Clinical Nephrology – Epidemiology – Clinical Trials

Kidney International (2005) 67, 2383–2392; doi:10.1111/j.1523-1755.2005.00345.x

Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin

PETER STENVINKEL, KAI WANG, ABDUL RASHID QURESHI, JONAS AXELSSON, ROBERTO PECOITS-FILHO, PING GAO, PETER BARANY, BENGT LINDHOLM, TOMAS JOGESTRAND, OLOF HEIMBÜRGER, CLIFFORD HOLMES, MARTIN SCHALLING and LOUISE NORDFORS

Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Karolinska University Hospital, Stockholm, Sweden; Epitope Diagnostics, Inc., San Diego, California; Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden; Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois; and Nephrogenetics Unit, Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

Correspondence: Peter Stenvinkel, M.D., Ph.D., Department of Renal Medicine K56, Karolinska Institutet, Karolinska University Hospital at Huddinge, 141 86 Stockholm, Sweden. E-mail:peter.stenvinkel@klinvet.ki.se

Received 8 June 2004; Revised 15 August 2004; Re-revised 8 October 2004; Re-revised 25 November 2004; Accepted 20 January 2005.

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Abstract

Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin.

Background

 

Vascular calcification is common among end-stage renal disease (ESRD) patients and a central characteristic of the atherosclerotic cardiovascular disease observed in dialysis patients. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In the present study, we evaluated the association between fetuin-A, clinical phenotype, and outcome, as well as the impact of fetuin gene (AHSG) polymorphisms on the protein product and outcome.

Methods

 

In a cohort of 258 (161 males) ESRD patients starting renal replacement therapy [glomerular filtration rate (GFR) 6.8 plusminus 0.2 mL/min] aged 52 plusminus 1 years the following parameters were studied: presence of malnutrition (subjective global assessment), comorbidity [diabetes mellitus and clinical manifest cardiovascular disease (CVD)], carotid plaques (N = 101), hs-CRP, fetuin-A, S-albumin, interleukin (IL)-6, and single nucleotide polymorphisms (SNPs) in the AHSG gene (N = 215) at amino acid positions Thr248Met (Cright arrowT), Thr256Ser (Cright arrowG), Asp276Asn (Gright arrowA), and Arg317Cys (Cright arrowT).

Results

 

Both all-cause (P < 0.001) and cardiovascular (P < 0.001) mortality were associated with low fetuin-A levels independently of age, smoking, diabetes, S-albumin, CVD, and inflammation (CRP greater than or equal to10 mg/L). Inflamed (0.199 vs. 0.247 g/L; P < 0.01) and malnourished (0.207 vs. 0.262 g/L; P < 0.05) patients had significantly lower median fetuin-A than noninflamed and well-nourished ESRD patients, respectively. In a logistic regression model (N = 101), fetuin-A was significantly (P < 0.05) associated with the presence of carotid plaques independently of age, CVD, diabetes, S-albumin, gender, and inflammation. Significant correlations were observed between fetuin-A and both S-albumin (Rho = 0.30; P < 0.0001) and IL-6 (Rho =-0.21; P < 0.01). Patients with the AHSG 256Ser allele had lower serum fetuin-A levels, and higher all-cause and cardiovascular mortality rate if they were inflamed.

Conclusion

 

The present study shows that a low fetuin-A level is associated with malnutrition, inflammation, and atherosclerosis (carotid plaques), as well as with increased cardiovascular and all-cause mortality. Because the present study demonstrates an effect of variations in the AHSG gene on both circulating fetuin-A levels and outcome, this indicates that ESRD patients with the AHSG 256Ser allele are at risk of accelerated vascular calcification.

Keywords:

fetuin-A, vascular calcification, inflammation, malnutrition, genetic polymorphism, S-albumin

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