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Abstract
Introduction Impaired physical function is relatively common in children/adolescents with chronic kidney disease (CKD), affecting not only patients’ daily lives but also the efficiency of later treatment and rehabilitation. Exercise is a recognised intervention to improve physical function and quality of life in adult patients with CKD. However, implementing this strategy in paediatric/adolescent populations remains relatively limited. For exercise training to be widely delivered as part of paediatric public health policy, a better understanding of the physical function and the impact of exercise interventions in children/adolescents with CKD is needed.
Methods and analysis A systematic review and meta-analysis will be conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to compare physical function in children/adolescents with CKD with healthy controls and the impact of exercise interventions on their outcomes. The systematic review will search the following databases: PubMed, Embase, Scopus and Web of Science. We will use the Risk Of Bias In Non-Randomised Studies-of Interventions and the second edition of the Cochrane Risk of Bias to assess the quality of the literature. Where feasible, we will conduct random effects meta-analyses where appropriate. If possible, we will conduct subgroup analyses to explore potential sources of heterogeneity.
Ethics and dissemination Due to the nature of the protocol, ethical approval is not required. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to disseminate the study results through publication and conference presentations.
PROSPERO registrationnumber CRD42023416208.
- Nephrology
- Rehabilitation
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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What is already known on this topic
Kidney disease can impair physical functioning in children/adolescents, affecting their daily life and the outcome of later treatments. Exercise is an effective non-pharmacological therapy to improve physical function. However, programmes to implement exercise interventions in children/adolescents populations are still limited.
What this study hopes to add
This systematic review and meta-analysis will quantify the extent of physical functioning in children/adolescents with chronic kidney disease (CKD) relative to matched healthy controls.
This study will cover various exercise types to assess the evidence-based outcomes of this non-pharmacological therapy for physical function in children/adolescents with CKD.
The level of evidence may be limited by the number of studies available and some studies may be at high risk of bias.
How this study might affect research, practice or policy
This systematic review and meta-analysis will further clarify the therapeutic role of exercise interventions on physical functioning in children/adolescents with CKD to guide clinical practice.
Introduction
Chronic kidney disease (CKD) is a major health problem that affects approximately 9.5% of adults worldwide.1 Although the prevalence of CKD in children/adolescents ranges from 3.0 to 17.5 cases per million,2 CKD in this population is associated with an increased risk of poor growth, cardiovascular disease and mortality, imposing a significant psychological and social burden on the child’s family.3 4
Physical function is intrinsic to maintaining children/adolescents’ learning activities and daily life and is a dimension of health-related quality of life assessment.5 However, the effects of kidney disease often result in children/adolescents having functional limitations and suffering activity-related injuries. Improving impaired physical function and preventing its decline is a crucial goal for maintaining the health and well-being of a wide range of adult patients with CKD and applies to the children/adolescent population.6
Increasing evidence suggests that exercise interventions are strongly associated with improvements in physical function and health-related quality of life in adult patients with CKD.7 In recent years, exercise-based non-pharmacological therapies have also been gradually extended to the children/adolescent CKD population to improve their prognosis.6 However, there is insufficient evidence for exercise interventions as the preferred strategy to improve physical function in children/adolescents with CKD. Therefore, the objectives of this systematic review and meta-analysis study included (1) to conduct a meta-analysis to systematically compare physical function between paediatric/adolescent patients with CKD and healthy controls and (2) to assess the role of exercise training on physical function in children/adolescents patients with CKD.
Methods
This systematic review protocol adheres to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P)8 (online supplemental table S1). The results of this systematic review and meta-analysis will be reported following the PRISMA 2020 statement.9 This systematic review protocol was registered with PROSPERO (registration number: CRD42023416208).
Supplemental material
Patient and public involvement
Patients and/or the public were not involved in this research’s design, conduct, reporting or dissemination plans.
Information sources and search strategy
Potentially eligible studies will be searched through the following scientific literature databases: PubMed, Embase, Scopus and Web of Science. The search strategy was proposed by the literature searcher after extensive reading of systematic reviews and articles on the topic and then refined with discussion by the third author. We used a combination of medical subject terms and keywords related to CKD, physical function and Boolean logic operators to develop a complete search strategy and slightly adapted the search syntax to the characteristics of each database. The search strategies for each database are shown in table 1 and online supplemental table S2. In addition, we will also manually search for records in the reference lists of previous systematic reviews. Literature downloaded from the databases will be imported into EndNote V.20 software for management. An updated search will be conducted 2 months before the publication of the review or before the final analysis to ensure that any relevant studies are included to the extent possible.
Search detail for PubMed database
Eligibility criteria
The inclusion criteria are specified according to Population (P), Intervention (I), Comparator (C) and Outcomes (O) (table 2). Exclusion criteria: (1) Patients affected by acute kidney failure. (2) Reviews, case reports, book chapters, conference abstracts, methodological papers, editorials, opinion papers, qualitative studies, research protocols and animal studies.
Eligibility criteria for the systematic review
Study selection
Two authors will independently review the literature for eligibility, and any conflicts will be determined through discussion. A third author will resolve the issue when a consensus cannot be reached. Reasons for exclusion will be documented and summarised in a PRISMA flow chart (figure 1).
Flow chart of literature screening.
Screening of eligible documents
The retrieved literature will be screened in EndNote V.20. First, we will use the find duplicates feature to remove duplicates. Duplicates that EndNote cannot identify will be manually screened. In the title/abstract filter, we will first use the search function to exclude irrelevant publication types. Documents with titles such as ‘case report’, ‘review’, ‘meta’, ‘letter’ and ‘guide’ will be excluded. Titles and abstracts will then be reviewed.
Records that cannot be determined to be relevant at the title/abstract screening stage will be eligible by reviewing the full text. A detailed list of excluded studies will be recorded in a table with reasons for exclusion (online supplemental table S3). The authors will be contacted to obtain the full text for records for which full text is unavailable. If it is still elusive, the paper will not be included in the meta-analysis, but the qualitative analysis will be performed.
We will identify a study by design, population and author affiliation if it is reported in multiple articles. When different original research datasets are reported in multiple articles, we will select the paper with the largest sample size reported. Disagreements between the two authors during the selection process will be resolved through discussion. If the discussion does not result in a consensus choice, a third reviewer will be involved and make the final decision.
Data extraction
Based on the predesigned information extraction table, the study feature information and the result data will be extracted by two authors independently. The information we will extract is shown in table 3. Any discrepancies will be resolved through discussion.
Data extraction elements
When the physical function was measured more than twice, baseline and final follow-up outcomes will be extracted. In studies comparing a particular intervention with usual care, when more than one intervention group of the same type was reported for a study (eg, resistance training vs aerobic exercise vs control), these intervention groups will be combined to avoid double counting the control group. If we encounter a study that presents results in the figure, we will use GetData software to extract the mean and SD.
To ensure correct and complete data extraction, we conducted a pilot extraction for five eligible studies (online supplemental tables S4 and S5), and the table will be subsequently revised as needed.
Quality assessment
The randomised controlled trials will be assessed by the Cochrane Collaborations’ second version of the risk of bias tool for randomised trials10 using the Excel macro tool (https://www.riskofbias.info/welcome). Quasi-experiment and single-arm trials were assessed using the Risk Of Bias In the Non-Randomised Studies-of Interventions tool.11
Handing missing data
For missing data that cannot be obtained from the text, we will contact the corresponding author, and if we do not hear back within 1 month, we will consider the contact a failure. Without a response, we will calculate effect estimates using the available data as described in the Cochrane Handbook,12 where possible. In the case of studies reporting data format of (1) median, first and third quartiles or minimum, and maximum; (2) mean, 95% CI; (3) median with IQR or median±SD and (4) mean, SE, we will use the following corresponding reference equations to estimate the mean and SD.
(1) Mean±SD will be estimated using the method of Luo et al13 and Wan et al.14 Calculation results are available on the web
(https://www.math.hkbu.edu.hk/%7Etongt/papers/median2mean.html).
(2) The formula A and B recommended by the Cochrane Handbook12 will be used to calculate the mean±SD.
Formula A (sample size of each group ≥100):
Formula B (sample size of each group <60):
(3) Mean±SD will be estimated by the method of Hozo et al.15 For studies with samples >25 per group, the mean was equal to the median, and the SD was calculated as IQR/4.
(4) SD=SE error ×√n.
Data analysis
Data synthesis
When data from at least two trials are available, we will perform a meta-analysis. Statistical analyses are based on the meta16 package and metafor17 package of R software (V.4.2.0). For each outcome, postintervention means±SD will be extracted, assessed with restricted estimation maximum likelihood for pool analysis, and express as weighted mean differences or standardised mean differences. Statistical heterogeneity between studies will be assessed with I2, a value greater than 50% will be considered to indicate substantial heterogeneity,18 in which case a random effects model will be used, and otherwise, a fixed effects model. In the analysis, a p<0.05 will be considered statistically significant.
Subgroup analysis
When enough studies are available, subgroup analysis will be used to explore potential sources of heterogeneity. Interventions and disease stages will be considered as possible sources of heterogeneity. We will investigate whether the effects of exercise interventions on physical function in children/adolescents with CKD are altered y (1) age (children, adolescents), (2) duration of exercise, (3) exercise type and (4) stage of disease (predialysis, peritoneal dialysis, haemodialysis and kidney transplant recipients). The results of the subgroup analysis will be presented in online supplemental table S6.
Publication bias
If at least 10 studies are included, we will assess publication bias by creating contour-enhanced funnel plots19 and Egger’s test.
Sensitivity analysis
We will perform a sensitivity analysis based on leaving one out, omitting each study consecutively, to explore its impact on the overall results.
Qualitative analysis
We will perform a narrative analysis to present the results for articles that meet the eligibility criteria set by this systematic review and meta-analysis, but for which meta-analysis is not possible (eg, incomplete data).
Grading of evidence assessment
We will assess the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology to determine the certainty of the evidence for the following five domains20:
Risk of bias: We will reduce the certainty of evidence if a sensitivity analysis shows significant differences between studies with low, medium or high bias.
Indirectness: If the research questions in the included studies are consistent with the PICO questions, the evidence level will not be downgraded.
Inconsistency: Unexplained heterogeneity will be a reason for downgrading, that is, I2 greater than 50%.
Imprecision: Whether the CI corresponding to the effect estimate is narrow enough.
Publication bias: If publication bias is found by funnel plot or Egger’s test, we will downgrade the evidence level of the domain.
The certainty of evidence will be rated as high, medium, low and very low by the GRADE tool. High means that further research is unlikely to change confidence in effect estimates; medium implies that further research is likely to have a significant impact on confidence in effect estimates; low means that further research is very likely to have an impact on confidence in effect estimates; and very low means that estimates of effects are very uncertain. The evidence summary table is provided in online supplemental table S7.
Discussion
In adults with CKD, low physical function, such as low cardiorespiratory fitness and handgrip strength, is associated with various adverse health outcomes and is a widely recognised independent predictor of all-cause mortality risk.21–24 In children and adolescents with CKD, the increased cardiovascular risk due to kidney disease, muscle atrophy/exhaustion after dialysis initiation and excessive weight gain observed after transplantation suggest that the healthcare team needs to work to optimise physical function by providing education, counselling and regular encouragement to participate in exercise interventions regularly.
Although some studies have shown a positive effect of exercise interventions on physical function improvement in children/adolescents with CKD, these studies have limited sample sizes and are not sufficiently representative. The results of this systematic review and meta-analysis will provide a scientific basis for managing exercise rehabilitation in children/adolescents with CKD. As data integration progresses, bias and significant heterogeneity may occur; therefore, subgroup and sensitivity analyses will be conducted as appropriate to explore the sources of heterogeneity as much as possible and ensure the results’ reliability.
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
Ethics statements
Patient consent for publication
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors QS and LH contributed to the study protocol design and refinement. FZ developed the search strategy. FZ and HW conducted a review of the literature for this research topic. FZ wrote the first draft, which was revised by HZ and QS. All authors read and approved the final manuscript.
Funding This study is supported by Longhua Hospital Shanghai University of Traditional Chinese Medicine (YW.006.032), Budgeted projects in Shanghai University of Traditional Chinese Medicine (2021WK118), 2022 Talent Development Continuing Education (RSC2301), and Shanghai Modern Nursing Vocational Education Group Special Adjunct Faculty Program (hlzjtpgr202327).
Competing interests No, there are no competing interests.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.