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NDT Advance Access first published online on May 7, 2008
This version published online on May 9, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn226
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not Matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis

Rukshana C Shroff1,2, Vanita Shah3, Melanie P Hiorns4, Michael Schoppet5, Lorenz C Hofbauer6, Gerhard Hawa7, Leon J Schurgers8, Atul Singhal9, Ian Merryweather9, Paul Brogan10, Catherine Shanahan11, John Deanfield2 and Lesley Rees1

1 Nephrourology 2 Vascular Physiology 3 Infectious Disease 4 Radiology Departments, Great Ormond Street Hospital & UCL Institute of Child Health, London, UK 5 Department of Internal Medicine and Cardiology, Philipps-University, Marburg 6 Division of Endocrinology and Metabolic Bone Disease, Technical University of Dresden, Dresden, Germany 7 Biomedica Medizinprodukte, Vienna, Austria 8 CARIM and VitaK, University of Maastricht, Maastricht, The Netherlands 9 Childhood Nutrition Research Centre 10 Department of Rheumatology, Great Ormond Street Hospital & UCL Institute of Child Health, London, UK 11 Cardiovascular Division, King's College London, UK

Correspondence and offprint requests to: Rukshana Shroff, Research Registrar, Nephrourology Unit, Institute of Child Health, 30, Guilford Street, London WC1N 1EH, UK. Tel: +44-020-7405-9200, ext 0065; Fax: +44-020-7813-8532; E-mail: ShrofR{at}gosh.nhs.uk



  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, ß = –0.45, model R2 = 48%) and fetuin-A and OPG predicted cardiac calcification (P = 0.02, ß = –0.29 and P = 0.014, ß = 0.33, respectively, model R2 = 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.

Keywords: dialysis; fetuin-A; matrix Gla protein; osteoprotegerin; vascular calcification

Received for publication: 23. 1.08
Accepted in revised form: 2. 4.08


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