The commercial kit used herein for anti-CL determinations is developed to not promote CL oxidation in the experimental settings

The commercial kit used herein for anti-CL determinations is developed to not promote CL oxidation in the experimental settings. We cannot exclude the possibility that some of the anti-OxCL binding to OxCL is present in immune complexes. operator characteristic (ROC) analysis, anti-OxCL [area under the curve (AUC) 062,P< 001], but not anti-CL (AUC 052,P= 02), is associated with mortality. In crude and adjusted Cox analysis, every log increase in anti-OxCL inversely predicted all-cause [adjusted hazard ratios (HR) 062 (043089)] and CVD-related [adjusted HR 056 (032098)] 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 ( = 057,P< 001), 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 2-GPI-independent; anti-CL from patients with anti-phospholipid antibody syndrome were 2-GPI-dependent, while sera from HD-patients less so. Sera from healthy donors was not 2-GPI-dependent. Anti-OxCL IgM is 2-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. Keywords:antibodies, atherosclerosis, cardiolipin, cardiovascular Dapson disease, haemodialysis, inflammation == Introduction == Patients with chronic kidney disease (CKD) have poor prognosis with increased mortality. Atherosclerosis and its consequences, cardiovascular disease (CVD) and infectious complications such as pneumonia, are the main causes of death in this underserved population [1]. Persistent low-grade inflammation and the development of protein-energy wasting (PEW) are believed to be important factors that predispose to premature mortality [2]. Atherosclerosis is the major cause of CVD such as stroke and myocardial infarction (MI), which is regarded Rabbit Polyclonal to SIK as an inflammatory disease, where activated immune competent cells producing cytokines are abundant [3]. Currently there are no anti-inflammatory or immune modulatory therapies developed to target CVD (or atherosclerosis). Further, there are few risk markers or risk factors which reflect inflammation, none of which target immune reactions. High-sensitivity C-reactive protein (hsCRP) is of interest in CVD, although volatility at the individual level of this measure may be a limitation [4,5]. Lipoprotein-associated phospholipase A2 (LP-PLA2) is another emerging inflammatory risk marker [6]. We have reported that natural antibodies against phosphorylcholine (PC) of immunoglobulin (IgM) subclass (anti-PC) are independently established risk factors associated negatively with the development of CVD, low levels leading to high risk [711]. As there is a need to identify uraemic patients at risk of developing serious infections, it is noteworthy that anti-PC inhibits the lethal effects of pneumococcal infection in mice [12]. Cardiolipin (CL) is a dimeric phospholipid, which is present in bacteria and in inner membranes of mitochondria of eucariotic cells more so when metabolic activity is high [13]. High content of double bonds renders Dapson CL easily susceptible to oxidation [13]. Antibodies against CL (aCL) are well-known risk factors for both venous and Dapson arterial thrombosis, especially in patients with rheumatic diseases such as systemic lupus erythematosus (SLE) [14]. The immunogenicity of CL is dependent upon plasma Dapson co-factors such as 2-glycoprotein 1 (2GP1). There is still a debate regarding the exact nature of how co-factors interact with CL so that it is recognized by thrombogenic antibodies [14]. Although little is known about the clinical role played by anti-OxCL, we have reported recently that low levels of these antibodies predict the development of CVD among healthy 60-year-olds [15]. In this study, we report that IgM antibodies against oxidized CL (anti-OxCL) but not anti-CL IgM are associated negatively (and independently of other known factors) with mortality risk among prevalent haemodialysis (HD) patients. The implications of these findings are discussed. == Subjects and methods == == Patients and experimental design == This study includes prevalent patients undergoing HD at six dialysis units in Stockholm and Uppsala, both in Sweden. This is apost-hocanalysis from a cross-sectional study with mortality follow-up that aimed originally at investigating the variability of inflammatory markers in HD patients. Patient recruitment took place between October 2003 and March 2004; the protocol has been described previously in more detail [16]. We have previously published the association between anti-PC and mortality in this patient material [17], data that will be used in the analyses of this study. From the 224 patients included in the study (who survived the first 3 months after inclusion) and followed further for assessment of overall and cardiovascular mortality, anti-OxCL and anti-CL levels were determined in 221 (not enough plasma was available in three patients). The Ethics Committee of Karolinska Institutet and Uppsala University Hospital approved the study protocols. Informed consent was obtained from all patients. A nephrologist reviewed each patient’s medical chart and extracted data pertaining to underlying kidney disease, history of CVD, other co-morbid conditions and survival data. The co-morbidity history of each patient was determined at baseline according to the Davies co-morbidity scoring on a seven-point scale that was simplified into a three-risk-category scale [18]. Nutritional status was.