title: Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia.
abstract: BACKGROUND
  The high rate of cardiovascular mortality in patients with end-stage renal disease (ESRD) is a significant barrier to improved life expectancy. Unique in this population is the marked development and aggressive worsening of vascular calcification (VC). Pyrophosphate (PPi), an endogenous molecule, appears to naturally inhibit soft tissue calcification, but may be depressed in chronic kidney disease (CKD) and ESRD. Although once thought to be a promising therapeutic, PPi's very short half-life in circulation curtailed earlier studies. We tested the possibility that a slow, continuous entry of PPi into the circulation and prevention of VC might be achieved by daily peritoneal dialysis (PD).
  
  
  METHODS
  Pharmacokinetic studies were first carried out in rats with renal impairment resulting from a 5/6 nephrectomy. Efficacy studies were then performed in the apolipoprotein E gene knockout mouse model overlaid with CKD. PPi was delivered by means of a permanent peritoneal catheter in a solution simulating PD, but without the timed removal of spent dialysate. von Kossa's staining followed by semiquantitative morphological image processing, with separation of inside (intimal) and outside (presumed medial) lesions, was used to determine aortic root calcification.
  
  
  RESULTS
  In comparison to an intravenous bolus, delivery of PPi in a PD solution resulted in a slower, extended delivery over >4 h. Next, the efficacy studies showed that a 6-day/week PD-simulated administration of PPi resulted in a dose-dependent inhibition of aortic calcification in both intimal and medial lesions. A dose-response effect on total aortic calcification was also documented, with a full inhibition seen at the highest dose. A limited peritoneal catheter-related inflammation was observed, as expected, and included the placebo-treated control groups. This inflammatory response could have masked a lower level PPi-specific adverse effect, but none was observed.
  
  
  CONCLUSIONS
  Our findings suggest potential for PPi, administered during PD, to prevent the development of VC and to potentially extend the life of ESRD patients.
authors.affiliation: Renal Division, Baxter Healthcare, McGaw Park, IL, USA. bruce_riser@baxter.com
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Riser
authors.forename: Fellype Carvalho
authors.initials: FC
authors.lastname: Barreto
authors.forename: Raja
authors.initials: R
authors.lastname: Rezg
authors.forename: Paul W
authors.initials: PW
authors.lastname: Valaitis
authors.forename: Chyung S
authors.initials: CS
authors.lastname: Cook
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: White
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Gass
authors.forename: Julien
authors.initials: J
authors.lastname: Maizel
authors.forename: Loic
authors.initials: L
authors.lastname: Louvet
authors.forename: Tilman B
authors.initials: TB
authors.lastname: Drueke
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Holmes
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015314:Dialysis Solutions / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011756:Diphosphates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000150:complications / Q000628:therapy*; D014018:Tissue Distribution; D014511:Uremia / Q000188:drug therapy / Q000209:etiology; D061205:Vascular Calcification / Q000209:etiology* / Q000517:prevention & control*
chemical_list: D001057:Apolipoproteins E; D015314:Dialysis Solutions; D011756:Diphosphates; C003319:sodium pyrophosphate; D002118:Calcium