Dear Dr. Gimena Muñoz,

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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Academic Editor

PLOS ONE

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I decide for a minor revision so you can update a revised version of your paper and abstract with all the needed section.

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Thank you for your work.

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Reviewers' comments:

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Dear Dr.  Gimena Muñoz,

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.

Please submit your revised manuscript by Jul 06 2025 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,

Daniele Romanello

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Partly

Reviewer #2: (No Response)

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: (No Response)

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: (No Response)

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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Reviewer #1: The true novelty of your study is the possible role of microvesicles, but you haven’t emphasized that in either your Results or Discussion. As evidenced by your review of the existing literature, frailty among patients with CKD has a well-established body of evidence, but that’s what you emphasize in both your Results and Discussion. I recommend that you refocus your report and emphasize your findings regarding microvesicles. Otherwise, your study doesn’t tell us anything that we don’t already know.

Abstract

The results you report here aren’t new except for the association between CMVs and frailty and that’s buried at the end of your results. The median followup isn’t really the point of your study. Report the data from the predictive model (Table 5). That’s far more meaningful than risk factors for frailty that was widely reported.

Introduction

Line 101-102 – Being “highly prevalent” isn’t very meaningful. Report the prevalence and cite your source. For example, you cite a meta-analysis of prevalence by Veronese et al. in your Discussion. What was the prevalence they reported?

Line 108 – The prevalence of frailty in ESRD is important but your focus is CKD. They’re not interchangeable. Can you report the prevalence in CKD as well, if only to provide a baseline for comparison with your own findings? Since your aim is to “analyze frailty” baseline data help readers contextualize your purpose.

Methods

Line 146 – Can you please clarify what you mean by “conservative treatment?” Since it’s an exclusion criteria, readers should have a clear definition.

Lines 150-151 – Please clarify how you measured “3 or more days of asthenia per week?”

Results

Because mortality and dialysis were your end-points, please report the number of patients for each outcome.

Lines 200-202 – Table 1 is not set up to support your statement regarding the prevalence of frailty in patients with type 2 DM and CVD. Table 1 compares frail and non-frail patients, not patients with or without type 2 DM and CVD.

Lines 220-222 –You report using age, T2DM, hemoglobin and total cMVs for the regression model but haven’t reported any differences in cMVs. To justify using total cMVs, it would be helpful to readers for you report differences between frail and non-frail patients before you describe this analysis.

Lines 242-244 – How were the variables for the hazard models chosen? Phosphorus wasn’t significant in the univariate or multivariate models.

Lines 244-245 – You allude to mortality and dialysis here but haven’t reported the actual numbers. Mortality and dialysis data should be reported.

Line 275 – The correlations you report are statistically significant but cannot be described as “strong.” Please see statistical references such as:

Schober P, Boer C, Schwarte LA. Correlation Coefficients: Appropriate Use and Interpretation. Anesth Analg. 2018;126(5):1763-1768.

https://doi.org/10.1213/ANE.0000000000002864

Line 286 – This is a minor point but I believe you have a comma instead of a decimal point for the Nagelkerke square value.

Discussion

You haven’t made good use of your Discussion to highlight the novelty and contribution of your study. Focus on cMVs rather than well known outcomes such as prevalence and risk factors. For example, you discuss phosphorous at length but that wasn’t significant in either the univariate or multivariate model. It doesn’t contribute to the purpose of your study. Tell readers why your findings regarding cMVs are significant. What do they contribute to what we know about frailty?

Line 340 – The correlations you found were statistically significant but they were not “strong.”

Reviewer #2: 1) What exactly is the author's main purpose? To assess the prevalence of frailty in advanced CKD? Or the association between time to dialysis initiation and death?

2) Were the inclusion criteria simply age >18 and eGFR <20? frailty is extremely prevalent in the elderly population, and did the authors consider subgroup comparisons of older and middle-aged patients?

3) Statistical analysis, I would suggest the authors to describe in further detail, especially cox regression, as well as exploring the role of microvesicles

4) Tables 1 and 2 could be combined

5) Table 4 could be considered for replacement with Figure

6) Didn't the article use cox regression? Why do the authors mention in the limitation that “Also, the analysis using estimative binary logistic regression models can be adjusted for a limited number of predictor variables. ”

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes:  Fan Zhang

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

Assessment of Frailty in patients with advanced chronic kidney disease, and the role of Microvesicles: A Single-Center Study

PONE-D-24-44013R2

Dear Dr. Gimena Muñoz,

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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Kind regards,

Miquel Vall-llosera Camps

Senior Staff Editor

PLOS One

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: (No Response)

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: (No Response)

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: (No Response)

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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Reviewer #1: Thank you for your detailed responses to my questions and comments. Your revisions are both thoughtful and effective, and as a result your manuscript now highlights the true novelty of your findings. In particular, the 41% variability in frailty explained by the three variables is impressive. There are just two points in the revised wording that I believe merit your further consideration.

Methods (line 156) – The structured questionnaire used for assessment of asthenia is intriguing. Weakness in frailty is typically assessed through objective measures such as hand grip strength. A self-report questionnaire would likely be of interest to readers. If the questionnaire you used has been previously reported or perhaps validated, you might cite those studies for interested readers.

Discussion (line 320-322) – The wording of this sentence is somewhat confusing. I think it’s just an English translation issue. Table 1 compares age by frailty status (frail vs. non-frail). It doesn’t compare frailty by age. The comparator (the “by XX” characteristic) is represented by the grouping along the X-axis, which in this case is frailty status.

Reviewer #2: The author has well explained and corrected the doubts raised by the reviewers. However, it is hoped that in future work, the sample size can be expanded and more stable statistical analysis methods can be adopted

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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: Yes:  Melissa J. Benton, PhD, RN, FACSM, FGSA

Reviewer #2: No

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