REgistry of actiVE renAL rehabilitation in Japanese Dialysis patients (Reveal-D): A protocol for retrospective cohort study

REgistry of actiVE renAL rehabilitation in Japanese Dialysis patients (Reveal-D): A protocol for retrospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article REgistry of actiVE renAL rehabilitation in Japanese Dialysis patients (Reveal-D): A protocol for retrospective cohort study Kenichi Kono, Masahiko Yazawa, Shizuka Kobayashi, Ryota Matsuzawa, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7872177/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jan, 2026 Read the published version in Renal Replacement Therapy → Version 1 posted You are reading this latest preprint version Abstract Background Renal rehabilitation, particularly exercise therapy, plays a vital role in maintaining physical function and improving outcomes in patients undergoing hemodialysis. In April 2022, Japan introduced an insurance reimbursement policy for exercise instruction during hemodialysis. However, the clinical effectiveness and broader impact of this policy remain unclear. Objective This study aims to evaluate the impact of renal rehabilitation, especially exercise therapy during dialysis, on clinical outcomes, including mortality and hospitalization, in Japanese hemodialysis patients. It also assesses secondary outcomes such as frailty, physical function, and nutritional status. Methods A retrospective cohort study was conducted using data from 10 dialysis facilities across Japan between January 2021 and January 2024. Adult patients receiving outpatient hemodialysis were included. The exercise group received regular intradialytic exercise therapy, while a matched control group did not. Primary outcomes included death and hospitalization. Secondary outcomes included changes in physical function (e.g., grip strength, gait speed), serum albumin/creatinine levels, frailty scores, and care needs. Subgroup analyses were performed based on the presence of reimbursement claims for exercise instruction. Expected Results This multicenter study will provide the first large-scale evidence on the real-world impact of exercise therapy during hemodialysis following the 2022 reimbursement policy. It will also explore the association between exercise and improved physical, nutritional, and psychosocial outcomes. Conclusion The eventual findings from this study may clarify the role of structured exercise programs in dialysis care and have the potential to inform future health policy decisions in Japan and globally. These results could also help guide best practices in renal rehabilitation and optimize patient-oriented outcomes. renal rehabilitation exercise study protocol Figures Figure 1 Introduction Rehabilitation is defined by the World Health Organization (WHO) as all measures taken to alleviate the effects of potential disabilities and social disadvantages and to achieve social integration of people with disabilities and social disadvantages. The Japanese Society Renal Rehabilitation (JSRR) was established in 2011 as an academic organization related to the rehabilitation of patients with chronic kidney disease (CKD), including patients with dialysis therapy. The Renal rehabilitation has been defined as a comprehensive long-term program consisting of exercise, diet, fluid management, medication, education, and psychological and spiritual support to alleviate the physical and psychological effects of kidney disease and dialysis therapy, to prolong life, to reduce any CKD burdens, such as cardiovascular disease and progression of CKD, and to improve psychosocial and vocational status. Thus, the definition of rehabilitation is a long-term comprehensive program to improve vocational conditions [ 1 ]. Among these, exercise is the core of renal rehabilitation and is essential for maintaining and improving physical function in patients with CKD and dialysis. Frailty in dialysis patients is a global problem [ 2 ], and 21% of patients in Japan have been reported to be frail [ 3 ]. Dialysis patients with probable sarcopenia [ 4 ], low physical activity [ 5 – 7 ], and declining muscle strength [ 8 ] have been shown to have a poor prognosis [ 9 ], even in Japan where is the most excellent survival rate among patients with dialysis therapy. Exercise has been shown to improve physical function in dialysis patients in several previous studies [ 10 – 12 ], and Japan is the first country in the world to publish clinical practice guidelines for renal rehabilitation [ 1 ]. Exercise has also been shown to be effective for geriatric dialysis patients [ 13 ]. Despite the demonstrated efficacy of exercise in controlled settings, the actual implementation status and long-term clinical consequences of comprehensive renal rehabilitation in real-world Japanese dialysis facilities remain largely unknown at a large scale. In this background, In April 2022, an additional medical fee for exercise instruction during hemodialysis treatment was approved for insurance claims in Japan. This additional fee can be claimed when physicians, physical therapists, occupational therapists, or nurses who have received special training in renal rehabilitation from the JSRR provide hemodialysis education to patients during their treatment. Exercise therapy may be provided at times other than during hemodialysis. Claims may be submitted if exercise instruction is provided for at least 20 consecutive minutes during a hemodialysis treatment and for no more than 90 days. Several clinical questions have been proposed from the survey of renal rehabilitation for patients with dialysis therapy conducted after above-mentioned medical-fee claim [ 14 ]. This survey was based on the descriptive observational manner; and thus, the effect of exercise therapy during dialysis especially in the proving by the trained health care providers in terms of not only physical function but also psychosocial, vocational, nutritional function have been not investigated. Ultimately, we have to elucidate the hard outcomes including survival, cardiovascular disease, hospitalization, and fracture as well as any harms related to exercise therapy during dialysis. In this regard, JSRR strives to evaluate the effects and consequences of renal rehabilitation during dialysis therapy using multicenter from different regions of Japan, especially before and after new claim of medical fee for exercise instruction during hemodialysis treatment. Therefore, we are now conducting the retrospective cohort study as RE gistry of acti VE ren AL rehabilitation in Japanese D ialysis patients (Reveal-D). Although Reveal-D is a retrospective cohort study, we prioritize publishing this protocol prior to data analysis to ensure maximum transparency in our research design and statistical methods, thereby minimizing post-hoc bias and enhancing the scientific rigor of our findings. The primary objective of the Reveal-D study is to elucidate the association between the implementation of specialized renal rehabilitation and a comprehensive range of outcomes, including all-cause mortality, cardiovascular events, hospitalization, and changes in physical, nutritional, and biochemical markers. This research is crucial for developing evidence-based clinical practice guidelines and informing future national healthcare policies. Study Protocol Target population and participating Institutions The study period is from January 2021 to January 2024 and target population and setting are patients with hemodialysis (HD) and outpatient dialysis clinics either having admission beds or not. Inclusion criteria are patients aged 18 years or older. Exclusion criteria included those who were bedridden and deemed unsuitable for the study by the primary researcher, those with limb loss and severe dementia, and those could be followed for less than 6 months during the study period. Regarding participated facilities, ten facilities that agreed to participate in this study were selected. The facilities included in this study were selected according to the following criteria. First, they had responded to a nationwide questionnaire survey conducted by the Academic Committee of the JSRR [ 14 ]. Second, they had agreed to participate in the study upon receiving a formal request from the same committee. Third, these facilities were actively providing intradialytic exercise therapy in accordance with structured exercise instructions during hemodialysis treatment. Exposure and control groups The primary exposure of interest was patients undergoing exercise therapy (exercise group) regardless of exercised methods. The control group was those who were not undergoing exercise therapy (non-exercise group). The non-exercise group was randomly selected from each facility by the data management center to match the exercise group in a 2:1 ratio, based on four matching criteria: dialysis session timing (morning or afternoon), diabetes status, age, and dialysis vintage. In this study, exercise was defined as resistance or aerobic exercise and did not include very low-impact exercise, such as stretching [ 15 ]. Exercise content performed per year was determined for the period from January 2021 to January 2024. Physician-supervised exercise therapy on dialysis treatment days is examined in terms of time per session, number of sessions per week, time per week for aerobic and resistance exercise, and duration of exercise that could be performed. Exercise on non-dialysis days is also assessed for the number of times per week that exercise was performed for at least 20 minutes per session. Date collection A central data management center will be established at the outsourcing site for data collection, and the principal investigator will instruct the outsourcing site. Ten surveyed institutions will be asked to complete a paper case report form (CRF). At that time, a researcher from the outsourcing organization will be sent to partially assist in the completion of the survey form. This study only collect data from the paper survey forms and does not process samples collected directly from patients. The survey forms were mailed from the study sites to the data management center, and the data were converted into a database. The database data were made available to the collaborating institutions by the principal investigator (Figure.1). Outcome measures: Primary endpoint Outcome measures: Primary endpoint The primary outcomes were set as death and hospitalization during the study period. The cause of death was classified by heart failure, ischemic heart disease, infection, malignancy, dialysis discontinuation, or other. Cause of hospitalization was also identified as: fracture due to fall, foot lesions, limb amputation, heart failure including ischemic heart disease, stroke, infection, malignancy, shunt related, or other. The date of each outcome was also captured for time-to-event analysis. We intend to compare the association between exposure (exercise) and each outcome. Outcome measures: Sub outcome measures We intend to compare the presence or absence of clinical events (fall-related fractures, hospitalizations, and death), as well as surrogate markers such as serum albumin and serum creatinine levels, according to whether or not facilities have claimed reimbursement for the additional fee for exercise instruction during dialysis. In particular, because the reimbursement for the additional fee for exercise instruction during dialysis was launched in April 2022, we also intend to examine changes before and after its implementation. We also intend to analyze the association between patient-oriented outcomes, such as frailty and activity levels in daily life and exercise therapy. The Clinical Frailty Scale [ 16 , 17 ] for frailty assessment was selected by the assessor from nine levels, ranging from very fit 1 to terminally ill 9, the state that best matched the illustration and description of the condition shown on the scale. Activity level was defined as the classification confirmed in a statistical survey by the Japanese Society for Dialysis Therapy [ 18 ]. Baseline variables We intend to capture several components as baseline characteristics as follows: 1) basic patient information, 2) dialysis treatment information, 3) medications, 4) Blood biochemistry test, 5) Physical function and physical performance, 6) The means of transportation to the dialysis facility, 7) Level of care required in Japan's long-term care insurance, and 8)Nutritional support and status. The individual items are summarized in Table 1 . As physical function and performance are the key baseline variable, the detailed information was described below. Table 1 Baseline variables Core items Individual variable Basic Patient Information Height, Weight (dry weight), Age, Sex, Insurance status, Smoking history Primary disease (using the Japanese Society for Dialysis Therapy statistical survey code) Comorbidities (dementia, diabetes, ischemic heart disease, stroke, limb amputation, proximal femur fracture, dialysis amyloidosis) Dialysis Treatment Information Time of dialysis treatment (morning, afternoon, evening) Dialysis time (minutes) Blood flow rate Dialyzer membrane area (m 2 ) Dialysis type (HD, HDF, other) Medications Cardiovascular related drugs: • Antihypertensives: ARBs, ACE inhibitors, ARNIs, MRBs, CCBs • Sympatholytics: Alpha blockers, beta blockers • Diuretics • Antiarrhythmic agents • Antiplatelet agents • Anticoagulants Metabolic and Endocrine drugs: • lipid-lowering agents (Statins, others) • Uric acid-lowering agents • Anti-thyroid hormone agents • Hypoglycemic agents • Osteoporosis treatments Renal and Electrolyte Management drugs: • Phosphorus binders • Calcium binders • Vitamin D analogs (active vitamin D) • Calcium receptor agonists • Renal anemia treatments: ESA, HIF-Phi, iron supplements Gastrointestinal related drugs: • Proton pump inhibitors Blood biochemistry test Hematology: • White blood cell count (WBC) • Peripheral blood lymphocyte count • Hemoglobin (Hb) • Hematocrit (Hct) • Mean corpuscular volume (MCV) Iron Metabolism: • Serum iron • Total iron-binding capacity (TIBC) • Ferritin Nutritional Markers: • Serum albumin • Cholinesterase • Total cholesterol • HDL cholesterol • LDL cholesterol • Triglycerides Electrolytes & Minerals: • Sodium (Na) • Potassium (K) • Chloride (Cl) • Calcium (Ca) • Phosphorus (P) Kidney related and dialysis adequate maker: • Blood urea nitrogen (BUN) • Serum creatinine (Cr) • Kt/V (dialysis adequacy marker) Inflammatory & Hormonal Markers: • C-reactive protein (CRP) • Intact parathyroid hormone (iPTH) Metabolic & Cardiovascular Markers: • Normalized protein catabolic rate (nPCR) • Atrial natriuretic peptide (ANP) • Brain natriuretic peptide (BNP) • Abbreviations: HD: Hemodialysis, HDF: Hemodiafiltration, ARBs: Angiotensin II Receptor Blockers, ACE inhibitors: Angiotensin-Converting Enzyme Inhibitors, ARNIs: Angiotensin Receptor-Neprilysin Inhibitors, MRBs: Mineralocorticoid Receptor Blockers, CCBs: Calcium Channel Blockers, ESA: Erythropoiesis-Stimulating Agent, HIF-Phi: Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors Physical function and physical performance Physical function will be checked every year during the observation period from January 2021 to 2024. January is the month in which the reference will be measured, and the data will be measured in the six months before and after will be taken as the measured data for that year. ・Hand grip Handgrip strength was measured twice on each side using a digital dynamometer according to a standard protocol [ 19 ]. Maximal isometric voluntary contractions of the hands for 3 s each were collected, and the highest value was used in the analyses. ・Calf Circumference The recommended protocol for Calf Circumference measures the maximum value of both calves using a nonelastic tape [ 19 ], which has moderate-to-high sensitivity and specificity in predicting sarcopenia or low skeletal muscle mass. ・One leg standing time(OLST) The patients were required to stand on one leg for up to 60s with the hands placed on the hips and the eyes open. A digital stopwatch was used to determine OLST and was stopped if the patients made contact with any part of the room with any part of the body other than the supporting foot, began to hop around, or moved their hand off the hip [ 20 ]. ・Physical performance Gait speed, 5-time chair stands, and short physical performance battery (SPPB) are used in this study to assess physical performance. To test gait speed, was the time taken to walk 4 m at a normal pace from a moving start without deceleration [ 21 ], taking the average result of 2 trials. Velocity is converted to meters per second. Patients with a gait speed of < 1.0 m/s were identified as low physical performance [ 19 ]. To test the ability to rise from a chair, patients are asked to fold their arms across their chest and to stand up once from a chair. If successful, they will be asked to stand up and sit down five times as quickly as possible and will be timed from the initial sitting position to the final standing position at the end of the fifth stand. A chair-stand time of 12s is used as the cut-off points for low physical performance [ 19 ]. The SPPB, which consists of 3 components, gait speed, repeated chair stands, and standing balance, will be measured according to established methods [ 21 ]. The SPPB score ranged from 0 to 12 [ 19 ]. ・໿The means of transportation to the dialysis facility : The three tiers are classified as: dependent on others (e.g., taxis and shuttles), independent but not requiring physical activity (e.g., driving one's own car), and independent and requiring physical activity (e.g., public transportation, walking) [ 22 ]. ・Level of care required in Japan's long-term care insurance Japanese long-term care insurance categories of independence, support 1, support 2, long-term care 1, long-term care 2, long-term care 3, long-term care 4, or long-term care 5 will be surveyed. ・Nutritional support We ask whether nutritional supplements or infusions were prescribed during or after dialysis, in addition to regular meals. Statistical analysis Descriptive statistics will be presented for all patients and for the exercise and non-exercise groups. Data are expressed as mean ± standard deviation or median (interquartile range [IQR]) for continuous variables and numbers (%) for categorical variables. Group differences were assessed using Student's t-test or Wilcoxon Rank-Sum test for continuous variables and the chi-square test (or Fisher’s exact test) for categorical variables. Time-to-event analysis of death and hospitalization between the exercise and non-exercise groups during the observation period will be performed using the log-rank test, and the adjusted hazard ratio (aHR) will be calculated by Cox regression hazard model adjusted by prespecified confounders. As a subgroup analysis, comparisons will be made between patients who did or did not receive the additional reimbursement for exercise instruction during dialysis after April 2022, as well as between those who did or did not undergo renal rehabilitation. Outcomes will be evaluated at 90 days post-reimbursement, at each measurement point, and at the time of reimbursement approval. Furthermore, surrogate markers including changes in serum albumin and creatinine levels from baseline will also be analyzed using mixed-effects models or change rates to assess group differences. In addition, surrogate markers such as changes in serum albumin and creatinine levels from baseline at the start of the study will be analyzed. Between-group comparisons will be conducted using either the percentage change or a mixed-effects model. Since the implementation of renal rehabilitation may be influenced by facility size and characteristics, sensitivity analysis will be performed using an instrumental variable approach that incorporates dialysis facility information. Ethic and Dissemination At Tokyo Women's Medical University, a batch review was conducted and approval was obtained from the research ethics committee of the institution to which the principal investigator belongs (Approval No.:2023–2024). When receiving information from institutions providing existing information, they would make sure that permission had been obtained from the head of each institution and that opt-outs were in place at each institution. The person in charge of such research shall obtain the review and approval of the Conflict-of-Interest Management Committee, as appropriate, in accordance with the provisions of the Conflict-of-Interest management regulations. Conflicts of interest of researchers in joint research institutions shall be appropriately reviewed and managed by the Conflict-of-Interest Management Committee of each institution. Expected Results This multicenter retrospective cohort study is anticipated to provide the first large-scale, real-world evidence regarding the impact of exercise therapy during dialysis following the 2022 medical fee reimbursement policy change in Japan. The findings from this research are expected to clarify the association between exercise therapy and the following primary and secondary outcomes, consistent with the study’s objectives and methods. ・Anticipated Findings for Primary Outcomes The association between the exercise group and the non-exercise group concerning the risk of the primary outcomes, all-cause mortality and hospitalization, will be elucidated through time-to-event analysis. ・Anticipated Findings for Secondary Outcomes It is expected that the study will reveal how exercise therapy is associated with patient-oriented outcomes, including physical function (e.g., grip strength, gait speed, SPPB), frailty (Clinical Frailty Scale), nutritional status (e.g., serum albumin and creatinine levels), and activity levels. Specifically, the impact of the insurance reimbursement system for exercise instruction on clinical events and surrogate markers will be examined through subgroup analyses based on the presence or absence of reimbursement claims for exercise instruction. Strengths and Limitations The study will be the first to examine the effectiveness of insurance reimbursement for exercise during hemodialysis treatment. The classification of the effects and difficulties of additional reimbursement for exercise during dialysis may have a significant impact on the progress of renal rehabilitation for hemodialysis patients. In addition, Japan is the first country in the world not only to published renal rehabilitation guideline based on academic society level and systematic review and metanalysis but also to approve this treatment for reimbursement and may serve as a reference for countries and regions considering adding this coverage in the future. The practicality of this additional reimbursement was investigated by Sofue et al. [ 14 ], 13% percent of hemodialysis facilities in Japan provided exercise instruction during hemodialysis treatment, and 65% of these facilities claimed the additional reimbursement. Exercise instruction was generally lower limb resistance training and aerobic exercise or a combination of these, with 66% of facilities focusing on muscle strength to determine effectiveness. No life-threatening adverse events were reported. In order to expand exercise for dialysis patients in the future, the certainty of the effects of exercise should be widely investigated. The study design allows us to explore the type of exercise, the duration of exercise, and the duration of exercise over time, as well as which exercise should be performed, how much, and for how long. Furthermore, although this is a retrospective study and missing data may be present, we plan to investigate patient-oriented outcomes, nutritional status, and physical function to the extent possible. In addition, the control group was randomly selected from patients of the same sex, age, and comorbidities as the exercise group to avoid selection bias. Limitation We acknowledge several limitations inherent to the design and conduct of the REVEAL-D study. As a retrospective cohort study, we are limited to demonstrating an association between exercise and outcomes; therefore, a definitive causal relationship cannot be established. This design also makes the study susceptible to missing data for certain variables, which is a known challenge. Although a matched representative sample was randomly selected in a 1:2 ratio to the exercise group, the possibility of selection bias cannot be completely excluded. Furthermore, while dialysis prescriptions are guided by standard guidelines, the detailed setting of dialysis treatment may still differ among the 10 medical institutions. Similarly, although exercise is defined as aerobic and resistance exercise, the equipment used and the instruction provided by instructors may differ, potentially affecting the consistency of the intervention. Finally, the physical function is scheduled to be checked only once per year, which may limit our ability to capture short-term or transient effects of the intervention. Declarations Ethics and Consent to Participate declarations: All procedures in this study were conducted in accordance with the ethical standards of the Ethics Review Committee of Tokyo Women's Medical University Hospital (IRB No. 2023-0204). This retrospective observational study involved no new interventions or invasive procedures and was conducted based on the “Ethical Guidelines for Medical Research Involving Human Subjects” established by the Ministry of Health, Labour and Welfare and the regulations of the Tokyo Women's Medical University Ethics Committee. Participants were provided with the opportunity to refuse participation through opt-out. Consent publication: The requirement for written informed consent was waived for all participants. An opt-out method was used to obtain consent for this study. Availability of data and materials: All data in this study are available upon request. Conflicts of interest The authors have declared that no conflict of interest exists. However, we disclose that Ichiei Narita, one of the co-authors, is an Editorial Board Member of this journal. The authors confirm that the Editorial Board Member was not involved in the peer-review process of this manuscript. Funding This work was supported by Japanese Society of Renal Rehabilitation, and JH’s grant from JSPS KAKENHI Grant Number JP24K14335. Author Contributors KKo, MY, SK, KKi, RM and JH led the design of the study. KKo, MY, SK, KKi, RM, YOt, YOu, TH and JH were involved in the design of the study. KKo drafted the manuscript. MY, KKi, SK, R M, YOt, JH, IN, and KY provided feedback on the manuscript; all authors approved the final version. Acknowledgments The results of this study have not been previously published, either in whole or in part Data Availability Statement All clinical data will available from the electronic medical records at Tokyo Women's Medical University. The data supporting the findings of this study are available from the corresponding author upon reasonable request. Disclosure None. References Yamagata K, Hoshino J, Sugiyama H, et al. 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Japanese Society for Dialysis Therapy Clinical Guideline for “Hemodialysis Initiation for Maintenance Hemodialysis.” Ther Apher Dial . 2015;19(S1):93–107. doi: 10.1111/1744-9987.12293 Watanabe Y, Hirakata H, Okada K, et al. Proposal for the Shared Decision-Making Process Regarding Initiation and Continuation of Maintenance Hemodialysis. Ther Apher Dial . 2015;19(S1):108–117. doi: 10.1111/1744-9987.12295 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 23 Jan, 2026 Read the published version in Renal Replacement Therapy → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7872177","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":546681002,"identity":"2f0bcfc3-4312-4e4f-9110-c8b7cdea6f81","order_by":0,"name":"Kenichi Kono","email":"","orcid":"","institution":"International University of Health and Welfare","correspondingAuthor":false,"prefix":"","firstName":"Kenichi","middleName":"","lastName":"Kono","suffix":""},{"id":546681003,"identity":"48cf7950-cafc-4f69-b36b-f1fce88858c5","order_by":1,"name":"Masahiko Yazawa","email":"","orcid":"","institution":"Yokohama General 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University","correspondingAuthor":false,"prefix":"","firstName":"Yuhei","middleName":"","lastName":"Otobe","suffix":""},{"id":546681007,"identity":"11aaa9ce-af61-484b-91e4-60c8c5dd8a26","order_by":5,"name":"Yuta Ouchi","email":"","orcid":"","institution":"Aozora Clinic","correspondingAuthor":false,"prefix":"","firstName":"Yuta","middleName":"","lastName":"Ouchi","suffix":""},{"id":546681008,"identity":"426702da-4721-4a28-9d73-83100b5316db","order_by":6,"name":"Takeshi Hasegawa","email":"","orcid":"","institution":"Showa Medical University","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Hasegawa","suffix":""},{"id":546681009,"identity":"3f4d3161-c255-4c39-a2a8-134828724ba1","order_by":7,"name":"Ichiei Narita","email":"","orcid":"","institution":"Niigata Sports Association","correspondingAuthor":false,"prefix":"","firstName":"Ichiei","middleName":"","lastName":"Narita","suffix":""},{"id":546681010,"identity":"e518033e-8a99-4d92-96fa-0aa4eb456b36","order_by":8,"name":"Kunihiro Yamagata","email":"","orcid":"","institution":"University of Tsukuba, University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Kunihiro","middleName":"","lastName":"Yamagata","suffix":""},{"id":546681011,"identity":"bf56d759-2b12-4b40-b18d-06a386f43993","order_by":9,"name":"Keisuke Kida","email":"data:image/png;base64,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","orcid":"","institution":"St. Marianna University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Keisuke","middleName":"","lastName":"Kida","suffix":""},{"id":546681012,"identity":"2f829434-a1fc-401c-8a80-053457fd0a46","order_by":10,"name":"Junichi Hoshino","email":"","orcid":"","institution":"Tokyo Women's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Junichi","middleName":"","lastName":"Hoshino","suffix":""}],"badges":[],"createdAt":"2025-10-16 01:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7872177/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7872177/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41100-026-00703-5","type":"published","date":"2026-01-23T15:57:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":96967335,"identity":"116bfa09-01c2-44c4-ba4c-a9dd7b88d367","added_by":"auto","created_at":"2025-11-28 06:54:22","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":301074,"visible":true,"origin":"","legend":"","description":"","filename":"REVEALDretroprotocolv05revise.docx","url":"https://assets-eu.researchsquare.com/files/rs-7872177/v1/3d282c55cb7202f19ebb2e38.docx"},{"id":96967329,"identity":"c164fb49-e16d-4b2a-bf70-6d59fe1e2a8c","added_by":"auto","created_at":"2025-11-28 06:54:21","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11598,"visible":true,"origin":"","legend":"","description":"","filename":"d51249e000294857aa3bd09f4f95219a.json","url":"https://assets-eu.researchsquare.com/files/rs-7872177/v1/ea489281e95e0329a163675a.json"},{"id":96967333,"identity":"3f8e292b-f9eb-4288-9733-d4c2122d07ea","added_by":"auto","created_at":"2025-11-28 06:54:22","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90273,"visible":true,"origin":"","legend":"","description":"","filename":"d51249e000294857aa3bd09f4f95219a1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7872177/v1/239f710033c94a3cfbcaeefc.xml"},{"id":96967340,"identity":"a2025b2b-5733-4c57-9317-2563fb429710","added_by":"auto","created_at":"2025-11-28 06:54:22","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":251086,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7872177/v1/bdd2b1c8189b78e02662ac78.png"},{"id":96967351,"identity":"2c3f842d-4f8a-44d4-aeca-ab33861e0a0e","added_by":"auto","created_at":"2025-11-28 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06:54:26","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":100714,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7872177/v1/f09b8649f64c12a605cac21b.html"},{"id":96967337,"identity":"1e4a187d-8b67-4a91-bb65-bce9aaf79e80","added_by":"auto","created_at":"2025-11-28 06:54:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":300743,"visible":true,"origin":"","legend":"\u003cp\u003eShort Title\u003c/p\u003e\n\u003cp\u003eFlowchart of data collection and management in the REVEAL-D retrospective cohort study\u003c/p\u003e\n\u003cp\u003eDetail legends\u003c/p\u003e\n\u003cp\u003eThis figure outlines the study design and data flow for the REgistry of actiVE renAL rehabilitation in Japanese Dialysis patients (REVEAL-D) study. The study retrospectively collects data from multiple hemodialysis facilities across Japan. Study sites use standardized Case Report Forms (CRFs) to capture essential patient data, including demographics, clinical labs, and the nature of renal rehabilitation interventions. The CRFs are submitted to a central data management center, which then creates a secure, de-identified electronic database after meticulous data entry and quality checks. This central database is used for comprehensive statistical analysis, with adjustment for potential selection bias when comparing outcomes between rehabilitation and non-rehabilitation groups.\u003c/p\u003e","description":"","filename":"Picture1.png","url":"https://assets-eu.researchsquare.com/files/rs-7872177/v1/c36e29068779932dfe7ad839.png"},{"id":101152188,"identity":"40a49f4c-f79c-46fb-b182-d93fb1f5ca8c","added_by":"auto","created_at":"2026-01-26 16:10:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1037194,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7872177/v1/41d2ff77-da65-403c-aec6-fdea9a1bfd42.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"REgistry of actiVE renAL rehabilitation in Japanese Dialysis patients (Reveal-D): A protocol for retrospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRehabilitation is defined by the World Health Organization (WHO) as all measures taken to alleviate the effects of potential disabilities and social disadvantages and to achieve social integration of people with disabilities and social disadvantages. The Japanese Society Renal Rehabilitation (JSRR) was established in 2011 as an academic organization related to the rehabilitation of patients with chronic kidney disease (CKD), including patients with dialysis therapy. The Renal rehabilitation has been defined as a comprehensive long-term program consisting of exercise, diet, fluid management, medication, education, and psychological and spiritual support to alleviate the physical and psychological effects of kidney disease and dialysis therapy, to prolong life, to reduce any CKD burdens, such as cardiovascular disease and progression of CKD, and to improve psychosocial and vocational status. Thus, the definition of rehabilitation is a long-term comprehensive program to improve vocational conditions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong these, exercise is the core of renal rehabilitation and is essential for maintaining and improving physical function in patients with CKD and dialysis. Frailty in dialysis patients is a global problem [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], and 21% of patients in Japan have been reported to be frail [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Dialysis patients with probable sarcopenia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], low physical activity [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and declining muscle strength [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] have been shown to have a poor prognosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], even in Japan where is the most excellent survival rate among patients with dialysis therapy. Exercise has been shown to improve physical function in dialysis patients in several previous studies [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and Japan is the first country in the world to publish clinical practice guidelines for renal rehabilitation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Exercise has also been shown to be effective for geriatric dialysis patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Despite the demonstrated efficacy of exercise in controlled settings, the actual implementation status and long-term clinical consequences of comprehensive renal rehabilitation in real-world Japanese dialysis facilities remain largely unknown at a large scale.\u003c/p\u003e\u003cp\u003eIn this background, In April 2022, an additional medical fee for exercise instruction during hemodialysis treatment was approved for insurance claims in Japan. This additional fee can be claimed when physicians, physical therapists, occupational therapists, or nurses who have received special training in renal rehabilitation from the JSRR provide hemodialysis education to patients during their treatment. Exercise therapy may be provided at times other than during hemodialysis. Claims may be submitted if exercise instruction is provided for at least 20 consecutive minutes during a hemodialysis treatment and for no more than 90 days. Several clinical questions have been proposed from the survey of renal rehabilitation for patients with dialysis therapy conducted after above-mentioned medical-fee claim [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This survey was based on the descriptive observational manner; and thus, the effect of exercise therapy during dialysis especially in the proving by the trained health care providers in terms of not only physical function but also psychosocial, vocational, nutritional function have been not investigated. Ultimately, we have to elucidate the hard outcomes including survival, cardiovascular disease, hospitalization, and fracture as well as any harms related to exercise therapy during dialysis.\u003c/p\u003e\u003cp\u003eIn this regard, JSRR strives to evaluate the effects and consequences of renal rehabilitation during dialysis therapy using multicenter from different regions of Japan, especially before and after new claim of medical fee for exercise instruction during hemodialysis treatment. Therefore, we are now conducting the retrospective cohort study as \u003cb\u003eRE\u003c/b\u003egistry of acti\u003cb\u003eVE\u003c/b\u003e ren\u003cb\u003eAL\u003c/b\u003e rehabilitation in Japanese \u003cb\u003eD\u003c/b\u003eialysis patients (Reveal-D). Although Reveal-D is a retrospective cohort study, we prioritize publishing this protocol prior to data analysis to ensure maximum transparency in our research design and statistical methods, thereby minimizing post-hoc bias and enhancing the scientific rigor of our findings. The primary objective of the Reveal-D study is to elucidate the association between the implementation of specialized renal rehabilitation and a comprehensive range of outcomes, including all-cause mortality, cardiovascular events, hospitalization, and changes in physical, nutritional, and biochemical markers. This research is crucial for developing evidence-based clinical practice guidelines and informing future national healthcare policies.\u003c/p\u003e"},{"header":"Study Protocol","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eTarget population and participating Institutions\u003c/h2\u003e\u003cp\u003eThe study period is from January 2021 to January 2024 and target population and setting are patients with hemodialysis (HD) and outpatient dialysis clinics either having admission beds or not. Inclusion criteria are patients aged 18 years or older. Exclusion criteria included those who were bedridden and deemed unsuitable for the study by the primary researcher, those with limb loss and severe dementia, and those could be followed for less than 6 months during the study period. Regarding participated facilities, ten facilities that agreed to participate in this study were selected. The facilities included in this study were selected according to the following criteria. First, they had responded to a nationwide questionnaire survey conducted by the Academic Committee of the JSRR [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Second, they had agreed to participate in the study upon receiving a formal request from the same committee. Third, these facilities were actively providing intradialytic exercise therapy in accordance with structured exercise instructions during hemodialysis treatment.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eExposure and control groups\u003c/h3\u003e\n\u003cp\u003eThe primary exposure of interest was patients undergoing exercise therapy (exercise group) regardless of exercised methods. The control group was those who were not undergoing exercise therapy (non-exercise group). The non-exercise group was randomly selected from each facility by the data management center to match the exercise group in a 2:1 ratio, based on four matching criteria: dialysis session timing (morning or afternoon), diabetes status, age, and dialysis vintage. In this study, exercise was defined as resistance or aerobic exercise and did not include very low-impact exercise, such as stretching [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Exercise content performed per year was determined for the period from January 2021 to January 2024. Physician-supervised exercise therapy on dialysis treatment days is examined in terms of time per session, number of sessions per week, time per week for aerobic and resistance exercise, and duration of exercise that could be performed. Exercise on non-dialysis days is also assessed for the number of times per week that exercise was performed for at least 20 minutes per session.\u003c/p\u003e\n\u003ch3\u003eDate collection\u003c/h3\u003e\n\u003cp\u003eA central data management center will be established at the outsourcing site for data collection, and the principal investigator will instruct the outsourcing site. Ten surveyed institutions will be asked to complete a paper case report form (CRF). At that time, a researcher from the outsourcing organization will be sent to partially assist in the completion of the survey form. This study only collect data from the paper survey forms and does not process samples collected directly from patients. The survey forms were mailed from the study sites to the data management center, and the data were converted into a database. The database data were made available to the collaborating institutions by the principal investigator (Figure.1).\u003c/p\u003e\n\u003ch3\u003eOutcome measures: Primary endpoint\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eOutcome measures: Primary endpoint\u003c/div\u003e\u003cp\u003eThe primary outcomes were set as death and hospitalization during the study period. The cause of death was classified by heart failure, ischemic heart disease, infection, malignancy, dialysis discontinuation, or other. Cause of hospitalization was also identified as: fracture due to fall, foot lesions, limb amputation, heart failure including ischemic heart disease, stroke, infection, malignancy, shunt related, or other. The date of each outcome was also captured for time-to-event analysis. We intend to compare the association between exposure (exercise) and each outcome.\u003c/p\u003e\n\u003ch3\u003eOutcome measures: Sub outcome measures\u003c/h3\u003e\n\u003cp\u003eWe intend to compare the presence or absence of clinical events (fall-related fractures, hospitalizations, and death), as well as surrogate markers such as serum albumin and serum creatinine levels, according to whether or not facilities have claimed reimbursement for the additional fee for exercise instruction during dialysis. In particular, because the reimbursement for the additional fee for exercise instruction during dialysis was launched in April 2022, we also intend to examine changes before and after its implementation. We also intend to analyze the association between patient-oriented outcomes, such as frailty and activity levels in daily life and exercise therapy. The Clinical Frailty Scale [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] for frailty assessment was selected by the assessor from nine levels, ranging from very fit 1 to terminally ill 9, the state that best matched the illustration and description of the condition shown on the scale. Activity level was defined as the classification confirmed in a statistical survey by the Japanese Society for Dialysis Therapy [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eBaseline variables\u003c/h2\u003e\u003cp\u003eWe intend to capture several components as baseline characteristics as follows: 1) basic patient information, 2) dialysis treatment information, 3) medications, 4) Blood biochemistry test, 5) Physical function and physical performance, 6) The means of transportation to the dialysis facility, 7) Level of care required in Japan's long-term care insurance, and 8)Nutritional support and status. The individual items are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. As physical function and performance are the key baseline variable, the detailed information was described below.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline variables\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCore items\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIndividual variable\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBasic Patient Information\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeight, Weight (dry weight), Age, Sex,\u003c/p\u003e\u003cp\u003eInsurance status, Smoking history\u003c/p\u003e\u003cp\u003ePrimary disease (using the Japanese Society for Dialysis Therapy statistical survey code)\u003c/p\u003e\u003cp\u003eComorbidities (dementia, diabetes, ischemic heart disease, stroke, limb amputation, proximal femur fracture, dialysis amyloidosis)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDialysis Treatment Information\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTime of dialysis treatment (morning, afternoon, evening)\u003c/p\u003e\u003cp\u003eDialysis time (minutes)\u003c/p\u003e\u003cp\u003eBlood flow rate\u003c/p\u003e\u003cp\u003eDialyzer membrane area (m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003cp\u003eDialysis type (HD, HDF, other)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCardiovascular related drugs:\u003c/p\u003e\u003cp\u003e\u0026bull; Antihypertensives: ARBs, ACE inhibitors, ARNIs, MRBs, CCBs\u003c/p\u003e\u003cp\u003e\u0026bull; Sympatholytics: Alpha blockers, beta blockers\u003c/p\u003e\u003cp\u003e\u0026bull; Diuretics\u003c/p\u003e\u003cp\u003e\u0026bull; Antiarrhythmic agents\u003c/p\u003e\u003cp\u003e\u0026bull; Antiplatelet agents\u003c/p\u003e\u003cp\u003e\u0026bull; Anticoagulants\u003c/p\u003e\u003cp\u003eMetabolic and Endocrine drugs:\u003c/p\u003e\u003cp\u003e\u0026bull; lipid-lowering agents (Statins, others)\u003c/p\u003e\u003cp\u003e\u0026bull; Uric acid-lowering agents\u003c/p\u003e\u003cp\u003e\u0026bull; Anti-thyroid hormone agents\u003c/p\u003e\u003cp\u003e\u0026bull; Hypoglycemic agents\u003c/p\u003e\u003cp\u003e\u0026bull; Osteoporosis treatments\u003c/p\u003e\u003cp\u003eRenal and Electrolyte Management drugs:\u003c/p\u003e\u003cp\u003e\u0026bull; Phosphorus binders\u003c/p\u003e\u003cp\u003e\u0026bull; Calcium binders\u003c/p\u003e\u003cp\u003e\u0026bull; Vitamin D analogs (active vitamin D)\u003c/p\u003e\u003cp\u003e\u0026bull; Calcium receptor agonists\u003c/p\u003e\u003cp\u003e\u0026bull; Renal anemia treatments: ESA, HIF-Phi, iron supplements\u003c/p\u003e\u003cp\u003eGastrointestinal related drugs:\u003c/p\u003e\u003cp\u003e\u0026bull; Proton pump inhibitors\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood biochemistry test\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHematology:\u003c/p\u003e\u003cp\u003e\u0026bull; White blood cell count (WBC)\u003c/p\u003e\u003cp\u003e\u0026bull; Peripheral blood lymphocyte count\u003c/p\u003e\u003cp\u003e\u0026bull; Hemoglobin (Hb)\u003c/p\u003e\u003cp\u003e\u0026bull; Hematocrit (Hct)\u003c/p\u003e\u003cp\u003e\u0026bull; Mean corpuscular volume (MCV)\u003c/p\u003e\u003cp\u003eIron Metabolism:\u003c/p\u003e\u003cp\u003e\u0026bull; Serum iron\u003c/p\u003e\u003cp\u003e\u0026bull; Total iron-binding capacity (TIBC)\u003c/p\u003e\u003cp\u003e\u0026bull; Ferritin\u003c/p\u003e\u003cp\u003eNutritional Markers:\u003c/p\u003e\u003cp\u003e\u0026bull; Serum albumin\u003c/p\u003e\u003cp\u003e\u0026bull; Cholinesterase\u003c/p\u003e\u003cp\u003e\u0026bull; Total cholesterol\u003c/p\u003e\u003cp\u003e\u0026bull; HDL cholesterol\u003c/p\u003e\u003cp\u003e\u0026bull; LDL cholesterol\u003c/p\u003e\u003cp\u003e\u0026bull; Triglycerides\u003c/p\u003e\u003cp\u003eElectrolytes \u0026amp; Minerals:\u003c/p\u003e\u003cp\u003e\u0026bull; Sodium (Na)\u003c/p\u003e\u003cp\u003e\u0026bull; Potassium (K)\u003c/p\u003e\u003cp\u003e\u0026bull; Chloride (Cl)\u003c/p\u003e\u003cp\u003e\u0026bull; Calcium (Ca)\u003c/p\u003e\u003cp\u003e\u0026bull; Phosphorus (P)\u003c/p\u003e\u003cp\u003eKidney related and dialysis adequate maker:\u003c/p\u003e\u003cp\u003e\u0026bull; Blood urea nitrogen (BUN)\u003c/p\u003e\u003cp\u003e\u0026bull; Serum creatinine (Cr)\u003c/p\u003e\u003cp\u003e\u0026bull; Kt/V (dialysis adequacy marker)\u003c/p\u003e\u003cp\u003eInflammatory \u0026amp; Hormonal Markers:\u003c/p\u003e\u003cp\u003e\u0026bull; C-reactive protein (CRP)\u003c/p\u003e\u003cp\u003e\u0026bull; Intact parathyroid hormone (iPTH)\u003c/p\u003e\u003cp\u003eMetabolic \u0026amp; Cardiovascular Markers:\u003c/p\u003e\u003cp\u003e\u0026bull; Normalized protein catabolic rate (nPCR)\u003c/p\u003e\u003cp\u003e\u0026bull; Atrial natriuretic peptide (ANP)\u003c/p\u003e\u003cp\u003e\u0026bull; Brain natriuretic peptide (BNP)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u0026bull; Abbreviations: HD: Hemodialysis, HDF: Hemodiafiltration, ARBs: Angiotensin II Receptor Blockers, ACE inhibitors: Angiotensin-Converting Enzyme Inhibitors, ARNIs: Angiotensin Receptor-Neprilysin Inhibitors, MRBs: Mineralocorticoid Receptor Blockers, CCBs: Calcium Channel Blockers, ESA: Erythropoiesis-Stimulating Agent, HIF-Phi: Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePhysical function and physical performance\u003c/h3\u003e\n\u003cp\u003ePhysical function will be checked every year during the observation period from January 2021 to 2024. January is the month in which the reference will be measured, and the data will be measured in the six months before and after will be taken as the measured data for that year.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e・Hand grip\u003c/strong\u003e\u003cp\u003eHandgrip strength was measured twice on each side using a digital dynamometer according to a standard protocol [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Maximal isometric voluntary contractions of the hands for 3 s each were collected, and the highest value was used in the analyses.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e・Calf Circumference\u003c/strong\u003e\u003cp\u003eThe recommended protocol for Calf Circumference measures the maximum value of both calves using a nonelastic tape [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], which has moderate-to-high sensitivity and specificity in predicting sarcopenia or low skeletal muscle mass.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e・One leg standing time(OLST)\u003c/strong\u003e\u003cp\u003eThe patients were required to stand on one leg for up to 60s with the hands placed on the hips and the eyes open. A digital stopwatch was used to determine OLST and was stopped if the patients made contact with any part of the room with any part of the body other than the supporting foot, began to hop around, or moved their hand off the hip [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e・Physical performance\u003c/strong\u003e\u003cp\u003eGait speed, 5-time chair stands, and short physical performance battery (SPPB) are used in this study to assess physical performance. To test gait speed, was the time taken to walk 4 m at a normal pace from a moving start without deceleration [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], taking the average result of 2 trials. Velocity is converted to meters per second. Patients with a gait speed of \u0026lt;\u0026thinsp;1.0 m/s were identified as low physical performance [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. To test the ability to rise from a chair, patients are asked to fold their arms across their chest and to stand up once from a chair. If successful, they will be asked to stand up and sit down five times as quickly as possible and will be timed from the initial sitting position to the final standing position at the end of the fifth stand. A chair-stand time of 12s is used as the cut-off points for low physical performance [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The SPPB, which consists of 3 components, gait speed, repeated chair stands, and standing balance, will be measured according to established methods [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The SPPB score ranged from 0 to 12 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e・໿The means of transportation to the dialysis facility\u003c/b\u003e: The three tiers are classified as: dependent on others (e.g., taxis and shuttles), independent but not requiring physical activity (e.g., driving one's own car), and independent and requiring physical activity (e.g., public transportation, walking) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e・Level of care required in Japan's long-term care insurance\u003c/strong\u003e\u003cp\u003eJapanese long-term care insurance categories of independence, support 1, support 2, long-term care 1, long-term care 2, long-term care 3, long-term care 4, or long-term care 5 will be surveyed.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e・Nutritional support\u003c/strong\u003e\u003cp\u003eWe ask whether nutritional supplements or infusions were prescribed during or after dialysis, in addition to regular meals.\u003c/p\u003e\u003c/p\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics will be presented for all patients and for the exercise and non-exercise groups. Data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range [IQR]) for continuous variables and numbers (%) for categorical variables. Group differences were assessed using Student's t-test or Wilcoxon Rank-Sum test for continuous variables and the chi-square test (or Fisher\u0026rsquo;s exact test) for categorical variables. Time-to-event analysis of death and hospitalization between the exercise and non-exercise groups during the observation period will be performed using the log-rank test, and the adjusted hazard ratio (aHR) will be calculated by Cox regression hazard model adjusted by prespecified confounders. As a subgroup analysis, comparisons will be made between patients who did or did not receive the additional reimbursement for exercise instruction during dialysis after April 2022, as well as between those who did or did not undergo renal rehabilitation. Outcomes will be evaluated at 90 days post-reimbursement, at each measurement point, and at the time of reimbursement approval. Furthermore, surrogate markers including changes in serum albumin and creatinine levels from baseline will also be analyzed using mixed-effects models or change rates to assess group differences. In addition, surrogate markers such as changes in serum albumin and creatinine levels from baseline at the start of the study will be analyzed. Between-group comparisons will be conducted using either the percentage change or a mixed-effects model. Since the implementation of renal rehabilitation may be influenced by facility size and characteristics, sensitivity analysis will be performed using an instrumental variable approach that incorporates dialysis facility information.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eEthic and Dissemination\u003c/h2\u003e\u003cp\u003e At Tokyo Women's Medical University, a batch review was conducted and approval was obtained from the research ethics committee of the institution to which the principal investigator belongs (Approval No.:2023\u0026ndash;2024). When receiving information from institutions providing existing information, they would make sure that permission had been obtained from the head of each institution and that opt-outs were in place at each institution. The person in charge of such research shall obtain the review and approval of the Conflict-of-Interest Management Committee, as appropriate, in accordance with the provisions of the Conflict-of-Interest management regulations. Conflicts of interest of researchers in joint research institutions shall be appropriately reviewed and managed by the Conflict-of-Interest Management Committee of each institution.\u003c/p\u003e\u003c/div\u003e"},{"header":"Expected Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003cp\u003eThis multicenter retrospective cohort study is anticipated to provide the first large-scale, real-world evidence regarding the impact of exercise therapy during dialysis following the 2022 medical fee reimbursement policy change in Japan. The findings from this research are expected to clarify the association between exercise therapy and the following primary and secondary outcomes, consistent with the study\u0026rsquo;s objectives and methods.\u003c/p\u003e\u003cp\u003e・Anticipated Findings for Primary Outcomes\u003c/p\u003e\u003cp\u003eThe association between the exercise group and the non-exercise group concerning the risk of the primary outcomes, all-cause mortality and hospitalization, will be elucidated through time-to-event analysis.\u003c/p\u003e\u003cp\u003e・Anticipated Findings for Secondary Outcomes\u003c/p\u003e\u003cp\u003eIt is expected that the study will reveal how exercise therapy is associated with patient-oriented outcomes, including physical function (e.g., grip strength, gait speed, SPPB), frailty (Clinical Frailty Scale), nutritional status (e.g., serum albumin and creatinine levels), and activity levels. Specifically, the impact of the insurance reimbursement system for exercise instruction on clinical events and surrogate markers will be examined through subgroup analyses based on the presence or absence of reimbursement claims for exercise instruction.\u003c/p\u003e\u003c/div\u003e"},{"header":"Strengths and Limitations","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003cp\u003eThe study will be the first to examine the effectiveness of insurance reimbursement for exercise during hemodialysis treatment. The classification of the effects and difficulties of additional reimbursement for exercise during dialysis may have a significant impact on the progress of renal rehabilitation for hemodialysis patients. In addition, Japan is the first country in the world not only to published renal rehabilitation guideline based on academic society level and systematic review and metanalysis but also to approve this treatment for reimbursement and may serve as a reference for countries and regions considering adding this coverage in the future. The practicality of this additional reimbursement was investigated by Sofue et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], 13% percent of hemodialysis facilities in Japan provided exercise instruction during hemodialysis treatment, and 65% of these facilities claimed the additional reimbursement. Exercise instruction was generally lower limb resistance training and aerobic exercise or a combination of these, with 66% of facilities focusing on muscle strength to determine effectiveness. No life-threatening adverse events were reported.\u003c/p\u003e\u003cp\u003eIn order to expand exercise for dialysis patients in the future, the certainty of the effects of exercise should be widely investigated. The study design allows us to explore the type of exercise, the duration of exercise, and the duration of exercise over time, as well as which exercise should be performed, how much, and for how long. Furthermore, although this is a retrospective study and missing data may be present, we plan to investigate patient-oriented outcomes, nutritional status, and physical function to the extent possible. In addition, the control group was randomly selected from patients of the same sex, age, and comorbidities as the exercise group to avoid selection bias.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eLimitation\u003c/h2\u003e\u003cp\u003eWe acknowledge several limitations inherent to the design and conduct of the REVEAL-D study. As a retrospective cohort study, we are limited to demonstrating an association between exercise and outcomes; therefore, a definitive causal relationship cannot be established. This design also makes the study susceptible to missing data for certain variables, which is a known challenge. Although a matched representative sample was randomly selected in a 1:2 ratio to the exercise group, the possibility of selection bias cannot be completely excluded. Furthermore, while dialysis prescriptions are guided by standard guidelines, the detailed setting of dialysis treatment may still differ among the 10 medical institutions. Similarly, although exercise is defined as aerobic and resistance exercise, the equipment used and the instruction provided by instructors may differ, potentially affecting the consistency of the intervention. Finally, the physical function is scheduled to be checked only once per year, which may limit our ability to capture short-term or transient effects of the intervention.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics and Consent to Participate declarations:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures in this study were conducted in accordance with the ethical standards of the Ethics Review Committee of Tokyo Women\u0026apos;s Medical University Hospital (IRB No. 2023-0204). This retrospective observational study involved no new interventions or invasive procedures and was conducted based on the \u0026ldquo;Ethical Guidelines for Medical Research Involving Human Subjects\u0026rdquo; established by the Ministry of Health, Labour and Welfare and the regulations of the Tokyo Women\u0026apos;s Medical University Ethics Committee. Participants were provided with the opportunity to refuse participation through opt-out.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe requirement for written informed consent was waived for all participants.\u0026nbsp;An opt-out method was used to obtain consent for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data in this study are available upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors have declared that no conflict of interest exists.\u0026nbsp;However, we disclose that Ichiei Narita, one of the co-authors, is an Editorial Board Member of this journal. The authors confirm that the Editorial Board Member was not involved in the peer-review process of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis work was supported by Japanese Society of Renal Rehabilitation, and JH\u0026rsquo;s grant from JSPS KAKENHI Grant Number JP24K14335.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributors\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKKo, MY, SK, KKi, RM and JH led the design of the study. KKo, MY, SK, KKi, RM, YOt, YOu, TH and JH were involved in the design of the study. KKo drafted the manuscript. MY, KKi, SK, R M, YOt, JH, IN, and KY provided feedback on the manuscript; all authors approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of this study have not been previously published, either in whole or in part\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll clinical data will available from the electronic medical records at Tokyo Women\u0026apos;s Medical University. The data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYamagata K, Hoshino J, Sugiyama H, et al. Clinical practice guideline for renal rehabilitation: systematic reviews and recommendations of exercise therapies in patients with kidney diseases. \u003cem\u003eRen Replace Ther\u003c/em\u003e. 2019;5(1):1\u0026ndash;19. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s41100-019-0209-8\u003c/span\u003e\u003cspan address=\"10.1186/s41100-019-0209-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChan GC kau, Kalantar-zadeh K, Ng JK chung, et al. 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In April 2022, Japan introduced an insurance reimbursement policy for exercise instruction during hemodialysis. However, the clinical effectiveness and broader impact of this policy remain unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aims to evaluate the impact of renal rehabilitation, especially exercise therapy during dialysis, on clinical outcomes, including mortality and hospitalization, in Japanese hemodialysis patients. It also assesses secondary outcomes such as frailty, physical function, and nutritional status.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective cohort study was conducted using data from 10 dialysis facilities across Japan between January 2021 and January 2024. Adult patients receiving outpatient hemodialysis were included. The exercise group received regular intradialytic exercise therapy, while a matched control group did not. Primary outcomes included death and hospitalization. Secondary outcomes included changes in physical function (e.g., grip strength, gait speed), serum albumin/creatinine levels, frailty scores, and care needs. Subgroup analyses were performed based on the presence of reimbursement claims for exercise instruction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpected Results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter study will provide the first large-scale evidence on the real-world impact of exercise therapy during hemodialysis following the 2022 reimbursement policy. It will also explore the association between exercise and improved physical, nutritional, and psychosocial outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe eventual findings from this study may clarify the role of structured exercise programs in dialysis care and have the potential to inform future health policy decisions in Japan and globally. These results could also help guide best practices in renal rehabilitation and optimize patient-oriented outcomes.\u003c/p\u003e","manuscriptTitle":"REgistry of actiVE renAL rehabilitation in Japanese Dialysis patients (Reveal-D): A protocol for retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-28 06:54:07","doi":"10.21203/rs.3.rs-7872177/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e415b5ce-e9c9-43f1-b18b-e8f8c80b6075","owner":[],"postedDate":"November 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T16:07:39+00:00","versionOfRecord":{"articleIdentity":"rs-7872177","link":"https://doi.org/10.1186/s41100-026-00703-5","journal":{"identity":"renal-replacement-therapy","isVorOnly":false,"title":"Renal Replacement Therapy"},"publishedOn":"2026-01-23 15:57:44","publishedOnDateReadable":"January 23rd, 2026"},"versionCreatedAt":"2025-11-28 06:54:07","video":"","vorDoi":"10.1186/s41100-026-00703-5","vorDoiUrl":"https://doi.org/10.1186/s41100-026-00703-5","workflowStages":[]},"version":"v1","identity":"rs-7872177","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7872177","identity":"rs-7872177","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}