Background Oxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the ...potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis. Study Design Placebo-controlled, 3-arm, double-blind, randomized, clinical trial. Setting & Participants 65 patients undergoing thrice-weekly maintenance hemodialysis. Intervention Patients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10 ; 600 or 1,200 mg) or matching placebo for 4 months. Outcomes The primary outcome was plasma oxidative stress, defined as plasma concentration of F2 -isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability. Measurements F2 -isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro−brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months. Results Of 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200 mg, but not 600 mg, of CoQ10 significantly reduced plasma F2 -isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of −10.7 95% CI, −7.1 to −14.3 pg/mL P < 0.001 and −8.3 95% CI, −5.5 to −11.0 pg/mL P = 0.1, respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures. Limitations Study not powered to detect small treatment effects; difference in baseline characteristics among randomized groups. Conclusions In patients undergoing maintenance hemodialysis, daily supplementation with 1,200 mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2 -isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.
While major depression is known to be associated with glomerular filtration rate (GFR) decline, there is a lack of data on the association of other mental illnesses like posttraumatic stress disorder ...(PTSD) with kidney disease. In 640 adult participants of the Heart and Soul Study (mean baseline age of 66.2 years) with a high prevalence cardiovascular disease, hypertension and diabetes, we examined the association of PTSD with GFR decline over a 5‐year follow‐up. We observed a significantly greater estimated (e) GFR decline over time in those with PTSD compared to those without (2.97 vs. 2.11 ml/min/1.73 m2/year; p = .022). PTSD was associated with 91% (95% CI 12%–225%) higher odds of ‘rapid’ versus ‘mild’ (>3.0 vs. <3.0 ml/min/1.73 m2/per year) eGFR decline. These associations remained consistent despite controlling for demographics, medical comorbidities, other mental disorders and psychiatric medications. In conclusion, our study provides evidence that PTSD is independently associated with GFR decline in middle‐aged adults with a high comorbidity burden. This association needs to be examined in larger cohorts with longer follow‐ups.
Summary at a Glance
There is lack of data on the association of posttraumatic stress disorder (PTSD) with kidney disease. In middle aged adults with a high comorbidity burden, we observed a significantly greater eGFR decline over time in those with PTSD compared to those without after controlling for demographics, medical comorbidities, other mental disorders and psychiatric medications.
Background Frailty is a construct developed to characterize a state of reduced functional capacity in older adults. However, there are limited data describing the prevalence or consequences of ...frailty in middle-aged patients with chronic kidney disease (CKD). Study Design Observational study. Setting & Participants 336 non–dialysis-dependent patients with stages 1-4 CKD with estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2 (by the CKD-EPI CKD Epidemiology Collaboration serum creatinine–based equation) or evidence of microalbuminuria enrolled in the Seattle Kidney Study, a clinic-based cohort study. Findings were compared with community-dwelling older adults in the Cardiovascular Health Study. Outcome Prevalence and determinants of frailty in addition to its association with the combined outcome of all-cause mortality or renal replacement therapy. Measurements We defined frailty according to established criteria as 3 or more of the following characteristics: slow gait, weakness, unintentional weight loss, exhaustion, and low physical activity. We estimated kidney function using serum cystatin C concentrations (eGFRcys ) to minimize confounding due to relationships of serum creatinine levels with muscle mass and frailty. Results The mean age of the study population was 59 years and mean eGFRcys was 51 mL/min/1.73 m2 . The prevalence of frailty (14.0%) was twice that of the much older non-CKD reference population ( P < 0.01). The most common frailty components were physical inactivity and exhaustion. After adjustment including diabetes, eGFRcys categories of <30 and 30-44 mL/min/1.73 m2 were associated with a 2.8- (95% CI, 1.3-6.3) and 2.1 (95% CI, 1.0-4.7)-fold greater prevalence of frailty compared with GFRcys ≥60 mL/min/1.73 m2 . There were 63 events during a median 987 days of follow-up. After adjustment, the frailty phenotype was associated with an estimated 2.5 (95% CI, 1.4-4.4)-fold greater risk of death or dialysis therapy. Limitations Cross-sectional study design obscures inference regarding temporal relationships between CKD and frailty. Conclusions Frailty is relatively common in middle-aged patients with CKD and is associated with lower eGFRcys and increased risk of death or dialysis therapy.
Background Genetics, along with lifestyle and behavioral characteristics, play an important role in hypertension in adults. Our aim was to identify genetic variants associated with blood pressure in ...childhood and adolescence. Methods and Results We conducted a candidate single-nucleotide polymorphism (SNP) analysis and genome-wide association study among 9778 participants aged <18 years in BioVU, the Vanderbilt University Medical Center biobank. The outcome was childhood blood pressure percentile from age 0 to 18 years. For the candidate SNP analysis, a total of 457 previously identified SNPs were examined. Linear regression was used to test the association between genetic variants and median systolic blood pressure (SBP) percentile. Adjusted models included median age, self-reported sex, race, the first 4 principal components of ancestry, and median body mass index
score. Analyses were conducted in the overall cohort and stratified by age group. A polygenic risk score was calculated for each participant, and the association between polygenic risk score and median SBP percentile in childhood was examined using linear regression. In the overall candidate SNP analysis, 2 SNPs reached significance:
(
;
=1.0×10
) and
(
;
=1.4×10
). In the postpuberty age group, 1 SNP reached significance:
(
;
=2.2×10
). In the genome-wide association study of all participants, no SNPs reached genome-wide significance. Higher polygenic risk score was associated with higher SBP percentile (β, 0.35 95% CI, 0.10-0.60), and there was a significant interaction with age (
for interaction<0.01). Conclusions These findings suggest that genetic variants play an important role in SBP in childhood and adolescence and provide evidence for age-specific genetic associations with SBP.
Background Chronic kidney disease is associated with malnutrition and inflammation. These processes may lead to loss of skeletal muscle and reduced physical performance. Associations of kidney ...function with muscle composition and longitudinal measures of physical performance are unknown. Study Design Prospective cohort study. Setting & Participants We evaluated 826 community-dwelling older adults enrolled in the Invecchiare in Chianti (InCHIANTI) Study who were free of baseline stroke or activities of daily living disability. Predictor Baseline creatinine clearance (Clcr) based on 24-hour urine collection. Outcomes Cross-sectional and longitudinal trajectories of physical performance measured by 7-m usual gait speed, 400-m fast gait speed, and knee extension strength using isometric dynamometry. Calf muscle composition assessed by quantitative computed tomography. Results Mean age of participants was 74 ± 7 (SD) years, with 183 having Clcr < 60 mL/min/1.73 m2 . After adjustment, each 10–mL/min/1.73 m2 decrement in Clcr was associated with 0.01 (95% CI, 0.004-0.017) m/s slower 7-m usual walking speed and 0.008 (95% CI, 0.002-0.014) m/s slower 400-m walking speed. Each 10–mL/min/1.73 m2 decrement in Clcr was associated with 28 (95% CI, 0.8-55) mm2 lower muscle area and 0.15 (95% CI, 0.04-0.26) mg/cm3 lower muscle density. After adjustment, lower Clcr was associated with slower mean 7-m ( P = 0.005) and 400-m ( P = 0.02) walk and knee extension strength ( P = 0.001) during the course of follow-up. During a mean follow-up of 7.1 ± 2.5 years, each 10–mL/min/1.73 m2 lower baseline Clcr was associated with 0.024 (95% CI, 0.01-0.037) kg/y greater decline in knee strength. Limitations Single baseline measurement of Clcr and 3-year interval between follow-up visits may lead to nondifferential misclassification and attenuation of estimates. Conclusions Among older adults, lower Clcr is associated with muscle atrophy, reduced walking speed, and more rapid declines in lower-extremity strength over time.
Background Sodium (Na
) stored in skin and muscle tissue is associated with essential hypertension. Sodium magnetic resonance imaging is a validated method of quantifying tissue stores of Na
. In ...this study, we evaluated tissue Na
in patients with elevated blood pressure or stage I hypertension in response to diuretic therapy or low Na
diet. Methods and Results In a double-blinded, placebo-controlled trial, patients with systolic blood pressure 120 to 139 mm Hg were randomized to low sodium diet (<2 g of sodium), chlorthalidone, spironolactone, or placebo for 8 weeks. Muscle and skin Na
using sodium magnetic resonance imaging and pulse wave velocity were assessed at the beginning and end of the study. Ninety-eight patients were enrolled to undergo baseline measurements and 54 completed randomization. Median baseline muscle and skin Na
in 98 patients were 16.4 mmol/L (14.9, 18.9) and 13.1 mmol/L (11.1, 16.1), respectively. After 8 weeks, muscle Na
increased in the diet and chlorthalidone arms compared with placebo. Skin sodium was decreased only in the diet arm compared with placebo. These associations remained significant after adjustment for age, sex, body mass index, systolic blood pressure, and urinary sodium. No changes were observed in pulse wave velocity among the different groups when compared with placebo. Conclusions Diuretic therapy for 8 weeks did not decrease muscle or skin sodium or improve pulse wave velocity in patients with elevated blood pressure or stage I hypertension. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02236520.
Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 ...(GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD.
Observational cohort study.
Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study).
Circulating GDF-15, Gal-3, and sST2 measured at baseline.
Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident.
Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function.
Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m2. Higher GDF-15 (adjusted HR aHR per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events.
Event rates for heart failure and atherosclerotic CVD were low.
Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.
Growth differentiation factor-15 (GDF-15) is a member of the TGF-
cytokine superfamily that is widely expressed and may be induced in response to tissue injury. Elevations in GDF-15 may identify a ...novel pathway involved in loss of kidney function among patients with CKD. Among participants in the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS), we tested whether kidney tissue expression of
mRNA correlates with circulating levels of GDF-15 and whether elevations in circulating GDF-15 are associated with decline in kidney function. In matching samples of 24 patients with CKD from the C-PROBE study, circulating GDF-15 levels significantly correlated with intrarenal
transcript levels (
=0.54,
=0.01). Among the 224 C-PROBE and 297 SKS participants, 72 (32.1%) and 94 (32.0%) patients, respectively, reached a composite end point of 30% decline in eGFR or progression to ESRD over a median of 1.8 and 2.0 years of follow up, respectively. In multivariable models, after adjusting for potential confounders, every doubling of GDF-15 level associated with a 72% higher (95% confidence interval, 1.21 to 4.45;
=0.003) and 65% higher (95% confidence interval, 1.08 to 2.50;
=0.02) risk of progression of kidney disease in C-PROBE and SKS participants, respectively. These results show that circulating GDF-15 levels strongly correlated with intrarenal expression of
and significantly associated with increased risk of CKD progression in two independent cohorts. Circulating GDF-15 may be a marker for intrarenal
-related signaling pathways associated with CKD and CKD progression.
Background The ratio of 24,25-dihydroxyvitamin D
/25-hydroxyvitamin D
(vitamin D metabolite ratio VDMR) may reflect functional vitamin D activity. We examined associations of the VDMR, ...25-hydroxyvitamin D (25OHD), and 1,25-dihydroxyvitamin D (1,25OH
D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D
, 25(OH)D, and 1,25(OH)
D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)
D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)
D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR 95% CI, 0.95-1.31). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m
per 10 ng/mL lower 95% CI, 0.0-1.3). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)
D were not associated with incident CVD in chronic kidney disease.
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