Acute high-dose MitoQ does not increase urinary kidney injury markers in healthy adults: a randomized crossover trial.

Several human studies have used the mitochondrial antioxidant MitoQ. Recent in vitro data indicating that MitoQ may induce nephrotoxicity caused concern regarding the safety of MitoQ on the kidneys, but the doses were supraphysiological. Therefore, we sought to determine whether acute MitoQ elicits changes in urinary biomarkers associated with tubular injury in healthy adults with our hypothesis being there would be no changes. Using a randomized crossover design, 32 healthy adults (16 females and 16 males, 29 ± 11 yr old) consumed MitoQ (100-160 mg based on body mass) or placebo capsules. We obtained serum samples and a 4- to 6-h postcapsule consumption urine sample. We assessed creatinine clearance and urine kidney injury biomarkers including the chitinase 3-like-1 gene product YKL-40, kidney-injury marker-1, monocyte chemoattractant protein-1, epidermal growth factor, neutrophil gelatinase-associated lipocalin, interleukin-18, and uromodulin using multiplex assays. We used t tests, Wilcoxon tests, and Hotelling's T2 to assess global differences in urinary kidney injury markers between conditions. Acute MitoQ supplementation did not influence urine flow rate (P = 0.086, rrb = 0.39), creatinine clearance (P = 0.085, rrb = 0.42), or urinary kidney injury markers (T22,8 = 30.6, P = 0.121, univariate ps > 0.064). Using exploratory univariate analysis, MitoQ did not alter individual injury markers compared with placebo (e.g., placebo vs. MitoQ: YKL-40, 507 ± 241 vs. 442 ± 236 pg/min, P = 0.241; kidney injury molecule-1, 84.1 ± 43.2 vs. 76.2 ± 51.2 pg/min, P = 0.890; and neutrophil gelatinase-associated lipocalin, 10.8 ± 10.1 vs. 9.83 ± 8.06 ng/min, P = 0.609). In conclusion, although longer-term surveillance and data are needed in clinical populations, our findings suggest that acute high-dose MitoQ had no effect on urinary kidney injury markers in healthy adults.NEW & NOTEWORTHY We found acute high-dose mitochondria-targeted antioxidant (MitoQ) supplementation was not nephrotoxic and had no effect on markers of acute kidney injury in healthy adults. These findings can help bolster further confidence in the safety of MitoQ, particularly for future investigations seeking to examine the role of mitochondrial oxidative stress, via acute MitoQ supplementation, on various physiological outcomes.

Exercise for chronic kidney disease: effects on vascular and cardiopulmonary function.

Patients with chronic kidney disease (CKD) have an exacerbated prevalence of cardiovascular disease (CVD). Vascular dysfunction, characterized by impaired endothelial function and arterial stiffness, and markedly low cardiorespiratory fitness levels are hallmark manifestations of the disease that contribute to the CVD burden. Despite advancements in blood pressure and lipid lowering pharmacological therapies, CVD remains markedly prevalent across the spectrum of CKD. This highlights a stagnation in effective clinical strategies to improve cardiovascular health and reinforces the critical need for adjuvant lifestyle strategies such as physical activity and exercise training to be incorporated into routine clinical care. This narrative review provides an overview of the known effects of exercise on vascular and cardiopulmonary function across the spectrum of CKD. The physiological mechanisms of vascular dysfunction that serve as exercise-specific therapeutic targets are highlighted and future perspectives are discussed.

Reduced metabolic flexibility is a predictor of weight gain among liver transplant recipients.

Metabolic flexibility is the ability to match biofuel availability to utilization and is inversely associated with increased metabolic burden among liver transplant (LT) recipients. The present study evaluated the impact of metabolic flexibility on weight gain following LT. LT recipients were enrolled prospectively (n = 47) and followed for 6 months. Metabolic flexibility was measured using whole-room calorimetry and is expressed as a respiratory quotient (RQ). Peak RQ represents maximal carbohydrate metabolism and occurs in the post-prandial state, while trough RQ represents maximal fatty acid metabolism occurring in the fasted state. The clinical, metabolic, and laboratory characteristics of the study cohort of lost weight (n = 14) and gained weight (n = 33) were similar at baseline. Patients who lost weight were more likely to reach maximal RQ (maximal carbohydrate oxidation) early and rapidly transitioned to trough RQ (maximal fatty acid oxidation). In contrast, patients who gained weight had delayed time to peak RQ and trough RQ. In multivariate modeling, time to peak RQ (ß-coefficient 0.509, p = 0.01), time from peak RQ to trough RQ (ß-coefficient 0.634, p = 0.006), and interaction between time to peak RQ to trough RQ and fasting RQ (ß-coefficient 0.447, p = 0.02) directly correlated with the severity of weight gain. No statistically significant relationship between peak RQ, trough RQ, and weight change was demonstrated. Inefficient transition between biofuels (carbohydrates and fatty acids) is associated with weight gain in LT recipients that is independent of clinical metabolic risk. These data offer novel insight into the physiology of obesity after LT with the potential to develop new diagnostics and therapeutics.

Chrono-nutrition for hypertension.

Despite the advancement in blood pressure (BP) lowering medications, uncontrolled hypertension persists, underscoring a stagnation of effective clinical strategies. Novel and effective lifestyle therapies are needed to prevent and manage hypertension to mitigate future progression to cardiovascular and chronic kidney diseases. Chrono-nutrition, aligning the timing of eating with environmental cues and internal biological clocks, has emerged as a potential strategy to improve BP in high-risk populations. The aim of this review is to provide an overview of the circadian physiology of BP with an emphasis on renal and vascular circadian biology. The potential of Chrono-nutrition as a lifestyle intervention for hypertension is discussed and current evidence for the efficacy of time-restricted eating is presented.

Time of eating and mortality in U.S. adults with heart failure: Analyses of the National Health and Nutrition Examination Survey 2003-2018.

BACKGROUND AND AIMS: Promising associations have been demonstrated between delayed last eating occasion and cardiorespiratory fitness in adults with heart failure (HF), however, it is unknown if time of eating is associated with clinical endpoints such as mortality. This study aimed to examine associations between time of eating variables and all-cause and cardiovascular mortality in the National Health and Nutrition Examination Survey (NHANES). METHODS AND RESULTS: Participants self-disclosed HF diagnosis. Two dietary recalls were obtained and categorical variables were created based on mean time of first eating occasion (8:31 AM), last eating occasion (7:33 PM) and eating window (11.02 h). Mortality was obtained through linkage to the National Death Index. Covariate-adjusted Cox proportional hazard regression models were created examining the association between time of eating and mortality. Participants (n = 991) were 68 (95 % CI 67-69) years of age, 52.6 (95 % CI 49.0-56.3)% men and had a body mass index of 32.5 (95 % CI 31.8-33.2) kg/m2 with follow up time of 68.9 (95 % CI 64.8-72.9) person-months. When models were adjusted for time of eating variables and all other covariates, extending the eating window beyond 11.02 h was associated with decreased risk of cardiovascular (HR 0.36 [95 % CI 0.16-0.81]), but not all-cause mortality. Time of first and last eating occasions were not associated with mortality. CONCLUSIONS: In adults with HF, an extended eating window is associated with reduced risk for cardiovascular mortality. Randomized controlled trials should examine if extending the eating window can improve prognostic indicators such as cardiorespiratory fitness in this population.

Effects of a mitochondrial-targeted ubiquinol on vascular function and exercise capacity in chronic kidney disease: a randomized controlled pilot study.

Mitochondria-derived oxidative stress has been implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (means ± SE, age: 62 ± 3 yr and estimated glomerular filtration rate: 45 ± 3 mL/min/1.73 m2) received 4 wk of 20 mg/day MitoQ (MTQ group) or placebo (PLB). Outcomes assessed at baseline and follow-up included macrovascular function measured by flow-mediated dilation, microvascular function assessed by laser-Doppler flowmetry combined with intradermal microdialysis, aortic hemodynamics assessed by oscillometry, and exercise capacity assessed by cardiopulmonary exercise testing. Compared with PLB, MitoQ improved flow-mediated dilation (baseline vs. follow-up: MTQ, 2.4 ± 0.3% vs. 4.0 ± 0.9%, and PLB, 4.2 ± 1.0% vs. 2.5 ± 1.0%, P = 0.04). MitoQ improved microvascular function (change in cutaneous vascular conductance: MTQ 4.50 ± 2.57% vs. PLB -2.22 ± 2.67%, P = 0.053). Central aortic systolic and pulse pressures were unchanged; however, MitoQ prevented increases in augmentation pressures that were observed in the PLB group (P = 0.026). MitoQ did not affect exercise capacity. In conclusion, this study demonstrates the potential for a MitoQ to improve vascular function in CKD. The findings hold promise for future investigations of mitochondria-targeted therapies in CKD.NEW & NOTEWORTHY In this randomized controlled pilot study, we investigated the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in chronic kidney disease. Our novel findings showed that 4-wk supplementation of MitoQ was well tolerated and improved macrovascular endothelial function, arterial hemodynamics, and microvascular function in patients with stage 3-4 chronic kidney disease. Our mechanistic findings also suggest that MitoQ improved microvascular function in part by reducing the NADPH oxidase contribution to vascular dysfunction.

Melatonin supplementation reduces nighttime blood pressure but does not affect blood pressure reactivity in normotensive adults on a high-sodium diet.

High-sodium diets (HSDs) can cause exaggerated increases in blood pressure (BP) during physiological perturbations that cause sympathetic activation, which is related to cardiovascular risk. Melatonin supplementation has been shown to play a role in BP regulation. Our aim was to examine the effects of melatonin taken during an HSD on 24-h BP and BP reactivity during isometric handgrip (IHG) exercise, postexercise ischemia (PEI), and the cold pressor test (CPT). Twenty-two participants (11 men/11 women, 26.5 ± 3.1 yr, BMI: 24.1 ± 1.8 kg/m2, BP: 111 ± 9/67 ± 7 mmHg) were randomized to a 10-day HSD (6,900 mg sodium/day) that was supplemented with either 10 mg/day of melatonin (HSD + MEL) or placebo (HSD + PL). Twenty-four-hour ambulatory BP monitoring was assessed starting on day 9. Mean arterial pressure (MAP) was quantified during the last 30 s of IHG at 40% of maximal voluntary contraction and CPT, and during 3 min of PEI. Melatonin did not change 24-h MAP (HSD + PL: 83 ± 6 mmHg; HSD + MEL: 82 ± 5 mmHg; P = 0.23) but decreased nighttime peripheral (HSD + PL: 105 ± 10 mmHg; HSD + MEL: 100 ± 10 mmHg; P = 0.01) and central systolic BP (HSD + PL: 97 ± 9 mmHg; HSD + MEL: 93 ± 8 mmHg; P = 0.04) on the HSD compared with the HSD + PL. The absolute and percent change in MAP during IHG was not different between conditions (all P > 0.05). In conclusion, melatonin supplementation did not alter BP reactivity to the perturbations tested on an HSD but may be beneficial in lowering BP in young healthy normotensive adults.NEW & NOTEWORTHY BP reactivity was assessed during isometric handgrip (IHG) exercise, postexercise ischemia (PEI), and the cold pressor test (CPT) after 10 days of a high-sodium diet with and without melatonin supplementation. Melatonin did not alter BP reactivity in healthy normotensive men and women. However, melatonin did decrease nighttime peripheral and central systolic BP, suggesting it may be beneficial in lowering BP even in those with a normal BP.

Sex differences in microvascular function and arterial hemodynamics in nondialysis chronic kidney disease.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). Abnormal arterial hemodynamics contribute to CVD, a relationship that can be mediated by microvascular dysfunction. The purpose of this study was to investigate potential sex differences in arterial hemodynamics and microvascular dysfunction in patients with stages 3 to 4 CKD. Vascular function was assessed in 22 male (mean ± SD; age, 56 ± 13 yr) and 10 female (age, 63 ± 9 yr) patients. Arterial hemodynamics were acquired with combined tonometry and oscillometry. Skin blood flow was used as a model of microvascular function. Participants were instrumented with three microdialysis fibers for the delivery of 1) Ringer's solution; 2) superoxide dismutase mimetic, Tempol; and 3) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin. Blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). Central pulse pressure (mean ± SE; 62 ± 9 vs. 46 ± 3 mmHg; P = 0.01) and augmentation index (36 ± 3 vs. 26 ± 3%; P = 0.03) were higher in females. There was a trend for higher central systolic pressures in females (146 ± 9 vs. 131 ± 3 mmHg; P = 0.06). Females reported higher forward (39 ± 4 vs. 29 ± 2 mmHg; P = 0.004) and reflected (27 ± 3 vs. 19 ± 1 mmHg; P < 0.001) wave amplitudes. Cutaneous vascular function was impaired in females compared with males (77 ± 3 vs. 89 ± 1%, P = 0.001). Microvascular function was improved following the delivery of Tempol and apocynin in females but not in males. Female patients with CKD had poorer central hemodynamics and reduced microvascular function compared with their male counterparts. Oxidative stress may contribute to lower microvascular function observed in females.NEW & NOTEWORTHY There are limited data regarding the physiological mechanisms of potential sex differences in central hemodynamics and vascular function in chronic kidney disease (CKD). We report that older female patients with nondialysis CKD have higher central pulse pressures compared with male patients with CKD. In addition, older females with CKD have lower microvascular function compared with their male counterparts, and oxidative stress contributes to the lower microvascular function in older female patients with CKD.

Differential fuel utilization in liver transplant recipients and its relationship with non-alcoholic fatty liver disease.

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT). METHODS: Patients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation). RESULTS: The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue. CONCLUSION: Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT.

Exercise intolerance in kidney diseases: physiological contributors and therapeutic strategies.

Exertional fatigue, defined as the overwhelming and debilitating sense of sustained exhaustion that impacts the ability to perform activities of daily living, is highly prevalent in chronic kidney disease (CKD) and end-stage renal disease (ESRD). Subjective reports of exertional fatigue are paralleled by objective measurements of exercise intolerance throughout the spectrum of the disease. The prevalence of exercise intolerance is clinically noteworthy, as it leads to increased frailty, worsened quality of life, and an increased risk of mortality. The physiological underpinnings of exercise intolerance are multifaceted and still not fully understood. This review aims to provide a comprehensive outline of the potential physiological contributors, both central and peripheral, to kidney disease-related exercise intolerance and highlight current and prospective interventions to target this symptom. In this review, the CKD-related metabolic derangements, cardiac and pulmonary dysfunction, altered physiological responses to oxygen consumption, vascular derangements, and sarcopenia are discussed in the context of exercise intolerance. Lifestyle interventions to improve exertional fatigue, such as aerobic and resistance exercise training, are discussed, and the lack of dietary interventions to improve exercise tolerance is highlighted. Current and prospective pharmaceutical and nutraceutical strategies to improve exertional fatigue are also broached. An extensive understanding of the pathophysiological mechanisms of exercise intolerance will allow for the development of more targeted therapeutic approached to improve exertional fatigue and health-related quality of life in CKD and ESRD.

Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases.

Cardiovascular disease (CVD) affects one in three adults and remains the leading cause of death in America. Advancing age is a major risk factor for CVD. Recent plateaus in CVD-related mortality rates in high-income countries after decades of decline highlight a critical need to identify novel therapeutic targets and strategies to mitigate and manage the risk of CVD development and progression. Vascular dysfunction, characterized by endothelial dysfunction and large elastic artery stiffening, is independently associated with an increased CVD risk and incidence and is therefore an attractive target for CVD prevention and management. Vascular mitochondria have emerged as an important player in maintaining vascular homeostasis. As such, age- and disease-related impairments in mitochondrial function contribute to vascular dysfunction and consequent increases in CVD risk. This review outlines the role of mitochondria in vascular function and discusses the ramifications of mitochondrial dysfunction on vascular health in the setting of age and disease. The adverse vascular consequences of increased mitochondrial-derived reactive oxygen species, impaired mitochondrial quality control, and defective mitochondrial calcium cycling are emphasized, in particular. Current evidence for both lifestyle and pharmaceutical mitochondrial-targeted strategies to improve vascular function is also presented.

The effect of dietary nitrate on exercise capacity in chronic kidney disease: a randomized controlled pilot study.

BACKGROUND: Chronic Kidney Disease (CKD) patients exhibit a reduced exercise capacity that impacts quality of life. Dietary nitrate supplementation has been shown to have favorable effects on exercise capacity in disease populations by reducing the oxygen cost of exercise. This study investigated whether dietary nitrates would acutely improve exercise capacity in CKD patients. METHODS AND RESULTS: In this randomized, double-blinded crossover study, 12 Stage 3-4 CKD patients (Mean ± SEM: Age, 60 ± 5yrs; eGFR, 50.3 ± 4.6 ml/min/1.73 m2) received an acute dose of 12.6 mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) and a nitrate depleted placebo (PLA). Skeletal muscle mitochondrial oxidative function was assessed using near-infrared spectroscopy. Cardiopulmonary exercise testing was performed on a cycle ergometer, with intensity increased by 25 W every 3 min until volitional fatigue. Plasma nitric oxide (NO) metabolites (NOm; nitrate, nitrite, low molecular weight S-nitrosothiols, and metal bound NO) were determined by gas-phase chemiluminescence. Plasma NOm values were significantly increased following BRJ (BRJ vs. PLA: 1074.4 ± 120.4 µM vs. 28.4 ± 6.6 µM, p < 0.001). Total work performed (44.4 ± 10.6 vs 39.6 ± 9.9 kJ, p = 0.03) and total exercise time (674 ± 85 vs 627 ± 86s, p = 0.04) were significantly greater following BRJ. Oxygen consumption at the ventilatory threshold was also improved by BRJ (0.90 ± 0.08 vs. 0.74 ± 0.06 L/min, p = 0.04). These changes occurred in the absence of improved skeletal muscle mitochondrial oxidative capacity (p = 0.52) and VO2peak (p = 0.35). CONCLUSIONS: Our findings demonstrate that inorganic nitrate can acutely improve exercise capacity in CKD patients. The effects of chronic nitrate supplementation on CKD related exercise intolerance should be investigated in future studies.

Time of eating and cardiorespiratory fitness in patients with heart failure with preserved ejection fraction and obesity.

BACKGROUND AND AIMS: Our objective was to examine the impact of caloric intake before or after the mean time of evening meal on cardiorespiratory fitness (CRF) in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. METHODS AND RESULTS: Twelve patients with HFpEF and obesity completed a cardiorespiratory exercise test to measure CRF, defined as peak oxygen consumption (VO2). Three five-pass 24-h dietary recalls were performed for each participant and mean evening meal time was determined for each participant individually as well as the group. Participants were divided into those who ate before (Group I) and after (Group II) the mean time of evening meal, 7:25 PM. Peak VO2 and exercise time were significantly greater in Group II compared to Group I, moreover, delaying time of evening meal was associated with greater peak VO2. CONCLUSION: Caloric intake after the mean time of evening meal was associated with better CRF in patients with HFpEF and concomitant obesity. Later nutrient intake may help prevent fasting related stress associated with cardiac metabolic disturbances present in HFpEF. Based on these findings, prospective trials aimed at examining the effects of later evening meal times in patients with HFpEF and obesity are warranted.

Office-Based Weight Loss Counseling Is Ineffective in Liver Transplant Recipients.

BACKGROUND: Weight gain after liver transplantation (LT) is a predictor of major morbidity and mortality post-LT; however, there are no data regarding weight loss following LT. The current study evaluates the effectiveness of standard lifestyle intervention in LT recipients. METHODS: All adult LT recipients with body mass index (BMI) ≥ 25 kg/m2 who followed up in post-LT clinic from January 2013 to January 2016 were given standard lifestyle advice based on societal recommendations which was reinforced at 24 weeks. Patients were followed for a total of 48 weeks to assess the impact of such advice on weight. Primary outcome was achieving weight loss ≥ 5% of the body weight after 48 weeks of follow-up. RESULTS: A total of 151 patients with 86 (56.0%) overweight and 65 (44.0%) obese patients were enrolled in the study. The mean BMI at baseline increased from 30.2 ± 3.7 to 30.9 ± 4.3 kg/m2 at 48-week follow-up (p = 0.001). Over the course of study, 58 (38.4%) patients lost any weight and weight loss greater than 5% and 10% occurred in only 18 (11.9%) and 8 (5.3%) of the entire cohort, respectively. Higher level of education was associated with increased likelihood of weight loss (OR 9.8, 95% CI 2.6, 36.9, p = 0.001), while nonalcoholic steatohepatitis as etiology of liver disease (HR 3.7, 95% CI 1.4, 9.7, p = 0.007) was associated with weight gain. CONCLUSION: The practice of office-based lifestyle intervention is ineffective in achieving clinically significant weight loss in LT recipients, and additional strategies are required to mitigate post-LT weight gain.

Effects of aerobic exercise on vascular function in nondialysis chronic kidney disease: a randomized controlled trial.

Endothelial dysfunction and arterial stiffness are nontraditional risk factors of chronic kidney disease (CKD)-related cardiovascular disease (CVD) that could be targeted with exercise. This study investigated the effect of moderate to vigorous aerobic exercise on vascular function in nondialysis CKD. In this randomized, controlled trial, 36 nondialysis patients with CKD (means ± SE, age: 58 ± 2 yr, estimated glomerular filtration rate: 44 ± 2 ml·min-1·1.73 m-2) were allocated to an exercise training (EXT) or control (CON) arm. The EXT group performed 3 × 45 min of supervised exercise per week at 60-85% heart rate reserve for 12 wk, whereas the CON group received routine care. Outcomes were assessed at 0 and 12 wk. The primary outcome, microvascular function, was assessed via cutaneous vasodilation during local heating measured by laser-Doppler flowmetry coupled with microdialysis. Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution and 2) the superoxide scavenger tempol. Conduit artery function was assessed via brachial artery flow-mediated dilation. Aortic pressure waveforms and pulse wave velocity were acquired with tonometry and oscillometry. Microvascular function improved after EXT (week 0 vs.week 12, EXT: 87 ± 2% vs. 91 ± 2% and CON: 86 ± 2% vs. 84 ± 3%, P = 0.03). At baseline, pharmacological delivery of tempol improved microvascular function (Ringer solution vs. tempol: 86 ± 1% vs. 90 ± 1%, P = 0.02) but was no longer effective after EXT (91 ± 2% vs. 87 ± 1%, P = 0.2), suggesting that an improved redox balance plays a role in EXT-related improvements. Brachial artery flow-mediated dilation was maintained after EXT (EXT: 2.6 ± 0.4% vs. 3.8 ± 0.8% and CON: 3.5 ± 0.6% vs. 2.3 ± 0.4%, P = 0.02). Central arterial hemodynamics and arterial stiffness were unchanged after EXT. Aerobic exercise improved microvascular function and maintained conduit artery function and should be considered as an adjunct therapy to reduce CVD risk in CKD.

The Impact of Coronary Artery Disease and Statins on Survival After Liver Transplantation.

Cardiovascular disease (CVD) is a major contributor to longterm mortality after liver transplantation (LT) necessitating aggressive modification of CVD risk. However, it is unclear how coronary artery disease (CAD) and the development of dyslipidemia following LT impacts clinical outcomes and how management of these factors may impact survival. Patients undergoing LT at Virginia Commonwealth University from January 2007 to January 2017 were included (n = 495). CAD and risk factors in all potential liver transplantation recipients (LTRs) over the age of 50 years were evaluated via coronary angiography. The impact of pre-LT CAD after transplantation was evaluated via a survival analysis. Additionally, factors associated with new-onset dyslipidemia, statin use, and mortality were assessed using multiple logistic regression or Cox proportional hazards models. The mean age of the cohort was 55.3 ± 9.3 years at the time of LT, and median follow-up was 4.5 years. CAD was noted in 129 (26.1%) patients during the pre-LT evaluation. The presence or severity of pre-LT CAD did not impact post-LT survival. Dyslipidemia was present in 96 patients at LT, and 157 patients developed new-onset dyslipidemia after LT. Statins were underused as only 45.7% of patients with known CAD were on therapy. In patients with new-onset dyslipidemia, statin therapy was initiated in 111 (71.1%), and median time to initiation of statin therapy was 2.5 years. Statin use conferred survival benefit (hazard ratio, 0.25; 95% confidence interval, 0.12-0.49) and was well tolerated with only 12% of patients developing an adverse event requiring the cessation of therapy. In conclusion, pre-LT CAD did not impact survival after LT, potentially suggesting a role of accelerated atherosclerosis that may not be captured on pre-LT testing. Although statin therapy confers survival benefit, it is underused in LTRs.

The effects of intradialytic exercise on hemodialysis adequacy: A systematic review.

Dialysis adequacy is an independent predictor of high mortality rates in hemodialysis patients. Intradialytic exercise is a potential strategy to increase uremic solute removal by increasing blood flow to low perfusion tissue beds. The purpose of this review is to establish the efficacy of intradialytic exercise for hemodialysis adequacy. Additionally, this review aims to provide practical information to aid health care professionals implement intradialytic exercise for dialysis adequacy. Database and hand searches identified 15 published interventional studies that implemented intradialytic exercise for dialysis adequacy as a primary outcome measure in adult maintenance hemodialysis patients. Data pertaining to dialytic solute clearance of urea, creatinine, beta2 microglobulin, phosphate, and potassium were extracted. Mean differences, normalized to percentages, and effect sizes were calculated and reported. The current data pertaining to the use of intradialytic exercise for improving dialysis adequacy in terms of Kt/Vurea or small molecule uremic toxin clearance are equivocal. Limited data showed that intradialytic exercise has no effect middle molecule toxin (beta2 - microglobulin) clearance. Intradialytic exercise favored increased phosphate removal showing medium to large effects for reduced serum concentrations, reduced rebound and increased clearance. In summary, supervised light to moderate intradialytic aerobic cycling appears to be beneficial for increasing phosphate removal and may be an adjunct therapy for patients failing to meet clinical phosphate targets. Further work is required to establish the effect of intradialytic exercise on Kt/Vurea and other middle molecule and protein bound solutes. Research aimed at establishing the most effective exercise prescription for improved solute clearance is warranted.

Role of mitochondria-derived reactive oxygen species in microvascular dysfunction in chronic kidney disease.

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3-5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 ± 13 yr; estimated glomerular filtration rate (eGFR) 46 ± 13 ml·kg-1·1.73 m-2] and 11 matched healthy participants (58 ± 2 yr; eGFR >90 ml·kg-1·1.73 m-2). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43°C. Urinary isofuran/F2-isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F2-isoprostane ratios were increased in CKD patients (3.08 ± 0.32 vs. 1.69 ± 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 ± 1 vs. 92 ± 1%CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 ± 1 vs. 93 ± 1%CVCmax; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.