PONE-D-23-01693Bevacizumab-induced proteinuria and its association with antihypertensive drugs: a retrospective cohort study using a Japanese administrative databasePLOS ONE

Dear Dr Kiyomi.

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. Although of retrospective neture, I find this study interesting and clinically important. Please kindly try to respond to all reviewers' comments. However, if the data the reviewers ask for are not available in the administrative database you use for this study please clearly state it when responsing to the reviewers.

Please submit your revised manuscript by March 14th 2023 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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Mirosława Püsküllüoğlu, MD, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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

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4. 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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5. Review Comments to the Author

Reviewer #1: In this study

Age, BMI, Charlson Index, type of Cancer, previous Chemotherapy and death were not associated with protU.

Lower eGFR is associated with protU but without a direct correlation

Predictive risk factors for protU after use of bevacizumab were nursing dependency and systolic blood pressure.

It is necessary to define nursing dependency in this population; you should compare patients with and without nursing dependency. This will possibly help to clarify and identify the factors associated with development of protU in this population. The comorbidity index that could be associated with nursing dependency did not differentiate the development of protU.

Were the renin-angiotensin-aldosterone inhibitors, used to prevent proteinuria, not useful in these patients?

The Table results is difficult to read. It is presented in successive pages and the first line of new pages has no information – ProtU, noProtU and p-value, etc. should be added in every new page

Reviewer #2: Dear Authors,

I have reviewed your work titled "Bevacizumab-induced proteinuria and its association with antihypertensive drugs: a retrospective cohort study using a Japanese administrative database".

It was direct with well outlined research question and objectives.

It would be interesting to note what the relationship of the occurrence of proteinuria and renal funciotn would be if the relationship were assessed according to current CKD GFR staging 1 to 5. The authors note that the exclusion of patients on dialysis (and thus the lower patient numbers) accounted for the relationship observed between Bevacizumab and eGFR <45. However eGFR <45 encompasses a broad group of patients from CKD 3b - CKD 5 for whom proteinuria risk profiles might be different.

The authors are however correct in pointing out that there may not be enough numbers in the group of GFR < 45 due to a form of selection bias with respect to the patient who gets the medication in the first place i.e. indication bias.

As you have rightly highlighted in the limitations, the role of continued use of antihypertensives in modifying the outcome of proteinuria is one that must be borne in mind but your study could not unfortunately evaluate. As your data was from an administrative data set, I would suspect that data can be gathered for this information and incorporated into this study.

The higher occurrence of proteinuria reported in this study than that documented in the medications drug insert does raise some concerns and hopefully triggers further research and clarifications.

Thank you.

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Reviewer #1: Yes: Teresa Adragao

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Bevacizumab induced proteinuria.docx

PONE-D-23-01693R1Bevacizumab-induced proteinuria and its association with antihypertensive drugs: a retrospective cohort study using a Japanese administrative databasePLOS ONE

Dear Dr. Kiyomi,

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 19 2023 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.

Please include the following items when submitting your revised manuscript:

• 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,

Mirosława Püsküllüoğlu, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: No

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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

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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 #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Dear Authors,

Thank you for addressing all concerns raised at the initial review of this manuscript.

Reviewer #3: Dear Authors,

I have thoroughly reviewed your paper and find it to be highly interesting and valuable for clinical practice. The clarity, transparency, conciseness, and readability of the text are commendable. However, I have some suggestions that I believe will further enhance the scientific robustness and readiness of this article.

Language: The English language usage in the paper is understandable and flows smoothly. I have no specific remarks in this regard.

Major remark: The core findings of the paper rely on subgroup comparisons and univariate analysis. Considering that proteinuria can be influenced by various factors, such as hypertension, diabetes, and obesity (Ong et al., Nephrology (Carlton), 2013), it is advisable to standardize the presented data to account for these factors and eliminate their influence on the established results. I recommend consulting with a statistician and considering the incorporation of multivariate analysis with standardization to the aforementioned factors.

Minor remarks:

Line 82: It would be beneficial to provide an explanation for why weight and height values were considered exclusion criteria.

Line 109-110: Could you please clarify whether the proteinuria values mentioned are equal? If so, providing a reference for these information would be helpful.

Line 129: It would be beneficial to specify the chemotherapeutic agents coded in the Anatomical Therapeutic Chemical (ATC) classification. Are they the same as those listed in Table 4?

Line 164-165: The information provided here is somewhat unclear and may not be necessary. If you intended to convey that during observation period, 15.1% of patients with proteinuria and 15.2% of patients without proteinuria died, it is important to provide more precise details or at least specify the time period during which these deaths occurred and the reasons behind them. Otherwise, readers may mistakenly assume that proteinuria was the direct cause of death in these individuals.

Table 1: Is it possible to include p-values for the different types of cancers rather than providing only general information for all diseases? I would suggest replacing the +/- symbols in the "chemotherapy before the index day" row with descriptive terms such as "Applied" and "Non-applied." Additionally, since readers may not be familiar with the International Classification of Diseases (ICD) codes, it would be helpful to provide their specific definitions in a footnote.

Regarding lines 212-225, as detailed data are already presented in Table 3, I recommend avoiding repetition and transforming this paragraph into a more narrative and descriptive form. For example, you could state that XYZ increases the risk of proteinuria by 20%.

Overall, I commend your work and believe that addressing these suggestions will further enhance the quality and impact of your research. I look forward to seeing the revised version of your paper.

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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 #2: No

Reviewer #3: Yes: Renata Pacholczak-Madej

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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.

Bevacizumab-induced proteinuria and its association with antihypertensive drugs: A retrospective cohort study using a Japanese administrative database

PONE-D-23-01693R2

Dear Dr. Kiyomi,

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,

Mirosława Püsküllüoğlu, MD, PhD

Academic Editor

PLOS ONE

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