Dear Dr. Niroshika,

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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We look forward to receiving your revised manuscript.

Kind regards,

Jie Yang, M.D.

Guest Editor

PLOS One

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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?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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??>

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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.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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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.

Reviewer #1: Thank you for raising this search to identify potential new culprits implicated in CKD progression an identify gaps in knowledge.

Reviewer #2: This protocol outlines a scoping review based on the Arksey & O’Malley and JBI frameworks to systematically map the evidence on the role of TRAIL (TNFSF10) and its receptors (DR4, DR5, DcR1, DcR2, OPG) in chronic kidney disease (CKD). The authors plan to include human, animal, and in vitro studies, focusing on TRAIL expression, regulatory mechanisms, and associations with disease progression and clinical outcomes.

If executed rigorously, this scoping review can serve as a critical foundation for future prognostic or interventional studies, making its clinical potential meaningful.

[Major Concerns (Required Revisions)]

/Database coverage is incomplete.

EMBASE and Web of Science should be added, as they capture much of the biomedical and pharmacological literature.

Clinical trial registries (ClinicalTrials.gov, WHO ICTRP) and preprint servers (medRxiv, bioRxiv) should also be considered.

/Incomplete search strategy reporting.

The manuscript provides only partial search terms.

A full Boolean search string for each database (including synonyms such as TNFSF10, APO2L, CD253) should be added as a Supplementary File.

/Language bias.

Restricting to English-only publications may exclude relevant non-English epidemiologic or regional studies. Consider including papers with English abstracts or at least acknowledging this limitation explicitly.

/Clarify the purpose of MMAT quality assessment.

Scoping reviews typically do not exclude studies based on quality. Please clarify whether MMAT will be used descriptively (to summarize evidence quality) rather than for exclusion.

/Timeline inconsistency.

The text states “articles published up to July 2025” but does not specify the actual search date.Indicate the exact date of the search (e.g., Search conducted on August 31, 2025).

/Outcome definition unclear.

“Clinical outcomes” should be better defined (e.g., mortality, dialysis initiation, eGFR decline rate, cardiovascular events). Separate primary and secondary outcomes where possible.

/Assay variability not addressed.

Measurement of soluble TRAIL is highly method-dependent (different ELISA kits, storage conditions).Include assay type and sample source (plasma vs tissue) as data extraction items.

This is a well-structured and potentially impactful protocol.

By improving transparency in your search and data extraction methods, and by clearly defining how findings could inform biomarker or therapeutic development, your review will provide genuine value to both nephrology and translational immunology communities.

Reviewer #3: The manuscript is well-structured, clearly written, and methodologically sound. The authors have followed established frameworks (Arksey & O’Malley, JBI) and adhered to reporting guidelines (PRISMA-ScR), and the protocol is appropriately registered. The topic is relevant and addresses a notable gap in synthesizing the role of TRAIL in CKD.

Key Questions and Comments:

1. The PCC framework includes “all human studies, animal models, cell lines, and computational models.” Given the breadth of study types, how will the authors ensure a meaningful synthesis across such heterogeneous data? Will separate analyses or subgroup summaries be provided?

2. Table 2 is detailed and appropriate. However, it may be beneficial to add a field for “type of CKD stage” (e.g., CKD stages 1-5, ESRD) under “Population characteristics” to facilitate staging-related analysis. Additionally, the authors mention thematic analysis for qualitative data. Will a specific framework (e.g., Braun & Clarke) be used? If so, please specify.

3. The mixed-method appraisal tool (MMAT 2018) has been selected for quality appraisal, but the protocol states that “no studies will be excluded solely based on low scores.” How will low-quality studies (e.g., those with an MMAT score <50%) be handled in the synthesis? Will they be flagged, or will their findings be weighted differently to avoid misleading conclusions?

4. In the Introduction, the authors state: “Chronic kidney disease (CKD) is defined as kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m² for 3 months or more… affecting more than 700 million people worldwide.” The KDIGO 2021 update—which revises CKD staging and prevalence estimates—has not been cited. This outdated definition weakens the background. The protocol should reference the latest KDIGO guidelines (e.g., 2021 or 2024) for the definition of CKD.

5. Please include a concept summary figure or graphical abstract to explain the entire implementation plan.

Minor Corrections & Suggestions:

• Abstract line 37: Rephrase “Google Scholar reference lists of review articles as grey literature sources” for clarity. Suggested revision: “Reference lists of relevant reviews retrieved from Google Scholar will also be screened for grey literature.”

• Line 47-48: The definition of CKD is from 2005. Please consider citing more recent KDIGO guidelines (e.g., the 2024 update).

• Line 183-190 (Synthesis methods): Consider clarifying whether a meta-analysis is possible or if a narrative synthesis alone will be used.

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..-->

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

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Mapping the role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors in chronic kidney disease- a scoping review protocol

PONE-D-25-42046R1

Dear Dr. Niroshika,

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,

Jie Yang, M.D.

Guest Editor

PLOS One

Additional Editor Comments (optional):

Thanks for the authors' efforts to comprehensively improve your manuscript according to editor's and reviewers' comments. I am pleased to inform you that your paper can be accepted for publication now.

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?

Reviewer #2: Yes

Reviewer #3: 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??>

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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.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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

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.

Reviewer #2: The authors have addressed all of my previous concerns thoroughly and sincerely. The additional data provided have significantly strengthened the manuscript. I am now satisfied with the quality of the work and believe it meets the standards for publication.

Reviewer #3: After revision, this manuscript meets the requirements for publication in the journal and is approved for publication.

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..-->

Reviewer #2: No

Reviewer #3: No

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