Exercise as a therapeutic intervention in chronic kidney disease: are we nearly there yet?

PURPOSE OF REVIEW: The opportunity to review the more recent evidence for prescribing exercise-based physical rehabilitation for people living with chronic kidney disease (CKD) is timely. There has been a recent global focus evaluating how physical activity interventions might improve health-related quality of life and outcomes for people living with chronic health conditions in a post-COVID era. There is finally a long overdue commitment from the kidney research and clinical community to deliver pragmatic interventions to help people living with CKD to be able to live well with their condition. RECENT FINDINGS: This article reviews recent research, and discusses the challenges and potential solutions, for providing exercise-based therapeutic options for people living with CKD; including predialysis self-management interventions, options for both prehabilitation and posttransplant rehabilitation, pragmatic considerations for delivery of exercise therapy for people receiving haemodialysis treatment and the role of virtual kidney-specific rehabilitation. SUMMARY: Whilst there remains a need for further research in this area of patient care, there is now a body of evidence and kidney-specific guidelines that firmly support a rollout of pragmatic and scalable exercise-based interventions for people living with CKD. We are indeed nearly there now.

Perceptions and Experiences of High-Intensity Interval Training in Kidney Transplant Recipients: A Big HIIT?

High-intensity interval training (HIIT) is considered a novel and time-efficient method to reduce cardiovascular disease risk, a leading cause of mortality in kidney transplant recipients. However, research in this population is severely limited. The aim of this study was to understand kidney transplant recipients' perceptions and experiences of HIIT and their readiness to participate in HIIT. Individual, semi-structured interviews were conducted in adults with a kidney transplant (n = 13; 53±13 years). Interviews were audiorecorded, transcribed verbatim, and subjected to framework analysis. Overall, participants had a good knowledge of HIIT and were open to participation. Acknowledgment of the superior benefits to cardiovascular, mental, and general health, as well as the lower time commitment, were all motivators for participation. There were some heightened concerns around damaging the kidney and 'knowing your limits. Personalization, physician's approval, and supervision were all important factors in participation. This study provides evidence that HIIT would be, in principle, largely accepted by recipients of a kidney transplant. However, several considerations are also identified in the present study, which would be essential to the success of any future efficacy trial or rehabilitation program.

Effect of high intensity interval training and moderate intensity continuous training on lymphoid, myeloid and inflammatory cells in kidney transplant recipients.

Kidney transplantations are seen to be a double-edge sword. Transplantations help to partially restore renal function, however there are a number of health-related co-morbidities associated with transplantation. Cardiovascular disease (CVD), malignancy and infections all limit patient and graft survival. Immunosuppressive medications alter innate and adaptive immunity and can result in immune dysfunction. Over suppression of the immune system can result in infections whereas under suppression can result in graft rejection. Exercise is a known therapeutic intervention with many physiological benefits. Its effects on immune function are not well characterised and may include both positive and negative influences depending on the type, intensity, and duration of the exercise bout. High intensity interval training (HIIT) has become more popular due to it resulting in improvements to tradional and inflammatory markers of cardiovascular (CV) risk in clinical and non-clinical populations. Though these improvements are similar to those seen with moderate intensity exercise, HIIT requires a shorter overall time commitment, whilst improvements can also be seen even with a reduced exercise volume. The purpose of this study was to explore the physiolocial and immunological impact of 8-weeks of HIIT and moderate intensity continuous training (MICT) in kidney transplan recipients (KTRs). In addition, the natural variations of immune and inflammatory cells in KTRs and non-CKD controls over a longitudinal period are explored. Newly developed multi-colour flow cytometry methods were devised to identify and characterise immune cell populations. Twenty-six KTRs were randomised into one of two HIIT protocols or MICT: HIIT A (n=8; 4-, 2-, and 1-min intervals; 80-90% VO2peak), HIIT B (n=8, 4x4 min intervals; 80-90% VO2peak), or MICT (n=8, ~40 min; 50-60% VO2peak) for 24 supervised sessions on a stationary bike (approx. 3x/week over 8 ± 2 weeks). Blood samples taken pre-training, mid training, post-training and 3 months later. Novel multi-colour flow cytometric panels were developed to characterise lymphoid and myeloid cell population from peripheral blood mononuclear cells. No changes were observed for circulating immune and inflammatory cells over the 8-week interventions. The feasibility study does not suggest that exercise programmes using HIIT and MICT protocols elicit adverse negative effects on immunity in KTRs. Therefore, such protocols may be immunologically safe for these patients. The inability of the participants to achieve the target exercise intensities may be due to physiological abnormalities in this population which warrants further investigation.

Perceived barriers and facilitators to exercise in kidney transplant recipients: A qualitative study.

BACKGROUND: Exercise has the potential to attenuate the high levels of cardiovascular morbidity and mortality present in kidney transplant recipients (KTRs). Despite this, activity levels in KTRs remain low. The aim of this qualitative study was to explore the barriers and facilitators of exercise in KTRs. METHODS: Thirteen KTRs (eight males; mean ± SD; age 53 ± 13 years; estimated glomerular filtration rate 53 ± 21 ml/min/1.73 m2 ) were recruited and completed semistructured one-to-one interviews at University Hospitals of Leicester NHS Trust. All KTRs were eligible if their kidney transplant was completed >12 weeks before interview and their consultant considered them to have no major contraindications to exercise. All interviews were audio recorded, transcribed verbatim and subject to framework analysis to identify and report themes. RESULTS: Themes were organized into personal, behavioural and environmental factors based on social cognitive theory. Facilitators of exercise were largely internal: enjoyment, exercise for general health and health of the transplanted kidney and desire to maintain normality. Social interaction, support and guidance of healthcare professionals and goal setting were perceived as motivational. Harming the kidney, a lack of guidance, self-motivation and accessibility were barriers to exercise. CONCLUSION: These results provide detailed insight into the development of interventions designed to increase physical activity in KTRs. They provide strong evidence that specific exercise guidelines are required for this population and that the healthcare system could have a key role in supporting KTRs to become more physically active. Interventions need to be multifaceted to appeal to the differing levels of support desired by KTRs. PATIENT OR PUBLIC CONTRIBUTION: KTRs were involved in the development of the interview topic guide to ensure all relevant topics were explored.

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.

Characteristics of effective home-based resistance training in patients with noncommunicable chronic diseases: a systematic scoping review of randomised controlled trials.

Skeletal muscle atrophy, dysfunction, and weakness are consequences of noncommunicable diseases which result in exercise and functional limitations which contribute to poor quality of life and increased mortality. Home-based resistance training may promote skeletal muscle health. Electronic-based systematic searches were performed identifying randomised controlled trials utilising home-based resistance training in patients with noncommunicable diseases defined as cancer, cardiovascular disease, diabetes mellitus (type 1 and 2), chronic kidney disease (including dialysis), and chronic respiratory disease (asthma, chronic obstructive pulmonary disease, pulmonary hypertension). A comparator group was defined as one containing "non-exercise" or "usual care". Of the 239 studies identified (published between 1996 and 2020), 22 met the inclusion criteria. Sixteen studies contained an adjunct aerobic training component. Study designs and outcome measures showed large variation. Reporting of the principles of training applied within interventions was poor. Heterogeneity in study characteristics, and poor reporting of training characteristics, prevents formal recommendations for optimising home-based resistance training. However, home-based interventions are less resource-intensive than supervised programmes and appear to have the ability to improve or preserve pertinent outcomes such as strength, functional ability, and quality of life; potentially reducing the risk of mortality in patients with chronic disease.

The association of micro and macro worries with psychological distress in people living with chronic kidney disease during the COVID-19 pandemic.

BACKGROUND: Psychological distress can be exacerbated by micro (personal) and macro (societal) worries, especially during challenging times. Exploration of this relationship in people with chronic kidney disease is limited. OBJECTIVES: (1) To identify the types and levels of worries concerning people with chronic kidney disease in the context of the COVID-19 pandemic; (2) to explore the association of worries with psychological distress including depression, stress, anxiety, and health anxiety. DESIGN AND PARTICIPANTS: A cross-sectional online survey collected data at two time points (Autumn 2020, n = 528; Spring 2021, n = 241). Participants included kidney transplant recipients and people with non-dialysis dependent chronic kidney disease. MEASUREMENTS: The survey included questions about worry taken from the World Health Organisation COVID-19 Survey, the Depression, Anxiety and Stress Scale, and the Short Health Anxiety Index. Data were analysed using descriptive statistics and multiple regression. RESULTS: Worries about loved ones' health, the healthcare system becoming overloaded, losing a loved one, economic recession, and physical health were the highest rated concerns. Worrying about mental health was associated with higher depression, stress, anxiety, and health anxiety. Worrying about physical health was associated with anxiety and health anxiety. Worrying about losing a loved one was associated with health anxiety, and worrying about not being able to pay bills was associated with stress. CONCLUSIONS: People with kidney disease reported micro and macro worries associated with psychological distress during the COVID-19 pandemic. This study highlights factors that should be considered to improve the mental health and well-being of people with kidney disease.

Impact of physical activity on surrogate markers of cardiovascular disease in the haemodialysis population.

Background: The haemodialysis (HD) population is sedentary, with substantial cardiovascular disease risk. In the general population, small increases in daily step count associate with significant reductions in cardiovascular mortality. This study explores the relationship between daily step count and surrogate markers of cardiovascular disease, including left ventricular ejection fraction (LVEF) and native T1 (a marker of diffuse myocardial fibrosis), within the HD population. Methods: This was a post hoc analysis of the association between daily step count and metabolic equivalent of task (MET) and prognostically important cardiac magnetic resonance imaging parameters from the CYCLE-HD study (ISRCTN11299707). Unadjusted linear regression and multiple linear regression adjusted for age, body mass index, dialysis vintage, haemoglobin, hypertension and ultrafiltration volume were performed. Significant relationships were explored with natural cubic spline models with four degrees of freedom (five knots). Results: A total of 107 participants were included [age 56.3 ± 14.1 years, 79 (73.8%) males]. The median daily step count was 2558 (interquartile range 1054-4352). There were significant associations between steps and LVEF (ß = 0.292; P = .009) and steps and native T1 (ß = -0.245; P = .035). Further modelling demonstrated most of the increase in LVEF occurred at up to 2000 steps/day and there was an inverse dose-response relationship between steps and native T1, with the most pronounced reduction in native T1 between ≈2500 and 6000 steps/day. Conclusions: The results suggest an association between daily step count and parameters of cardiovascular health in the HD population. These findings support the recommendations for encouraging physical activity but are not the justification. Further research should evaluate whether a simple physical activity intervention improves cardiovascular outcomes in individuals receiving maintenance HD.

Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK.

BACKGROUND: Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life. METHODS: In a single-blind, randomised controlled trial conducted at 11 centres in the UK, adult participants (aged ≥18 years) with chronic kidney disease were recruited and randomly assigned (1:1) to the Kidney BEAM physical activity digital health intervention or a waiting list control group. Randomisation was performed with a web-based system, in randomly permuted blocks of six. Outcome assessors were masked to treatment allocation. The primary outcome was the difference in the Kidney Disease Quality of Life Short Form version 1.3 Mental Component Summary (KDQoL-SF1.3 MCS) between baseline and 12 weeks. The trial was powered to detect a clinically meaningful difference of 3 arbitrary units (AU) in KDQoL-SF1.3 MCS. Outcomes were analysed by an intention-to-treat approach using an analysis of covariance model, with baseline measures and age as covariates. The trial was registered with ClinicalTrials.gov, NCT04872933. FINDINGS: Between May 6, 2021, and Oct 30, 2022, 1102 individuals were assessed for eligibility, of whom 340 participants were enrolled and randomly assigned to the Kidney BEAM intervention group (n=173) or the waiting list control group (n=167). 268 participants completed the trial (112 in the Kidney BEAM group and 156 in the waiting list control group). All 340 randomly assigned participants were included in the intention-to treat population. At 12 weeks, there was a significant improvement in KDQoL-SF.13 MCS score in the Kidney BEAM group (from mean 44·6 AU [SD 10·8] at baseline to 47·0 AU [10·6] at 12 weeks) compared with the waiting list control group (from 46·1 AU [10·5] to 45·0 AU [10·1]; between-group difference of 3·1 AU [95% CI 1·8-4·4]; p<0·0001). INTERPRETATION: The Kidney BEAM physical activity platform is an efficacious digital health intervention to improve mental health-related quality of life in patients with chronic kidney disease. These findings could facilitate the incorporation of remote digital health interventions into clinical practice and offer a potential intervention worthy of investigation in other chronic conditions. FUNDING: Kidney Research UK.

The development and internal pilot trial of a digital physical activity and emotional well-being intervention (Kidney BEAM) for people with chronic kidney disease.

This trial assessed the feasibility and acceptability of Kidney BEAM, a physical activity and emotional well-being self-management digital health intervention (DHI) for people with chronic kidney disease (CKD), which offers live and on-demand physical activity sessions, educational blogs and videos, and peer support. In this mixed-methods, multicentre randomised waitlist-controlled internal pilot, adults with established CKD were recruited from five NHS hospitals and randomised 1:1 to Kidney BEAM or waitlist control. Feasibility outcomes were based upon a priori progression criteria. Acceptability was primarily explored via individual semi-structured interviews (n = 15). Of 763 individuals screened, n = 519 (68%, 95% CI 65 to 71%) were eligible. Of those eligible, n = 303 (58%, 95% CI 54-63%) did not respond to an invitation to participate by the end of the pilot period. Of the 216 responders, 50 (23%, 95% CI 18-29%) consented. Of the 42 randomised, n = 22 (10 (45%) male; 49 ± 16 years; 14 (64%) White British) were allocated to Kidney BEAM and n = 20 (12 (55%) male; 56 ± 11 years; 15 (68%) White British) to the waitlist control group. Overall, n = 15 (30%, 95% CI 18-45%) withdrew during the pilot phase. Participants completed a median of 14 (IQR 5-21) sessions. At baseline, 90-100% of outcome data (patient reported outcome measures and a remotely conducted physical function test) were completed and 62-83% completed at 12 weeks follow-up. Interview data revealed that remote trial procedures were acceptable. Participants' reported that Kidney BEAM increased their opportunity and motivation to be physically active, however, lack of time remained an ongoing barrier to engagement with the DHI. An randomised controlled trial of Kidney BEAM is feasible and acceptable, with adaptations to increase recruitment, retention and engagement.Trial registration NCT04872933. Date of first registration 05/05/2021.

Associations of health literacy with self-management behaviours and health outcomes in chronic kidney disease: a systematic review.

INTRODUCTION: Low health literacy is widely reported in people with chronic kidney disease (CKD) and has been associated with reduced disease self-management, poor health outcomes, increased mortality and poorer quality of life. However, these associations are still not well understood. METHODS: Electronic-based systematic searches were performed to identify studies examining associations between health literacy and self-management behaviours and/or health outcomes in patients with CKD. A tabular and narrative synthesis of the data was performed. Meta-analysis was not appropriate due to the heterogeneity of study designs and methods. RESULTS: Searches identified 48 studies that met the inclusion criteria. A total of 41 published articles, six conference abstracts, and one thesis were included. Of the 48 studies, 11 were cohort and 37 were cross-sectional. In total there were 25,671 patients; 16,952 from cohort studies. Median study sample size was 159 (IQR 92-275). Study quality was high (5), moderate (24) and poor (19). Thirteen measures of health literacy were used. Despite the limitations of the available evidence, there appear to be consistent relationships between higher health literacy and favourable self-management behaviours for patients with CKD. Definitive relationships between health literacy and patient outcomes are far less clear and remain incompletely understood. DISCUSSION: Conclusive evidence describing a causal link between health literacy and patient outcomes remains limited, but for many outcomes, a consistent association is described. In addition to associations with mortality, hospitalisation and clinical events, there were consistent associations between health literacy and favourable self-management behaviours which could support the development of patient education aimed at improving health literacy.

Feasibility and acceptability of high-intensity interval training and moderate-intensity continuous training in kidney transplant recipients: the PACE-KD study.

BACKGROUND: Kidney transplant recipients (KTRs) exhibit unique elevated inflammation, impaired immune function, and increased cardiovascular risk. Although exercise reduces cardiovascular risk, there is limited research on this population, particularly surrounding novel high-intensity interval training (HIIT). The purpose of this pilot study was to determine the feasibility and acceptability of HIIT in KTRs. METHODS: Twenty KTRs (male 14; eGFR 58±19 mL/min/1.73 m2; age 49±11 years) were randomised and completed one of three trials: HIIT A (4-, 2-, and 1-min intervals; 80-90% watts at V̇O2peak), HIITB (4×4 min intervals; 80-90% V̇O2peak) or MICT (~40 min; 50-60% V̇O2peak) for 24 supervised sessions on a stationary bike (approx. 3x/week over 8 weeks) and followed up for 3 months. Feasibility was assessed by recruitment, retention, and intervention acceptability and adherence. RESULTS: Twenty participants completed the intervention, and 8 of whom achieved the required intensity based on power output (HIIT A, 0/6 [0%]; HIITB, 3/8 [38%]; MICT, 5/6 [83%]). Participants completed 92% of the 24 sessions with 105 cancelled and rescheduled sessions and an average of 10 weeks to complete the intervention. Pre-intervention versus post-intervention V̇O2peak (mL/kg-1/min-1) was 24.28±4.91 versus 27.06±4.82 in HIITA, 24.65±7.67 versus 27.48±8.23 in HIIT B, and 29.33±9.04 versus 33.05±9.90 in MICT. No adverse events were reported. CONCLUSIONS: This is the first study to report the feasibility of HIIT in KTRs. Although participants struggled to achieve the required intensity (power), this study highlights the potential that exercise has to reduce cardiovascular risk in KTRs. HIIT and MICT performed on a cycle, with some modification, could be considered safe and feasible in KTRs. Larger scale trials are required to assess the efficacy of HIIT in KTRs and in particular identify the most appropriate intensities, recovery periods, and session duration. Some flexibility in delivery, such as incorporating home-based sessions, may need to be considered to improve recruitment and retention. TRIAL REGISTRATION: ISRCTN, ISRCTN17122775 . Registered on 30 January 2017.

The Effect of Non-Pharmacological and Pharmacological Interventions on Measures Associated with Sarcopenia in End-Stage Kidney Disease: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis provides a synthesis of the available evidence for the effects of interventions on outcome measures associated with sarcopenia in end-stage kidney disease (ESKD). Thirteen databases were searched, supplemented with internet and hand searching. Randomised controlled trials of non-pharmacological or pharmacological interventions in adults with ESKD were eligible. Trials were restricted to those which had reported measures of sarcopenia. Primary outcome measures were hand grip strength and sit-to-stand tests. Sixty-four trials were eligible (with nineteen being included in meta-analyses). Synthesised data indicated that intradialytic exercise increased hand grip strength (standardised mean difference, 0.58; 0.24 to 0.91; p = 0.0007; I2 = 40%), and sit-to-stand (STS) 60 score (mean difference, 3.74 repetitions; 2.35 to 5.14; p < 0.001; I2 = 0%). Intradialytic exercise alone, and protein supplementation alone, resulted in no statistically significant change in STS5 (−0.78 s; −1.86 to 0.30; p = 0.16; I2 = 0%), and STS30 (MD, 0.97 repetitions; −0.16 to 2.10; p = 0.09; I2 = 0%) performance, respectively. For secondary outcomes, L-carnitine and nandrolone-decanoate resulted in significant increases in muscle quantity in the dialysis population. Intradialytic exercise modifies measures of sarcopenia in the haemodialysis population; however, the majority of trials were low in quality. There is limited evidence for efficacious interventions in the peritoneal dialysis and transplant recipient populations.

The cardiovascular determinants of physical function in patients with end-stage kidney disease on haemodialysis.

Patients with end-stage kidney disease (ESKD) are often sedentary and decreased functional capacity associates with mortality. The relationship between cardiovascular disease (CVD) and physical function has not been fully explored. Understanding the relationships between prognostically relevant measures of CVD and physical function may offer insight into how exercise interventions might target specific elements of CVD. 130 patients on haemodialysis (mean age 57 ± 15 years, 73% male, dialysis vintage 1.3 years (0.5, 3.4), recruited to the CYCLE-HD trial (ISRCTN11299707), underwent cardiovascular phenotyping with cardiac MRI (left ventricular (LV) structure and function, pulse wave velocity (PWV) and native T1 mapping) and cardiac biomarker assessment. Participants completed the incremental shuttle walk test (ISWT) and sit-to-stand 60 (STS60) as field-tests of physical function. Linear regression models identified CV determinants of physical function measures, adjusted for age, gender, BMI, diabetes, ethnicity and systolic blood pressure. Troponin I, PWV and global native T1 were univariate determinants of ISWT and STS60 performance. NT pro-BNP was a univariate determinant of ISWT performance. In multivariate models, NT pro-BNP and global native T1 were independent determinants of ISWT and STS60 performance. LV ejection fraction was an independent determinant of ISWT distance. However, age and diabetes had the strongest relationships with physical function. In conclusion, NT pro-BNP, global native T1 and LV ejection fraction were independent CV determinants of physical function. However, age and diabetes had the greatest independent influence. Targeting diabetic care may ameliorate deconditioning in these patients and a multimorbidity approach should be considered when developing exercise interventions.

A pilot randomised controlled trial of a structured, home-based exercise programme on cardiovascular structure and function in kidney transplant recipients: the ECSERT study design and methods.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in kidney transplant recipients (KTRs). CVD risk scores underestimate risk in this population as CVD is driven by clustering of traditional and non-traditional risk factors, which lead to prognostic pathological changes in cardiovascular structure and function. While exercise may mitigate CVD in this population, evidence is limited, and physical activity levels and patient activation towards exercise and self-management are low. This pilot study will assess the feasibility of delivering a structured, home-based exercise intervention in a population of KTRs at increased cardiometabolic risk and evaluate the putative effects on cardiovascular structural and functional changes, cardiorespiratory fitness, quality of life, patient activation, healthcare utilisation and engagement with the prescribed exercise programme. METHODS AND ANALYSIS: Fifty KTRs will be randomised 1:1 to: (1) the intervention; a 12week, home-based combined resistance and aerobic exercise intervention; or (2) the control; usual care. Intervention participants will have one introductory session for instruction and practice of the recommended exercises prior to receiving an exercise diary, dumbbells, resistance bands and access to instructional videos. The study will evaluate the feasibility of recruitment, randomisation, retention, assessment procedures and the intervention implementation. Outcomes, to be assessed prior to randomisation and postintervention, include: cardiac structure and function with stress perfusion cardiac MRI, cardiorespiratory fitness, physical function, blood biomarkers of cardiometabolic health, quality of life and patient activation. These data will be used to inform the power calculations for future definitive trials. ETHICS AND DISSEMINATION: The protocol was reviewed and given favourable opinion by the East Midlands-Nottingham 2 Research Ethics Committee (reference: 19/EM/0209; 14 October 2019). Results will be published in peer-reviewed academic journals and will be disseminated to the patient and public community via social media, newsletter articles and presentations at conferences. TRIAL REGISTRATION NUMBER: NCT04123951.