Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD.

BACKGROUND: Patients with chronic kidney disease (CKD) experience high rates of atherosclerotic cardiovascular disease and death that are not fully explained by traditional risk factors. In animal studies, defective cellular cholesterol efflux pathways which are mediated by the ATP binding cassette transporters ABCA1 and ABCG1 are associated with accelerated atherosclerosis. We hypothesized that cholesterol efflux in humans would vary in terms of cellular components, with potential implications for cardiovascular disease. METHODS: We recruited 120 CKD patients (eGFR<30mL/min/1.73m2) and 120 control subjects (eGFR ≥60mL/min/1.73m2) in order to measure cholesterol efflux using either patients' HDL and THP-1 macrophages or patients' monocytes and a flow cytometry based cholesterol efflux assay. We also measured cell-surface levels of the common ß subunit of the IL-3/GM-CSF receptor (IL-3Rß) which has been linked to defective cholesterol homeostasis and may promote monocytosis. In addition, we measured plasma inflammatory cytokines and plasma metabolite profiles. RESULTS: There was a strong positive correlation between cell-surface IL-3Rß levels and monocyte counts in CKD (P<0.001). ABCA1 mRNA was reduced in CKD vs. control monocytes (P<0.05), across various etiologies of CKD. Cholesterol efflux to apolipoprotein A1 was impaired in monocytes from CKD patients with diabetic nephropathy (P<0.05), but we found no evidence for a circulating HDL-mediated defect in cholesterol efflux in CKD. Profiling of plasma metabolites showed that medium-chain acylcarnitines were both independently associated with lower levels of cholesterol transporter mRNA in CKD monocytes at baseline (P<0.05), and with cardiovascular events in CKD patients after median 2.6years of follow-up. CONCLUSIONS: Cholesterol efflux in humans varies in terms of cellular components. We report a cellular defect in ABCA1-mediated cholesterol efflux in monocytes from CKD patients with diabetic nephropathy. Unlike several traditional risk factors for atherosclerotic cardiovascular disease, plasma metabolites inversely associated with endogenous cholesterol transporters predicted cardiovascular events in CKD patients. (Funded by the National Institute of Diabetes and Digestive and Kidney DiseasesK23DK097288 and others.).

Adiponectin and all-cause mortality in elderly people with type 2 diabetes.

OBJECTIVE: To assess the association between serum adiponectin level and all-cause mortality in people with type 2 diabetes. Because of the insulin-sensitizing, anti-inflammatory, and antiatherogenic effects of adiponectin, we hypothesized that higher adiponectin level would be associated with lower all-cause mortality. RESEARCH DESIGN AND METHODS: A total of 609 men and women aged 72 ± 6.3 years with type 2 diabetes and information on total and high molecular weight adiponectin were followed for a median of 5 years. The longitudinal association between adiponectin and all-cause mortality was analyzed with Cox proportional hazards models with time from adiponectin measurement to death as the time-to-event variable. Analyses were adjusted for demographic variables and significant diabetes parameters, significant cardiovascular parameters, and significant diabetes medications. RESULTS: Total and high molecular weight adiponectin were highly correlated. The highest adiponectin quartile was strongly associated with higher all-cause mortality compared with the lowest quartile (hazard ratio = 4.0 [95% CI: 1.7-9.2]) in the fully adjusted model. These results did not change in analyses stratified by sex and thiazolidinedione use, after exclusion of people who died within one year of adiponectin measurement, or when change in weight before adiponectin measurement was considered. CONCLUSIONS: Contrary to our hypothesis, higher adiponectin level was related to higher all-cause mortality. This association was not explained by confounding by other characteristics, including medications or preceding weight loss.