The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis.
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.
Shroff
Rukshana C
RC
Nephrourology Unit, Great Ormond Street Hospital & UCL Institute of Child Health, London WC1N 1EH, UK. ShrofR@gosh.nhs.uk
Shah
Vanita
V
Hiorns
Melanie P
MP
Schoppet
Michael
M
Hofbauer
Lorenz C
LC
Hawa
Gerhard
G
Schurgers
Leon J
LJ
Singhal
Atul
A
Merryweather
Ian
I
Brogan
Paul
P
Shanahan
Catherine
C
Deanfield
John
J
Rees
Lesley
L
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
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