Dear Dr. Ribeiro,

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.

==============================

ACADEMIC EDITOR: 

Dear Dr. Ribeiro,

as you will read below, I agree with Reviewer 1 on two major concerns that I believe should be addressed to strengthen the manuscript. First, quadriceps ultrasound, considered a reliable method for assessing muscle mass, was available but not used to define confirmed sarcopenia, whereas calf circumference has known limitations. Second, creatinine-based eGFR likely overestimates kidney function in sarcopenic patients, which may lead to an underestimation of CKD prevalence and severity. This issue should be discussed more explicitly.

Please submit your revised manuscript by  Oct 25 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,

Diego Moriconi

Academic Editor

PLOS ONE

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“This study receives funding from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grant 22/01769-5) and from Instituto Todos pela Saúde (ITpS; grant C1721). EAB receives a research grant (Bolsa de Produtividade em Pesquisa, 304743/2017-8) from The National Council for Scientific and Technological Development (CNPq). HSR receives a postdoctoral scholarship from FAPESP (24/04564-0).”

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Additional Editor Comments:

Reviewer #1:

The study by Ribeiro et al. is a single-center cross-sectional study that aimed to assess the relationship between muscle mass and function parameters and kidney health in 743 survivors of the first wave of COVID-19.

While there are published data on muscle-kidney cross-talk, there are no data on this topic in the context of COVID-19, which makes this study original.

My questions and comments are as follows:

- The revised European consensus on the definition and diagnosis of sarcopenia (ref 21) states that ”Although anthropometry is sometimes used to reflect nutritional status in older adults, it is not a good measure of muscle mass [78]. Calf circumference has been shown to predict performance and survival in older people (cut-off point <31 cm) [79]. As such, calf circumference measures may be used as a diagnostic proxy for older adults in settings where no other muscle mass diagnostic methods are available.” There is therefore some uncertainty about the reliability of this method for measuring muscle mass. Since the patients in the study had their quadriceps muscle thickness measured by ultrasound (a method considered reliable for measuring muscle mass), why was the definition of confirmed sarcopenia not based on this ultrasound method?

- The decrease in muscle strength and function may also be due to a change in muscle quality, in addition to muscle quantity (see, for example, 10.1093/ndt/gfy139). Were muscle quality parameters also measured during the quadriceps ultrasound?

- None of the patients in the study had severe sarcopenia. Could this be explained by the following exclusion criterion? “insufficient physical mobility to leave home during follow-up assessments”

- In the results section, on page 10, regarding the following sentence “Table 1 shows that patients with sarcopenia were older (52% vs. 40%; p = 0.002)”, it should be explicitly specified that this refers to patients over the age of 60.

- In the results section, on page 11, regarding the following sentence “Hospital admission and clinical characteristics based on sarcopenia status are described in Supplementary Table S3”, It would be useful to specify in the manuscript that at the time of hospitalization for COVID-19 infection, there was no significant difference in eGFR, and that at discharge from the hospital, the GFR of patients with sarcopenia already tended to be lower (0.051).

- The following statement on page 13 of the discussion is incorrect “The reduction in muscle mass frequently observed in critical illnesses, like COVID-19, may compromise the reliability of sCr as a primary kidney function marker. However, in our cohort, survivors 284 were assessed 7±2 months after hospital discharge, a period when sCr levels are expected to have reached a steady state, making it a more reliable marker of kidney function than during the acute phase of the critical illness”. At a steady state, if a patient has decreased muscle mass, creatinine will be abnormally low relative to the true GFR, and therefore the creatinine-based estimated GFR will overestimate the GFR.

- It is therefore likely that the prevalence and severity of CKD in the group of patients with sarcopenia is underestimated. This should probably be discussed more explicitly.

- The following two studies could deserve to be cited and briefly discussed in the introduction and/or discussion section:

* Cho et al, Associations of MRI-derived kidney volume, kidney function, body composition and physical performance in ≈38 000 UK Biobank participants: a population-based observational study. Clin Kidney J. 2024 Mar 15;17(4):sfae068. doi: 10.1093/ckj/sfae068.

* Tanaka et al, Trunk muscle quality and quantity are associated with renal volume in nondiabetic people. Clin Kidney J. 2023 Aug 25;16(12):2597-2604. doi: 10.1093/ckj/sfad202. PMID: 38046018; PMCID: PMC10689130.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

The PLOS Data policy

Reviewer #1: No

**********

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

Reviewer #1: Yes

**********

Reviewer #1: The study by Ribeiro et al. is a single-center cross-sectional study that aimed to assess the relationship between muscle mass and function parameters and kidney health in 743 survivors of the first wave of COVID-19.

While there are published data on muscle-kidney cross-talk, there are no data on this topic in the context of COVID-19, which makes this study original.

My questions and comments are as follows:

- The revised European consensus on the definition and diagnosis of sarcopenia (ref 21) states that ”Although anthropometry is sometimes used to reflect nutritional status in older adults, it is not a good measure of muscle mass [78]. Calf circumference has been shown to predict performance and survival in older people (cut-off point <31 cm) [79]. As such, calf circumference measures may be used as a diagnostic proxy for older adults in settings where no other muscle mass diagnostic methods are available.” There is therefore some uncertainty about the reliability of this method for measuring muscle mass. Since the patients in the study had their quadriceps muscle thickness measured by ultrasound (a method considered reliable for measuring muscle mass), why was the definition of confirmed sarcopenia not based on this ultrasound method?

- The decrease in muscle strength and function may also be due to a change in muscle quality, in addition to muscle quantity (see, for example, 10.1093/ndt/gfy139). Were muscle quality parameters also measured during the quadriceps ultrasound?

- None of the patients in the study had severe sarcopenia. Could this be explained by the following exclusion criterion? “insufficient physical mobility to leave home during follow-up assessments”

- In the results section, on page 10, regarding the following sentence “Table 1 shows that patients with sarcopenia were older (52% vs. 40%; p = 0.002)”, it should be explicitly specified that this refers to patients over the age of 60.

- In the results section, on page 11, regarding the following sentence “Hospital admission and clinical characteristics based on sarcopenia status are described in Supplementary Table S3”, It would be useful to specify in the manuscript that at the time of hospitalization for COVID-19 infection, there was no significant difference in eGFR, and that at discharge from the hospital, the GFR of patients with sarcopenia already tended to be lower (0.051).

- The following statement on page 13 of the discussion is incorrect “The reduction in muscle mass frequently observed in critical illnesses, like COVID-19, may compromise the reliability of sCr as a primary kidney function marker. However, in our cohort, survivors 284 were assessed 7±2 months after hospital discharge, a period when sCr levels are expected to have reached a steady state, making it a more reliable marker of kidney function than during the acute phase of the critical illness”. At a steady state, if a patient has decreased muscle mass, creatinine will be abnormally low relative to the true GFR, and therefore the creatinine-based estimated GFR will overestimate the GFR.

- It is therefore likely that the prevalence and severity of CKD in the group of patients with sarcopenia is underestimated. This should probably be discussed more explicitly.

- The following two studies could deserve to be cited and briefly discussed in the introduction and/or discussion section:

* Cho et al, Associations of MRI-derived kidney volume, kidney function, body composition and physical performance in ≈38 000 UK Biobank participants: a population-based observational study. Clin Kidney J. 2024 Mar 15;17(4):sfae068. doi: 10.1093/ckj/sfae068.

* Tanaka et al, Trunk muscle quality and quantity are associated with renal volume in nondiabetic people. Clin Kidney J. 2023 Aug 25;16(12):2597-2604. doi: 10.1093/ckj/sfad202. PMID: 38046018; PMCID: PMC10689130.

**********

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Reviewer #1: Yes:  Thomas Stehlé

**********

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Dear Dr. Ribeiro,

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 Jan 08 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.

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

Journal Requirements:

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. 

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

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

Reviewer #1: Partly

**********

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

Reviewer #1: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

Reviewer #1: I congratulate the authors on the changes made to the manuscript.

The concluding sentence stating that sarcopenia is associated with a lower eGFR (page 15, lines 320 to 322) is not fully supported by the results, since in the binary logistic regression, after adjusting for age, sex, diabetes, and ICU admission, sarcopenia was not associated with eGFR.

I suggest either tempering the conclusion (the conclusion in the abstract is more appropriate)

Or conducting further analyses to try to find and demonstrate a statistically significant link between muscle and eGFR. :

- Multiple linear or polynomial regression to study the impact of sarcopenia, adjusted for other variables, on eGFR.

- Test whether the association between muscle mass (as measured by ultrasound) and eGFR, found in univariate analysis, persists in multivariate analysis.

**********

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

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Reviewer #1: Yes:  Dr Thomas Stehlé

**********

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Skeletal Muscle-Kidney Crosstalk in a Cohort of Critical Illness Survivors

PONE-D-25-13841R2

Dear Dr. Rebeiro,

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.

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Kind regards,

Masaki Mogi

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

Reviewer #1: (No Response)

**********

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:  Thomas Stehlé

**********