amiens, France have no competing interest.

Human and Animal Rights and Informed Consent

All animals were handled in accordance with French legislation and to the international guidelines. The protocol was approved by an institutional animal care committee.

Author information

Author notes

  1. Rodrigo B. de Oliveira

    Present address: Division of Nephrology, Department of Internal Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil

Authors and Affiliations

  1. INSERM Unit 1088, UFR de Médecine et de Pharmacie, University of Picardie Jules Verne (UPJV), 1 rue des Louvels, 80037, Amiens, France

    Rodrigo B. de Oliveira, Loïc Louvet, Fellype C. Barreto, Joyce Benchitrit, Raja Rezg, Sabrina Poirot, Tilman B. Drüeke & Ziad A. Massy

  2. BLR BIO, LLC, 313 54th Street, Kenosha, WI, 53140, USA

    Bruce L. Riser

  3. Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, USA

    Bruce L. Riser

  4. Division of Nephrology, São Paulo University, Av. Dr. Arnaldo, 455, 3º andar, sala 3342, CEP 01246-903, São Paulo, SP, Brazil

    Fellype C. Barreto & Vanda Jorgetti

  5. Division of Nephrology, Ambroise Paré Hospital, APHP, Paris Ile de France Ouest University (UVSQ), 9 Avenue Charles de Gaulle, 92100, Boulogne Billancourt, France

    Ziad A. Massy

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  1. Rodrigo B. de Oliveira
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  2. Loïc Louvet
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  3. Bruce L. Riser
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  4. Fellype C. Barreto
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  9. Tilman B. Drüeke
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Corresponding author

Correspondence to Ziad A. Massy.

Additional information

Drs. Loïc Louvet and Rodrigo B. de Oliveira equally contributed to the study.

Drs. Ziad A. Massy and Bruce L. Riser equally contributed as originators and supervisors of the study.

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de Oliveira, R.B., Louvet, L., Riser, B.L. et al. Peritoneal Delivery of Sodium Pyrophosphate Blocks the Progression of Pre-existing Vascular Calcification in Uremic Apolipoprotein-E Knockout Mice. Calcif Tissue Int 97, 179–192 (2015). https://doi.org/10.1007/s00223-015-0020-7

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