title: The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis.
abstract: BACKGROUND
  Vascular calcification occurs in the majority of patients with chronic kidney disease, but a subset of patients does not develop calcification despite exposure to a similar uraemic environment. Physiological inhibitors of calcification, fetuin-A, osteoprotegerin (OPG) and undercarboxylated-matrix Gla protein (uc-MGP) may play a role in preventing the development and progression of ectopic calcification, but there are scarce and conflicting data from clinical studies.
  
  
  METHODS
  We measured fetuin-A, OPG and uc-MGP in 61 children on dialysis and studied their associations with clinical, biochemical and vascular measures.
  
  
  RESULTS
  Fetuin-A and OPG were higher and uc-MGP lower in dialysis patients than controls. In controls, fetuin-A and OPG increased with age. Fetuin-A showed an inverse correlation with dialysis vintage (P = 0.0013), time-averaged serum phosphate (P = 0.03) and hs-CRP (P = 0.001). Aortic pulse wave velocity (PWV) and augmentation index showed a negative correlation with fetuin-A while a positive correlation was seen with PWV and OPG. Patients with calcification had lower fetuin-A and higher OPG than those without calcification. On multiple linear regression analysis Fetuin-A independently predicted aortic PWV (P = 0.004, beta = -0.45, model R(2) = 48%) and fetuin-A and OPG predicted cardiac calcification (P = 0.02, beta = -0.29 and P = 0.014, ss = 0.33, respectively, model R(2) = 32%).
  
  
  CONCLUSIONS
  This is the first study to define normal levels of the calcification inhibitors in children and show that fetuin-A and OPG are associated with increased vascular stiffness and calcification in children on dialysis. Higher levels of fetuin-A in children suggest a possible protective upregulation of fetuin-A in the early stages of exposure to the pro-calcific and pro-inflammatory uraemic environment.
authors.affiliation: Nephrourology Unit, Great Ormond Street Hospital & UCL Institute of Child Health, London WC1N 1EH, UK. ShrofR@gosh.nhs.uk
authors.forename: Rukshana C
authors.initials: RC
authors.lastname: Shroff
authors.forename: Vanita
authors.initials: V
authors.lastname: Shah
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Hiorns
authors.forename: Michael
authors.initials: M
authors.lastname: Schoppet
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hawa
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: Atul
authors.initials: A
authors.lastname: Singhal
authors.forename: Ian
authors.initials: I
authors.lastname: Merryweather
authors.forename: Paul
authors.initials: P
authors.lastname: Brogan
authors.forename: Catherine
authors.initials: C
authors.lastname: Shanahan
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
authors.forename: Lesley
authors.initials: L
authors.lastname: Rees
mesh_terms: D000293:Adolescent; D001783:Blood Flow Velocity; D001798:Blood Proteins / Q000378:metabolism*; D001808:Blood Vessels / Q000473:pathology* / Q000503:physiopathology*; D002114:Calcinosis / Q000473:pathology* / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016326:Extracellular Matrix Proteins / Q000097:blood*; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D008297:Male; D053244:Osteoprotegerin / Q000097:blood*; D006435:Renal Dialysis; D060749:alpha-2-HS-Glycoprotein; D000097568:Matrix Gla Protein
chemical_list: D001798:Blood Proteins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D053244:Osteoprotegerin; D060749:alpha-2-HS-Glycoprotein; D000097568:Matrix Gla Protein; C556354:AHSG protein, human; C506030:TNFRSF11B protein, human