Inflammation and physical dysfunction: responses to moderate intensity exercise in chronic kidney disease.

BACKGROUND: People with chronic kidney disease (CKD) experience skeletal muscle wasting, reduced levels of physical function and performance, and chronic systemic inflammation. While it is known that a relationship exists between inflammation and muscle wasting, the association between inflammation and physical function or performance in CKD has not been well studied. Exercise has anti-inflammatory effects, but little is known regarding the effect of moderate intensity exercise. This study aimed to (i) compare systemic and intramuscular inflammation between CKD stage G3b-5 and non-CKD controls; (ii) establish whether a relationship exists between physical performance, exercise capacity and inflammation in CKD; (iii) determine changes in systemic and intramuscular inflammation following 12 weeks of exercise; and (iv) investigate whether improving inflammatory status via training contributes to improvements in physical performance and muscle mass. METHODS: This is a secondary analysis of previously collected data. CKD patients stages G3b-5 (n = 84, n = 43 males) and non-CKD controls (n = 26, n = 17 males) underwent tests of physical performance, exercise capacity, muscle strength and muscle size. In addition, a subgroup of CKD participants underwent 12 weeks of exercise training, randomized to aerobic (AE, n = 21) or combined (CE, n = 20) training. Plasma and intramuscular inflammation and myostatin were measured at rest and following exercise. RESULTS: Tumour necrosis factor-α was negatively associated with lower $^{^{^{.}}}{\rm V}$O2Peak (P = 0.01), Rectus femoris-cross sectional area (P = 0.002) and incremental shuttle walk test performance (P < 0.001). Interleukin-6 was negatively associated with sit-to-stand 60 performances (P = 0.006) and hand grip strength (P = 0.001). Unaccustomed exercise created an intramuscular inflammatory response that was attenuated following 12 weeks of training. Exercise training did not reduce systemic inflammation, but AE training did significantly reduce mature myostatin levels (P = 0.02). Changes in inflammation were not associated with changes in physical performance. CONCLUSIONS: Systemic inflammation may contribute to reduced physical function in CKD. Twelve weeks of exercise training was unable to reduce the level of chronic systemic inflammation in these patients, but did reduce plasma myostatin concentrations. Further research is required to further investigate this.

Twelve-week combined resistance and aerobic training confers greater benefits than aerobic training alone in nondialysis CKD.

There is a growing consensus that patients with chronic kidney disease (CKD) should engage in regular exercise, but there is a lack of formal guidelines. In this report, we determined whether combined aerobic and resistance exercise would elicit superior physiological gains, in particular muscular strength, compared with aerobic training alone in nondialysis CKD. Nondialysis patients with CKD stages 3b-5 were randomly allocated to aerobic exercise {AE, n = 21; 9 men; median age 63 [interquartile range (IQR) 58-71] yr; median estimated glomerular filtration rate (eGFR) 24 (IQR 20-30) ml·min-1·1.73 m-2} or combined exercise [CE, n = 20, 9 men, median age 63 (IQR 51-69) yr, median eGFR 27 (IQR 22-32) ml·min-1·1.73 m-2], preceded by a 6-wk run-in control period. Patients then underwent 12 wk of supervised AE (treadmill, rowing, or cycling exercise) or CE training (as AE plus leg extension and leg press exercise) performed three times per week. Outcome assessments of knee extensor muscle strength, quadriceps muscle volume, exercise capacity, and central hemodynamics were performed at baseline, following the 6-wk control period, and at the end of the intervention. AE and CE resulted in significant increases in knee extensor strength of 16 ± 19% (mean ± SD; P = 0.001) and 48 ± 37% ( P < 0.001), respectively, which were greater after CE ( P = 0.02). AE and CE resulted in 5 ± 7% ( P = 0.04) and 9 ± 7% ( P < 0.001) increases in quadriceps volume, respectively ( P < 0.001), which were greater after CE ( P = 0.01). Both AE and CE increased distance walked in the incremental shuttle walk test [28 ± 44 m ( P = 0.01) and 32 ± 45 m ( P = 0.01), respectively]. In nondialysis CKD, the addition of resistance exercise to aerobic exercise confers greater increases in muscle mass and strength than aerobic exercise alone.

Association between vitamin D deficiency and exercise capacity in patients with CKD, a cross-sectional analysis.

BACKGROUND: Evidence is growing for a role of vitamin D in regulating skeletal muscle mass, strength and functional capacity. Given the role the kidneys play in activating total vitamin D, and the high prevalence of vitamin D deficiency in Chronic Kidney Disease (CKD), it is possible that deficiency contributes to the low levels of physical function and muscle mass in these patients. METHODS: This is a secondary cross-sectional analysis of previously published interventional study, with in vitro follow up work. 34 CKD patients at stages G3b-5 (eGFR 25.5 ± 8.3 mL/min/1.73m2; age 61 ± 12 years) were recruited, with a sub-group (n = 20) also donating a muscle biopsy. Vitamin D and associated metabolites were analysed in plasma by liquid chromatography tandem-mass spectroscopy and correlated to a range of physiological tests of muscle size, function, exercise capacity and body composition. The effects of 1α,25(OH)2D3 supplementation on myogenesis and myotube size was investigated in primary skeletal muscle cells from vitamin D deficient donors. RESULTS: In vivo, there was no association between total or active vitamin D and muscle size or strength, but a significant correlation with V̇O2Peak was seen with total vitamin D (25OHD). in vitro, 1α,25(OH)2D3 supplementation reduced IL-6 mRNA expression, but had no effect upon proliferation, differentiation or myotube diameter. CONCLUSIONS: Vitamin D deficiency is not a prominent factor driving the loss of muscle mass in CKD, but may play a role in reduced exercise capacity.

The "Minimum Clinically Important Difference" in Frequently Reported Objective Physical Function Tests After a 12-Week Renal Rehabilitation Exercise Intervention in Nondialysis Chronic Kidney Disease.

OBJECTIVE: Chronic kidney disease patients are characterized by impaired physical function. The goal of exercise-based interventions is an improvement in functional performance. However, improvements are often determined by "statistically significant" changes. We investigated the "minimum clinically important difference," "the smallest change that is important to the patient," for commonly reported physical function tests. DESIGN: Nondialysis chronic kidney disease patients completed 12-wks of a combined aerobic (plus resistance training). The incremental shuttle walking test, sit-to-stand 5 and 60, estimated 1-repetition maximum for the knee extensors, and VO2peak were assessed. After the intervention, patients rated their perceived change in health. Both anchor- and distribution-based minimum clinically important difference approaches were calculated. RESULTS: The minimum clinically important difference was calculated as follows: incremental shuttle walking test, +45 m; sit-to-stand 5, -4.2 secs; VO2peak, +1.5 ml/kg per min. Because of comparable increases in "anchor" groups, no minimum clinically important difference was estimated for the sit-to-stand 60 or estimated 1-repetition maximum. CONCLUSIONS: We have established the minimum clinically important difference in chronic kidney disease for common tests of physical function. These values represent the minimum change required for patients to perceive noticeable and beneficial change to their health. These scores will help interpret changes after exercise interventions where these tests are used. These minimum clinically important differences can be used to power future studies to detect clinically important changes. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Define the "minimum clinically important difference"; (2) Distinguish between concepts of minimum clinically important difference, "minimal detectable change,", and "statistically significant change"; and (3) Interpret other study findings and their own results in the context of the minimum clinically important difference rather than statistically significant changes. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Peak aerobic capacity from incremental shuttle walk test in chronic kidney disease.

BACKGROUND: Assessment of cardiorespiratory fitness is an important outcome in chronic kidney disease (CKD). We aimed to develop a predictive equation to estimate peak oxygen uptake (VO2peak ) and power output (WPeak ), as measured during a cardiopulmonary exercise test (CPET), from the distance walked (DW) during the incremental shuttle walk test (ISWT). METHODS: Thirty-six non-dialysing patients with CKD [17 male, age: 61 ± 12 years, eGFR: 25±7 ml/min/1.73 m2 , body mass index (BMI): 31 ± 6 kg/m2 ] carried out laboratory-based CPET on a cycle ergometer and ISWT on two separate occasions. RESULTS: Linear regression revealed that DW/BMI was a significant predictor of VO2Peak (r = 0.78) (VO2Peak (ml/min/kg) = [0.5688 × (DW/BMI) (m)] + 11.50). No difference (p = 0.66) between CPET VO2Peak (19.9 ± 5.5 ml/min/kg) and predicted VO2Peak (19.9 ± 4.3 ml/min/kg) was observed. DW multiplied by body mass (BM) was a significant predictor of WPeak (r = 0.80) [WPeak (W) = (0.0018 × (DW × BM)) + 50.47]. No difference (p = 0.97) between CPET WPeak (116.2 ± 38.9 W) and estimated WPeak (113.9 ± 30.1 W) was seen. CONCLUSION: The present study demonstrates that VO2Peak and WPeak can be accurately estimated using the DW during an ISWT in CKD populations.

Ultrasound assessment of muscle mass in response to exercise training in chronic kidney disease: a comparison with MRI.

BACKGROUND: Chronic kidney disease (CKD) is a catabolic condition associated with muscle wasting and dysfunction, which associates with morbidity and mortality. There is a need for simple techniques capable of monitoring changes in muscle size with disease progression and in response to interventions aiming to increase muscle mass and function. Ultrasound is one such technique; however, it is unknown how well changes in muscle cross-sectional area (CSA) measured using ultrasound relate to changes in whole muscle volume measured using magnetic resonance imaging. We tested whether rectus femoris CSA (RF-CSA) could be used as a valid indication of changes in quadriceps muscle volume as a single measure of muscle size and following a 12 week exercise intervention that resulted in muscle hypertrophy. METHODS: Secondary analysis of data was collected from the ExTra CKD study (ISRCTN 36489137). Quadriceps muscle size was assessed from 36 patients with non-dialysis CKD before and after 12 weeks of supervised exercise that resulted in muscle hypertrophy. RESULTS: Strong positive correlations were observed between RF-CSA and quadriceps volume at baseline (r2 = 0.815, CI 0.661 to 0.903; P < 0.001) and following 12 week exercise (r2 = 0.845, CI 0.700 to 0.923; P < 0.001). A moderate positive association was also observed between changes in RF-CSA and quadriceps following exercise training (rho = 0.441, CI 0.085 to 0.697; P = 0.015). Bland-Altman analysis revealed a small bias (bias 0.6% ± 12.5) between the mean percentage changes in RF-CSA and quadriceps volume but wide limits of agreement from -24 to 25. CONCLUSIONS: Rectus femoris CSA appears to be a reliable index of total quadriceps volume as a simple measure of muscle size, both as a single observation and in response to exercise training in non-dialysis CKD patients.

Test-retest reliability, validation, and "minimal detectable change" scores for frequently reported tests of objective physical function in patients with non-dialysis chronic kidney disease.

Physical function is an important outcome in chronic kidney disease (CKD). We aimed to establish the reliability, validity, and the "minimal detectable change" (MDC) of several common tests used in renal rehabilitation and research. In a repeated measures design, 41 patients with CKD not requiring dialysis (stage 3b to 5) were assessed at an interval of 6 weeks. The tests were the incremental shuttle walk test (ISWT), "sit-to-stand" (STS) test, estimated 1 repetition maximum for quadriceps strength (e1RM), and VO2peak by cardiopulmonary exercise testing (CPET). Reliability was assessed using intraclass correlation coefficient and Bland-Altman analysis, and absolute reliability by standard error of measurement and MDC. The ISWT, STS-60, e1RM, and CPET had "good" to "excellent" reliability (0.973, 0.927, 0.927, and 0.866), respectively. STS-5 reliability was poor (0.676). The MDC is ISWT, 20 m; STS-5, 7.5 s; STS-60, 4 reps; e1RM, 6.4 kg; VO2peak, 2.8 ml/kg/min. There was strong correlation between the ISWT and VO2peak (r = 0.73 and 0.74). While there was poor correlation between the STS-5 and e1RM (r = 0.14 and 0.47), better correlation was seen between STS-5 and ISWT (r = 0.55 and 0.74). In conclusion, the ISWT, STS-60, e1RM, and CPET are reliable tests of function in CKD. The ISWT is a valid means of exercise capacity. The MDC can help researchers and rehabilitation professionals interpret changes following an intervention.

Twelve weeks of supervised exercise improves self-reported symptom burden and fatigue in chronic kidney disease: a secondary analysis of the 'ExTra CKD' trial.

BACKGROUND: Chronic kidney disease (CKD) patients experience a high symptom burden including fatigue, sleep difficulties, muscle weakness and pain. These symptoms reduce levels of physical function (PF) and activity, and contribute to poor health-related quality of life (HRQoL). Despite the gathering evidence of positive physiological changes following exercise in CKD, there is limited evidence on its effect on self-reported symptom burden, fatigue, HRQoL and physical activity. METHODS: Thirty-six patients [mean ± SD 61.6 ± 11.8 years, 22 (61%) females, estimated glomerular filtration rate: 25.5 ± 7.8 mL/min/1.73 m2] not requiring renal replacement therapy underwent 12 weeks (3 times/week) of supervised aerobic exercise (AE), or a combination (CE) of AE plus resistance training. Outcomes included self-reported symptom burden, fatigue, HRQoL and physical activity. RESULTS: Exercise reduced the total number of symptoms reported by 17% and had favourable effects on fatigue in both groups. AE reduced the frequency of 'itching', 'impotence' and 'shortness of breath' symptoms, and the intrusiveness for symptoms of 'sleep disturbance', 'loss of muscular strength/power', 'muscle spasm/stiffness' and 'restless legs'. The addition of resistance exercise in the CE group saw a reduction in 'loss of muscular strength/power'. No changes were seen in subjective PF or physical activity levels. AE increased self-efficacy for physical activity. CONCLUSIONS: Supervised exercise had favourable effects on symptom frequency and intrusiveness, including substantial improvements in fatigue. Although the intervention did not improve self-reported physical activity levels, AE increased patients' self-efficacy for physical activity. These favourable changes in self-reported outcomes support the important role of exercise in CKD.

The association of physical function and physical activity with all-cause mortality and adverse clinical outcomes in nondialysis chronic kidney disease: a systematic review.

OBJECTIVE: People with nondialysis-dependent chronic kidney disease (CKD) and renal transplant recipients (RTRs) have compromised physical function and reduced physical activity (PA) levels. Whilst established in healthy older adults and other chronic diseases, this association remains underexplored in CKD. We aimed to review the existing research investigating poor physical function and PA with clinical outcome in nondialysis CKD. DATA SOURCES: Electronic databases (PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials) were searched until December 2017 for cohort studies reporting objective or subjective measures of PA and physical function and the associations with adverse clinical outcomes and all-cause mortality in patients with nondialysis CKD stages 1-5 and RTRs. The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42016039060). REVIEW METHODS: Study quality was assessed using the Newcastle-Ottawa Scale and the Agency for Healthcare and Research Quality (AHRQ) standards. RESULTS: A total of 29 studies were included; 12 reporting on physical function and 17 on PA. Only eight studies were conducted with RTRs. The majority were classified as 'good' according to the AHRQ standards. Although not appropriate for meta-analysis due to variance in the outcome measures reported, a coherent pattern was seen with higher mortality rates or prevalence of adverse clinical events associated with lower PA and physical function levels, irrespective of the measurement tool used. Sources of bias included incomplete description of participant flow through the study and over reliance on self-report measures. CONCLUSIONS: In nondialysis CKD, survival rates correlate with greater PA and physical function levels. Further trials are required to investigate causality and the effectiveness of physical function and PA interventions in improving outcomes. Future work should identify standard assessment protocols for PA and physical function.

An evaluation of low volume high-intensity intermittent training (HIIT) for health risk reduction in overweight and obese men.

ᅟ: Both sprint interval training (SIT) and high-intensity intermittent training (HIIT) have been described as time-efficient strategies for inducing favourable metabolic and cardiorespiratory adaptations in healthy and diseased participants. BACKGROUND: To date, little attention has been given to profiling the potential health benefits of HIIT or modified HIIT training within overweight and obese cohorts with particular focus on inflammation. Within this pilot trial, we tested the hypothesis that 6 sessions of HIIT performed over 2 weeks with 1-2 days' rest would improve aerobic capacity, glucose metabolism and inflammatory profile in an overweight and obese male cohort. Additionally, we profiled the potential health benefits of 4 HIIT sessions performed over the same period. METHODS: 18 overweight or obese males (BMI = 31.2 ± 3.6; V̇O2 = 30.3 ± 4.4 ml.kg.min-1) were studied before and 72 h after HIIT. Training sessions consisted of 10 x 1 min intervals at 90% HRpeak separated by 1 min recovery periods. Exercise was performed either 6 (group 1, n = 8) or 4 (group 2, n = 10) times over a 2 week period. RESULTS: After training no changes were detected from baseline for body composition, aerobic capacity, glucose metabolism or inflammatory profile (p > 0.05) in either group. CONCLUSION: Both 6 and 4 sessions of HIIT performed over a 2-week period are ineffective in improving selected health markers within an overweight and obese cohort. TRIAL REGISTRATION: This trial reports data from human participants and was retrospectively registered on 22/02/2017 with the ISRCTN registry, trial number ISRCTN90672085.

Appetite-regulatory hormone responses on the day following a prolonged bout of moderate-intensity exercise.

Exercise increases energy expenditure however acutely this does not cause compensatory changes in appetite or food intake. This unresponsiveness contrasts the rapid counter-regulatory changes seen after food restriction. The present investigation examined whether corrective changes in appetite-regulatory parameters occur after a time delay, namely, on the day after a single bout of exercise. Nine healthy males completed two, two-day trials (exercise & control) in a random order. On the exercise trial participants completed 90 min of moderate-intensity treadmill running on day one (10:30-12:00h). On day two appetite-regulatory hormones and subjective appetite perceptions were assessed frequently in response to two test meals provided at 08:00 and 12:00 h. Identical procedures occurred in the control trial except no exercise was performed on day one. Circulating levels of leptin were reduced on the day after exercise (AUC 5841 ± 3335 vs. 7266 ± 3949 ng(-1)·mL(-1)·7h, P=0.012). Conversely, no compensatory changes were seen for circulating acylated ghrelin, total PYY, insulin or appetite perceptions. Unexpectedly, levels of acylated ghrelin were reduced on the exercise trial following the second test meal on day two (AUC 279 ± 136 vs. 326 ± 136 pg(-1)·mL(-1)·3h, P=0.021). These findings indicate that short-term energy deficits induced by exercise initially prompt a compensatory response by chronic but not acute hormonal regulators of appetite and energy balance. Within this 24h time-frame however there is no conscious recognition of the perturbation to energy balance.