Non-invasive Quantification of Fat Deposits in Skeletal Muscle Predicts Cardiovascular Outcome in Kidney Failure.
ABSTRACT: Fat accumulation in skeletal muscle was recently established as a major risk factor for cardiovascular disease (CVD) in the general population, but its relevance for patients with kidney failure is unknown. Here we examined the potential association between muscle radiation attenuation (MRA), a non-invasive indicator of fat deposits in muscle, and cardiovascular events in patients with kidney failure treated with peritoneal dialysis (PD) and investigated dynamic changes and determinants of MRA in this population. We retrospectively assessed MRA on computed tomography images collected yearly in 101 incident patients with kidney failure starting PD between January 2006 and December 2015. After a median of 21 months on dialysis, 34 patients had 58 non-fatal cardiovascular events, and 22 patients had died. Baseline MRA was associated with cardiovascular events during time on dialysis, and patients with higher MRA (reflecting lower amounts of fat in muscle) showed a reduced incidence of CVD, independently of traditional risk factors (adjusted HR, 0.91; 95% CI, 0.86-0.97, P = 0.006). Multivariate regression analysis identified old age, female gender, visceral fat area, and low residual urine volume as independent determinants of MRA. As compared with reference values from a healthy population, patients with kidney failure had lower MRA (i.e., increased fat accumulation), independently of age, gender, and body-mass index. The subset of patients who underwent kidney transplantation showed a significant increase in MRA after restoration of kidney function. These observations expand the association between ectopic fat accumulation and CVD to the population on dialysis, and suggest that kidney failure is reversibly associated with fatty muscle infiltration.
Project description:Cardiovascular disease (CVD) is exceedingly severe in patients with chronic kidney disease (CKD) and further aggravated by peritoneal dialysis (PD), exposing the patients to excessive amounts of intraperitoneal glucose. Children are devoid of pre-existing CVD and give insight into specific uremia and PD induced pathomechanisms. Fat surrounded omental arterioles beyond PD fluid penetration level were microdissected from uremic children at time of first PD catheter insertion (n=8), children on PD (n=5), and age and gender matched non-uremic children as controls (n=6). Adjacent sections of 4 arterioles per patient were used for transcriptomic analyses.
Project description:Cardiovascular disease (CVD) is exceedingly severe in patients with chronic kidney disease (CKD) and further aggravated by peritoneal dialysis (PD), exposing the patients to excessive amounts of intraperitoneal glucose. Children are devoid of pre-existing CVD and give insight into specific uremia and PD induced pathomechanisms. Fat surrounded omental arterioles beyond PD fluid penetration level were microdissected from uremic children at time of first PD catheter insertion (n=8), children on PD (n=5), and age and gender matched non-uremic children as controls (n=6). Adjacent sections of 4 arterioles per patient were used for proteomic analyses.
Project description:Cardiovascular disease (CVD) is the main cause of premature death in patients with chronic kidney disease (CKD). The underlying mechanisms of CVD in patients with mild to moderate CKD are different from those with end-stage renal disease (ESRD). While serum cholesterol is frequently elevated and contributes to atherosclerosis in many CKD patients, particularly those with nephrotic proteinuria, it is usually normal, even subnormal, in most ESRD patients receiving hemodialysis. CVD in the ESRD population is primarily driven by oxidative stress, inflammation, accumulation of the oxidation-prone intermediate-density lipoproteins, chylomicron remnants and small dense low-density lipoprotein particles as well as high-density lipoprotein deficiency and dysfunction, hypertension, vascular calcification, and arrhythmias. Only a minority of hemodialysis patients have hypercholesterolemia which is most likely due to genetic or unrelated factors. In addition, due to peritoneal losses of proteins which simulate nephrotic syndrome, peritoneal dialysis patients often exhibit hypercholesterolemia. Clearly when present, hypercholesterolemia contributes to CVD in the CKD and ESRD population and justifies cholesterol-lowering therapy. However, the majority of ESRD patients and a subpopulation of CKD patients with minimal proteinuria have normal or subnormal serum cholesterol levels and do not benefit from and can be potentially harmed by statin therapy. In fact the lack of efficacy of statins in hemodialysis patients has been demonstrated in several randomized clinical trials. This review is intended to provide an overview of the mechanisms responsible for the failure of statins to reduce cardiovascular morbidity and mortality in most ESRD patients and to advocate the adoption of individualized care principles in the management of dyslipidemia in this population.
Project description:Blood pressure is a modifiable risk for cardiovascular disease (CVD). Among hemodialysis patients, there is a U-shaped association between blood pressure and risk of death. However, few studies have examined the association between blood pressure and CVD in patients with stage 4 and 5 chronic kidney disease. Here we studied 1795 Chronic Renal Insufficiency Cohort (CRIC) Study participants with estimated glomerular filtration rate <30 ml/min per 1.73 m2 and not on dialysis. The association of systolic (SBP), diastolic (DBP), and pulse pressure with the risk of physician-adjudicated atherosclerotic CVD (stroke, myocardial infarction, or peripheral arterial disease) and heart failure was tested using Cox regression adjusted for demographics, comorbidity and medications. There was a significant association with higher SBP (adjusted hazard ratio 2.04 [95% confidence interval: 1.46-2.84]) for SBP over 140 vs under 120 mmHg, higher DBP (2.52 [1.54-4.11]) for DBP >90 mm Hg versus <80 mm Hg and higher pulse pressure (2.67 [1.82-3.92]) for pulse pressure >68 mm Hg versus <51 mm Hg with atherosclerotic CVD. For heart failure, there was a significant association with higher pulse pressure only (1.42 [1.05-1.92]) for pulse pressure >68 mm Hg versus <51 mmHg, but not for SBP or DBP. Thus, among participants with stage 4 and 5 chronic kidney disease, there was an independent association between higher SBP, DBP, and pulse pressure with the risk of atherosclerotic CVD, whereas only higher pulse pressure was independently associated with a greater risk of heart failure. Further trials are needed to determine whether aggressive reduction of blood pressure decreases the risk of CVD events in patients with stage 4 and 5 chronic kidney disease.
Project description:Objective:Linagliptin, a dipeptidyl peptidase-4 inhibitor, demonstrated cardiovascular and renal safety in type 2 diabetes mellitus (T2DM) patients with established cardiovascular disease (CVD) with albuminuria and/or kidney disease in the multinational CARMELINA® trial. We investigated the effects of linagliptin in Asian patients in CARMELINA®. Methods:T2DM patients with HbA1c 6.5-10.0% and established CVD with urinary albumin-to-creatinine ratio (UACR)?>?30 mg/g, and/or prevalent kidney disease (estimated glomerular filtration rate [eGFR] 15-<?45 ml/min/1.73 m2 or ??45-75 with UACR >?200 mg/g), were randomized to linagliptin or placebo added to usual care. The primary endpoint was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE). Results:Of the 6979 patients, 555 (8.0%) were Asians living in Asia. During a median follow-up of 2.2 years, 3-point MACE occurred in 29/272 (10.7%) and 33/283 (11.7%) of linagliptin and placebo patients, respectively (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.55-1.48), consistent with the overall population (HR 1.02; 95% CI 0.89-1.17; P value for treatment-by-region interaction: 0.3349). Similar neutrality in Asian patients was seen for other cardiorenal events including the secondary kidney endpoint of death from renal failure, progression to end-stage kidney disease, or???40% eGFR decrease (HR 0.96; 95% CI 0.58-1.59). Linagliptin was associated with a nominal decrease in the risk of hospitalization for heart failure (HR 0.47; 95% CI 0.24-0.95). Overall in Asian patients, linagliptin had an adverse event rate similar to placebo, consistent with the overall population. Conclusions:Linagliptin showed cardiovascular and renal safety in Asian patients with T2DM and established CVD with albuminuria and/or kidney disease.
Project description:BACKGROUND: About 39,000 patients were newly prescribed renal replacement therapy in Japan in 2011, resulting in a total of more than 300,000 patients being treated with dialysis. This high prevalence of treated end stage kidney disease (ESKD) patients is an emergent problem that requires immediate attention. We launched a prospective cohort study to evaluate population specific characteristics of the progression of chronic kidney disease (CKD). In this report, we describe the baseline characteristics and risk factors for cardiovascular disease (CVD) prevalence among this cohort. METHODS: New patients from 16 nephrology centers who were older than 20 years of age and who visited or were referred for the treatment of CKD stage 2-5, but were not on dialysis therapy, were recruited in this study. At enrollment, medical history, lifestyle behaviors, functional status and current medications were recorded, and blood and urine samples were collected. Estimated glomerular filtration rate (eGFR) was calculated by a modified three-variable equation. RESULTS: We enrolled 1138 patients, 69.6% of whom were male, with a mean age of 68 years. Compared with Western cohorts, patients in this study had a lower body mass index (BMI) and higher proteinuria. The prevalence of CVD was 26.8%, which was lower than that in Western cohorts but higher than that in the general Japanese population. Multivariate analysis demonstrated the following association with CVD prevalence: hypertension (adjusted odds ratio (aOR) 3.57; 95% confidence interval (CI) 1.82-7.02); diabetes (aOR 2.45; 95% CI 1.86-3.23); hemoglobin level less than 11 g/dl (aOR 1.61; 95% CI 1.21-2.15); receiving anti-hypertensive agents (aOR 3.54; 95% CI 2.27-5.53); and statin therapy (aOR 2.73; 95% CI 2.04-3.66). The combination of decreased eGFR and increased proteinuria was also associated with a higher prevalence of CVD. CONCLUSIONS: The participants in this cohort had a lower BMI, higher proteinuria and lower prevalence of CVD compared with Western cohorts. Lower eGFR and high proteinuria were associated with CVD prevalence. Prospective follow up of these study patients will contribute to establishment of individual population-based treatment of CKD.
Project description:Perceived risks of hyperkalemia and acute renal insufficiency may limit use of mineralocorticoid receptor antagonist (MRA) therapy in patients with heart failure, especially those with diabetes mellitus or chronic kidney disease.Using clinical registry data linked to Medicare claims, we analyzed patients hospitalized with heart failure between 2005 and 2013 with a history of diabetes mellitus or chronic kidney disease. We stratified patients by MRA use at discharge. We used inverse probability-weighted proportional hazards models to assess associations between MRA therapy and 30-day, 1-year, and 3-year mortality, all-cause readmission, and readmission for heart failure, hyperkalemia, and acute renal insufficiency. We performed interaction analyses for differential effects on 3-year outcomes for reduced, borderline, and preserved ejection fraction. Of 16 848 patients, 12.3% received MRA therapy at discharge. Higher serum creatinine was associated with lower odds of MRA use (odds ratio, 0.66; 95% confidence interval, 0.61-0.71); serum potassium was not (odds ratio, 1.00; 95% confidence interval, 0.90-1.11). There was no mortality difference between groups. MRA therapy was associated with greater risks of readmission for hyperkalemia and acute renal insufficiency and lower risks of long-term all-cause readmission. Patients on MRA therapy with borderline or preserved ejection fraction had greater risks of readmission for hyperkalemia (P=0.02) and acute renal insufficiency (P<0.001); patients with reduced ejection fraction did not.Among patients with heart failure and diabetes mellitus or chronic kidney disease, MRA use was associated with lower risk of all-cause readmission despite greater risk of hyperkalemia and acute renal insufficiency.
Project description:Leptin and adiponectin are important regulators of energy metabolism and body composition. Leptin exerts cardiodepressive effects, whereas adiponectin has cardioprotective effects, but several conflicting findings have been reported. The aim of the present study was to assess the relationship between serum leptin and adiponectin levels and echocardiographic parameters and pathophysiological states in patients with cardiovascular disease (CVD) receiving cardiovascular surgery. A total of 128 patients (79 males, average age 69.6 years) that had surgery for CVD including coronary artery bypass graft (CABG) and valve replacement were recruited in this study. Preoperative serum adiponectin and leptin concentrations were measured by enzyme-linked immunosorbent assay and compared with preoperative echocardiographic findings. Body fat volume and skeletal muscle volume index (SMI) were estimated using bioelectrical impedance analysis. We also measured grip strength and gait speed. Sarcopenia was diagnosed based on the recommendations of the Asian Working Group on Sarcopenia. Positive correlations were found between adiponectin and brain natriuretic peptide (BNP), age, left atrial diameter (LAD), E/e' (early-diastolic left ventricular inflow velocity / early-diastolic mitral annular velocity), and left atrial volume index (LAVI). Negative correlations were observed between adiponectin and body mass index (BMI), estimated glomerular filtration rate (eGFR), triglyceride, hemoglobin, and albumin. Serum leptin was positively correlated with BMI, total cholesterol, triglyceride, albumin, body fat volume, and LV ejection fraction (LVEF), whereas it was negatively correlated with BNP and echocardiographic parameters (LAD, LV mass index (LVMI), and LAVI). Multiple regression analysis showed associations between log (leptin) and log (adiponectin) and echocardiographic parameters after adjusting for age, sex, and BMI. Serum adiponectin was negatively correlated with leptin, but positively correlated with tumor necrosis factor ? (TNF?), an inflammatory cytokine. In males, serum leptin level had a positive correlation with skeletal muscle volume and SMI. However, adiponectin had a negative correlation with anterior mid-thigh muscle thickness, skeletal muscle volume and SMI. And, it was an independent predictive factor in males for sarcopenia even after adjusted by age. These results suggest that leptin and adiponectin may play a role in cardiac remodeling in CVD patients receiving cardiovascular surgery. And, adiponectin appears to be a marker of impaired metabolic signaling that is linked to heart failure progression including inflammation, poor nutrition, and muscle wasting in CVD patients receiving cardiovascular surgery.
Project description:<label>BACKGROUND</label>Heart failure guidelines recommend routine monitoring of serum potassium, and renal function in patients treated with a mineralocorticoid receptor antagonist (MRA). How these recommendations are implemented in high-risk patients or according to setting of drug initiation is poorly characterized.<label>METHODS AND RESULTS</label>We conducted a retrospective cohort study of Medicare beneficiaries linked to laboratory data in 10 states with prevalent heart failure as of July 1, 2011, and incident MRA use between May 1 and September 30, 2011. Outcomes included laboratory testing before MRA initiation and in the early (days 1-10) and extended (days 11-90) post-initiation periods, based on setting of drug initiation and the presence of renal insufficiency. Additional outcomes included abnormal laboratory results and adverse events proximate to MRA initiation. Of 10?443 Medicare beneficiaries with heart failure started on an MRA, 19.7% were initiated during a hospitalization. Appropriate follow-up laboratory testing across all time periods occurred in 25.2% of patients with inpatient initiation compared with 2.8% of patients begun as an outpatient. Patients with chronic kidney disease had higher rates of both hyperkalemia and acute kidney failure in the early (1.3% and 2.7%, respectively) and extended (5.6% and 9.8%, respectively) post-initiation periods compared with those without chronic kidney disease.<label>CONCLUSIONS</label>Patients initiated on MRA therapy as an outpatient had extremely poor rates of guideline indicated follow-up laboratory monitoring after drug initiation. In particular, patients with chronic kidney disease are at high risk for adverse events after MRA initiation. Quality improvement initiatives focused on systems to improve appropriate laboratory monitoring are needed.
Project description:Although central fat is a well-known risk factor for cardiovascular disease (CVD) and cardiometabolic disorders, the effect of other regional fats or muscle distribution on CVD risk has not been fully investigated.This was a cross-sectional study using nationally representative samples of 15,686 subjects from the 2008-2011 Korea National Health and Nutrition Examination Survey. Individual CVD risk was evaluated in adults aged ?20 without prior CVD, using atherosclerotic cardiovascular disease (ASCVD) risk equations according to the 2013 ACC/AHA guidelines. Body composition was assessed by dual X-ray absorptiometry.Ratio of leg fat to total fat (LF/TF ratio) was the most predictive for CVD among body fat or muscle distribution parameters (AUC = 0.748, 95% CI 0.741-0.755). ASCVD risk score was gradually increased with decreased LF/TF ratio (P < 0.001), and individuals whose LF/TF ratio in lowest tertile tended to belong to the high-risk (10-year risk >10%) group compared to those in the highest tertile (OR = 6.25, 95% CI 5.60-6.98). Subjects in the lowest tertile showed increased risk of cardiometabolic risk factor components including obesity, hypertension, diabetes, dyslipidemia, chronic kidney disease, and albuminuria (OR range 2.57-11.24, all P < 0.001). In addition, a higher LF/TF ratio was associated with decreased ASCVD risk, even in subjects with multiple CVD risk factors. Multiple logistic regression analyses also demonstrated this association (OR = 1.85, 95% CI 1.36-2.52).Among various body composition parameters, LF/TF ratio was superior in predicting higher CVD risk and a higher LF/TF ratio was independently associated with decreased risk of CVD and each cardiometabolic risk factor.