Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.

BACKGROUND: Coenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress. METHODS: We performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships. RESULTS: Fifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study. CONCLUSIONS: CoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis. TRIAL REGISTRATION: This clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009.

Glycemic load is associated with oxidative stress among prevalent maintenance hemodialysis patients.

BACKGROUND: High glycemic index (GI) and glycemic load (GL) are associated with increased levels of oxidative stress and systemic inflammation in the general population. Maintenance hemodialysis (MHD) patients are known to have excessive oxidative stress burden and inflammation. In this study, we examined the relationship between dietary GI or GL and markers of oxidative stress or inflammation among prevalent MHD patients. METHODS: A registered dietitian obtained GI, GL and other dietary data from 58 MHD patients. Two separate 24-h diet recalls (a hemodialysis day and a non-hemodialysis day) were analyzed using the Nutrition Data System for Research (NDS-R) software. Plasma or serum concentrations of F2-isoprostanes, high sensitivity C-reactive protein (hsCRP), leptin and adiponectin (ADPN) were measured in fasting state. Fat mass was measured by dual-energy X-ray absorptiometry (DEXA). Cross-sectional associations between GI, GL and markers of interest were examined by multiple regression analysis with adjustment for potential covariates. RESULTS: Mean (±SD) age, body mass index (BMI) and total trunk fat were 47 ± 12 years, 29.5 ± 6.8 kg/m(2) and 16.4 ± 8.8 kg, respectively. Dietary GI was associated with trunk fat (r = -0.182, P = 0.05) but not with F2-isoprostanes and hsCRP. In contrast, GL was significantly associated with F2-isoprostanes (P = 0.002), in unadjusted analysis, which remained in adjusted analyses, adjusting for age and sex (P = 0.005), and after adjusting for BMI, trunk fat and waist/hip ratio (P = 0.004). Addition of leptin or ADPN did not alter the significance of the association. GL also correlated with hsCRP (P = 0.03), but this association was modified by BMI and trunk fat. CONCLUSIONS: Dietary GL is significantly associated with markers of oxidative stress and inflammation among prevalent MHD patients, independent of the body composition and adipocytokines. These data indicate the importance of the contents of dietary nutrient intake composition and its potential role in determining the metabolic disturbances in MHD patients.

Development of a predictive energy equation for maintenance hemodialysis patients: a pilot study.

OBJECTIVE: The study objectives were to explore the predictors of measured resting energy expenditure (mREE) among a sample of maintenance hemodialysis (MHD) patients, to generate a predictive energy equation (MHDE), and to compare such models to another commonly used predictive energy equation in nutritional care, the Mifflin-St. Jeor equation (MSJE). DESIGN AND METHODS: The study was a retrospective, cross-sectional cohort design conducted at the Vanderbilt University Medical Center. Study subjects were adult MHD patients (N = 67). Data collected from several clinical trials were analyzed using Pearson's correlation and multivariate linear regression procedures. Demographic, anthropometric, clinical, and laboratory data were examined as potential predictors of mREE. Limits of agreement between the MHDE and the MSJE were evaluated using Bland-Altman plots. The a priori α was set at P < .05. The main outcome measure was mREE. RESULTS: The mean age of the sample was 47 ± 13 years. Fifty participants (75.6%) were African American, 7.5% were Hispanic, and 73.1% were males. Fat-free mass (FFM), serum albumin (ALB), age, weight, serum creatinine (CR), height, body mass index, sex, high-sensitivity C-reactive protein (CRP), and fat mass (FM) were all significantly (P < .05) correlated with mREE. After screening for multi-collinearity, the best predictive model (MHDE-lean body mass [LBM]) of mREE included (R(2) = 0.489) FFM, ALB, age, and CRP. Two additional models (MHDE-CRP and MHDE-CR) with acceptable predictability (R(2) = 0.460 and R(2) = 0.451) were derived to improve the clinical utility of the developed energy equation (MHDE-LBM). Using Bland-Altman plots, the MHDE over- and underpredicted mREE less often than the MSJE. CONCLUSIONS: Predictive models (MHDE) including selective demographic, clinical, and anthropometric data explained less than 50% variance of mREE but had better precision in determining energy requirements for MHD patients when compared with MSJE. Further research is necessary to improve predictive models of mREE in the MHD population and to test its validity and clinical application.

A pilot study of active vitamin D administration and insulin resistance in African American patients undergoing chronic hemodialysis.

OBJECTIVE: Insulin resistance (IR) is associated with increased cardiovascular risk in multiple patient populations, including those undergoing chronic hemodialysis (CHD). Active vitamin D deficiency has been proposed to play a role in the extent of IR observed in patients with CHD. We postulated that administration of paracalcitol, an active vitamin D medication, influences IR in patients with CHD. DESIGN AND METHODS: This was a pilot randomized controlled trial. Ten prevalent CHD patients receiving a stable dose of paracalcitol were recruited. Paracalcitol was withheld for 8 weeks in all patients (phase I). Parathyroid hormone levels were managed with the calcium-sensing receptor agonist cinacalcet. At week 8, patients were randomized to continue cinacalcet or to restart paracalcitol for 8 weeks (phase II). The primary outcome was the change in IR measured by the glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp (HEGC) method. Secondary outcomes included changes in IR between groups in indirect indices of IR, biomarkers of inflammation, and adipokine levels. RESULTS: The mean age was 49 years (range, 46-57 years) and 40% of patients were women. There was no detectable change in the GDR at the end of phase I (P = .7) when compared with baseline values. There was also no statistically significant difference in GDR between groups at the end of phase II (P = .9). No changes were observed in indirect indices of IR, adipokine levels, or biomarkers of inflammation in either phase. CONCLUSION: The results of this pilot study suggest that withdrawal of paracalcitol over 8 to 16 weeks and replacement for 8 weeks after withdrawal does not influence IR measured by HEGC in patients receiving CHD.

Insulin resistance and protein metabolism in chronic hemodialysis patients.

OBJECTIVE: Loss of lean body mass (sarcopenia) is associated with increased morbidity and mortality in patients receiving chronic hemodialysis (CHD). Insulin resistance (IR), which is highly prevalent in patients receiving CHD, has been proposed to play a critical role in the development of sarcopenia. The aim of this study was to examine the effect of IR on amino acid metabolism in patients receiving CHD. DESIGN: This was a cross-sectional study. SUBJECTS: The study included 12 prevalent (i.e., patients that have been on dialysis for more than 90 days) African American patients receiving CHD. METHODS: IR was measured as glucose disposal rate (GDR) determined from hyperinsulinemic euglycemic clamp (HGEC) studies performed 3 consecutive times. Plasma amino acid (AA) concentrations were measured by real-time high-performance liquid chromatography (HPLC) throughout the clamp study. The primary outcome was percentage change in leucine concentrations during the clamp study. The main predictor was the GDR measured simultaneously during the HGEC studies. Mixed model analysis was used to account for repeated measures. RESULTS: All individual AA concentrations declined significantly in response to high-dose insulin administration (P < .001). There was a significant direct association between GDR by HECG studies and the percentage change in leucine concentration (P = .02). Although positive correlations were observed between GDR values and concentration changes from baseline for other AAs, these associations did not reach statistical significance. CONCLUSIONS: Our results suggest that the severity of IR of carbohydrate metabolism is associated with a lesser decline in plasma leucine concentrations, suggesting a similar resistance to protein anabolism. Insulin resistance represents a potential mechanism for sarcopenia commonly observed in patients receiving CHD.

A comparison of novel and commonly-used indices of insulin sensitivity in African American chronic hemodialysis patients.

BACKGROUND: Insulin resistance (IR) is highly prevalent in chronic hemodialysis (CHD) patients and is associated with poor cardiovascular outcomes. Hyperinsulinemic euglycemic glucose clamp (HEGC) is the gold standard for measuring IR. The comparison of commonly-used indirect indices of IR to HEGC has not been adequately performed in this population. Furthermore, the validity of newly proposed adipokine-based IR indices has not been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is an observational study performed in a single center, involving 12 prevalent CHD patients (50 ± 9 years old, 100% African American, 33% women, body mass index of 34.4 ± 7.6 kg/m(2)) who were studied three consecutive times. IR was assessed by HEGC (glucose-disposal rate [GDR]), homeostatic model assessment of IR (HOMA-IR), HOMA-IR corrected by adiponectin (HOMA-AD), leptin adiponectin ratio (LAR), QUICKI, and the McAuley's index at each time point. RESULTS: Eighty-three percent of the subjects displayed either glucose intolerance or overt insulin resistance by HEGC (GDR median, 5.71; interquartile range [IQR], 4.16, 6.81). LAR and HOMA-AD were the best correlates of IR measured by HEGC (r=-0.72, P<0.001, and -0.67, P<0.001), respectively. Fat percentage, interleukin-6, and adipokines (leptin, adiponectin, and resistin) were strongly associated with GDR. HEGC, LAR, and HOMA-AD had the best intraclass correlation coefficients. CONCLUSION: IR is common in CHD patients. Adipokine-based indices are the best correlates of IR measurements by HEGC. HOMA-IR and QUICKI are reasonable alternatives. Use of these indices may allow better detection of alterations in insulin sensitivity in CHD patients.

The effect of resistance exercise to augment long-term benefits of intradialytic oral nutritional supplementation in chronic hemodialysis patients.

BACKGROUND: Resistance exercise combined with intradialytic oral nutrition (IDON) supplementation improves net protein balance in the acute setting in chronic hemodialysis patients. We hypothesized that combination of long-term resistance exercise and IDON would improve markers of muscle mass and strength further compared with IDON alone. METHODS: Thirty-two participants (21 male; mean age, 43 ± 13 years) on chronic hemodialysis were randomly assigned to IDON plus resistance exercise (NS + EX), or IDON (NS) alone for 6 months. IDON consisted of a lactose-free formula consisting of protein, carbohydrate, and fat. Three sets of 12 repetitions of leg-press were completed before each dialysis session in the NS + EX arm. Primary outcome measurement was lean body mass. Muscle strength and other nutritional parameters were measured as secondary outcomes. RESULTS: Of 32 participants, 22 completed the 6-month intervention. There were no statistically significant differences between the study interventions with respect to changes in lean body mass and body weight, when comparing NS + EX to NS. There were also no statistically significant differences in any of the secondary outcomes measured in the study. Body weight (80.3 ± 16.6 kg, 81.1 ± 17.5 kg, and 80.9 ± 18.2 kg at baseline, month 3, and month 6, respectively; P = .02) and 1-repetition maximum (468 ± 148 lb, 535 ± 144 lb, and 552 ± 142 lb, respectively; P = .001) increased statistically significantly during the study for all patients combined. CONCLUSION: This study did not show further benefits of additional resistance exercise on long-term somatic protein accretion above and beyond nutritional supplementation alone. When both treatments groups were combined, body weight and muscle strength improved during the study.

Oral protein supplementation alone improves anabolism in a dose-dependent manner in chronic hemodialysis patients.

OBJECTIVE: We examined the protein anabolic effects of Pro-Stat 64, a high nitrogen-containing, enzyme-hydrolyzed, tryptophan-fortified, collagen protein supplement administrated during hemodialysis, at two different dosing regimens. DESIGN: This was a randomized, controlled, prospective study with 3 different groups: control, single dose of supplementation, and double dose of supplementation. SETTING: This study was performed at a clinical research center. PATIENTS: Six prevalent chronic hemodialysis (HD) patients were enrolled: 5 males, 1 female, 4 African Americans, and 2 Caucasians. Their mean age was 45 +/- 11 years (S.D.). Two patients were diabetic. METHODS: Protein turnover studies were performed using amino-acid (AA) balance and primed constant infusion of L-(1-(13)C) leucine. MAIN OUTCOME MEASURE: Whole-body protein balance was determined according to substrate kinetics. RESULTS: There were no statistically significant difference at any time point between protocols for blood chemistries and hormonal markers, except for minor variations in plasma glucose. All plasma AA groups displayed decreases during a control study, in which no supplementation was given. Compared with the control group, plasma nonessential AA and total AA concentrations were statistically significantly higher during HD after both single and double doses of supplementation. The forearm arteriovenous AA balance was statistically significantly better for essential, nonessential, and total AA uptake after both single-dose and double-dose supplementation compared with the control group, except for nonessential AA, which was significantly better only after a double dose. Whole-body protein breakdown and net protein balance were statistically significantly better during HD with a double-dose administration in a dose-dependent manner, compared with the control and single-dose groups. CONCLUSIONS: Oral AA supplementation alone improves whole-body and skeletal muscle protein anabolism in a dose-dependent manner in chronic HD patients. These data should be taken into account during clinical decision-making or when designing clinical trials of nutritional supplementation.