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Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

ABSTRACT: Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD.Cross-sectional and longitudinal observational analysis.Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study.Quartiles of plasma CX3CL1 levels at baseline.Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality.Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04).Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect.Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.

SUBMITTER: Shah R

PROVIDER: S-EPMC4516570 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Shah Rachana R Matthews Gregory J GJ Shah Rhia Y RY McLaughlin Catherine C Chen Jing J Wolman Melanie M Master Stephen R SR Chai Boyang B Xie Dawei D Rader Daniel J DJ Raj Dominic S DS Mehta Nehal N NN Budoff Matthew M Fischer Michael J MJ Go Alan S AS Townsend Raymond R RR He Jiang J Kusek John W JW Feldman Harold I HI Foulkes Andrea S AS Reilly Muredach P MP

American journal of kidney diseases : the official journal of the National Kidney Foundation 20150317 2

<h4>Background</h4>Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD.<h4>Study design</h4>Cross-sectional and longitudinal observational analysis.<h4>Setting & participants</h4>A ...[more]

PMID: 25795074

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Project description:Rationale & objectiveLow serum magnesium level has been shown to be associated with increased mortality, but its role as a predictor of cardiovascular disease is unclear. This study evaluates the association between serum magnesium level and cardiovascular events and all-cause mortality in a large cohort of individuals with chronic kidney disease (CKD).Study designProspective cohort study.Setting & participants3,867 participants with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.ExposuresSerum magnesium measured at study baseline.OutcomesComposite cardiovascular events (myocardial infarction, cerebrovascular accident, heart failure, and peripheral arterial disease) and all-cause mortality.Analytical approachCox proportional hazards models adjusted for demographic, clinical, and laboratory characteristics.ResultsDuring the 14.6 (4.4) years (standard deviation) of follow-up, 1,384 participants died (36/1,000 person-years), and 1,227 (40/1,000 person-years) had a composite cardiovascular event. There was a nonlinear association between serum magnesium level and all-cause mortality. Low and high magnesium levels were associated with greater rates of all-cause mortality after adjusting for demographics, comorbid conditions, medications including diuretics, estimated glomerular filtration rate, and proteinuria (P < 0.001). No significant associations were observed between serum magnesium levels and the composite cardiovascular events. Low serum magnesium level was associated with incident atrial fibrillation (HR, 1.36; 95% CI, 1.01-1.82; P = 0.04).LimitationsSingle measurement of serum magnesium.ConclusionsIn this large CKD cohort, serum magnesium level < 1.9 mg/dL and >2.1 mg/dL was associated with increased risk for all-cause mortality. Low magnesium level was associated with incident atrial fibrillation but not with composite cardiovascular disease events. Further studies are needed to determine the optimal range of serum magnesium in CKD to prevent adverse clinical outcomes.

Project description:Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease. We investigated the association between serum aldosterone and death and end-stage renal disease in 3866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and renin-angiotensin-aldosterone system inhibitors. During a median follow-up period of 5.4 years, 587 participants died, 743 developed end-stage renal disease, 187 developed congestive heart failure, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per SD of the log-transformed aldosterone) were not an independent risk factor for death (adjusted hazard ratio, 1.00; 95% confidence interval, 0.93-1.12), end-stage renal disease (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.17), or atherosclerotic events (adjusted hazard ratio, 1.04; 95% confidence interval, 0.85-1.18). Aldosterone was associated with congestive heart failure (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02-1.35). Among participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with chronic kidney disease because elevated cortisol levels may activate the mineralocorticoid receptor.

Project description:BackgroundNon-Hispanic blacks and Hispanics with end-stage renal disease have a lower risk for death than non-Hispanic whites, but data for racial/ethnic variation in cardiovascular outcomes for non-dialysis-dependent chronic kidney disease are limited.Study designProspective cohort.Setting & participants3,785 adults with entry estimated glomerular filtration rates of 20 to 70mL/min/1.73m(2) enrolled in the CRIC (Chronic Renal Insufficiency Cohort) Study.PredictorsRace/ethnicity (non-Hispanic white, non-Hispanic black, and Hispanic).OutcomesCardiovascular outcomes (atherosclerotic events [myocardial infarction, stroke, or peripheral arterial disease] and heart failure) and a composite of each cardiovascular outcome or all-cause death.MeasurementsMultivariable Cox proportional hazards.ResultsDuring a median follow-up of 6.6 years, we observed 506 atherosclerotic events, 551 heart failure events, and 692 deaths. In regression analyses, there were no significant differences in atherosclerotic events among the 3 racial/ethnic groups. In analyses stratified by clinical site, non-Hispanic blacks had a higher risk for heart failure events (HR, 1.59; 95% CI, 1.29-1.95), which became nonsignificant after adjustment for demographic factors and baseline kidney function. In contrast, Hispanics had similar risk for heart failure events as non-Hispanic whites. In analyses stratified by clinical site, compared with non-Hispanic whites, non-Hispanic blacks were at similar risk for atherosclerotic events or death. However, after further adjustment for cardiovascular risk factors, medications, and mineral metabolism markers, non-Hispanic blacks had 17% lower risk for the outcome (HR, 0.83; 95% CI, 0.69-0.99) than non-Hispanic whites, whereas there was no significant association with Hispanic ethnicity.LimitationsHispanics were largely recruited from a single center, and the study was underpowered to evaluate the association between Hispanic ethnicity and mortality.ConclusionsThere were no significant racial/ethnic differences in adjusted risk for atherosclerotic or heart failure outcomes. Future research is needed to better explain the reduced risk for atherosclerotic events or death in non-Hispanic blacks compared with non-Hispanic whites.

Project description:Rationale & objectiveFew studies have examined incident type 2 diabetes mellitus (T2DM) in chronic kidney disease (CKD). Our objective was to examine rates of and risk factors for T2DM in CKD, using several alternative measures of glycemic control.Study designProspective cohort study.Setting & participants1,713 participants with reduced glomerular filtration rates and without diabetes at baseline, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.PredictorsMeasures of kidney function and damage, fasting blood glucose, hemoglobin A1c (HbA1c), HOMA-IR (homeostatic model assessment of insulin resistance), demographics, family history of diabetes mellitus (DM), smoking status, medication use, systolic blood pressure, triglyceride level, high-density lipoprotein cholesterol level, body mass index, and physical activity.OutcomeIncident T2DM (defined as fasting blood glucose ≥ 126mg/dL or prescription of insulin or oral hypoglycemic agents).Analytical approachConcordance between fasting blood glucose and HbA1c levels was assessed using κ. Cause-specific hazards modeling, treating death and end-stage kidney disease as competing events, was used to predict incident T2DM.ResultsOverall T2DM incidence rate was 17.81 cases/1,000 person-years. Concordance between fasting blood glucose and HbA1c levels was low (κ for categorical versions of fasting blood glucose and HbA1c = 13%). Unadjusted associations of measures of kidney function and damage with incident T2DM were nonsignificant (P ≥ 0.4). In multivariable models, T2DM was significantly associated with fasting blood glucose level (P = 0.002) and family history of DM (P = 0.03). The adjusted association of HOMA-IR with T2DM was comparable to that of fasting blood glucose level; the association of HbA1c level was nonsignificant (P ≥ 0.1). Harrell's C for the models ranged from 0.62 to 0.68.LimitationsLimited number of outcome events; predictors limited to measures taken at baseline.ConclusionsThe T2DM incidence rate among individuals with CKD is markedly higher than in the general population, supporting the need for greater vigilance in this population. Measures of glycemic control and family history of DM were independently associated with incident T2DM.

Project description:Rationale & objectivesFew studies have investigated racial disparities in survival among dialysis patients in a manner that considers risk factors and mortality during the phase of kidney disease before maintenance dialysis. Our objective was to explore racial variations in survival among dialysis patients and relate them to racial differences in comorbid conditions and rates of death in the setting of kidney disease not yet requiring dialysis therapy.Study designRetrospective cohort study.Settings & participants3,288 black and white participants in the Chronic Renal Insufficiency Cohort (CRIC), none of whom were receiving dialysis at enrollment.ExposureRace.OutcomeMortality.Analytic approachCox proportional hazards regression was used to examine the association between race and mortality starting at: (1) time of dialysis initiation and (2) entry into the CRIC.ResultsDuring 7.1 years of median follow-up, 678 CRIC participants started dialysis. Starting from the time of dialysis initiation, blacks had lower risk for death (unadjusted HR, 0.67; 95% CI, 0.51-0.87) compared with whites. Starting from baseline CRIC enrollment, the strength of the association between some risk factors and dialysis was notably stronger for whites than blacks. For example, the HR for dialysis onset in the presence (vs absence) of heart failure at CRIC enrollment was 1.30 (95% CI, 1.01-1.68) for blacks versus 2.78 (95% CI, 1.90-4.50) for whites, suggesting differential severity of these risk factors by race. When we included deaths occurring both before and after dialysis, risk for death was higher among blacks (vs whites) starting from CRIC enrollment (HR, 1.41; 95% CI, 1.22-1.64), but this finding was attenuated in adjusted models (HR, 1.08; 95% CI, 0.91-1.28).LimitationsResidual confounding.ConclusionsThe apparent survival advantage among blacks over whites treated with dialysis may be attributed to selected transition of a subset of whites with more severe comorbid conditions onto dialysis.

Project description:Rationale & objectiveDysnatremias have been associated with an increased risk of mortality in the chronic kidney disease (CKD) population. Our objective is to identify the prevalence of and risk factors associated with dysnatremias in a CKD population and assess the association of dysnatremias with kidney failure and mortality among patients with CKD enrolled in the Chronic Renal Insufficiency Cohort Study.Study designAnalysis of prospective cohort study.Setting & participantsAdult patients aged 21-74 years with CKD from the Chronic Renal Insufficiency Cohort study.PredictorsBaseline and time-dependent hyponatremia and hypernatremia.OutcomesAll-cause mortality and kidney failure.Analytical approachBaseline characteristics were compared using χ2 tests for categorical variables, analysis of variance for age, and Kruskal-Wallis tests for laboratory variables. Cox proportional hazards models and competing risk models were used to evaluate the association between baseline sodium level and overall mortality.ResultsOf a total of 5,444 patients with CKD, 486 (9%) had hyponatremia and 53 (1%) had hypernatremia. Altogether, 1,508 patients died and 1,206 reached kidney failure. In adjusted Cox models, time-dependent dysnatremias were strongly associated with mortality for both hyponatremia (HR, 1.38; 95% CI, 1.16-1.64) and hypernatremia (HR, 1.54; 95% CI, 1.04-2.29). Factors associated with hyponatremia included female sex, diabetes, and hypertension. Regardless of age, time-dependent hypernatremia was associated with an increased risk of kidney failure (HR, 1.64; 95% CI, 1.06-2.53). Baseline and time-dependent hyponatremia were associated with an increased risk of kidney failure in patients younger than 65 (baseline hyponatremia HR, 1.30; 95% CI, 1.03-1.64 and time-dependent hyponatremia HR, 1.36; 95% CI, 1.09-1.70) but not among patients aged >65 years.LimitationsInability to establish causality and lack of generalizability to hospitalized patients.ConclusionsDysnatremias are prevalent among ambulatory CKD patients and are associated with mortality and kidney failure. Time-dependent dysnatremias were significantly associated with mortality in patients with CKD. Time-dependent hypernatremia was associated with progression to kidney failure. Baseline and time-dependent hyponatremia were associated with an increased risk of progression to kidney failure in those younger than 65 years.

Project description:Rationale & objectiveQuality of life in chronic kidney disease (CKD) is impaired by a large burden of symptoms including some that overlap with the symptoms of heart failure (HF). We studied a group of individuals with CKD to understand the patterns and trajectories of HF-type symptoms in this setting.Study designProspective cohort study.Setting & participants3,044 participants in the Chronic Renal Insufficiency Cohort (CRIC) without prior diagnosis of HF.PredictorsSociodemographics, medical history, medications, vital signs, laboratory values, echocardiographic and electrocardiographic parameters.OutcomeTrajectory over 5.5 years of a HF-type symptom score (modified Kansas City Cardiomyopathy Questionnaire [KCCQ] Overall Summary Score with a range of 0-100 where<75 reflects clinically significant symptoms).Analytical approachLatent class mixed models were used to model trajectories. Multinomial logistic regression was used to model relationships of predictors with trajectory group membership.ResultsFive trajectories of KCCQ score were identified in the cohort of 3,044 adults, 45% of whom were female, and whose median age was 61 years. Group 1 (41.7%) had a stable high score (minimal symptoms, average score of 96); groups 2 (35.6%) and 3 (15.6%) had stable but lower scores (mild symptoms [average of 81] and clinically significant symptoms [average of 52], respectively). Group 4 (4.9%) had a substantial worsening in symptoms over time (mean 31-point decline), and group 5 (2.2%) had a substantial improvement (mean 33-point increase) in KCCQ score. A majority of group 1 was male, without diabetes or obesity, and this group had higher baseline kidney function. A majority of groups 2 and 3 had diabetes and obesity. A majority of group 4 was male and had substantial proteinuria. Group 5 had the highest proportion of baseline cardiovascular disease (CVD).LimitationsNo validation cohort available, CKD management changes in recent years may alter trajectories, and latent class models depend on the missing at random assumption.ConclusionsDistinct HF-type symptom burden trajectories were identified in the setting of CKD, corresponding to different baseline characteristics. These results highlight the diversity of HF-type symptom experiences in individuals with CKD.

Project description:We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis patients when SBP is measured outside of the dialysis unit (out-of-dialysis-unit-SBP), despite there being a U-shaped association between SBP measured at the dialysis unit (dialysis-unit-SBP) with risk of mortality. Here, we explored the relationship between SBP with cardiovascular events, which has important treatment implications but has not been well elucidated. Among 383 hemodialysis participants enrolled in the prospective CRIC study (Chronic Renal Insufficiency Cohort), multivariable splines and Cox models were used to study the association between SBP and adjudicated cardiovascular events (heart failure, myocardial infarction, ischemic stroke, and peripheral artery disease), controlling for differences in demographics, cardiovascular disease risk factors, and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (r=0.34; P<0.001). We noted a U-shaped association of dialysis-unit-SBP and risk of cardiovascular events, with the nadir risk between 140 and 170 mm Hg. In contrast, there was a linear stepwise association between out-of-dialysis-unit-SBP with risk of cardiovascular events. Participants with out-of-dialysis-unit-SBP ≥128 mm Hg (top 2 quartiles) had >2-fold increased risk of cardiovascular events compared with those with out-of-dialysis-unit-SBP ≤112 mm Hg (3rd SBP quartile: adjusted hazard ratio, 2.08 [95% confidence interval, 1.12-3.87] and fourth SBP quartile: adjusted hazard ratio, 2.76 [95% confidence interval, 1.42-5.33]). In conclusion, among hemodialysis patients, although there is a U-shaped (paradoxical) association of dialysis-unit-SBP and risk of cardiovascular disease, there is a linear association of out-of-dialysis-unit-SBP with risk of cardiovascular disease. Out-of-dialysis-unit blood pressure provides key information and may be an important therapeutic target.

Dataset Information

Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Publications

Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

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