title: Peritoneal delivery of sodium pyrophosphate blocks the progression of pre-existing vascular calcification in uremic apolipoprotein-E knockout mice.
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.
authors.affiliation: INSERM Unit 1088, UFR de Médecine et de Pharmacie, University of Picardie Jules Verne (UPJV), 1 rue des Louvels, 80037, Amiens, France.
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: de Oliveira
authors.forename: Loïc
authors.initials: L
authors.lastname: Louvet
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Riser
authors.forename: Fellype C
authors.initials: FC
authors.lastname: Barreto
authors.forename: Joyce
authors.initials: J
authors.lastname: Benchitrit
authors.forename: Raja
authors.initials: R
authors.lastname: Rezg
authors.forename: Sabrina
authors.initials: S
authors.lastname: Poirot
authors.forename: Vanda
authors.initials: V
authors.lastname: Jorgetti
authors.forename: Tilman B
authors.initials: TB
authors.lastname: Drüeke
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D011756:Diphosphates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D018450:Disease Progression; D007263:Infusions, Parenteral; D051379:Mice; D018345:Mice, Knockout; D051436:Renal Insufficiency, Chronic / Q000150:complications; D014511:Uremia / Q000150:complications; D061205:Vascular Calcification / Q000473:pathology* / Q000517:prevention & control
chemical_list: D001057:Apolipoproteins E; D011756:Diphosphates; C003319:sodium pyrophosphate