Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia

Riser, Bruce L.; Barreto, Fellype Carvalho; Rezg, Raja; Valaitis, Paul W.; Cook, Chyung S.; White, Jeffrey A.; Gass, Jerome H.; Maizel, Julien; Louvet, Loı̈c; Drueke, Tilman B.; Holmes, Clifford J.; Massy, Ziad A.

doi:10.1093/ndt/gfr039

Cited by 61 publications

(36 citation statements)

References 26 publications

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“…The high prevalence of vascular calcification in chronic kidney disease patients on dialysis is associated with reduced plasma PP i levels, 53 and recent findings in mice suggest that vascular calcification might be prevented by inclusion of PP i in dialysis solutions. 73 In mice lacking functional ANK, there is intracellular trapping of PP i and reduced levels of extracellular PP i , which leads to ectopic mineralization in many locations. 41 Interestingly, vascular mineralization does not occur in Ank -/-mice, suggesting that there is sufficient ENPP1-mediated generation of PP i to prevent ectopic calcification in vessel walls.…”

Section: Discussionmentioning

confidence: 99%

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

et al. 2012

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The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b -/-embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a-/-mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c-/-mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c -/-mice.Keywords amelogenesis imperfecta, knockout, rickets, phosphatonin, ectopic mineralization, biomineralization, dentin, osteomalacia, osteosclerosisThe FAM20 family of secreted proteins in mammals consists of three members (FAM20A, FAM20B, and FAM20C) that were initially thought to have roles in regulating the differentiation and function of hematopoietic and other tissues. 65 Since then, there have been reports linking mutations in both FAM20A and FAM20C to developmental disorders involving bones and/or teeth, suggesting a role for FAM20 proteins in modulating biomineralization processes. In humans, a mutation in FAM20A was recently linked to the occurrence of amelogenesis imperfecta and gingival hyperplasia in a consanguineous family. 69 However, lesions were not reported in bones or teeth of transgenic mice with a partial deletion of Fam20a, and their stunted growth was attributed to malnutrition and an unspecified metabolic disorder. 4 To the best of our knowledge, there have been only two reports elucidating the function FAM20B, which was shown to be a kinase that phosphorylates glycosaminoglycans 50 and in vivo to be involved in cartilage matrix production and skeletal development in zebrafish. 2...

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Section: Discussionmentioning

confidence: 99%

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

et al. 2012

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“…Under conditions of chronic uremia, diminished circulating concentrations of PPi are paralleled by an increase of TNAP acitivity [129,130,131,132,133]. Recent studies with uremic rats indicate that administration of PPi is able to revert this mechanism and to prevent vascular calcification [134,135]. …”

Section: Calcification Inhibitorsmentioning

confidence: 99%

Cardiovascular Risk and Mineral Bone Disorder in Patients with Chronic Kidney Disease

Staude

Jeske

Schmitz

et al. 2013

Kidney Blood Press Res

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The term chronic kidney disease-mineral bone disorder has been coined recently to highlight that the disturbed mineral and bone metabolism is a major contributor to vascular calcification and finally cardiovascular disease. This syndrome is characterized by clinical, biochemical and/or histological findings, i.e. i) biochemical alterations in the homeostasis of calcium, phosphate and their key player parathyroid hormone (PTH), Fibroblast growth factor-23 (FGF-23), klotho and vitamin-D, ii) the occurrence of vascular and/or soft tissue calcification, and iii) an abnormal bone structure and/or turnover. Apart from the combined and synergistic action of "traditional" and uremia-related risk factors, promoters and inhibitors of calcification have to be considered as well. This review will focus on the disturbed mineral metabolism as the triggering force behind distortion of vascular integrity and cardiovascular malfunction in CKD patients.

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“…In our previous animal study, we showed that PPi was able to prevent the progression of VC when PPi was administrated by the intraperitoneal route, simulating a peritoneal dialysis delivery, and immediately after the creation of CKD [13]. Since these studies demonstrated robust efficacy of PPi therapy on VC that was probably harmless regarding the bone [16], and since human patients treatment is likely justified only after the establishment of VC, we sought here for the first time to determine if such a treatment is able to block or reverse the progression of established VC.…”

Section: Introductionmentioning

confidence: 98%

“…Two experimental studies were conducted recently to explore this possibility. In these ''prevention'' studies, O'Neill et al [12] and our group [13] administered PPi via the subcutaneous or the peritoneal route to rats or mice with CKD, i.e., over 1 and 2 months, respectively. The studies showed that long-term PPi treatment was able to slow and even to halt the progression of VC in a dose-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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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Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia

Abstract: Our findings suggest potential for PPi, administered during PD, to prevent the development of VC and to potentially extend the life of ESRD patients.

Cited by 61 publications

References 26 publications

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

Cardiovascular Risk and Mineral Bone Disorder in Patients with Chronic Kidney Disease

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

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