title: Immunoglobulin (Ig)M antibodies against oxidized cardiolipin but not native cardiolipin are novel biomarkers in haemodialysis patients, associated negatively with mortality.
abstract: The risk of premature death is high in haemodialysis (HD) patients. Antibodies against cardiolipin (anti-CL) are thrombogenic in diseases such as systemic lupus erythematosus (SLE). CL is easily oxidized (Ox) and plays a role in apoptosis. In this work we studied immunoglobulin (Ig)M anti-CL and anti-OxCL in HD-patients. We conducted an observational study with a prospective follow-up examining the relationship between anti-CL, anti-OxCL and mortality risk in a well-characterized cohort of 221 prevalent HD patients [56% men, median age 66 (interquartile range 51-74) years, vintage time 29 (15-58) months] with a mean follow-up period of 41 (20-48 months). According to the receiver operator characteristic (ROC) analysis, anti-OxCL [area under the curve (AUC) 0·62, P < 0·01], but not anti-CL (AUC 0·52, P = 0·2), is associated with mortality. In crude and adjusted Cox analysis, every log increase in anti-OxCL inversely predicted all-cause [adjusted hazard ratios (HR) 0·62 (0·43-0·89)] and CVD-related [adjusted HR 0·56 (0·32-0·98)] mortality. Patients with anti-OxCL levels below median also had increased all-cause and cardiovascular disease (CVD)-related mortality. Although anti-OxCL and anti-phosphorylcholine (PC) were related positively to each other (ρ = 0·57, P < 0·01), patients with one or two of these autoantibody levels below the median were associated with an incrementally increased death risk. Anti-OxCL were co-factor β2-GPI-independent; anti-CL from patients with anti-phospholipid antibody syndrome were β2-GPI-dependent, while sera from HD-patients less so. Sera from healthy donors was not β2-GPI-dependent. Anti-OxCL IgM is β2-glycoprotein 1 (GPI)-independent and a novel biomarker; low levels are associated with death among HD patients (and high levels with decreased risk). Combination with anti-PC increases this association. Putative therapeutic implications warrant further investigation.
authors.affiliation: Unit of Immunology and Chronic Disease, Division of Physiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A G
authors.initials: AG
authors.lastname: Frostegård
authors.forename: X
authors.initials: X
authors.lastname: Hua
authors.forename: J
authors.initials: J
authors.lastname: Su
authors.forename: J J
authors.initials: JJ
authors.lastname: Carrero
authors.forename: O
authors.initials: O
authors.lastname: Heimbürger
authors.forename: P
authors.initials: P
authors.lastname: Bárány
authors.forename: P
authors.initials: P
authors.lastname: Stenvinkel
authors.forename: J
authors.initials: J
authors.lastname: Frostegård
mesh_terms: D000368:Aged; D017153:Antibodies, Anticardiolipin / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology; D017209:Apoptosis; D050197:Atherosclerosis; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers; D002308:Cardiolipins / Q000276:immunology* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000276:immunology / Q000401:mortality*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D006435:Renal Dialysis / Q000401:mortality*; D012306:Risk; D053482:beta 2-Glycoprotein I
chemical_list: D017153:Antibodies, Anticardiolipin; D001323:Autoantibodies; D015415:Biomarkers; D002308:Cardiolipins; D007075:Immunoglobulin M; D053482:beta 2-Glycoprotein I
keywords: antibodies; atherosclerosis; cardiolipin; cardiovascular disease; haemodialysis; inflammation