Skeletal Muscle Texture Assessment Using Ultrasonography: Comparison with Magnetic Resonance Imaging in Chronic Kidney Disease.

Skeletal muscle dysfunction is common in chronic kidney disease (CKD). Of interest is the concept of "muscle quality," of which measures include ultrasound-derived echo intensity (EI). Alternative parameters of muscle texture, for example, gray level of co-occurrence matrix (GCLM), are available and may circumvent limitations in EI. The validity of EI is limited in humans, particularly in chronic diseases. This study aimed to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Images of the thigh were acquired using a 3 Tesla MRI scanner. Quantification of muscle (contractile), fat (non-contractile), and miscellaneous (connective tissue, fascia) components were estimated. Anatomical rectus femoris cross-sectional area was measured using B-mode 2D ultrasonography. To assess muscle texture, first (i.e., EI)- and second (i.e., GLCM)-order statistical analyses were performed. Fourteen participants with CKD were included (age: 58.0 ± 11.9 years, 50% male, eGFR: 27.0 ± 7.4 ml/min/1.73m2, 55% Stage 4). Higher EI was associated with lower muscle % (quadriceps: ß = -.568, p = .034; hamstrings: ß = -.644, p = .010). Higher EI was associated with a higher fat % in the hamstrings (ß = -.626, p = .017). A higher angular second moment from GLCM analysis was associated with greater muscle % (ß = .570, p = .033) and lower fat % (ß = -.534, p = .049). A higher inverse difference moment was associated with greater muscle % (ß = .610, p = .021 and lower fat % (ß = -.599, p = .024). This is the first study to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Our preliminary findings suggest ultrasound-derived texture analysis provides a novel indicator of reduced skeletal muscle % and thus increased intramuscular fat.

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.

Selecting Portable Ankle/Toe Brachial Pressure Index Systems for a Peripheral Arterial Disease Population Screening Programme: a Systematic Review, Clinical Evaluation Exercise, and Consensus Process.

OBJECTIVE: To provide an overview of systems available for peripheral arterial disease (PAD) screening, together with respective accuracies and a clinical evaluation to identify a system suitable for use in a community screening programme. METHODS: A systematic review of the diagnostic accuracy of six ankle brachial pressure index (ABPI) and toe brachial pressure index (TBPI) devices deemed to be portable, which were Conformité Européenne (CE) marked, and were automated or semi-automated was carried out compared with gold standard handheld Doppler and duplex ultrasound. The devices were MESI-ABPI-MD, Huntleigh Dopplex Ability, Huntleigh ABPI and TBPI systems, Systoe TBPI system, and BlueDop. Seven databases (MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials (CENTRAL), and Cumulative Index to Nursing and Allied Health Literature (CINAHL)) were searched, and 11 studies were identified as eligible for review. This was followed by hands on clinical evaluation by abdominal aortic aneurysm (AAA) screening staff (n = 39). During this, devices were demonstrated to staff which they then tested on volunteers and gave feedback using pre-designed questionnaires on their suitability for use in a screening programme. Finally, accuracy data and staff preferences were combined during a consensus conference that was held between study and screening staff to determine the most appropriate device to use in a community screening programme. RESULTS: Generally, the evaluated systems have a moderate level of sensitivity and a high level of specificity: Dopplex ability sensitivity 20% - 70%, specificity 86% - 96%; MESI sensitivity 57% - 74%, specificity 85% - 99%; BlueDop sensitivity 95%, specificity 89%; and Systoe sensitivity 71%, specificity 77%. Clinical evaluation by screening staff identified a preference for the MESI system. The consensus conference concluded that the MESI device was a good candidate for use in a community PAD screening programme. CONCLUSION: The MESI system is a good candidate to consider for community PAD screening.

A Systematic Review of Handgrip Strength Measurement in Clinical and Epidemiological Studies of Kidney Disease: Toward a Standardized Approach.

In chronic kidney disease (CKD), handgrip strength (HGS) is recommended as a surrogate measure of protein-energy status and functional status. However, it is not routinely used because of inconsistencies such as the optimal timing of the HGS measurement and unclear guidance regarding technique. We aimed to determine the extent of variation in the protocols and methods of HGS assessment. We aimed to identify clinical and epidemiological studies conducted on CKD that reported on the use of HGS as an outcome. A systematic literature search identified n = 129 studies with a total participant population of n = 35,192. We identified large variations in all aspects of the methodology including body and arm position, repetitions, rest time, timing, familiarization, and how scores were calculated. The heterogeneous methodologies used reinforce the need to standardize HGS measurement. After reviewing previously employed methodology in the literature, we propose a comprehensive HGS assessment protocol for use in CKD.

Perceptions and Experiences of a Progressive Resistance Exercise Program in People with Chronic Kidney Disease.

Muscle wasting is highly prevalent in chronic conditions, such as chronic kidney disease (CKD), and can result in decreased physical functioning and strength, and impaired ability to perform daily tasks, thus impacting quality of life. Exercise, particularly resistance training, promotes a multitude of benefits, including prevention and management of muscle dysfunction; however, engagement in resistance training is poor. The aim of this study was to understand the views of people with CKD who participated in a research study evaluating a progressive resistance exercise program. Semi-structured interviews were conducted with 11 people with CKD Stage 3 and 4. Five themes were identified: experiences of muscle weakness; preconceptions of resistance exercise; experiences of participating in a resistance exercise program; perceived impact of the resistance exercise program; and maintenance of resistance exercise. Parti - cipants believed the resistance exercise program could improve their functional performance and quality of life. They disclosed factors that can enable or deter both uptake and maintenance in training, which can be considered when developing resistance-based exercise programs. Findings highlight the need for patient education and counselling about the importance and implementation of appropriate and progressive resistance exercise training.

Muscle-Bone Crosstalk in Chronic Kidney Disease: The Potential Modulatory Effects of Exercise.

Chronic kidney disease (CKD) is a prevalent worldwide public burden that increasingly compromises overall health as the disease progresses. Two of the most negatively affected tissues are bone and skeletal muscle, with CKD negatively impacting their structure, function and activity, impairing the quality of life of these patients and contributing to morbidity and mortality. Whereas skeletal health in this population has conventionally been associated with bone and mineral disorders, sarcopenia has been observed to impact skeletal muscle health in CKD. Indeed, bone and muscle tissues are linked anatomically and physiologically, and together regulate functional and metabolic mechanisms. With the initial crosstalk between the skeleton and muscle proposed to explain bone formation through muscle contraction, it is now understood that this communication occurs through the interaction of myokines and osteokines, with the skeletal muscle secretome playing a pivotal role in the regulation of bone activity. Regular exercise has been reported to be beneficial to overall health. Also, the positive regulatory effect that exercise has been proposed to have on bone and muscle anatomical, functional, and metabolic activity has led to the proposal of regular physical exercise as a therapeutic strategy for muscle and bone-related disorders. The detection of bone- and muscle-derived cytokine secretion following physical exercise has strengthened the idea of a cross communication between these organs. Hence, this review presents an overview of the impact of CKD in bone and skeletal muscle, and narrates how these tissues intrinsically communicate with each other, with focus on the potential effect of exercise in the modulation of this intercommunication.

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) exhibit reduced exercise capacity, poor physical function and symptoms of fatigue. The mechanisms that contribute to this are not clearly defined but may involve reductions in mitochondrial function, mass and biogenesis. Here we report on the effect of non-dialysis dependent CKD (NDD-CKD) on mitochondrial mass and basal expression of transcription factors involved in mitochondrial biogenesis compared to a healthy control cohort (HC). In addition, we sought to investigate the effect of a 12-week exercise-training programme on these aspects of mitochondrial dysfunction in a NDD-CKD cohort.For the comparison between NDD-CKD and HC populations, skeletal muscle biopsies were collected from the vastus lateralis (VL) of n=16 non-dialysis dependent CKD patient's stage 3b-5 (NDD-CKD) and n=16 healthy controls matched for age, gender and physical activity (HC). To investigate the effect of exercise training, VL biopsies were collected from n=17 NDD-CKD patients before and after a 12-week exercise intervention that was comprised of aerobic exercise (AE) or a combination of aerobic exercise and resistance training (CE). Mitochondrial mass was analysed by citrate synthase activity and mitochondrial protein content by Porin expression, whilst the expression of transcription factors involved in mitochondrial biogenesis were quantified by real-time qPCR. NDD-CKD patients exhibited a significant reduction in mitochondrial mass when compared to HC, coupled to a reduction in PGC-1α, NRF-1, Nrf2, TFam, mfn2 and SOD1/2 gene expression. 12-weeks of exercise training resulted in a significant increase in PGC-1α expression in both groups, with no further changes seen across indicators of mitochondrial biogenesis. No significant changes in mitochondrial mass were observed in response to either exercise programme. NDD-CKD patients exhibit reduced skeletal muscle mitochondrial mass and gene expression of transcription factors involved in mitochondrial biogenesis compared to HC. These reductions were not restored following 12-weeks of exercise training implying exercise resistance in this cohort. The reasons for this lack of improvement are currently unknown and require further investigation, as reversing the dysregulation of these processes in NDD-CKD may provide a therapeutic opportunity to improve muscle fatigue and dysfunction in this population.

Muscle power and physical dysfunction: A model for tailoring rehabilitation in chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is characterized by adverse physical function. Mechanical muscle power describes the product of muscular force and velocity of contraction. In CKD, the role of mechanical muscle power is poorly understood and often overlooked as a target in rehabilitation. The aims of this study were to investigate the association of mechanical power with the ability to complete activities of daily living and physical performance. METHOD: Mechanical muscle power was estimated using the sit-to-stand-5 test. Legs lean mass was derived using bioelectrical impedance analysis. Physical performance was assessed using gait speed and 'timed-up-and-go' (TUAG) tests. Self-reported activities of daily living (ADLs) were assessed via the Duke Activity Status Index. Balance and postural stability (postural sway and velocity) was assessed using a FysioMeter. Sex-specific tertiles were used to determine low levels of power. RESULTS: One hundred and two non-dialysis CKD participants were included (age: 62.0 (±14.1) years, n = 49 males (48%), eGFR: 38.0 (±21.5) ml/min/1.73m2 ). The mean relative power was 3.1 (±1.5) W/kg in females and 3.3 (±1.3) W/kg in males. Low relative power was found in 34% of patients. Relative power was an independent predictor of ADLs (ß = .413, p = .004), and TUAG (ß = -.719, p < .001) and gait speed (ß = .404, p = .003) performance. Skeletal muscle mass was not associated with any outcomes. CONCLUSION: Knowledge of the factors that mediate physical function impairment is crucial for developing effective interventions. Incorporation of power-based training focusing primarily on movement velocity may present the best strategy for improving physical function in CKD, above those that focus on increasing muscle mass.

Utility of Ultrasound as a Valid and Accurate Diagnostic Tool for Sarcopenia: Sex-Specific Cutoff Values in Chronic Kidney Disease.

OBJECTIVES: Patients with chronic kidney disease (CKD) have aberrant changes in body composition, including low skeletal muscle mass, a feature of "sarcopenia." The measurement of the (quadriceps) rectus femoris (RF) cross-sectional area (CSA) is widely used as a marker of muscle size. Cutoff values are needed to help discriminate the condition of an individual's muscle (eg, presence of sarcopenia) quickly and accurately. This could help distinguish those at greater risk and aid in targeted treatment programs. METHODS: Transverse images of the RF were obtained by B-mode 2-dimensional ultrasound imaging. Sarcopenic levels of muscle mass were defined by established criteria (1, appendicular skeletal muscle mass [ASM]; 2, ASM/height2 ; and 3, ASM/body mass index) based on the ASM and total muscle mass measured by a bioelectrical impedance analysis. The discriminative power of RF-CSA was assessed by receiver operating characteristic curves, and optimal cutoffs were determined by the maximum Youden index (J). RESULTS: One hundred thirteen patients with CKD (mean age [SD], 62.0 [14.1] years; 48% male; estimated glomerular filtration rate, 38.0 [21.5] mL/min/1.73m2 ) were included. The RF-CSA was a moderate predictor of ASM (R2 = 0.426; P < .001) and total muscle mass (R2 = 0.438; P < .001). With a maximum J of 0.47, in male patients, an RF-CSA cutoff of less than 8.9 cm2 was deemed an appropriate cutoff for detecting sarcopenic muscle mass. In female patients, an RF-CSA cutoff of less than 5.7 cm2 was calculated on the basis of ASM/height2 (J = 0.71). CONCLUSIONS: Ultrasound may provide a low-cost and simple means to diagnose sarcopenia in patients with CKD. This would allow for early management and timely intervention to help mitigate the effects in this group.

Quantitative Muscle Ultrasonography Using 2D Textural Analysis: A Novel Approach to Assess Skeletal Muscle Structure and Quality in Chronic Kidney Disease.

Chronic kidney disease (CKD) is characterized by progressive reductions in skeletal muscle function and size. The concept of muscle quality is increasingly being used to assess muscle health, although the best means of assessment remains unidentified. The use of muscle echogenicity is limited by an inability to be compared across devices. Gray level of co-occurrence matrix (GLCM), a form of image texture analysis, may provide a measure of muscle quality, robust to scanner settings. This study aimed to identify GLCM values from skeletal muscle images in CKD and investigate their association with physical performance and strength (a surrogate of muscle function). Transverse images of the rectus femoris muscle were obtained using B-mode 2D ultrasound imaging. Texture analysis (GLCM) was performed using ImageJ. Five different GLCM features were quantified: energy or angular second moment (ASM), entropy, homogeneity, or inverse difference moment (IDM), correlation, and contrast. Physical function and strength were assessed using tests of handgrip strength, sit to stand-60, gait speed, incremental shuttle walk test, and timed up-and-go. Correlation coefficients between GLCM indices were compared to each objective functional measure. A total of 90 CKD patients (age 64.6 (10.9) years, 44% male, eGFR 33.8 (15.7) mL/minutes/1.73 m2) were included. Better muscle function was largely associated with those values suggestive of greater image texture homogeneity (i.e., greater ASM, correlation, and IDM, lower entropy and contrast). Entropy showed the greatest association across all the functional assessments (r = -.177). All GLCM parameters, a form of higher-order texture analysis, were associated with muscle function, although the largest association as seen with image entropy. Image homogeneity likely indicates lower muscle infiltration of fat and fibrosis. Texture analysis may provide a novel indicator of muscle quality that is robust to changes in scanner settings. Further research is needed to substantiate our findings.

Skeletal muscle wasting in chronic kidney disease: the emerging role of microRNAs.

Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. Evidence suggests that increasing skeletal muscle mass improves outcomes in CKD, making this a clinically important research focus. Despite extensive research, the pathogenesis of skeletal muscle wasting is not completely understood. It is widely recognized that microRNAs (miRNAs), a family of short non-coding RNAs, are pivotal in the regulation of skeletal muscle homoeostasis, with significant roles in regulating muscle growth, regeneration and metabolism. The abnormal expression of miRNAs in skeletal muscle during disease has been well described in cellular and animal models of muscle atrophy, and in recent years, the involvement of miRNAs in the regulation of muscle atrophy in CKD has been demonstrated. As this exciting field evolves, there is emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit the progression of CKD. In this article, we describe the pathophysiological mechanisms of muscle wasting and explore the contribution of miRNAs to the development of muscle wasting in CKD. We also discuss advances in our understanding of miRNAs in muscle-organ crosstalk and summarize miRNA-based therapeutics currently in clinical trials.

Quality over quantity? Association of skeletal muscle myosteatosis and myofibrosis on physical function in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is characterized by adverse changes in body composition, which are associated with poor clinical outcome and physical functioning. Whilst size is the 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-60s (STS-60) test, incremental (ISWT) and endurance shuttle walk tests, lower limb and handgrip strength, exercise capacity (VO2peak) and gait speed. RESULTS: A total of 61 patients (58.5 ± 14.9 years, 46% female, estimated glomerular filtration rate 31.1 ± 20.2 mL/min/1.73 m2) were recruited. Lower EI (i.e. higher muscle quality) was significantly associated with better physical performance [STS-60 (r = 0.363) and ISWT (r = 0.320)], and greater VO2peak (r = 0.439). The qualitative rating was closely associated with EI values, and significant differences in function were 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.

Characterising skeletal muscle haemoglobin saturation during exercise using near-infrared spectroscopy in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) patients have reduced exercise capacity. Possible contributing factors may include impaired muscle O2 utilisation through reduced mitochondria number and/or function slowing the restoration of muscle ATP concentrations via oxidative phosphorylation. Using near-infrared spectroscopy (NIRS), we explored changes in skeletal muscle haemoglobin/myoglobin O2 saturation (SMO2%) during exercise. METHODS: 24 CKD patients [58.3 (± 16.5) years, eGFR 56.4 (± 22.3) ml/min/1.73 m2] completed the incremental shuttle walk test (ISWT) as a marker of exercise capacity. Using NIRS, SMO2% was measured continuously before, during, and after (recovery) exercise. Exploratory differences were investigated between exercise capacity tertiles in CKD, and compared with six healthy controls. RESULTS: We identified two discrete phases; a decline in SMO2% during incremental exercise, followed by rapid increase upon cessation (recovery). Compared to patients with low exercise capacity [distance walked during ISWT, 269.0 (± 35.9) m], patients with a higher exercise capacity [727.1 (± 38.1) m] took 45% longer to reach their minimum SMO2% (P = .038) and recovered (half-time recovery) 79% faster (P = .046). Compared to controls, CKD patients took significantly 56% longer to recover (i.e., restore SMO2% to baseline, full recovery) (P = .014). CONCLUSIONS: Using NIRS, we have determined for the first time in CKD, that favourable SMO2% kinetics (slower deoxygenation rate, quicker recovery) are associated with greater exercise capacity. These dysfunctional kinetics may indicate reduced mitochondria capacity to perform oxidative phosphorylation-a process essential for carrying out even simple activities of daily living. Accordingly, NIRS may provide a simple, low cost, and non-invasive means to evaluate muscle O2 kinetics in CKD.

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.

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(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(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.

Evidence for anti-inflammatory effects of exercise in CKD.

CKD is associated with a complex state of immune dysfunction characterized by immune depression, predisposing patients to infections, and immune activation, resulting in inflammation that associates with higher risk of cardiovascular disease. Physical exercise may enhance immune function and exert anti-inflammatory effects, but such effects are unclear in CKD. We investigated the separate effects of acute and regular moderate-intensity aerobic exercise on neutrophil degranulation (elastase release), activation of T lymphocytes (CD69 expression) and monocytes (CD86 and HLA-DR expression), and plasma inflammatory markers (IL-6, IL-10, soluble TNF-receptors, and C-reactive protein) in patients with predialysis CKD. A single 30-minute (acute) bout of walking induced a normal pattern of leukocyte mobilization and had no effect on T-lymphocyte and monocyte activation but improved neutrophil responsiveness to a bacterial challenge in the postexercise period. Furthermore, acute exercise induced a systemic anti-inflammatory environment, evidenced by a marked increase in plasma IL-10 levels (peaked at 1 hour postexercise), that was most likely mediated by increased plasma IL-6 levels (peaked immediately postexercise). Six months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation, but it had no effect on circulating immune cell numbers or neutrophil degranulation responses. Renal function, proteinuria, and BP were also unaffected. These findings provide compelling evidence that walking exercise is safe with regard to immune and inflammatory responses and has the potential to be an effective anti-inflammatory therapy in predialysis CKD.

Physiological benefits of exercise in pre-dialysis chronic kidney disease.

Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and muscle wasting, arising from numerous factors associated with declining renal function and lifestyle factors. Exercise has the ability to impact beneficially on the comorbidities associated with CKD and is accepted as an important intervention in the treatment, prevention and rehabilitation of other chronic diseases, however, the role of exercise in CKD is overlooked, with the provision of rehabilitation programmes well behind those of cardiology and respiratory services. Whilst there is now a large evidence base demonstrating the efficacy and safety of exercise training interventions in patients receiving dialysis, and this is now becoming incorporated into clinical guidelines for treatment of dialysis patients, there is a paucity of research evaluating the effectiveness of exercise in patients with CKD who are not on dialysis. Despite this, existing studies indicate that exercise can improve physical functioning and impact positively on the mediators of co-morbid diseases and upstream factors associated with progression of renal disease. Although preliminary evidence appears positive, more research is required to identify the best modes, frequency and intensities of exercise in order to optimise exercise prescription in pre-dialysis CKD patients. This review summarizes what is known about the main effects of exercise in pre-dialysis CKD patients, discusses the potential of exercise in the rehabilitation and treatment of disease and highlights the need for further research.

Diagnostic accuracy of a 'sarcopenia index' based on serum biomarkers creatinine and cystatin C in 458,702 UK Biobank participants.

BACKGROUND & AIMS: There is an emerging and urgent need to identify biomarkers of sarcopenia. A novel sarcopenia index (SI), based on serum creatinine and cystatin C, has emerged as a potential biomarker for use. The SI can predict clinical outcomes and discriminate between the presence of sarcopenia in a range of chronic and acute conditions. However, the SI has not yet been tested in a large real-world general population dataset. This study aimed to investigate the accuracy of the SI in the identification of sarcopenia in a large prospective general population cohort. METHODS: Data were taken from UK Biobank, a large prospective epidemiological study in the United Kingdom (UK). Serum creatinine and cystatin C values were used to calculate the SI [creatinine (mg/dl)/cystatin C (mg/dl) × 100]. Probable sarcopenia was defined by maximum handgrip strength (HGS). Muscle mass was assessed using bioelectrical impedance analysis. Low muscle mass was defined as an appendicular lean mass (ALM) index below prespecified thresholds. Confirmed sarcopenia was defined as both low HGS and low muscle mass. Pearson correlation coefficients and logistic regression were used to explore the association between various sarcopenia traits (probable sarcopenia, low ALM index, and confirmed sarcopenia) and the SI. The diagnostic value of the SI was investigated using the area under the receiver operating characteristic curve (area under the curve, AUC). RESULTS: 458,702 participants were included in the analysis (46.4% males, mean age, males: 68.7 (±8.2) years; females: 68.2 (±8.0) years)). Probable sarcopenia was observed in 4.5% of males and 6.1% of females; low ALM index in 2.8% of males and 0.7% of females; confirmed sarcopenia in 0.3% of males and 0.1% of females. SI was significantly lower in individuals with confirmed sarcopenia (males: 86.3 ± 16.6 vs. 99.5 ± 15.3, p < .01; females: 73.6 ± 13.7 vs. 84.6 ± 14.0, p < .01). For every 1-unit increase in the SI, the odds of confirmed sarcopenia were reduced by 5% in males (odds ratio (OR): 0.95, p < 0.001) and 7% in females (OR: 0.923, p < 0.001). The AUC showed acceptable discriminative ability of confirmed sarcopenia (males: AUC = 0.731; females: AUC = 0.711). CONCLUSIONS: Using a large real-world dataset of almost half a million people, our study indicated the SI has acceptable diagnostic accuracy when identifying those with sarcopenia and may be a useful biomarker to aid the stratification of those at risk and in need of intervention.

Combined walking exercise and alkali therapy in patients with CKD4-5 regulates intramuscular free amino acid pools and ubiquitin E3 ligase expression.

Muscle-wasting in chronic kidney disease (CKD) arises from several factors including sedentary behaviour and metabolic acidosis. Exercise is potentially beneficial but might worsen acidosis through exercise-induced lactic acidosis. We studied the chronic effects of exercise in CKD stage 4-5 patients (brisk walking, 30 min, 5 times/week), and non-exercising controls; each group receiving standard oral bicarbonate (STD), or additional bicarbonate (XS) (Total n = 26; Exercising + STD n = 9; Exercising +XS n = 6; Control + STD n = 8; Control + XS n = 3). Blood and vastus lateralis biopsies were drawn at baseline and 6 months. The rise in blood lactate in submaximal treadmill tests was suppressed in the Exercising + XS group. After 6 months, intramuscular free amino acids (including the branched chain amino acids) in the Exercising + STD group showed a striking chronic depletion. This did not occur in the Exercising + XS group. The effect in Exercising + XS patients was accompanied by reduced transcription of ubiquitin E3-ligase MuRF1 which activates proteolysis via the ubiquitin-proteasome pathway. Other anabolic indicators (Akt activation and suppression of the 14 kDa actin catabolic marker) were unaffected in Exercising + XS patients. Possibly because of this, overall suppression of myofibrillar proteolysis (3-methylhistidine output) was not observed. It is suggested that alkali effects in exercisers arose by countering exercise-induced acidosis. Whether further anabolic effects are attainable on combining alkali with enhanced exercise (e.g. resistance exercise) merits further investigation.

Exercise and chronic kidney disease: potential mechanisms underlying the physiological benefits.

Increasing evidence indicates that exercise has beneficial effects on chronic inflammation, cardiorespiratory function, muscle and bone strength and metabolic markers in adults with chronic kidney disease (CKD), kidney failure or kidney transplants. However, the mechanisms that underlie these benefits have received little attention, and the available clinical evidence is mainly from small, short-duration (<12 weeks) exercise intervention studies. The available data, mainly from patients with CKD or on dialysis, suggest that exercise-mediated shifts towards a less inflammatory immune cell profile, enhanced activity of the NRF2 pathway and reduced monocyte infiltration into adipose tissue may underlie improvements in inflammatory biomarkers. Exercise-mediated increases in nitric oxide release and bioavailability, reduced angiotensin II accumulation in the heart, left ventricular remodelling and reductions in myocardial fibrosis may contribute to improvements in left ventricular hypertrophy. Exercise stimulates an anabolic response in skeletal muscle in CKD, but increases in mitochondrial mass and satellite cell activation seem to be impaired in this population. Exercise-mediated activation of the canonical wnt pathway may lead to bone formation and improvements in the levels of the bone-derived hormones klotho and fibroblast growth factor 23 (FGF23). Longer duration studies with larger sample sizes are needed to confirm these mechanisms in CKD, kidney failure and kidney transplant populations and provide evidence for targeted exercise interventions.