Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.
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.
Ketteler
Markus
M
Department of Nephrology and Immunology, University Hospital Aachen, Aachen, Germany. mketteler@ukaachen.de
Bongartz
Philipp
P
Westenfeld
Ralf
R
Wildberger
Joachim Ernst
JE
Mahnken
Andreas Horst
AH
Böhm
Roland
R
Metzger
Thomas
T
Wanner
Christoph
C
Jahnen-Dechent
Willi
W
Floege
Jürgen
J
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
C556354:AHSG protein, human; D001798:Blood Proteins; D060749:alpha-2-HS-Glycoprotein