title: Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.
abstract: BACKGROUND
  Vascular calcification is the most prominent underlying pathological finding in patients with uraemia, and is a predictor of mortality in this population. Fetuin-A (alpha2-Heremans Schmid glycoprotein; AHSG) is an important circulating inhibitor of calcification in vivo, and is downregulated during the acute-phase response. We aimed to investigate the hypothesis that AHSG deficiency is directly related to uraemic vascular calcification.
  
  
  METHODS
  We did a cross-sectional study in 312 stable patients on haemodialysis to analyse the inter-relation of AHSG and C-reactive protein (CRP) and their predictive effect on all-cause and cardiovascular mortality, over a period of 32 months. Subsequently, we tested the capacity of serum to inhibit CaxPO4 precipitation in patients on long-term dialysis (n=17) with apparent soft-tissue calcifications, and in those on short-term dialysis (n=8) without evidence of calcifications and cardiovascular disease.
  
  
  RESULTS
  AHSG concentrations in serum were significantly lower in patients on haemodialysis (mean 0.66 g/L [SD 0.28]) than in healthy controls (0.72 [0.19]). Low concentrations of the glycoprotein were associated with raised amounts of CRP and with enhanced cardiovascular (p=0.031) and all-cause mortality (p=0.0013). Sera from patients on long-term dialysis with low AHSG concentrations showed impaired ex-vivo capacity to inhibit CaxPO4 precipitation (mean IC50: 9.0 microL serum [SD 3.1] vs 7.5 [0.8] in short-term patients and 6.4 [2.6] in controls). Reconstitution of sera with purified AHSG returned this impairment to normal. Interpretation AHSG deficiency is associated with inflammation and links vascular calcification to mortality in patients on dialysis. Activated acute-phase response and AHSG deficiency might account for accelerated atherosclerosis in uraemia.
authors.affiliation: Department of Nephrology and Immunology, University Hospital Aachen, Aachen, Germany. mketteler@ukaachen.de
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.forename: Philipp
authors.initials: P
authors.lastname: Bongartz
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
authors.forename: Joachim Ernst
authors.initials: JE
authors.lastname: Wildberger
authors.forename: Andreas Horst
authors.initials: AH
authors.lastname: Mahnken
authors.forename: Roland
authors.initials: R
authors.lastname: Böhm
authors.forename: Thomas
authors.initials: T
authors.lastname: Metzger
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
mesh_terms: D001798:Blood Proteins / Q000172:deficiency* / Q000378:metabolism; D002114:Calcinosis / Q000209:etiology; D002318:Cardiovascular Diseases / Q000097:blood / Q000401:mortality*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D060749:alpha-2-HS-Glycoprotein
chemical_list: C556354:AHSG protein, human; D001798:Blood Proteins; D060749:alpha-2-HS-Glycoprotein