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A clinical-genetic approach to assessing cardiovascular risk in patients with CKD.

ABSTRACT: BACKGROUND:Coronary heart disease (CHD) is the primary cause of death in individuals with chronic kidney disease (CKD), but current equations for assessing coronary risk have low accuracy in this group. We have reported that the addition of a genetic risk score (GRS) to the Framingham risk function improved its predictive capacity in the general population. The aims of this study were to evaluate the association between this GRS and coronary events in the CKD population and to determine whether the addition of the GRS to coronary risk prediction functions improves the estimation of coronary risk at the earliest possible stages of kidney disease. METHODS:A total of 632 CKD patients, aged 35-74?years, who had Stage 4-5 CKD, were on dialysis, had a functioning renal transplant or had returned to dialysis after transplant failure were included and followed up for a mean of 9.3?years. The transitions between disease states and the development of coronary events were registered. The increase in predictive ability that was obtained by including the GRS was measured as the improvement in the C-statistic and as the net reclassification index. RESULTS:The GRS was independently associated with the risk of CHD (hazards ratio 1.34; 95% confidence interval 1.04-1.71; P?=?0.022), especially in Stages 4 and 5 CKD, and kidney transplant patients. A coronary risk prediction function that incorporated chronic kidney disease (CKD) disease state, age, sex and the GRS had significantly greater predictive capacity (AUC 70.1, P?=?0.01) and showed good reclassification (net reclassification improvement 28.6). CONCLUSION:This new function, combining genetic and clinical data, identifies CKD patients with a high risk of coronary events more accurately, allowing us to prevent such events more effectively.

SUBMITTER: Rodrigo E

PROVIDER: S-EPMC5622901 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A clinical-genetic approach to assessing cardiovascular risk in patients with CKD.

Rodrigo Emilio E Pich Sara S Subirana Isaac I Fernandez-Fresnedo Gema G Barreda Paloma P Ferrer-Costa Carles C M de Francisco Ángel Luis ÁL Salas Eduardo E Elosua Roberto R Arias Manuel M

Clinical kidney journal 20170622 5

<h4>Background</h4>Coronary heart disease (CHD) is the primary cause of death in individuals with chronic kidney disease (CKD), but current equations for assessing coronary risk have low accuracy in this group. We have reported that the addition of a genetic risk score (GRS) to the Framingham risk function improved its predictive capacity in the general population. The aims of this study were to evaluate the association between this GRS and coronary events in the CKD population and to determine ...[more]

PMID: 28979779

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Project description:The high risk of cardiovascular disease (CVD) and premature death in patients with CKD associates with a plethora of elevated circulating biomarkers that may reflect distinct signaling pathways or simply, are epiphenomena of CKD. We compared the predictive strength of 12 biomarkers analyzed concomitantly in patients with stage 5 CKD.From 1994 to 2014, 543 patients with stage 5 CKD (median age =56 years old; 63% men; 199 patients had CVD) took part in our study on malnutrition, inflammation, and CVD in incident dialysis patients. Circulating levels of albumin, ferritin, high-sensitivity C-reactive protein (hsCRP), IGF-1, IL-6, orosomucoid, troponin T (TnT), TNF, soluble intracellular adhesion molecule, soluble vascular cellular adhesion molecule 1 (sVCAM-1), and platelet and white blood cell (WBC) counts were analyzed as predictors of the presence of clinically overt CVD at baseline, protein-energy wasting (PEW), and subsequent all-cause mortality. During follow-up for a median of 28 months, there were 149 deaths, 81 of which were caused by CVD.Most biomarkers were elevated compared with reference values and--except for albumin, ferritin, and IGF-1-higher in patients with CVD. In receiver operating characteristic analysis, age, IL-6, TnT, hsCRP, and IGF-1 were classifiers of baseline CVD and predictors of all-cause mortality. In addition to age, diabetes mellitus, smoking (for CVD), and PEW, only IL-6, relative risk (RR) 1.10 and 95% confidence interval ([95% CI], 1.02 to 1.19), sVCAM-1 RR 1.09 (95% CI, 1.01 to 1.17), and serum albumin RR 0.89 (95% CI, 0.83 to 0.95) associated with baseline CVD, and only WBC, hazard ratio (HR) 1.94 (95% CI, 1.34 to 2.82), IL-6 HR 1.79 (95% CI, 1.20 to 2.67), and TNF HR 0.65 (95% CI, 0.44 to 0.97) predicted all-cause mortality.In addition to age and comorbidities, only IL-6, sVCAM-1, and albumin could-independently of other biomarkers-classify clinical CVD, and only IL-6, WBC, and TNF could-independently of other biomarkers-predict all-cause mortality risk. These data underscore the robustness of IL-6 as a classifier of clinically overt CVD and predictor of all-cause mortality in patients with stage 5 CKD.

Project description:BackgroundPatients 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.MethodsWe 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 β subunit of the IL-3/GM-CSF receptor (IL-3Rβ) which has been linked to defective cholesterol homeostasis and may promote monocytosis. In addition, we measured plasma inflammatory cytokines and plasma metabolite profiles.ResultsThere was a strong positive correlation between cell-surface IL-3Rβ 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.ConclusionsCholesterol 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.).

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A clinical-genetic approach to assessing cardiovascular risk in patients with CKD.

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A clinical-genetic approach to assessing cardiovascular risk in patients with CKD.

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