PONE-D-21-37134

Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis

PLOS ONE

Dear Dr. Zhu,

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.

The manuscript focuses on a topic of potential interest. However, the study has major pitfalls that should be addressed to support the conclusion. To mention few of them, i) need to elaborate on the mechanism of action of the drug, as it is not known in western medicine world; ii) need to be more specific on the losartan mechanisms of action; iii) concern about the presentation  of Table 1, where intergroup difference is hard to read and is not self-explanatory; iv) need to add in the limitations that, since the study was conducted in Chinese population, this drug needs to be studied in other populations before it can become mainstream; v) concern about the fact that many of the studies cited are unavailable to non-Chinese readers and this is a problem for making context of this meta-analysis. Would it be possible to have at least the abstract of these studies translated in English to be added as supplementary material?; vii) unclear why they kept mentioning chronic glomerulonephritis as the most common glomerular disease worldwide. The introduction and early parts of the discussion should be re-written to reflect the actual report of worldwide literature on glomerular diseases; viii) need to clarify how chronic glomerulonephritis was defined in the included studies; ix) concern about the fact that the results presented in the abstract and section 3.3.1 of the Results seem to say the opposite of those reported in Figure 3; x) need to provide kidney function reported in the studies included; xi) need to support with references several statements made in the discussion; xii) need to improve the manuscript by a more detailed discussion into the main findings including, for instance, why the control group did better than the main group (Figure 3); xiii) need to provide the number (and percentage) of studies that were low-, moderate-, and high-risk of bias; xiv) need to provide the dose of losartan in the included studies.

Please submit your revised manuscript by Aug 20 2022 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,

Giuseppe Remuzzi

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: Yes

Reviewer #2: Partly

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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: No

Reviewer #2: Yes

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5. 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 #1: Feng et al. conducted meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis. The results showed that the total effective rate of patients in the study group was significantly improved after using the Shenyankangfu tablets in combination with losartan potassium. 24-hour urine protein, urine NAG enzyme, LKN-1 are lower than the control group. BUN and Cr were not very different between the groups and adverse reactions were less frequent in the study group.

1. Would recommend elaborating on the mechanism of action of the drug as it is not known in western medicine world. Also I would recommend being more specific in losartan's MOA (decrease glomerular hypertension from efferent dilatation, some direct podocyte effects and less fibrosis through TGF-B).

2.Table 1 intergroup difference is hard to read and is not self explanatory.

3. Would check for spelling and grammatical errors.

4. Since the study was conducted in Chinese population, this drug needs to be studied in other population before it can become mainstream.

Reviewer #2: Feng et al have conducted this meta-analysis on the effectiveness and safety of Shenyankangfu tablet combined with Losartan potassium in the treatment of chronic glomerulonephritis (CGN). Please see my comments on this manuscript:

MAJOR:

1. My main problem with this paper submitted to PLOS ONE with largely English readership (and the authors have listed this as a limitation to this study) is the inclusion of only Chinese studies (or studies published in Chinese literature). Many of the studies cited are unavailable to non-Chinese readers and this is a problem for making context of this meta-analysis.

2. It is unclear to me why the authors kept mentioning CGN as the most common glomerular disease worldwide. This is not substantiated in any report of worldwide literature on glomerular diseases. IgAN is the commonest GN in European and Asian countries (including China - See Nephrol Dial Transplant. 2010 Feb;25(2):334-6.) while MCD / FSGS is common in Latin Americans and Africa (see Nephrol Dial Transplant. 2010 Feb;25(2):490-6; and PLoS One. 2016 Mar 24;11(3):e0152203.). CGN represents the final common pathway of most glomerular disorders (primary or secondary) if not well treated or does not respond to therapies and is characterized by interstitial fibrosis, glomerulosclerosis and tubular atrophy. The introduction and early parts of the discussion should therefore be re-written to reflect this.

3. How was chronic glomerulonephritis defined in the included studies? Was this from the same type of primary or secondary GN?

4. Figure 3 clearly shows that the "Total effective rate" was higher (favors) the control group. The results you presented in the abstract and section 3.3.1 of the results seems to say the opposite. This should be clarified.

5. It is unclear about kidney function of the studies included. I think the authors should at least summarize baseline and end-of study serum creatinine, eGFR and ACR (and other tests) in a Table (main or supplementary) to improve context and understanding of the included studies.

6. Several statements were made in the discussion that were not backed up with references (e.g. "Modern pharmacological studies have found that Shenyankangfu tablets have the functions of anti-inflammatory, promoting liver protein synthesis, preventing protein loss, regulating immune function, and lowering blood pressure." Can you provide references to back up this statement as well as others?"

7. I think the study can be improved by a more detailed discussion into the main findings including, for instance, why the control group did better than the main group (Figure 3) amongst others to be discussed.

8. Based on the risk of bias analysis carried out, please clearly provide the number (and percentage) of studies that were low-, moderate- and high-risk of bias.

9. Did the included studies provide dose of Losartan? This should be provided as it has implications on the results provided.

MINOR

1. Please expand the abbreviations before first use (e.g. SMD; urine NAG, etc)

2. Provide the PROSPERO registration number for this study protocol

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Reviewer #1: No

Reviewer #2: Yes: Ikechi Okpechi

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PONE-D-21-37134R1Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritisPLOS ONE

Dear Dr. Zhu,

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.

The revised manuscript is improved. However, few points remain to be addressed, namely, i) need to elaborate more on RAAS blockers on lowering intraglomerular hypertension, direct podocyte effects by blocking ATII receptors; ii) need to provide more in depth details about the mechanism of action of Shenyankangfu tablets; iii) need minor revision regarding grammatical errors.

Please submit your revised manuscript by Oct 22 2022 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,

Giuseppe Remuzzi

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 #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?

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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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 #1: Yes

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: No

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. 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 #1: The authors have addressed most of the the comments from the reviewers. I would also recommend elaborating more on RAAS blockers on lowering intraglomerular hypertension, direct podocyte effects by blocking ATII receptors. Also would recommend delving deep in the mechanism of action of Shenyankangfu tablets. The manuscript still needs minor revision regarding grammatical errors.

Reviewer #2: A Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis. I have no further comments.

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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: No

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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.

Meta-analysis of the effectiveness and safety of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis

PONE-D-21-37134R2

Dear Dr. Zhu,

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.

The re-revised version of the manuscript is definitely improved. The authors have now properly addressed all the reviewers’ comments and criticisms.

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Giuseppe Remuzzi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #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?

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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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 #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. 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 #1: Combination of Shenyankangfu tablets combined with losartan potassium in the treatment of Chronic glomerulonephritis alleviates disease-related symptoms, reduces the influence of cytokine levels, and has fewer adverse reactions compared to losartan alone. This needs to be verified in other populations other than Han Chinese.

Reviewer #2: The authors have shown in their paper that it is safer to treat CGN with Shyenyankangfu tablets combined with losartan potassium. They also show that this compound alleviates disease-related symptoms, reduces the influence of cytokine levels, and has fewer adverse reactions. I have no further comments for the authors who have now responded to all queries.

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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: No

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