London Schools Excellence Fund: Final Report: Enhancing the teaching of STEM through Design and Technology

London Schools Excellence Fund: Final Report: Enhancing the teaching of STEM through Design and Technolog

Satellite Cell Function, Intramuscular Inflammation and Exercise in Chronic Kidney Disease

Skeletal muscle wasting is a common feature of Chronic Kidney Disease (CKD) and is clinically relevant due to associations with quality of life, physical functioning, mortality and a number of co-morbidities. Satellite cells are a population of skeletal muscle progenitor cells responsible for accrual and maintenance of muscle mass by providing new nuclei to myofibres. Recent evidence from animal models and human studies indicates CKD may negatively affect satellite cell abundance and function in response to stimuli such as exercise and damage. The aim of this review is to collate recent literature on the effect of CKD on satellite cells, with a particular focus on the myogenic response to exercise in this population. Exercise is widely recognised as important for the maintenance of healthy skeletal muscle mass and is increasingly advocated in the care of a number of chronic conditions. Therefore, a greater understanding of the impact of uremia upon satellite cells and the possible altered myogenic response in CKD is required to inform strategies to prevent uremic cachexia

The ‘minimum clinically important difference’ in frequently reported objective physical function tests following a 12-week renal rehabilitation exercise intervention in non-dialysis chronic kidney disease

Objective Chronic kidney disease (CKD) 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’ (MCID), ‘the smallest change that is important to the patient’, for commonly reported physical function tests. Design Non-dialysis CKD patients completed 12-weeks of a combined aerobic (plus resistance training). The incremental shuttle walking test (ISWT), sit-to-stand-5 (STS-5) and 60 (STS-60), estimated 1 repetition maximum (e1RM) for the knee extensors, and VO2peak were assessed. After the intervention, patients rated their perceived change in health. Both anchor- and distribution-based MCID approaches were calculated. Results The MCID was calculated as follows: ISWT, +45m; STS-5, -4.2 seconds; VO2peak, +1.5 ml/kg/min. Due to comparable increases in ‘anchor’ groups, no MCID was estimated for the STS-60 or e1RM. Conclusion We have established the MCID in CKD 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 following exercise interventions where these tests are employed. These MCIDs can be used to power future studies to detect clinically important changes

Quality over quantity? Effects of skeletal muscle myosteatosis and fibrosis on physical functioning in chronic kidney disease

Background Chronic kidney disease (CKD) is characterised by adverse changes in body composition, which are associated with poor clinical outcome and physical functioning. Whilst size is key for muscle functioning, changes in muscle quality specifically increase in intramuscular fat infiltration (myosteatosis) and fibrosis (myofibrosis) may be important. We investigated the role of muscle quality and size on physical performance in non-dialysis CKD patients. Methods Ultrasound (US) images of the rectus femoris (RF) were obtained. Muscle quality was assessed using echo intensity (EI), and qualitatively using Heckmatt’s visual rating scale. Muscle size was obtained from RF cross-sectional area (RF-CSA). Physical function was measured by the sit-to-stand-60 (STS-60) test, incremental (ISWT) and endurance shuttle walk tests (ESWT), lower limb and handgrip strength, exercise capacity (VO2peak), and gait speed. Results patients (58.5±14.9) years, 46% female, eGFR 31.1±20.2 mL/min/1.73m2 40 ) were recruited. Lower EI (i.e. higher muscle quality) was significantly associated with better physical performance [STS-60 (r=.363) and ISWT (r=.320)], and greater VO2peak (r=.439). The qualitative rating were closely associated with EI values, and significant differences in function was seen between the ratings. RF-CSA was a better predictor of performance than muscle quality. Conclusions In CKD, increased US-derived EI was negatively correlated with physical performance, however, muscle size remains the largest predictor of physical function. Therefore, in addition to the loss of muscle size, muscle quality should be considered an important factor that may contribute to deficits in mobility and function in CKD. Interventions such as exercise could improve both of these factors

The Effect of Resistance Exercise on Inflammatory and Myogenic Markers in Patients with Chronic Kidney Disease

Background: Muscle wasting is a common complication of Chronic Kidney Disease (CKD) and is clinically important given its strong association with morbidity and mortality in many other chronic conditions. Exercise provides physiological benefits for CKD patients, however the molecular response to exercise remains to be fully determined. We investigated the inflammatory and molecular response to resistance exercise before and after training in these patients. Methods: This is a secondary analysis of a randomized trial that investigated the effect of 8 week progressive resistance training on muscle mass and strength compared to non-exercising controls. A sub-set of the cohort consented to vastus lateralis skeletal muscle biopsies (n = 10 exercise, n = 7 control) in which the inflammatory response (IL-6, IL-15, MCP-1 TNF-α), myogenic (MyoD, myogenin, myostatin), anabolic (P-Akt, P-eEf2) and catabolic events (MuRF-1, MAFbx, 14 kDa, ubiquitin conjugates) and overall levels of oxidative stress have been studied. Results: A large inflammatory response to unaccustomed exercise was seen with IL-6, MCP-1, and TNF-α all significantly elevated from baseline by 53-fold (P < 0.001), 25-fold (P < 0.001), and 4-fold (P < 0.001), respectively. This response was reduced following training with IL-6, MCP-1, and TNF-α elevated non-significantly by 2-fold (P = 0.46), 2.4-fold (P = 0.19), and 2.5-fold (P = 0.06), respectively. In the untrained condition, an acute bout of resistance exercise did not result in increased phosphorylation of Akt (P = 0.84), but this was restored following training (P = 0.01). Neither unaccustomed nor accustomed exercise resulted in a change in myogenin or MyoD mRNA expression (P = 0.88, P = 0.90, respectively). There was no evidence that resistance exercise training created a prolonged oxidative stress response within the muscle, or increased catabolism. Conclusions: Unaccustomed exercise creates a large inflammatory response within the muscle, which is no longer present following a period of training. This indicates that resistance exercise does not provoke a detrimental on-going inflammatory response within the muscle

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

Progressive Resistance Exercise Training in CKD: A Feasibility Study

Background: Skeletal muscle wasting in chronic kidney disease (CKD) is associated with morbidity and mortality. Resistance exercise results in muscle hypertrophy in the healthy population, but is underinvestigated in CKD. We aimed to determine the feasibility of delivering a supervised progressive resistance exercise program in CKD, with secondary aims to investigate effects on muscle size, strength, and physical functioning. Study Design: Parallel randomized controlled feasibility study. Setting & Participants: Patients with CKD stages 3b to 4 were randomly assigned to the exercise (n = 20; 11 men; median age, 63 [IQR, 57-65] years; median estimated glomerular filtration rate, 28.5 [IQR, 19.0-32.0] mL/min/1.73 m[superscript: 2]) or nonexercise control (n = 18; 14 men; median age, 66 [IQR, 45-79] years; estimated glomerular filtration rate, 20.5 [IQR, 16.0-26.0] mL/min/1.73 m[superscript: 2]) group. Intervention: Patients in the exercise group undertook an 8-week progressive resistance exercise program consisting of 3 sets of 10 to 12 leg extensions at 70% of estimated 1-repetition maximum thrice weekly. Patients in the control group continued with usual physical activity. Outcomes: Primary outcomes were related to study feasibility: eligibility, recruitment, retention, and adherence rates. Secondary outcomes were muscle anatomical cross-sectional area, muscle volume, pennation angle, knee extensor strength, and exercise capacity. Measurements Two- and 3-dimensional ultrasonography of skeletal muscle, dynamometry, and shuttle walk tests at baseline and 8 weeks. Results: Of 2,349 patients screened, 403 were identified as eligible and 38 enrolled in the study. 33 (87%) completed the study, and those in the exercise group attended 92% of training sessions. No changes were seen in controls for any parameter. Progressive resistance exercise increased muscle anatomical cross-sectional area, muscle volume, knee extensor strength, and exercise capacity. Limitations: No blinded assessors, magnetic resonance imaging not used to assess muscle mass, lack of a healthy control group. Conclusions: This type of exercise is well tolerated by patients with CKD and confers important clinical benefits; however, low recruitment rates suggest that a supervised outpatient-based program is not the most practical implementation strategy

12-weeks combined resistance and aerobic training confers greater benefits than aerobic alone in non-dialysis CKD.

There is a growing consensus that chronic kidney disease (CKD) patients 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 to aerobic training alone in non-dialysis CKD. Non-dialysis CKD patients stage 3b-5 were randomly allocated to aerobic exercise (AE, n=21; 9 males; median age 63years [IQR, 58-71]; median eGFR 24[IQR, 20-30] mL/min/1.73m2) or combined exercise (CE, n=20, 9 males, median age 63years [IQR, 51-69], median eGFR 27[IQR, 22-32] mL/min/1.73m2), preceded by a 6-week run in control period. Patients then underwent 12-weeks of supervised AE (treadmill, rowing or cycling exercise) or CE training (as AE plus leg extension and leg press exercise) performed 3x/week. Outcome assessments of knee extensor muscle strength, quadriceps muscle volume, exercise capacity and central haemodynamics were performed at baseline, following the 6-week control period and at the end of the intervention. AE and CE resulted in significant increases in knee extensor strength of 1619% (P=0.001) and 4837% (P<0.001) respectively, which were greater after CE (P=0.02). AE and CE resulted in 57% (P=0.04) and 97% (P<0.001) increases in quadriceps volume respectively (P<0.001) which was greater after CE (P=0.01). Both AE and CE increased distance walked in ISWT (2844m; P=0.01 and 3245m P=0.01) respectively. In non-dialysis CKD, the addition of resistance exercise to aerobic exercise confers greater increases in muscle mass and strength than aerobic exercise alone

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

Objective: People with non-dialysis dependent chronic kidney disease (CKD) and renal transplant recipients (RTR) 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 non-dialysis 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/subjective measures of PA/physical function and the associations with adverse clinical outcomes/all-cause mortality for patients with non-dialysis chronic kidney disease stages 1 to 5 and RTR. 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: 29 studies were included; 12 reporting on physical function and 17 on PA. Only 8 studies were conducted with RTR. 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 and/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 non-dialysis CKD, survival rates correlate with greater PA and physical function levels. Further trials are required to investigate causality and the effectiveness of physical function/physical activity interventions in improving outcomes. Future work should identify standard assessment protocols for PA and physical function