Thomas J. Wilkinson

“Exercise as medicine” in chronic kidney disease

Exercise and physical activity are increasingly becoming key tools in the treatment and prevention of several medical conditions including arthritis and diabetes; this notion has been termed “exercise as medicine”. Exercise has favorable effects on reducing cardiovascular risk, inflammation, cachexia, and hypertension, in addition to increasing physical functioning, strength, and cardio‐respiratory capacity. Chronic kidney disease, a condition that affects around 10% of the population, is often overlooked as a target for exercise‐based therapy. Despite the vast range of severity in kidney disease (e.g., pre‐dialysis, dialysis, transplant), exercise has a potential role in all patients suffering from the condition. In this review, we summarise the important role exercise may have in the clinical management of kidney disease and how this form of ‘medicine’ should be best administered and ‘prescribed’.

Can Creatine Supplementation Improve Body Composition and Objective Physical Function in Rheumatoid Arthritis Patients? A Randomized Controlled Trial

Rheumatoid cachexia (muscle wasting) in rheumatoid arthritis (RA) patients contributes to substantial reductions in strength and impaired physical function. The objective of this randomized controlled trial was to investigate the effectiveness of oral creatine (Cr) supplementation in increasing lean mass and improving strength and physical function in RA 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

ABSTRACT 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.

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

Physical activity, immune function and inflammation in kidney patients (the PINK study): a feasibility trial protocol

Introduction Patients with chronic kidney disease (CKD) display increased infection-related mortality and elevated cardiovascular risk only partly attributed to traditional risk factors. Patients with CKD also exhibit a pro-inflammatory environment and impaired immune function. Aerobic exercise has the potential to positively impact these detriments, but is under-researched in this patient population. This feasibility study will investigate the effects of acute aerobic exercise on inflammation and immune function in patients with CKD to inform the design of larger studies intended to ultimately influence current exercise recommendations. Methods and analysis Patients with CKD, including renal transplant recipients, will visit the laboratory on two occasions, both preceded by appropriate exercise, alcohol and caffeine restrictions. On visit 1, baseline assessments will be completed, comprising anthropometrics, body composition, cardiovascular function and fatigue and leisure time exercise questionnaires. Participants will then undertake an incremental shuttle walk test to estimate predicted peak O2 consumption (VO2peak). On visit 2, participants will complete a 20 min shuttle walk at a constant speed to achieve 85% estimated VO2peak. Blood and saliva samples will be taken before, immediately after and 1 hour after this exercise bout. Muscle O2 saturation will be monitored throughout exercise and recovery. Age and sex-matched non-CKD ‘healthy control’ participants will complete an identical protocol. Blood and saliva samples will be analysed for markers of inflammation and immune function, using cytometric bead array and flow cytometry techniques. Appropriate statistical tests will be used to analyse the data. Ethics and dissemination A favourable opinion was granted by the East Midlands-Derby Research Ethics Committee on 18 September 2015 (ref 15/EM/0391), and the study was approved and sponsored by University Hospitals of Leicester Research and Innovation (ref 11444). The study was registered with ISRCTN (ref 38935454). The results will be presented at relevant conferences, and it is anticipated that the reports will be published in appropriate journals in 2018.

Commentary: rheumatoid Cachexia revisited: a metabolic Co-morbidity in rheumatoid arthritis

The “mini review” by Masuko (1) contains a quite extensive summary of “rheumatoid cachexia” (2) [i.e., loss of muscle mass in rheumatoid arthritis (RA)], an often overlooked and misdiagnosed co-morbidity. Masuko looks at the definition of “rheumatoid cachexia,” as well as the pathogenesis of the condition referring to the key role of pro-inflammatory cytokines. Interestingly, various strategic therapy options designed to attenuate rheumatoid cachexia by disease-modifying anti-rheumatic drugs (DMARDS), anti-cytokine therapies, and exercise training (i.e., resistance and endurance) are covered. However, what the review fails to mention or expand upon, is the relative ineffectiveness of exercise on “rheumatoid cachexia” once supervision is withdraw. The review also neglects to discuss (despite referencing a relevant trial) another potential key tool in the armory against “rheumatoid cachexia”: nutritional supplementation. This commentary will confine itself to briefly recounting some of these. As Masuko states that resistance training is the most beneficial means to increase both lean mass and physical function in RA. Both Marcora et al. (3) and Lemmey et al. (4) showed that progressive resistance training (PRT) for a period of 12 and 24 weeks (exercising two and three times per week, respectively) was able to attenuate the effects of rheumatoid cachexia, specifically increasing lean mass, strength, and physical function in patients with RA. However, a follow-up study for 3 years later by Lemmey et al. (5) found that once supervision was withdrawn, no subjects from the original study (4) were performing relevant PRT or any other form of regular high intense exercise and, as a result, lean mass had regressed to baseline levels, as had much of the trunk fat mass and body fat percentage. Lack of adherence to high-intense exercise in RA has been demonstrated by others (6). Unfortunately, it seems habitually performed, high-intensity exercise (i.e., PRT) is unlikely to be widely adopted as a general treatment strategy for reversing “rheumatoid cachexia” and restoring function, then the challenge to develop a treatment option that is easily administered, inexpensive, and makes limited demands of the patient remains. Anabolic nutritional supplementation offers a potential treatment option that is easily administered, inexpensive, and makes limited demands of the patient. Scientific evidence continues to suggest that nutrition should be part of routine care in those with muscle wasting disorders [for review, see Stamp et al. (7)]. Specifically, up to 75% of RA patients believe that food and nutrition play an important role in their symptom severity, with 50% of RA patients reportedly trying some form of dietary manipulation in an attempt to attenuate symptomology (7). Marcora et al. (8) previously investigated the effects of daily 12 weeks of a mixture of β-hydroxy-β-methylbutyrate, glutamine, and arginine (HMB/GLN/ARG) protein supplementation in 40 RA patients. The results showed that both HMB/GLN/ARG and a control mixture of other non-essential amino acids (alanine, glutamic acid, glycine, and serine) were both equally effective in increasing lean mass (~0.4 kg) and improving some measures of physical function and strength. Creatine monohydrate, a combination of essential amino acids, has generally been shown to be more effective in increasing lean mass and physical performance than other protein-based supplements, including HMB/GLN/ARG [for review, see Nissen (9)]. In the only study investigating the use of creatine in RA, Willer et al. (10) found that creatine supplementation increased muscle strength in 8 out of the 12 patients by an average of 14% as determined by the muscle strength index, although this increase in strength was not actually associated with changes of creatine (or phosphocreatine) levels in the muscle. Nonetheless, creatine has been shown to be effective, without additional exercise training, in range of clinical populations, including muscular dystrophy patients and the elderly who, like RA patients, present with reduced muscle mass and impaired physical function [for review, see Wilkinson et al. (11)]. Evidently, more research is needed, and as such we have just completed a randomized control trial investigating the effects of creatine in RA patients (manuscript in preparation). To summarize, although PRT exercise is arguably the most effective way to attenuate the effects of rheumatoid cachexia, due to its high-intense nature, it is unlikely to be widely adopted as a general treatment strategy. Nutritional supplementation, specifically those that focus on muscle anabolism may be a viable option. Alongside, HMB/GLN/ARG protein supplementation, creatine monohydrate may be a potential therapeutic option in RA, as it has been effective in range of clinical and elderly populations.

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.

The 8-foot up and go test is the best way to assess physical function in the rheumatoid arthritis clinic

Abstract Objectives RA is characterized by poor physical function, which compromises patients’ quality of life and outcome. Clinical assessment of function is usually performed using self-reported questionnaires, such as the Multi-Dimensional HAQ (MDHAQ) and the Short Form-36 (physical component) (SF36-PC). However, such subjective measures may not accurately reflect real functional status. This study aimed to determine: (i) which clinically practicable objective test best represents overall physical function; and (ii) the extent to which self-reported subjective functional measures reflect objectively assessed function. Methods Objective [isometric knee extensor strength, handgrip strength, sit-to-stands in 30 s, 8-foot up and go (8′UG), 50-foot walk (50′W) and estimated aerobic capacity (V̇O2max)] and subjective (MDHAQ and SF36-PC) measures of function were correlated with one another to determine the best overall test of functional status in 82 well-controlled RA patients (DAS28 (s.d.) = 2.8 (1.0)). Results In rank order of size, averaged correlations (r) to the other outcome measures were as follows: 8′UG: 0.650; 50′W: 0.636; isometric knee extensor strength: 0.502; handgrip strength: 0.449; sit-to-stands in 30 s: 0.432; and estimated V̇O2max: 0.358. The MDHAQ was weakly (0.361) and the SF36-PC moderately correlated (0.415) with objective measures. Conclusion Our results show that the most appropriate measure of objective physical function in RA patients is the 8′UG, followed by the 50′W. We found discordance between objectively and subjectively measured function. In clinical practice, an objective measure that is simple and quick to perform, such as the 8′UG, is advocated for assessing real functional status.

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

Abstract 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.

Muscle loss following a single high-dose intramuscular injection of corticosteroids to treat disease flare in patients with rheumatoid arthritis.

OBJECTIVE Adverse changes in body composition, specifically decreased muscle mass (MM) and increased fat mass, characterize rheumatoid arthritis (RA). These changes, termed rheumatoid cachexia (RC), are important contributors to the disability and elevated co-morbidity risk of RA. Recently, we observed substantial muscle loss (~2 kg) in a patient with RA following a single intramuscular (IM) corticosteroid (CS) injection to treat a disease flare. The aim of the current study is to determine whether this apparent iatrogenic effect of IM CS is typical, i.e., does this routine, recommended treatment contribute to RC? METHODS Body composition was assessed by dual-energy X-ray absorptiometry (DXA) in eight patients with established RA who received a 120 mg IM methylprednisolone injection to treat a disease flare. DXA scans estimated appendicular lean mass (ALM; a surrogate measure of MM), total lean mass (LM), and total and regional adiposity at baseline (injection day) and 4 weeks and 6-9 months post-injection. Statistical analysis was performed using one-way ANOVA. RESULTS There was significant loss of ALM (-0.93 kg, p=0.001, 95% CI [-0.49, -1.36]) and a trend toward reduced LM (-1.10 kg, p=0.165, 95% CI [0.58, -2.79]) at 4 weeks relative to baseline. At 6-9 months despite control of inflammation and disease activity, these losses remained. CONCLUSION Substantial muscle loss occurred in patients with RA following IM CS injection to treat a disease flare. Thus, this recommended treatment appears to exacerbate RC, thereby potentially increasing disability and co-morbidity risk. If this effect is confirmed by larger studies, the role of one-off high-dose CS in the treatment of RA should be reviewed.