The Effect Of Non-Pharmacological And Pharmacological Interventions On Measures Associated With Sarcopenia in End-Stage Kidney Disease: A Systematic Review And Meta-Analysis

Abstract

This systematic review and meta-analysis provide 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. Randomized 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). Synthesized data indicated that intradialytic exercise increased hand grip strength (standardized mean difference, 0.58; 0.24 to 0.91; p = 0.0007; I 2 = 40%), and sit-to-stand (STS) 60 score (mean difference, 3.74 repetitions; 2.35 to 5.14; p < 0.001; I 2 = 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; I 2 = 0%), and STS30 (MD, 0.97 repetitions; −0.16 to 2.10; p = 0.09; I 2 = 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 hemodialysis 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.

Keywords

end-stage kidney disease; dialysis; transplant; systematic review; meta-analysis; exercise; nutrition

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Introduction

Sarcopenia, originally believed to be a condition related to age, is the term used to indicate a progressive reduction in muscle strength, quantity or quality, and function, and is now considered a muscle disease [1]. It is now recognized as being associated with several catabolic diseases. One of these diseases which can expedite changes in measures related to sarcopenia is chronic kidney disease (CKD). Sarcopenia is reported as a common comorbidity in individuals with CKD, with a prevalence of around 10% in non-dialysis-dependent individuals [2,3], and increasing up to 37% in those individuals with end-stage kidney disease [4]. The presence of sarcopenia in individuals with CKD is associated with low quality of life, major adverse cardiovascular events, and mortality [2,5]. The underlying mechanisms of sarcopenia in CKD are believed to revolve around the concomitant loss of strength and muscle mass [6]. The cause of this in the CKD population is multifactorial and numerous, but negative protein balance, sedentary behavior, physical inactivity, metabolic acidosis, inflammation, anorexia, and disturbed appetite regulation all play a role [3,7]. The loss of muscle mass and strength is more common in individuals with end-stage kidney disease (ESKD) compared to individuals with less advanced kidney disease [8,9].

There is currently a lack of effective interventions for the treatment of sarcopenia, particularly in the ESKD population. However, a previous clinical practice guideline has provided strong recommendations for exercise as the primary treatment of sarcopenia [10]. The evidence for other non-pharmacological interventions such as nutritional is less clear [11]. Currently, there are no specific drugs approved for the treatment of sarcopenia; however, recently there has been a growing interest in new therapeutic approaches in the CKD population [12]. Therefore, the aim of this systematic review (and meta-analysis) was to investigate the effect of non-pharmacological and pharmacological interventions on outcome measures associated with sarcopenia (as defined by the European Working Group on Sarcopenia in Older People (EWGSOP) [1]) in the ESKD population.

Materials and Methods

1. Protocol Registration

Methods were prespecified and documented in a protocol that was registered on the International Prospective Register of Systematic Reviews; www.crd.york.ac.uk/PROSPERO (PROSPERO) with the identifier CRD42020199301.

2. Settings and Trial Population

Individuals with ESKD who have received a transplant, or are receiving dialysis (hemodialysis and peritoneal dialysis) or conservative management (for those with an estimated glomerular filtration rate < 15) over the age of 18 years were included.

3. Intervention

Trials were considered eligible if they contained non-pharmacological (for this review, these were defined as either containing diet, exercise, or lifestyle components) or pharmacological interventions (e.g., growth hormone, combined estrogen-progesterone, dehydroepiandrosterone).

4. Comparison

Any concurrent control group that is receiving usual care could serve as the control. Control groups that receive usual care or a placebo (for dietary or pharmacological interventions), or who did not receive an intervention designed to modulate sarcopenia were included. Exercise trials that had included active control groups (e.g., stretching) were excluded, as were trials of acute interventions.

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5. Outcome

Recently, the European Working Group on Sarcopenia in Older People (EWGSOP) published a consensus paper [1] highlighting several outcome measures to assess, confirm, and determine the severity of sarcopenia. The outcomes in this review were chosen as a result of their inclusion in this paper. The primary outcome was muscle strength (hand grip strength (HGS) and the following sit-to-stand tests (STS), 5, 30, and 60). The secondary outcomes were muscle quality and quantity (assessed by magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry (DEXA), bioelectrical impedance analysis (BIA), and computed tomography (CT) imaging), physical performance (assessed by the short physical performance battery (SPPB), the timed-up-and-go test (TUG), 400 m walk test, and gait speed), and sarcopenia health-related quality of life as assessed by the SARQoL questionnaire.

6. Trial Design

Trials included in this review had to have adhered to the following trial designs: parallel-group randomized controlled trials (allocation at individual or cluster levels) or crossover randomized trials.

7. Search Strategy

Searches were conducted to identify any relevant completed or ongoing systematic reviews using the following resources: Cochrane, PROSPERO, and the National Health Service Centre for Reviews and Dissemination (Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effects (DARE)). The following bibliographical databases and trial registers were searched for completed and ongoing trials: MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and the ISCRTN Registry. British Library (ETHOS), OpenGrey, and Conference Proceedings Citation Index (Web of Science™ Core Collection) were searched for unpublished data. All databases were searched from inception to 19 July 2021, and no limits on language were set. Database searches were supplemented with internet searches (e.g., Google Scholar), and contact with the Physical Activity and Wellbeing Kidney Research Study Group (in the United Kingdom). An example of a full search strategy for MEDLINE, EMBASE, and CINAHL databases is presented in Tables S1 and S2. Other databases were searched by using different combinations Of these search terms. Search results were compiled using the web-based screening and data extraction tool Covidence (Veritas Health Innovation Ltd., Melbourne, Australia) as recommended by the Cochrane Collaboration. Duplicate citations were removed, and the title and abstracts were screened independently by two reviewers against the inclusion criteria (if there was disagreement, then this was settled through the use of a third reviewer). Full-text articles of trials not excluded based on title or abstracts were retrieved and assessed by two reviewers. Conference abstracts and trials included on registries only (e.g., ClinicalTrials.gov) were excluded.

8. Selection Criteria, Data Extraction, and Quality Appraisal

We developed, tested, and refined a structured data collection form based on the Cochrane Data Extraction Template for interventions. For each included trial, information on trial methods, participants, interventions/comparator, and outcomes were extracted and cross-checked by one reviewer (DSM). The risk of bias for each trial was assessed using the Cochrane Risk of Bias Tool across five domains. Each domain was classified as adequate, unclear, or inadequate, with risk of bias for each trial to be classified using the following criteria: (1) low risk of bias (all criteria are deemed adequate), (2) moderate risk of bias (one criterion graded as inadequate or two graded as unclear), and (3) high risk of bias (more than one criterion is deemed inadequate, or more than two are graded unclear). Funnel plots were used to visually assess publication bias in the meta-analyses performed for the primary outcome only. Formal testing for plot asymmetry would only be performed where the meta-analysis contains more than ten trials [13].

9. Data Synthesis

Where means and standard deviation of outcome measures were not available, they were estimated from medians and interquartile ranges [14]. Gait speed data were converted from cm/s to m/s for one trial [15] and were provided by the authors for another [16]. HGS was converted from lbs to kg for one trial [17]. Data for the mid-arm muscle area (MAMA) were subtracted for one trial [18] using Web-Plot Digitizer version 4.5 [19] and 95% confidence intervals were converted to standard deviations [13]. A meta-analysis was performed for trials that reported the same outcome measures using a generic inverse variance random effects method via Review Manager (RevMan) version 5.3.26 (The Cochrane Collaboration, 2020). Primary and secondary measures of efficacy were treated as continuous data and interpreted as either difference in means or standardized mean differences dependent on the methods of measurement. Analysis was based on the final (post-intervention) values only (at the last follow-up) except mean change data from two trials [15,20]. Statistical heterogeneity was interpreted using the I 2 value. Data were not pooled (or subgroup analysis was considered) if I 2 > 40% (this is the threshold to which heterogeneity is considered important). A separate analysis was performed for each type of population (dialysis and transplant) and each non-pharmacological and pharmacological intervention. We had prospectively planned a network meta-analysis (NMA); however, this was not possible as a result of a limited number of trials for each population reporting the same sarcopenia-associated outcome. In addition, variances between the delivered interventions within the included trials suggested that the transitivity assumption (needed for NMA) was unlikely to be met.

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Discussion

This is the first review that has aimed to synthesize the effect of non-pharmacological and pharmacological interventions for sarcopenia outcomes (using the most up-to-date and widely accepted definition [1]) in the ESKD population. The main findings of this review were that intradialytic exercise significantly improved measures of muscle strength (HGS and STS60) and physical performance as measured by gait speed. However, the majority of trials included in the review were considered to be at high risk of bias. There was some evidence that programs of exercise in transplant recipients may improve STS scores. The evidence for nutritional and pharmacological interventions was less clear, with some tentative evidence that L-carnitine and nandrolone decanoate may have favorable effects on muscle quantity (MAMA and LBM, respectively) in individuals receiving hemodialysis. There was a lack of evidence for efficacious interventions to treat sarcopenia in the transplant and peritoneal dialysis population, and there were no included trials in those individuals with ESKD receiving conservative management.

A recent systematic review exploring the effect of exercise interventions on objective physical function in the ESKD population [79] reported that the majority of included trials reported a significant improvement in STS and HGS, although, unlike the present review, they were not able to perform a meta-analysis for these outcomes. This is in agreement with another review [80] that demonstrated that exercise training in the hemodialysis population was able to increase muscle strength. Our review confirms that exercise is efficacious at modifying outcomes associated with sarcopenia; however, the evidence for pharmacological and nutritional interventions is less clear. This review included trials with several heterogeneous nutritional and pharmacological interventions with a lack of evidence for their efficacy on measures of sarcopenia. However, this is except for synthesized data for L-carnitine and nandrolone-decanoate showing modifications to MAMA and LBM. However, it is unclear whether changes to these outcomes would translate to improvement in muscle strength and function.

Sarcopenia is highly prevalent in CKD [3], particularly for those with the advanced stages of the disease (ESKD) [6]. It is associated with hard endpoints including cardiovascular events and mortality [2,5]. With the prevalence of ESKD projected to increase [81], identifying effective interventions for the treatment of sarcopenia is particularly relevant. Therefore, the finding of this review, that intradialytic exercise improves HGS and gait speed, has clinical significance. A low walk (gait) speed is associated with mortality in 752 individuals receiving dialysis [82], with a walking speed of >0.6 m/s associated with greater survival [82]. Another study [83] has also reported that both low gait speed and HGS are predictors of cardiovascular events and all-cause mortality in individuals receiving hemodialysis [83]. This supports the recent shift from low muscle mass to low muscle strength as a key characteristic for the diagnosis of sarcopenia [1], as low muscle strength appears to be better at predicting outcomes [3,84]. Furthermore, muscle strength (STS and HGS) can be easily evaluated in the clinical setting (outpatient clinics and dialysis units, etc.). The evidence from this review that intradialytic exercise increases muscle strength, coupled with recent RCT data [16] (that this mode of exercise improves cardiovascular health and is safe), suggests that the methods of implementation should be considered as outlined in the recent Clinical Practice Guideline for Exercise and Lifestyle in CKD [85].

It is believed that increasing protein intake may be an effective countermeasure to sarcopenia for individuals with CKD. This is highlighted by the recommendation of increased intake (compared to the general population) for individuals with ESKD in the updated KDOQI Clinical Practice Guideline for Nutrition in CKD [86]. However, the present review found limited current RCT evidence for the efficacy of protein supplementation for sarcopenia in CKD, a point that has recently been highlighted by others [6]. Protein without an adequate exercise stimulus often provides little benefit, although notably the largest RCT to date in the ESKD population investigating the combined effect of exercise and protein supplementation found no effect on muscle strength or function [22]. This review identified a limited number of trials in the peritoneal dialysis and transplant recipient population. Given the positive effects that we have seen for exercise interventions (particularly for muscle strength in the hemodialysis population), it would be prudent to test these in future RCTs involving other ESKD populations. A recent review article [6] has highlighted several pharmacological interventions as having the potential to mitigate sarcopenia in the CKD population. However, this review found no evidence for the benefit of pharmacological interventions on muscle strength. There was some indication from synthesized data that nandrolone-decanoate increases LBM and individual data from two trials show that growth hormone may improve LBM. Whether these changes may improve outcomes is unlikely. A previous trial of nandrolone decanoate in individuals with rheumatoid arthritis found an increase in LBM but no accompanying change in muscle strength [87]. Properly powered (<50% of the included trials reported an a priori sample size calculation) trials are required to test both the efficacy and safety of pharmacological and nutritional interventions in the ESKD population. This should enable a wide range of evidence-based therapeutics to be available in line with a personalized medicine approach to tackling sarcopenia. Lastly, although we have shown that exercise programs may be an effective countermeasure to sarcopenia in the ESKD population, there remains a lack of evidence for these interventions on associated hard endpoints such as cardiovascular events and mortality. Despite the inclusion of 64 trials in the review, only a small number of these were able to be included in meta-analyses (with only fifteen trials being included in analyses for the primary outcome (muscle strength)) and the majority were assessed as having a high risk of bias.

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Conclusions

Currently, exercise appears to be the strongest therapeutic intervention for sarcopenia in the end-stage kidney disease population. There is a lack of proven efficacy for nutritional and pharmacological interventions.

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Daniel S. March 1,2, Thomas J. Wilkinson 3, Thomas Burnell 4, Roseanne E. Billany 2, Katherine Jackson 4, Luke A. Baker 5,6, Amal Thomas 7, Katherine A. Robinson 2, Emma L. Watson 2,6, Matthew P. M. Graham-Brown 2,6,7, Arwel W. Jones 8 and James O. Burton 2,6,7,9

1 York Trials Unit, Department of Health Sciences, University of York, York YO10 5DD, UK

2 Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK; r.billany@leicester.ac.uk (R.E.B.); katherine.robinson@cardiov.ox.ac.uk (K.A.R.); emma.watson@leicester.ac.uk (E.L.W.); mgb23@leicester.ac.uk (M.P.M.G.-B.); jb343@leicester.ac.uk (J.O.B.)

3 NIHR Applied Research Collaboration, Leicester Diabetes Centre, University of Leicester, Leicester LE5 4PW, UK; t.j.wilkinson@leicester.ac.uk

4 Leicester Medical School, University of Leicester, Leicester LE1 7HA, UK; tb259@student.le.ac.uk (T.B.); kj120@student.le.ac.uk (K.J.)

5 Department of Respiratory Sciences, College of Life Sciences, University of Leicester, Leicester LE1 7RH, UK; lab69@leicester.ac.uk

6 NIHR Leicester Biomedical Research Centre, University Hospital of Leicester NHS Trust, University of Leicester, Leicester LE5 4PW, UK

7 University Hospital of Leicester NHS Trust, Leicester LE1 5WW, UK; amalthomas@outlook.com

8 Central Clinical School, Monash University, Melbourne 3004, Australia; arwel.jones@monash.edu

9 School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK