The effect of exercise on vascular health in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease. This increased risk cannot be fully explained by traditional risk factors such as hypertension. Endothelial dysfunction and arterial stiffness have been suggested as factors that explain some of the increased risk and are independently associated with important cardiovascular outcomes in patients with CKD. Studies in other disease populations have shown the positive effects of exercise on vascular dysfunction. The aim of this review was to determine whether exercise training interventions improve measures of vascular function and morphology in patients across the spectrum of CKD and which exercise training interventions are most efficacious. A systematic search of Medline, Embase, and the Cochrane Central Register identified 25 randomized controlled trials. Only randomized control trials using an exercise intervention with a nonexercising control group and at least one measure of vascular function or morphology were included. Participants were patients with nondialysis CKD or transplant patients or those requiring dialysis therapy. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A meta-analysis was completed for pulse wave velocity, augmentation index, and measures of endothelium-dependent vasodilation. Data from 25 studies with 872 participants showed that exercise training reduced pulse wave velocity and augmentation index but had no effect on endothelium-dependent vasodilation. Subgroup analyses suggested that exercise interventions of at least moderate intensity were more likely to be effective. Limitations included the absence of observational studies or other interventions aimed at increasing habitual physical activity. Further studies are warranted to investigate which are the most effective exercise interventions.NEW & NOTEWORTHY A thorough systematic review and meta-analysis of the effects of exercise training on measures of vascular function in patients with chronic kidney disease, including arterial stiffness and endothelial function, were conducted. Subgroup analyses investigated how differences in exercise training, according to frequency, intensity, type, and timing, have an impact on the efficacy of the intervention.

Feasibility of randomized controlled trials and long-term implementation of interventions: Insights from a qualitative process evaluation of the PEDAL trial.

Introduction: A multi-site randomized controlled trial was carried out between 2015 and 2019 to evaluate the impacts on quality of life of an intradialytic exercise programme for people living with chronic kidney disease. This included a qualitative process evaluation which gave valuable insights in relation to feasibility of the trial and of the intervention in the long-term. These can inform future clinical Trial design and evaluation studies. Methods: A constructivist phenomenological approach underpinned face-to-face, semi-structured interviews. Purposive recruitment ensured inclusion of participants in different arms of the PEDAL Trial, providers with different roles and trial team members from seven Renal Units in five study regions. Following ethical review, those willing took part in one interview in the Renal Unit. Audio-recorded interviews were transcribed (intelligent verbatim) and inductively thematically analyzed. Results: Participants (n = 65) (Intervention arm: 26% completed; 13% who did not; Usual care arm: 13%; 46% women; 54% men; mean age 60 year) and providers (n = 39) were interviewed (23% PEDAL Trial team members). Three themes emerged: (1) Implementing the Intervention; (2) Implementing the trial; and (3) Engagement of the clinical team. Explanatory theory named "the Ideal Scenario" was developed, illustrating complex interactions between different aspects of intervention and trial implementation with the clinical context. This describes characteristics likely to optimize trial feasibility and intervention sustainability in the long-term. Key aspects of this relate to careful integration of the trial within the clinical context to optimize promotion of the trial in the short-term and engagement and ownership in the long-term. Strong leadership in both the clinical and trial teams is crucial to ensure a proactive and empowering culture. Conclusion: Novel explanatory theory is proposed with relevance for Implementation Science. The "Ideal Scenario" is provided to guide trialists in pre-emptive and ongoing risk analysis relating to trial feasibility and long-term intervention implementation. Alternative study designs should be explored to minimize the research-to-practice gap and optimize the likelihood of informative findings and long-term implementation. These might include Realist Randomized Controlled Trials and Hybrid Effectiveness-Implementation studies.

MEDEX 2015: Prophylactic Effects of Positive Expiratory Pressure in Trekkers at Very High Altitude.

Purpose: Positive expiratory pressure (PEP) breathing has been shown to increase arterial oxygenation during acute hypoxic exposure but the underlying mechanisms and consequences on symptoms during prolonged high-altitude exposure remain to be elucidated. Methods: Twenty-four males (41 ± 16 years) were investigated, at sea level and at 5,085 m after 18 days of trekking from 570 m. Participants breathed through a face-mask with PEP = 0 cmH2O (PEP0, 0-45th min) and with PEP = 10 cmH2O (PEP10, 46-90th min). Arterial (SpO2), quadriceps and prefrontal (near infrared spectroscopy) oxygenation was measured continuously. Middle cerebral artery blood velocity (MCAv, transcranial Doppler), cardiac function (2D-echocardiography), extravascular lung water accumulation (UsLC, thoracic ultrasound lung comets) and acute mountain sickness (Lake Louise score, LLS) were assessed during PEP0 and PEP10. Results: At 5,085 m with PEP0, SpO2 was 78 ± 4%, UsLC was 8 ± 5 (a.u.) and the LLS was 2.3 ± 1.7 (all P < 0.05 versus sea level). At 5,085 m, PEP10 increased significantly SpO2 (+9 ± 5%), quadriceps (+2 ± 2%) and prefrontal cortex (+2 ± 2%) oxygenation (P < 0.05), and decreased significantly MCAv (-16 ± 14 cm.s-1) and cardiac output (-0.7 ± 1.2 L.min-1) together with a reduced stroke volume (-9 ± 15 mL, all P < 0.05) and no systemic hypotension. PEP10 decreased slightly the number of UsLC (-1.4 ± 2.7, P = 0.04) while the incidence of acute mountain sickness (LLS ≥ 3) fell from 42% with PEP0 to 25% after PEP10 (P = 0.043). Conclusion: PEP10 breathing improved arterial and tissue oxygenation and symptoms of acute mountain sickness after trekking to very high altitude, despite reduced cerebral perfusion and cardiac output. Further studies are required to establish whether PEP-breathing prophylactic mechanisms also occur in participants with more severe acute mountain sickness.

The Effects of Beetroot Juice on Blood Pressure, Microvascular Function and Large-Vessel Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Pilot Study in Healthy Older Adults.

: Dietary nitrate (NO3-) has been reported to improve endothelial function (EF) and blood pressure (BP). However, most studies only assess large-vessel EF with little research on the microvasculature. Thus, the aim of the present pilot study is to examine NO3- supplementation on microvascular and large-vessel EF and BP. Twenty older adults (63 ± 6 years) were randomized to a beetroot juice (BRJ) or placebo (PLA) group for 28 (±7) days and attended three laboratory visitations. Across visitations, blood pressure, microvascular function and large-vessel EF were assessed by laser Doppler imaging (LDI) with iontophoresis of vasoactive substances and flow-mediated dilatation (FMD), respectively. Plasma NO3-concentrations, BP and the presence of NO3- reducing bacteria were also assessed. Plasma NO3- increased following two weeks of BRJ supplementation (p = 0.04) along with a concomitant decrease in systolic and diastolic BP of approximately -6 mmHg and -4 mmHg, respectively (p = 0.04; p = 0.01, respectively). BP remained unchanged in the PLA group. There were no significant differences in endothelium-dependent or endothelium-independent microvascular responses between groups. FMD increased by 1.5% following two weeks of BRJ (p = 0.04), with only a minimal (0.1%) change for the PLA group. In conclusion, this pilot study demonstrated that medium-term BRJ ingestion potentially improves SBP, DBP and large-vessel EF in healthy older adults. The improvements observed in the present study are likely to be greater in populations presenting with endothelial dysfunction. Thus, further prospective studies are warranted in individuals at greater risk for cardiovascular disease.

MEDEX 2015: Heart Rate Variability Predicts Development of Acute Mountain Sickness.

Sutherland, Angus, Joseph Freer, Laura Evans, Alberto Dolci, Matteo Crotti, and Jamie Hugo Macdonald. MEDEX 2015: Heart rate variability predicts development of acute mountain sickness. High Alt Med Biol. 18: 199-208, 2017. AIMS: Acute mountain sickness (AMS) develops when the body fails to acclimatize to atmospheric changes at altitude. Preascent prediction of susceptibility to AMS would be a useful tool to prevent subsequent harm. Changes to peripheral oxygen saturation (SpO2) on hypoxic exposure have previously been shown to be of poor predictive value. Heart rate variability (HRV) has shown promise in the early prediction of AMS, but its use pre-expedition has not previously been investigated. We aimed to determine whether pre- and intraexpedition HRV assessment could predict susceptibility to AMS at high altitude with better diagnostic accuracy than SpO2. METHODS: Forty-four healthy volunteers undertook an expedition in the Nepali Himalaya to >5000 m. SpO2 and HRV parameters were recorded at rest in normoxia and in a normobaric hypoxic chamber before the expedition. On the expedition HRV parameters and SpO2 were collected again at 3841 m. A daily Lake Louise Score was obtained to assess AMS symptomology. RESULTS: Low frequency/high frequency (LF/HF) ratio in normoxia (cutpoint ≤2.28 a.u.) and LF following 15 minutes of exposure to normobaric hypoxia had moderate (area under the curve ≥0.8) diagnostic accuracy. LF/HF ratio in normoxia had the highest sensitivity (85%) and specificity (88%) for predicting AMS on subsequent ascent to altitude. In contrast, pre-expedition SpO2 measurements had poor (area under the curve <0.7) diagnostic accuracy and inferior sensitivity and specificity. CONCLUSIONS: Pre-ascent measurement of HRV in normoxia was found to be of better diagnostic accuracy for AMS prediction than all measures of HRV in hypoxia, and better than peripheral oxygen saturation monitoring.

Beetroot juice does not enhance altitude running performance in well-trained athletes.

We hypothesized that acute dietary nitrate (NO3(-)) provided as concentrated beetroot juice supplement would improve endurance running performance of well-trained runners in normobaric hypoxia. Ten male runners (mean (SD): sea level maximal oxygen uptake, 66 (7) mL·kg(-1)·min(-1); 10 km personal best, 36 (2) min) completed incremental exercise to exhaustion at 4000 m and a 10-km treadmill time-trial at 2500 m simulated altitude on separate days after supplementation with ∼7 mmol NO3(-) and a placebo at 2.5 h before exercise. Oxygen cost, arterial oxygen saturation, heart rate, and ratings of perceived exertion (RPE) were determined during the incremental exercise test. Differences between treatments were determined using means [95% confidence intervals], paired sample t tests, and a probability of individual response analysis. NO3(-) supplementation increased plasma nitrite concentration (NO3(-), 473 (226) nmol·L(-1) vs. placebo, 61 (37) nmol·L(-1), P < 0.001) but did not alter time to exhaustion during the incremental test (NO3(-), 402 (80) s vs. placebo 393 (62) s, P = 0.5) or time to complete the 10-km time-trial (NO3(-), 2862 (233) s vs. placebo, 2874 (265) s, P = 0.6). Further, no practically meaningful beneficial effect on time-trial performance was observed as the 11 [-60 to 38] s improvement was less than the a priori determined minimum important difference (51 s), and only 3 runners experienced a "likely, probable" performance improvement. NO3(-) also did not alter oxygen cost, arterial oxygen saturation, heart rate, or RPE. Acute dietary NO3(-) supplementation did not consistently enhance running performance of well-trained athletes in normobaric hypoxia.

Muscle-damaging exercise increases heat strain during subsequent exercise heat stress.

PURPOSE: It remains unclear whether exercise-induced muscle damage (EIMD) increases heat strain during subsequent exercise heat stress, which in turn may increase the risk of exertional heat illness. We examined heat strain during exercise heat stress 30 min after EIMD to coincide with increases in circulating pyrogens (e.g., interleukin-6 [IL-6]) and 24 h after EIMD to coincide with the delayed muscle inflammatory response when a higher rate of metabolic energy expenditure (M˙) and thus decreased economy might also increase heat strain. METHODS: Thirteen non-heat-acclimated males (mean ± SD, age = 20 ± 2 yr) performed exercise heat stress tests (running for 40 min at 65% V˙O2max in 33°C, 50% humidity) 30 min (HS1) and 24 h (HS2) after treatment, involving running for 60 min at 65% V˙O2max on either -10% gradient (EIMD) or +1% gradient (CON) in a crossover design. Rectal (Tre) and skin (Tsk) temperature, local sweating rate, and M˙ were measured throughout HS tests. RESULTS: Compared with CON, EIMD evoked higher circulating IL-6 pre-HS1 (P < 0.01) and greater plasma creatine kinase and muscle soreness pre-HS2 (P < 0.01). The ΔTre was greater after EIMD than CON during HS1 (0.35°C, 95% confidence interval = 0.11°C-0.58°C, P < 0.01) and HS2 (0.17°C, 95% confidence interval = 0.07°C-0.28°C, P < 0.01). M˙ was higher on EIMD throughout HS1 and HS2 (P < 0.001). Thermoeffector responses (Tsk, sweating rate) were not altered by EIMD. Thermal sensation and RPE were higher on EIMD after 25 min during HS1 (P < 0.05). The final Tre during HS1 correlated with the pre-HS1 circulating IL-6 concentration (r = 0.67). CONCLUSIONS: Heat strain was increased during endurance exercise in the heat conducted 30 min after and, to a much lesser extent, 24 h after muscle-damaging exercise. These data indicate that EIMD is a likely risk factor for exertional heat illness particularly during exercise heat stress when behavioral thermoregulation cues are ignored.

Optic nerve sheath diameter is not related to high altitude headache: a randomized controlled trial.

The mechanism of high altitude headache (HAH) remains unknown. The aim of this study was to determine experimentally whether optic nerve sheath diameter (ONSD), as an indicator of intracranial pressure, is related to HAH. Following sea level measurements at 3 and 12 hours (SL), 23 subjects were passively transported to high altitude (3777 m, HA) via cable car. HAH, ONSD, arterial oxygen saturation (Spo(2)), and fluid balance were determined at 3, 12, 24, and 36 hours. After 12 hours exposure to HA, subjects were classified by visual analogue scale (VAS) as either HAH positive (HAH+) or HAH negative (HAH-). Acetazolamide (250 mg) or placebo was then randomly prescribed at 15, 20, and 28 hours. Outcome means were compared via analysis of variance, and relationships between variables were analyzed by longitudinal regression. Acetazolamide had no statistically significant effect on HAH (p=0.63) or ONSD (p=0.98), but produced a negative fluid balance (p<0.01) (and also increased Spo(2) in exploratory analyses). Spo(2) was lower in HAH+ than HAH- [85 (3)% versus 88 (2)%, p=0.03). Nevertheless, ONSD increased similarly in HAH+ and HAH- (interaction p=0.90). ONSD also remained significantly elevated above SL values for the entire HA period [SL, 5.2 (0.5) versus HA, 5.6 (0.5) mm, p<0.01], despite headache resolving with acclimatization [VAS: SL, 1/100 (3) mm versus HA 3 h, 9/100 (13); 12 h, 10/100 (14); 24 h, 8/100 (12); 36 h, 1/100 (4) mm, p<0.01]. Furthermore, HAH was significantly correlated with Spo(2) (ß=-1.39, p<0.01) but not with ONSD (ß=0.59, p=0.57). These data do not support that intracranial pressure is associated with the development or amelioration of mild HAH. Clinical trial registration NCT01288781.

Arteriovenous fistula complication following MRI.

Health professionals should be aware of medical procedures that cause vascular access complications. This case describes a haemodialysis patient who experienced pain, swelling and bruising over a radiocephalic fistula following MRI. Exactly the same signs and symptoms were evident following a second scan performed 3 months later. Plausible explanations include a radio frequency-induced electrical current being formed at the arteriovenous fistula, or varying gradients of the MRI sequence stimulating peripheral nerves, leading to a site of increased tissue stimulation. Of note, a juxta-anastomotic venous stenosis was confirmed by fistulogram 4 days after the second scan, although whether this access failure was due to the MRI scan per se could not be ascertained. Nevertheless, these previously undocumented observations suggest that careful patient and fistula monitoring is required when completing MRI scans in those with an arteriovenous fistula.

Physiological demands of mountain rescue work.

OBJECTIVE: To characterise the physical fitness of mountain rescue (MR) volunteers and the physical demands of a typical MR callout. METHODS: Eight MR volunteers (age ± SD: 45.5 ± 8.9 years) completed a laboratory-based treadmill exercise test to exhaustion. One week later subjects completed a field-based simulated callout to retrieve a casualty by stretcher. In both studies exercise intensity was evaluated by determination of oxygen uptake and other cardiovascular measures. RESULTS: The maximal oxygen uptake of the participants was 53 ml/kg/min (95% CI 45 to 60). In an unassisted callout, a typical rucksack load was 17% of body mass. Ascent time was 56 min (95% CI 40 to 72), of which 82% (95% CI 66% to 98%) was completed at hard or very hard intensity (above the respiratory compensation point). Descent time with a stretcher was 58 min (95% CI 52 to 64), of which only 6% (95% CI -4% to 16%) was completed at hard or very hard intensity. Correlations between heart rate and oxygen uptake were similar (p=0.254 by analysis of variance) during laboratory (r=0.72) and field testing, especially for the ascent (r=0.75). CONCLUSIONS: Mountain rescuers generally have high levels of physical fitness and are required to perform at very hard intensity for the majority of the ascent to a casualty. Heart rate is a simple yet valid measure of exercise intensity in MR personnel. These findings highlight important information on the unique physical demands faced by MR volunteers and provide direction for future research, volunteer selection and training.

Kidney transplantation: a systematic review of interventional and observational studies of physical activity on intermediate outcomes.

Kidney transplant patients have decreased quality and longevity of life. Whether exercise can positively affect associated outcomes such as physical functioning, metabolic syndrome, kidney function, and immune function, has only been addressed in relatively small studies. Thus the aim of this systematic review was to determine effects of physical activity level on these intermediate outcomes in kidney transplant patients. We electronically and hand searched to identify 21 studies (6 retrospective assessments of habitual physical activity and 15 intervention studies including 6 controlled trials). After study quality assessment, intermediate outcomes associated with quality and longevity of life were expressed as correlations or percentage changes in addition to effect sizes. Habitual physical activity level was positively associated with quality of life and aerobic fitness and negatively associated with body fat (medium to large effect sizes). Exercise interventions also showed medium to large positive effects on aerobic capacity (10%-114% increase) and muscle strength (10%-22% increase). However, exercise programs had minimal or contradictory effects on metabolic syndrome and immune and kidney function. In kidney transplant patients, physical activity intervention is warranted to enhance physical functioning. Whether exercise impacts on outcomes associated with longevity of life requires further study.

Response of electromyographic variables during incremental and fatiguing cycling.

PURPOSE: Surface electromyographic (EMG) variables allow study of the electrical activity of motor units within active skeletal muscle. Recent methodological advances permit the estimation of muscle fiber-conduction velocity (MFCV) from EMG signals recorded during dynamic exercise. However, EMG responses to incremental and fatiguing cycling are poorly understood. METHODS: Twenty males completed an incremental cycling protocol (20, 40, 60, and 80% of peak power output (PPO)) on two occasions separated by 5 d. The final stage was 6 min long, to induce muscle fatigue. EMG signals were recorded from the vastus lateralis and vastus medialis muscles, and root mean square (RMS) and MFCV values were estimated. RESULTS: For incremental exercise, EMG data were reliable between trials, especially for MFCV in the vastus lateralis at 40, 60, and 80% PPO (e.g., coefficient of variation < 6.3%; bias < 0.4 m.s (-1); limits of agreement < 1.2 m.s(-1)). Significant positive correlations were observed between RMS and MFCV (r = 0.79-0.83), as both measures increased with power output (repeated-measures analysis of variance all P = 0.001). For fatiguing exercise, many EMG variables showed systematic bias between trials. RMS (P = 0.009 to 0.051) but not MFCV (P = 0.236-0.578) significantly increased during fatiguing cycling. CONCLUSIONS: During dynamic cycle exercise, EMG variables are reliable and increase with power output. During fatiguing exercise, EMG variables may be sensitive to learning effects in the execution of the task. MFCV and RMS are correlated with varying power output in the nonfatigued muscle, but not during the development of fatigue.

The relationship between estimated glomerular filtration rate, demographic and anthropometric variables is mediated by muscle mass in non-diabetic patients with chronic kidney disease.

BACKGROUND: In this study (the first of two related papers), we report whether the relationship between the demographic and anthropometric variables (DA, i.e. age, gender, height and weight) employed in current creatinin (Cr)-based glomerular filtration rate (GFR) estimation equations and actual GFR is mediated by muscle mass. METHODS: We studied 77 patients (mean age +/- SD, 65.1 +/- 11.9 years) with chronic kidney disease (mean GFR 45.7 +/- 28.6 ml/min/1.73 m2). Actual GFR was measured by the renal clearance of inulin (GFR(inu)). Appendicular lean mass (ALM) and its index (ALMI) by dual energy X-ray absorptiometry provided markers of muscle mass. Multiple regression analyses identified variables explaining variance in (i) GFR, (ii) ALM and (iii) Cr. RESULTS: (i) The DA variables used in the abbreviated modification of diet in renal disease (MDRD) equation accounted for only 59.6% (P < 0.001) of the variance in GFR(inu), whilst adding ALMI explained an additional 10.4% variance (P < 0.001). If ALMI was entered first, the relationship between DA variables and GFR(inu) was reduced (for weight) or completely abolished (for age, gender and height). (ii) After inputting all the commonly used DA variables, 17.2% of the variance in ALM was unexplained. (iii) All the DA variables explained only 60.6% (P < 0.001) of the variance in Cr, whilst adding ALM explained an additional 4.2% variance (P < 0.005). CONCLUSIONS: Muscle mass explained more variance in GFR(inu) than MDRD DA variables and mediated the relationship between GFR(inu) and DA variables. Furthermore, DA variables failed to account for individual differences in muscle mass or Cr. Consequently, there is a need to validate simpler, clinically obtainable measures of muscle mass and determine whether these measures will improve GFR estimation.