Elsevier

The Lancet

Volume 361, Issue 9360, 8 March 2003, Pages 827-833
The Lancet

Mechanisms of Disease
Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study

https://doi.org/10.1016/S0140-6736(03)12710-9Get rights and content

Summary

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 (α2-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 Ca×PO4 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.

Findings

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 Ca×PO4 precipitation (mean IC50: 9·0 μL 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.

Introduction

Cardiovascular mortality in patients on dialysis is about 30 times higher than in the general population, and is 10–20 times higher when stratified for age, sex, and diabetes.1 Because of these facts, the term accelerated atherogenesis was coined for uraemic vascular disease, although the pathological mechanisms causing it remain incompletely understood.

One striking occurrence in patients on dialysis is the presence of severe vascular and valvular calcifications. Hyperphosphataemia-related increases in Ca×PO4 ion product in serum and secondary hyperparathyroidism are thought to be of pathophysiological relevance and associated with raised cardiovascular mortality in this population.2 Goodman and colleagues3 reported that more than 80% of young patients on dialysis showed substantial coronary-artery calcifications, as detected by electron-beam CT. Occurrence of these lesions correlated with raised serum phosphate concentrations, amplified Ca×PO4 ion product in serum, and a high daily calcium intake. However, severe extraosseus calcifications have also been described independent of pronounced hypercalcaemia or hyperphosphataemia in patients on dialysis and in parathyroidectomised patients with uraemia.

Extracellular calcium-regulatory proteins—including matrix gla protein (mgp) and human fetuin-a (AHSG; α2-Heremans Schmid glycoprotein)—are potent inhibitors of Ca×PO4 precipitation.4, 5, 6, 7 MGP seems to act locally as a potent inhibitor of aortic calcification.5 Correspondingly, MGP knockout mice develop severe arterial-media calcifications and die of aortic rupture at the age of 8 weeks.5

AHSG is ubiquitous and abundant in the extracellular space, and accounts for more than 50% of the precipitation inhibitory effect of serum.6, 7 Under usual conditions, the serum half-life of AHSG is estimated to be several days. A substantial proportion of this glycoprotein is probably cleared through binding to the asialoglycoprotein receptor, another quantity might be cleared by formation of a large complex consisting of AHSG, MGP, and mineral (calcium/phosphorus) compound.8, 9 On a cellular level, AHSG is a multifunctional molecule and acts as an antagonist of transforming growth factor β, regulating cytokine-dependent osteogenesis and inhibiting insulin receptor tyrosine kinase and some protease activities.10, 11 AHSG knockout mice develop severe soft-tissue and intravascular calcifications (W Jahnen-Dechent; unpublished observation).7

Unlike MGP, AHSG is regulated as a negative acute-phase protein in vivo, ie, serum concentrations fall during inflammation or trauma, as shown by Lebreton and coworkers.12 Since a state of chronic microinflammation—eg, indicated by raised C-reactive protein (CRP) concentrations—has been suggested to be a major cardiovascular risk factor in dialysis patients,13 we speculated that AHSG downregulation might be a direct link between chronic inflammation and vascular and valvular calcification, ultimately leading to cardiovascular disease. We aimed to investigate this hypothesis

Section snippets

Participants

We did a cross-sectional study in white patients undergoing haemodialysis at the dialysis unit of the University Hospital of Würzburg, Germany, and at three outpatient dialysis centres in the Würzburg region. All patients from these centres who were eligible and gave consent were included.

Controls consisted of blood donors older than age 50 years, who we judged healthy. Because the so-called average blood donor is younger than the mean age of our dialysis patients, we aimed to close this gap by

Results

We studied 312 patients recruited from the dialysis centres in the Würzburg region, and 76 healthy controls. 79 (25·4%) patients on dialysis had coronary artery disease, 35 (11·3%) had cerebrovascular disease, and 41 (13·2%) had intermittent claudication. Characteristics of patients and controls are shown in table 1.

We divided patients on dialysis into tertiles with respect to low (0·20–0·54 g/L), medium (0·55–0·71 g/L), and high (0·72–1·83 g/L) AHSG concentrations, and plotted them against

Discussion

The key finding of our study was identification of AHSG deficiency as a novel uraemia-related and inflammation-related mortality risk factor, and a potential missing link between a state of chronic inflammation and high incidence of cardiovascular events and mortality in patients on dialysis. The functional relevance of this finding is lent strong support by our demonstration that serum from AHSG-deficient patients on long-term dialysis, with clinical evidence of extraosseous calcifications,

GLOSSARY

accelerated atherogenesis
A term coined in the 1970s characterising the severely calcifying and rapidly progressive nature of atherosclerosis in patients on dialysis.
atomic absorption photometry
A technique to measure concentrations of ground state atoms (eg, Ca2, Mg2+) by spectrophotometric principle. Atomic vapour of an element is formed by flame, electric arcs, hydride generators, or graphite furnace to make use of its absorption.
chemiluminescence
A process where a chemical reaction causes the

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