-->PONE-D-25-55536-->-->The effectiveness of pharmacological and non-pharmacological interventions for fatigue in people living with chronic kidney disease: A protocol for a systematic review.-->-->PLOS One

Dear Dr. Young,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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The protocol is well written and the research question relevant but I agree with the two reviewers that the populations of interest are many despite they are all under CKD. I recommend avoiding the outcome inclusion within the search of keywords in order not to miss papers. Please provide a point-by-point response to both reviewers.

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Please submit your revised manuscript by Apr 16 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Mabel Aoun, MD, MPH

Academic Editor

PLOS One

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-->1. When submitting your revision, we need you to address these additional requirements.-->--> -->-->Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at -->-->https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and -->-->https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf-->--> -->-->2. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" OR If no pilot data are reported in the manuscript, “No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion” as your Data Availability Statement.-->--> -->-->3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.-->--> -->-->4. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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Reviewers' comments:

Reviewer's Responses to Questions-->

-->Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.-->

Reviewer #1: Yes

Reviewer #2: Yes

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-->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #1: Partly

Reviewer #2: Partly

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-->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #1: No

Reviewer #2: No

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-->4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: No

Reviewer #2: Yes

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-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

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-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: I read with great interest the protocol of the systematic review and meta-analysis (SRMA) evaluating the effectiveness of pharmacological and non-pharmacological interventions for fatigue in people living with chronic kidney disease (CKD).

The scope of this project is very broad and heterogeneous. The authors plan to assess all interventions targeting fatigue across all stages of CKD (eGFR < 60 mL/min/1.73 m²), including randomized controlled trials, non-randomized trials, and prospective studies, and additionally to conduct a qualitative systematic review of patient perspectives. While this ambition is commendable, the research question may be too wide and complex to address adequately within a single SRMA. A more focused scope—or clearer justification for combining such diverse interventions, populations, and study designs—would strengthen the protocol.

In addition, the introduction is overly long and would benefit from substantial condensation. It should be shortened to approximately one to one and a half pages, focusing more concisely on the rationale, existing gaps in the literature, and the specific objectives of the review.

I have two further comments:

1. Search strategy: The authors did not provide a sufficiently detailed description of the keywords and search terms that will be used. Including the full search strategy for at least one database would improve transparency and reproducibility.

2. Timeline inconsistency: The protocol was registered on PROSPERO in September 2025, yet the authors state that results will be available in July 2025. This appears to be a chronological error and should be clarified.

Reviewer #2: This protocol addresses an important and clinically relevant topic: the management of fatigue in individuals living with chronic kidney disease (CKD).

The proposed review is ambitious in scope, encompassing pharmacological and non-pharmacological interventions across the full CKD spectrum and integrating both quantitative and qualitative evidence. The protocol is generally well structured, registered in PROSPERO, and reports adherence to PRISMA-P guidance.

However, several methodological issues require clarification and refinement to ensure internal validity, feasibility, and interpretability of the planned analyses.

I recommend major revision prior to consideration for publication.

1. Clinical Heterogeneity

Multiple patient eligibility criteria (all CKD stages, HD, PD, transplanted patients…) and both pharmacological and non-pharmacological interventions are eligible, across multiple study designs (RCTs, non-randomised studies, before-after studies, qualitative studies).

The feasibility of synthesising such diverse populations and interventions is uncertain.

The protocol should:

- Provide a clearer justification of the transitivity assumption underpinning the proposed NMA.

- Clarify whether analyses will be stratified a priori by CKD population (e.g., dialysis vs non-dialysis vs transplant).

- Define conditions under which NMA would be deemed inappropriate due to heterogeneity.

2. Definition and Measurement of Fatigue

The protocol adopts a broad definition of fatigue. While this enhances inclusivity, it raises conceptual and statistical concerns: fatigue-specific instruments are not equivalent to fatigue subscales and different instruments may measure distinct fatigue dimensions.

The authors should:

- Define a hierarchy of outcome measures (e.g., fatigue-specific validated instruments as primary).

- Pre-specify how multidimensional fatigue instruments will be handled.

- Consider sensitivity analyses by instrument type.

3. Network Meta-Analysis: Feasibility and Assumptions

The planned NMA includes potentially diverse interventions

The protocol should clarify:

- Whether a frequentist or Bayesian NMA framework will be used.

- How multi-arm trials will be handled.

- How combination interventions will be classified.

4. Chronological Inconsistency

The protocol states that « Searches were conducted in July 2025. Screening anticipated completion in January 2025. Results expected July 2025. »

This timeline is internally inconsistent and must be corrected.

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Reviewer #1: No

Reviewer #2: No

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The effectiveness of pharmacological and non-pharmacological interventions for fatigue in people living with chronic kidney disease: A protocol for a systematic review.

PONE-D-25-55536R1

Dear Dr. Young,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Mabel Aoun, MD, MPH

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Thank you for addressing all the comments. The manuscript has improved and is now clearer for readers.

Reviewer #2: Thank you to the authors who responded to all the comments.

I think that the protocol is now ready to be published.

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-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

Reviewer #2: Yes: Ahmad MROUE

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