Jamie H. Macdonald

The functional, metabolic, and anabolic responses to exercise training in renal transplant and hemodialysis patients.

Background. Exercise intolerance is common in hemodialysis (HD) and renal transplant (RTx) patients and is related to muscle weakness. Its pathogenesis may vary between these groups leading to a different response to exercise. The aim of the study was to compare intrinsic muscular parameters between HD and RTx patients and controls, and to assess the response to exercise training on exercise capacity and muscular structure and function in these groups. Methods. Quadriceps function (isokinetic dynamometry), body composition (dual-energy x-ray absorptiometry), and vastus lateralis muscle biopsies were analyzed before and after a 12-week lasting training-program in 35 RTx patients, 16 HD patients, and 21 healthy controls. Results. At baseline, myosin heavy chain (MyHC) isoform composition and enzyme activities were not different between the groups. VO2peak and muscle strength improved significantly and comparably over the training-period in RTx, HD patients and controls (ptime<0.05). The proportion of MyHC type I isoforms decreased (ptime<0.001) and type IIa MyHC isoforms increased (ptime<0.05). The 3-hydroxyacyl-CoA-dehydrogenase activity increased (ptime=0.052). Intrinsic muscular changes were not significantly different between groups. In the HD group, changes in lean body mass were significantly related to changes in muscle insulin-like growth factor (IGF)-II and IGF binding protein-3. Conclusions. Abnormalities in metabolic enzyme activities or muscle fiber redistribution do not appear to be involved in muscle dysfunction in RTx and HD patients. Exercise training has comparable beneficial effects on functional and intrinsic muscular parameters in RTx patients, HD patients, and controls. In HD patients, the anabolic response to exercise training is related to changes in the muscle IGF system.

Intradialytic exercise as anabolic therapy in haemodialysis patients - a pilot study

Haemodialysis (HD) patients are characterized by muscle wasting and consequently decreased physical functioning and poor outcome. This pilot study investigated if a novel intradialytic exercise programme could increase lean mass via up‐regulation of the insulin‐like growth factor (IGF) system. Nine HD patients were assessed before (w‐12) and after a 3‐month control phase (w0), after a three‐month intradialytic interval training programme using high intensity cycle exercise (w12), and after a withdrawal of treatment phase (w24). Body composition was determined by dual energy X‐ray absorptiometry (DEXA) and bioelectrical impedance spectroscopy (BIS); physical functioning by knee extensor strength (KES) and 30‐s sit stand test (SST); and IGF‐I and IGFBP‐3 in serum and muscle by radioimmunoassay. Despite significant increases in training load (+274%, P<0·001), peak power output (+71%, P<0·001) and physical function (KES: +19%, P<0·05; SST: +20%, P<0·05) following the intervention phase, lean masses by DEXA, intra cellular water by BIS (a surrogate measure of body cell mass) and serum and muscle IGFs remained unchanged following training. Although this novel exercise programme, utilizing high intensity interval training, was safe, clinically feasible and beneficial in terms of physical functioning, the 12 weeks of intradialytic cycle exercise failed to reverse the muscle atrophy characteristic of this population. Future studies, using primary outcome measures similar to those employed in the present study, should investigate other anabolic interventions to determine potential treatments for the muscle wasting associated with end stage renal disease.

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.

Nandrolone Decanoate as Anabolic Therapy in Chronic Kidney Disease: A Randomized Phase II Dose-Finding Study

Background/Aims: In patients with chronic kidney disease (CKD) receiving adequate erythropoietin therapy, the ideal dose of nandrolone decanoate (ND) to enhance muscle mass is not known. Methods: In this phase II dose-finding study, 54 patients with CKD stage 5 were randomized to either low, medium or high doses of ND (50, 100 or 200 mg/week for 24 weeks, respectively, in males; doses halved in females), while 7 patients acted as non-randomized controls. The primary outcome measure was appendicular lean mass (ALM) by dual-energy X-ray absorptiometry. Fluid overload (hydration of the fat-free mass) and indicators of physical functioning were secondary measures. Harms were also recorded. Data were analysed using Quade’s (1967) non-parametric analysis of covariance. Results: ND increased ALM in a dose-responsive manner (change scores = 0.3 ± 0.3 vs. 0.8 ± 0.3 vs. 1.5 ± 0.5 vs. 2.1 ± 0.4 kg, control vs. low vs. medium vs. high dose groups, respectively, p < 0.001) with no increases in fluid overload but no consistent effect on physical functioning. The highest dose of ND (100 mg/week) was intolerable in females because of virilizing effects. Conclusion: If goals of future studies are to improve body composition, dosing of ND up to 200 mg/week in males and 50 mg/week in females should be investigated. However, to realize improvements in physical functioning, future phase III trials of ND may require additional interventions such as exercise training.

Body composition at high altitude: a randomized placebo-controlled trial of dietary carbohydrate supplementation

BACKGROUND Body mass loss is inevitable with chronic hypoxic exposure. However, the exact body-composition changes, their causes, and possible treatments remain unknown. OBJECTIVE The objective was to investigate body composition during a high-altitude expedition by using non-empirically derived methods, experimentally manipulating energy intake, and investigating the influence of initial body composition. DESIGN Forty-one participants completed a 21-d expedition in the Himalayas. Energy intake was manipulated with a double-blind, placebo-controlled, randomized trial of carbohydrate energy supplementation. Body composition was assessed before and after the expedition by using a 4-component model including fat mass, total body water, bone mineral mass, and residual mass (principally protein and glycogen). Data were analyzed by repeated-measures analysis of variance. RESULTS Participants allocated to receive carbohydrate were given an additional 15,058 +/- 6211 kcal over the 21-d expedition (>6 kcal x kg(-1) x d(-1)). Nevertheless, the functionally important residual mass decreased in both groups by 6% (main effect of time: P = 0.021), with no effect of allocation (interaction effect: P = 0.116). Similar decreases were observed for fat mass (11%) and total body water (3%), which were also unabated by allocation. Furthermore, high initial fat mass (by median split) did not preserve residual mass (high-fat compared with low-fat participants: residual loss = 5% compared with 8%; P = 0.990). CONCLUSIONS High-altitude exposure decreased body mass, including the functionally important residual component. These losses were not abated by increasing energy intake or an initially high fat mass. Factors other than negative energy balance must contribute to body-composition changes with chronic hypoxia. This trial was registered at clinicaltrials.gov as NCT00731510.

Exercising in a hot environment with muscle damage: Effects on acute kidney injury biomarkers and kidney function

Unaccustomed strenuous physical exertion in hot environments can result in heat stroke and acute kidney injury (AKI). Both exercise-induced muscle damage and AKI are associated with the release of interleukin-6, but whether muscle damage causes AKI in the heat is unknown. We hypothesized that muscle-damaging exercise, before exercise in the heat, would increase kidney stress. Ten healthy euhydrated men underwent a randomized, crossover trial involving both a 60-min downhill muscle-damaging run (exercise-induced muscle damage; EIMD), and an exercise intensity-matched non-muscle-damaging flat run (CON), in random order separated by 2 wk. Both treatments were followed by heat stress elicited by a 40-min run at 33°C. Urine and blood were sampled at baseline, after treatment, and after subjects ran in the heat. By design, EIMD induced higher plasma creatine kinase and interleukin-6 than CON. EIMD elevated kidney injury biomarkers (e.g., urinary neutrophil gelatinase-associated lipocalin (NGAL) after a run in the heat: EIMD-CON, mean difference [95% CI]: 12 [5, 19] ng/ml) and reduced kidney function (e.g., plasma creatinine after a run in the heat: EIMD-CON, mean difference [95% CI]: 0.2 [0.1, 0.3] mg/dl), where CI is the confidence interval. Plasma interleukin-6 was positively correlated with plasma NGAL (r = 0.9, P = 0.001). Moreover, following EIMD, 5 of 10 participants met AKIN criteria for AKI. Thus for the first time we demonstrate that muscle-damaging exercise before running in the heat results in a greater inflammatory state and kidney stress compared with non-muscle-damaging exercise. Muscle damage should therefore be considered a risk factor for AKI when performing exercise in hot environments.

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.

Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension

The study was undertaken to determine whether normobaric hypoxia causes elevated brain volume and intracranial pressure in individuals with symptoms consistent with acute mountain sickness (AMS).

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.

Physiological and psychological illness symptoms at high altitude and their relationship with acute mountain sickness: a prospective cohort study

BACKGROUND The aim of this prospective observational cohort study was to investigate relationships between acute mountain sickness (AMS) and physical and mental health during a high altitude expedition. METHODS Forty-four participants (mean age, 34 ± 13 y; body mass index, 23.6 ± 3.5 kg·m(2) ; 57% male) completed the Dhaulagiri base camp trek in Nepal, a 19-day expedition attaining 5,372 m. Participants self-reported the following daily physical and mental health: AMS (defined by Lake Louise diagnosis and individual and total symptom scores), upper respiratory symptoms, diarrhea, and anxiety, plus physiological and behavioral factors. RESULTS The rate of Lake Louise-defined AMS per 100 person days was 9.2 (95% CI: 7.2-11.7). All investigated illnesses except diarrhea increased with altitude (all p < 0.001 by analysis of variance). Total AMS symptom score was associated with a lower arterial oxygen saturation, higher resting heart rate, more upper respiratory and diarrhea symptoms, greater anxiety, and lower fluid intake (all p < 0.02 by longitudinal multiple regression analyses). However, only upper respiratory symptoms, heart rate, arterial oxygen saturation, and fluid intake predicted future AMS symptoms [eg, an increase in upper respiratory symptoms by 5 units predicted an increase in the following days AMS total symptom score by 0.72 units (0.54-0.89)]. CONCLUSIONS Upper respiratory symptoms and anxiety increasingly contributed to symptom burden as altitude was gained. Data were consistent with increased heart rate, decreased arterial oxygen saturation, reduced fluid intake, and upper respiratory symptoms being causally associated with AMS. Upper respiratory symptoms and fluid intake are the simplest targets for intervention to reduce AMS during high altitude exposure.