PEER REVIEW HISTORY ARTICLE DETAILS TITLE (PROVISIONAL)

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1 PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form ( and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. ARTICLE DETAILS TITLE (PROVISIONAL) AUTHORS Evaluating the effectiveness of exercise training on elderly patients who require hemodialysis: the study protocol for a systematic review and meta-analysis MATSUZAWA, RYOTA; Hoshi, Keika; Yoneki, Kei; Matsunaga, Atsuhiko VERSION 1 - REVIEW REVIEWER REVIEW RETURNED Patricia Palau Cardiology Department. Hospital de La Plana. Universitat Jaume I, Castellón, Spain 10-Jan-2016 GENERAL COMMENTS The protocol is well written and addresses an interesting topic. Some suggestions: 1) Please clarify the cut-off age to consider whether patients are elderly or non-elderly. 2) Please consider to add supervised home-based programs of exercise in the inclusion criteria. It would be interesting to see whether these progrmas are benefitial or not. 3) Please clarify the exercise parameters of exercise capacity or QoL that you want to evaluate (i.e. peak VO2, 6-MWT, METS, Minnesota Living With Heart Failure Questionnaire, 36-Item Short Form Health Survey, etc. ) REVIEWER REVIEW RETURNED Neil Smart University of New England, Armidale, NSW Australia 11-Jan-2016 GENERAL COMMENTS This is a well designed analysis, I do however have several suggestions to further improve the quality. 1. PEDro has been used for some time to assess physiotherapy type intervention studies, however a new tool (TESTEX) Int J Evid Based Healthc Mar;13(1):9-18. doi: /XEB has been validated that is specific to EXERCISE TRAINING STUDIES in patients with chronic disease such as CKD. The authors may wish to consider using TESTEX as it addresses several shortcomings that PEDro does not eg exercise adherence, withdrawal, relative exercise training intensity. In short, while the 2 tools are somewhat similar PEDRo is for physiotherapy but TESTEX is for exercise training interventions and there is a difference. Study quality assessment of training studies is more robust with TESEX. 2. In terms of inclusion criteria it is important to exclude

2 subjects<18 years as they have not experienced chronic deterioration to CKD, similarly studies of acute kidney injury or where patients >18 years have not had slow deterioration to CKD (eg healthy adults who have had emergency kidney surgery due to cancer) should be excluded also. 3. It is well known that about 65-70% of CKD patients will be determine dby their specialist as unsuitable to exercise, a further 10-30% of these will die or be unable to complete a 3 month training study, this is very important as exercise, while beneficial is not suitable for everyone with CKD. As such I think exercise session adherence rates and withdrawal should be outcome measures and these items are closely scrutinized in the TESTEX tool. 2. REVIEWER REVIEW RETURNED Dr. Anuradha Sawant London Health Sciences center canada 26-Jan-2016 GENERAL COMMENTS There are several reviews published in the area that the authors are proposing in this research proposal. More clarity is required as to how and why this systematic review is even required given that several reviews in this subject area have been published. The statistical methods to be used also require some consideration. given that the authors purpose is to evaluate the effect of age on the outcomes (elderly vs non elderly. There are not many studies out there that have specifically recruited elderly participants. this will impact the study results. How do the authors propose to come to a conclusion in the event there are not enough studies that have categorically recruited elderly people. How do they propose to conduct the subgroup analysis? REVIEWER REVIEW RETURNED Alessandro Capitanini ASL CENTRO Toscana, PISTOIA 31-Jan-2016 GENERAL COMMENTS THE AGE, IN MY OPINION, DOESN'T APPEAR TO BE DETERMINANT IN THIS SETTING. COMORBIDITIES AND CLINICAL SITUATION ARE THE MAJOR PROBLEMS. THEY REQUIRE CUSTOMIZED TRAINING PROGRAMS AND IT'S VERY DIFFICULT TO REALIZE. VERSION 1 AUTHOR RESPONSE Reviewer #1 (Comments to the Author): (The protocol is well written and addresses an interesting topic.) 1) Please clarify the cut-off age to consider whether patients are elderly or non-elderly. Thank you for your comment. For this paper, we will use 65 years of age and older as a definition of elderly as with the WHO stated definition. We added the information on the cut-off age of elderly or non-elderly into the part of METHODS, Statistical Analysis. (Page 10, Line )

3 (METHODS, Statistical Analysis) Statistical Analysis For our statistical analysis of the RCTs, the primary outcome will include physical functions and exercise tolerance. Secondary outcomes will include other clinical outcomes: activities of daily livings and quality of life. Outcome definitions will be based on those used in the included studies. We will conduct the subgroup analysis whether study subjects are elderly or nonelderly. We will use 65 years of age and older as a definition of elderly for this study. Additionally, we will also conduct the subgroup analyses to identify latent influence factors using comorbidities and training programs. The statistical strategy will involve finding the absolute change in means to endpoint from the baseline (and the 95% confidence interval) in the intervention and control groups. 2) Please consider to add supervised home-based programs of exercise in the inclusion criteria. It would be interesting to see whether these programs are beneficial or not. Thank you for your suggestion. To promote the participation in exercise training program for hemodialysis patients in clinical setting routinely will change the todays disease management of dialysis treatment to new one drastically. Hence, in this paper, we would like to reveal the effectiveness of supervised exercise in hemodialysis patients. This is a main theme of this study. However, we would need to consider the effect of exercise training program (e.g. intensity, duration or types). Therefore, ee will conduct the subgroup analysis using training programs. We changed METHODS, Inclusion/exclusion criteria part (Page 9, Line ) and added the description into the METHODS, Statistical Analysis part (Page 10, Line ). Please see below: (METHODS, Inclusion/exclusion criteria) 4. Interventions: supervised exercise including resistance training, aerobic exercise or combined exercise will be included. Abnormal types of exercise and home exercise will be excluded. (METHODS, Statistical Analysis) Statistical Analysis For our statistical analysis of the RCTs, the primary outcome will include physical functions and exercise tolerance. Secondary outcomes will include other clinical outcomes: activities of daily livings and quality of life. Outcome definitions will be based on those used in the included studies. We will conduct the subgroup analysis whether study subjects are elderly or nonelderly. We will use 65 years of age and older as a definition of elderly for this study. Additionally, we will also conduct the subgroup analyses to identify latent influence factors using comorbidities and training programs. The statistical strategy will involve finding the absolute change in means to endpoint from the baseline (and the 95% confidence interval) in the intervention and control groups. 3) Please clarify the exercise parameters of exercise capacity or QoL that you want to evaluate (i.e. peak VO2, 6-MWT, METS, Minnesota Living With Heart Failure Questionnaire, 36-Item Short Form Health Survey, etc.) Thank you for your comment. We clarified the details of our evaluating outcomes. Please see the Inclusion/exclusion criteria part. (Page 9, Line ) (METHODS, Inclusion/exclusion criteria) Outcomes: physical functions (muscle strength, sit-to-stand test), walking ability (gait

4 speed, 6-minute walk test and shuttle walk test), exercise tolerance (peak oxygen intake), activities of daily livings and health related quality of life (the 36-Item Short Form Health Survey and Kidney Disease Quality of Life). 7. ============== Reviewer #2 (Comments to the Author): (This is a well designed analysis. I do however have several suggestions to further improve the quality.) 1)-1 PEDro has been used for some time to assess physiotherapy type intervention studies, however a new tool (TESTEX) Int J Evid Based Healthc Mar;13(1):9-18. doi: /XEB has been validated that is specific to EXERCISE TRAINING STUDIES in patients with chronic disease such as CKD. The authors may wish to consider using TESTEX as it addresses several shortcomings that PEDro does not eg exercise adherence, withdrawal, relative exercise training intensity. In short, while the 2 tools are somewhat similar PEDRo is for physiotherapy but TESTEX is for exercise training interventions and there is a difference. Study quality assessment of training studies is more robust with TESEX. 1)-2 It is well known that about 65-70% of CKD patients will be determined by their specialist as unsuitable to exercise, a further 10-30% of these will die or be unable to complete a 3 month training study, this is very important as exercise, while beneficial is not suitable for everyone with CKD. As such I think exercise session adherence rates and withdrawal should be outcome measures and these items are closely scrutinized in the TESTEX tool. Thank you for your suggestions. We will assess the risk of bias of the studies using Cochrane Collaboration s tool, which consists of following 6 items: random sequence generation, allocation concealment,.blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. However, a new tool TESTEX you recommended would be robust to evaluate the quality of exercise training studies. We will assess the study quality using TESTEX in addition to Cochrane Collaboration s tool. Additionally, we revised #15 reference from paper by Savovic J et al. to that by Higgins JPT et al. We added the information on TESTEX into the ABSTRACT (Page 2, Line 33), METHODS, Statistical Analysis (Page 11, Line ) and REFERENCES parts (Page 16, Line ), please see below: (ABSTRACT) Methods and analyses: Published randomized controlled trials (RCTs) that assessed the effectiveness of exercise training in patients undergoing hemodialysis with physical function, exercise tolerance and quality of life will be included. Bibliographic databases include MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, CINAHL, Web of Science, PsycINFO and PEDro. The risk of bias of RCTs will be assessed using the Cochrane Collaboration s tool and TESTEX. The primary outcome will include physical function and exercise tolerance. This review protocol is reported according to Preferred Reporting Items for Systematic reviews and Meta-Analysis for protocols (PRISMA-P) 2015 checklist. Statistical analysis will be performed with Review Manager Software (RevMan version 5.3, Cochrane Collaboration, Oxford, England). (METHODS, Statistical Analysis) In addition, two reviewers will independently assess the risk of bias of the studies using the Cochrane Collaboration s tool 15, which consists of following 6 items: random sequence generation, allocation concealment,.blinding of participants and personnel, blinding of outcome

5 assessment, incomplete outcome data, selective reporting and other bias. Additionally, two reviewers will also assess the risk of bias using the Tool for the assessment of Study quality and reporting in EXercise (TESTEX) 16, which consists of 15 different items and is a new, reliable tool to facilitate a comprehensive review of exercise training trials. Furthermore, we will also assess the quality of the evidence associated with the result of each meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach 17-21, which gives an indication of the confidence that can be placed in the estimate of treatment effect. (REFERENCES) 15. Savovic J., Weeks L., Sterne J. A., et al.: Evaluation of the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials: focus groups, online survey, proposed recommendations and their implementation. Syst Rev 2014; 3: Higgins JPT Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration, Available from Smart N. A., Waldron M., Ismail H., et al.: Validation of a new tool for the assessment of study quality and reporting in exercise training studies: TESTEX. Int J Evid Based Healthc 2015; 13: Guyatt G. H., Oxman A. D., Kunz R., et al.: GRADE guidelines 6. Rating the quality of evidence--imprecision. J Clin Epidemiol 2011; 64: ) In terms of inclusion criteria it is important to exclude subjects<18 years as they have not experienced chronic deterioration to CKD, similarly studies of acute kidney injury or where patients >18 years have not had slow deterioration to CKD (eg healthy adults who have had emergency kidney surgery due to cancer) should be excluded also. Thank you for your suggestion. We revised Inclusion/exclusion criteria part. (Page 8, Line ) 1. Language: Published in English. 2. Participants: Patients aged at least 18 years and with chronic kidney disease undergoing maintenance hemodialysis therapy will be included. Patients aged under 18 years or undergoing other renal replacement therapy will be excluded. Patients affected by acute kidney failure will be also excluded. 3. Study design: ============== Reviewer #3 (Comments to the Author): 1)-1 There are several reviews published in the area that the authors are proposing in this research proposal. More clarity is required as to how and why this systematic review is even required given that several reviews in this subject area have been published. There are several reviews summarizing the available evidences from RCTs performing to the effects of exercise training in patients undergoing hemodialysis, as you indicated (Table X). Table X. Previously reported systematic reviews and meta analyses Author (year) Journal Subjects Type of Intervention Date of systematic search

6 Sheng KX et al. (2014) Am J Nephrol HD Only Intradialyticex. to 2014 Heiwe S et al. (2014) Am J Kidney Dis CKD Ex. to 2012 Smart N et al. (2011) Nephrology (Carlton) HD Ex. to 2010 However, new trials in this area continue to be reported. Previously reported meta-analyses covered only RCTs reported until In addition, theses meta-analyses did not include RCTs reported after On the other hand, we will include the trials, which had reported until August 2015, into our analysis. Our review will be performed using latest data. Furthermore, Lau J et al. claimed the importance of cumulative meta-analysis in their paper (N Engl J Med. 1992; 327: ). He concluded that cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy. Hence, we need to update the evidence of exercise training in hemodialysis patients frequently. We emphasized a reason why this systematic review is required in INTRODUCTION part. (Page 5-6, Line 80-82) (INTRODUCTION) Although, in meta-analyses, it had already been reported the effectiveness of exercise interventions on physical function, exercise capacity and quality of life in patients undergoing hemodialysis 10, 11, these analyses had been unconsidered whether subjects were elderly or not. Thus intervention for elderly patients on hemodialysis is complex and views on how to best manage these patients are unknown in the nephrology community. Thus, in fact, it is unclear whether exercise training improves physical function, exercise capacity and quality of life in elderly patients on hemodialysis. We need to analyze the effectiveness of exercise interventions on the outcomes in consideration of patient s age. Additionally, because new trials continue to be published in this area, we need to update the evidence of exercise training in hemodialysis patients. The main objective of this study is to systematically review the effect of exercise training on physical function, exercise capacity and quality of life in elderly patients on hemodialysis, and to update the relevant evidence. This protocol for a systematic review with meta-analysis is reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol (PRISMA-P) 2015 checklist 12, 13. 1)-2 The statistical methods to be used also require some consideration. given that the authors purpose is to evaluate the effect of age on the outcomes (elderly vs non elderly. There are not many studies out there that have specifically recruited elderly participants. this will impact the study results. How do the authors propose to come to a conclusion in the event there are not enough studies that have categorically recruited elderly people.how do they propose to conduct the subgroup analysis? Thank you for your comment. Matsufuji S et al. (J Ren Nutr. 2015; 25 (1): 17-24) and Groussard C et al. (Appl Physiol Nutr Metab. 2015; 40(6): ) have reported RCT which required elderly patients in 2015, respectively. And then, Chen JL et al. (Nephrol Dial Transplant. 2010; 25: ) have previously reported a similar trial. Although there are not many studies that recruited elderly participants as you commented, we believe that to give the fact of evidence is important for progression of research in this area.

7 We would need at least 2 papers to perform a meta-analysis. Although, there are a few papers as you commented, we will be able to conduct the subgroup analysis. ============== Reviewer #4 (Comments to the Author): (This is a well designed analysis, I do however have several suggestions to further improve the quality.) 1) THE AGE, IN MY OPINION, DOESN'T APPEAR TO BE DETERMINANT IN THIS SETTING. COMORBIDITIES AND CLINICAL SITUATION ARE THE MAJOR PROBLEMS. THEY REQUIRE CUSTOMIZED TRAINING PROGRAMS AND IT'S VERY DIFFICULT TO REALIZE. Thank you for your suggestions. Certainly, determination factor of effectiveness of exercise training seem to be not only age but also comorbidities and clinical situations in patients undergoing hemodialysis. We will conduct the subgroup analysis using comorbidities and training programs in addition to age. We changed the description of METHODS, Statistical Analysis part: See manuscript. (Page 10, Line ) (METHODS, Statistical Analysis) Statistical Analysis For our statistical analysis of the RCTs, the primary outcome will include physical functions and exercise tolerance. Secondary outcomes will include other clinical outcomes: activities of daily livings and quality of life. Outcome definitions will be based on those used in the included studies. We will conduct the subgroup analysis whether study subjects are elderly or nonelderly. We will use 65 years of age and older as a definition of elderly for this study. Additionally, we will also conduct the subgroup analyses to identify latent influence factors using comorbidities and training programs. VERSION 2 REVIEW REVIEWER REVIEW RETURNED Patricia Palau MD Cardiology Department. Hospital de La Plana. Universitat Jaume I, Castellón, Spain. 12-Feb-2016 GENERAL COMMENTS All my comments have been addressed and the manuscript has substantially improved. I have no comments REVIEWER REVIEW RETURNED Anuradha Sawant London Health Sciences Center London Ontario Canada 17-Feb-2016 GENERAL COMMENTS Major issues The authors have not clearly articulated the need for conductive such a review when a few such systematic reviews have

8 already been published; these include a Cochrane review as well. The authors require articulating what new information this study will add to the existing body of literature and why such a new review is even required. Line 79: If the authors are indeed planning an update for the previously performed systematic reviews, it is unclear why the search will be conducted from the inception of the electronic databases. (Lines ). The authors state that the main objective of the review is to review the effect of exercise training in the elderly population. However, they propose to include studies that have recruited participants over the age of 18 according to the Inclusion/exclusion criteria. What if no study has categorically recruited people over 60 years of age. Although they state that a sub-group analysis will be conducted they do not state the statistical method used to be used for these purposes. The authors require more clarity in their statements. For example they state Furthermore, 67 the proportions of elderly patients with > 60 years in new patients started on dialysis in 2012 and in all dialysis patients were 78.1% and 75.4%, respectively however they define age >65 years as elderly. If they wish to state the epidemiology of the elderly they need to stick to the gae that they define as elderly. The English language used in this protocol is unacceptable for publication and the writers require to find an English speaking person. e.g. 1. The population ageing is occurring throughout the world. 2. Although, in meta-analyses, it had already been reported the effectiveness 73 of exercise interventions on physical function, exercise capacity and quality of life in patients undergoing hemodialysis, these analyses had been unconsidered whether subjects were elderly or not These sentences require to be restructured for clarity Reviewer #1 (Comments to the Author): VERSION 2 AUTHOR RESPONSE 1) All my comments have been addressed and the manuscript has substantially improved. I have no comments.

9 Thank you very much. ============== Reviewer #3 (Comments to the Author): 1) The authors have not clearly articulated the need for conductive such a review when a few such systematic reviews have already been published; these include a Cochrane review as well. The authors require articulating what new information this study will add to the existing body of literature and why such a new review is even required. Thank you for your comments. We added and emphasized the clinical significance of our paper into the INTRODUCTION and REFERENCES part. (Page5-6, Line 79-95) (INTRODUCTION) Most of elderly patients on hemodialysis are frailer than non-elderly patients, and frailty is well known to be an indicator of disability and a poor prognosis in dialysis patients 8, 9. Exercise training is therefore in great need for elderly patients on hemodialysis. Although prior metaanalyses have already reported on the effectiveness of exercise interventions on the physical function, exercise capacity and quality of life of patients undergoing hemodialysis 10, 11, these analyses did not consider whether their subjects were elderly. Exercise intervention for elderly patients on hemodialysis is complex and controversial, and how to best manage these patients is poorly understood in the nephrology community. Furthermore, it is unclear whether exercise training improves the physical function, exercise capacity or quality of life of elderly patients on hemodialysis. We need to analyze the effectiveness of exercise interventions on these outcomes while taking into consideration the patient s age. Additionally, because new trials for elderly patients undergoing hemodialysis continue to be published in this area 12, 13, the evidence regarding the effectiveness of exercise training on hemodialysis patients must be updated using latest data. Thus cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm, and may be helpful making clinical recommendations for therapy 14. The main objective of this study (REFERENCES) Matsufuji S., Shoji T., Yano Y., et al.: Effect of chair stand exercise on activity of daily living: a randomized controlled trial in hemodialysis patients. J Ren Nutr 2015; 25: Groussard C., Rouchon-Isnard M., Coutard C., et al.: Beneficial effects of an intradialytic cycling training program in patients with end-stage kidney disease.

10 Appl Physiol Nutr Metab 2015; 40: Lau J., Antman E. M., Jimenez-Silva J., Kupelnick B., Mosteller F. and Chalmers T. C.: Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992; 327: ) Line 79: If the authors are indeed planning an update for the previously performed systematic reviews, it is unclear why the search will be conducted from the inception of the electronic databases. (Lines ). Thank you for your comments. We added the information on how to search the literatures into the METHODS part. (Page 8, Line ) (METHODS) Literature review Our electronic database search includes MEDLINE (from 1950 to August 2015), Embase (from 1974 to August 2015), the Cochrane Central Register of Controlled Trials (from start to August 2015), the Cochrane Database of Systematic Reviews (from 2005 to August 2015), CINAHL (from 1981 to August 2015), Web of Science (from 1900 to August 2015), PsycINFO (from 1806 to August 2015) and PEDro (from start to August 2015). We detail the electronic search strategy in Table 1, using MEDLINE as an example. We used the following terms: dialysis, kidney failure, renal replacement therapy, exercise, rehabilitation, physical fitness, cycling, walk, physical therapy, random and so on. Supplement 1 discusses the search strategy in more detail. We also plan to evaluate the reference lists of previously reported systematic reviews in addition to our electronic database search. 2) The authors state that the main objective of the review is to review the effect of exercise training in the elderly population. However, they propose to include studies that have recruited participants over the age of 18 according to the Inclusion/exclusion criteria. What if no study has categorically recruited people over 60 years of age. Although they state that a sub-group analysis will be conducted they do not state the statistical method used to be used for these purposes. The authors require more clarity in their statements. For example they state Furthermore, 67 the proportions of elderly patients with > 60 years in new patients started on dialysis in 2012 and in all dialysis patients were 78.1% and 75.4%, respectively however they define age >65 years as elderly. If they wish to state the epidemiology of the elderly they need to stick to the

11 gae that they define as elderly. Thank you for your comment. We change the definition of elderly from > 65 to > 60 according to INTRODUCTION. Although there might be no study which has categorically recruited only elderly patients as you pointed out, to clarify this current situation from our systematic review is very important for the further development of disease management in nephrology community. If there is no study recruited only elderly patients, we determine elderly based on mean age (> 60 years) in treatment group of each study. We added the description into the METHODS, Statistical Analysis part. (Page 11, Line ) (METHODS) Statistical Analysis Our primary outcomes will be physical functions and exercise tolerance. Secondary outcomes will be: activities of daily living and quality of life. Outcome definitions will be based upon those used in the included studies. We will conduct the sub-group analysis based on whether study subjects are elderly or non-elderly. Here we define elderly as those patients aged 60 years and older. If there is no study which recruited only patients aged 60 years and over, we determine elderly based on mean age in treatment group of each study. We will also conduct subgroup analyses to identify comorbidities and training programs that may be confounding factors. Our statistical analysis strategy will 3) The English language used in this protocol is unacceptable for publication and the writers require to find an English speaking person. (e.g. 1. The population ageing is occurring throughout the world.) Our manuscript has been corrected by an editor who is a native English speaker in Edanz Editing Group. We uploaded the certification form (file name: Certificate_of_Editing). Corrected sentences or words are in bold and red or strike-through in the revised manuscript. Thank you for your suggestion.

12 4) Although, in meta-analyses, it had already been reported the effectiveness 73 of exercise interventions on physical function, exercise capacity and quality of life in patients undergoing hemodialysis, these analyses had been unconsidered whether subjects were elderly or not. These sentences require to be restructured for clarity Thank you for your comment. We revised this part (Page5, Line 79-83). Plsase see below: (INTRODUCTION) Most of elderly patients on hemodialysis are frailer than non-elderly patients, and frailty is well known to be an indicator of disability and a poor prognosis in dialysis patients 8, 9. Exercise training is therefore in great need for elderly patients on hemodialysis. Although prior meta-analyses have already reported on the effectiveness of exercise interventions on the physical function, exercise capacity and quality of life of patients undergoing hemodialysis 10, 11, these analyses did not consider whether their subjects were elderly. Exercise intervention for elderly patients on hemodialysis is complex, and how to best manage these patients is poorly understood in the nephrology community. Furthermore, it is unclear whether exercise training improves the physical function, exercise capacity or quality of life of elderly patients on hemodialysis.