PONE-D-19-22245

Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients

PLOS ONE

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Hideharu Abe, M.D., Ph. D.

Academic Editor

PLOS ONE

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2. We noticed minor instances of text overlap with the following previous publication(s), which need to be addressed:

https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-4300-0

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: Maeda S et al explored the association between proton pump inhibitor use and peritonitis using single-center retrospective cohort in their hospital. As a total of 230 peritoneal dialysis patients in the past 20 years have been enrolled, this study is well designed as retrospective cohort study. However I think this work is suitable for being published in PLOS ONE, it cannot be accepted in its original form. I have a several queries such as unclear causal association between PPI use and the occurrence of peritonitis.

1) The authors define PPI group as ` The patients who took PPI at least 1 week. '. I think it does not include the information about the timing when PPI was taken.

2) Furthermore, this definition does not clarify whether peritonitis was developed within the period the patients took PPI.

3) The authors assume intestinal flora change and bacterial translocation due to oral PPI as the mechanism of peritonitis development. However, logical consistency is insufficient if peritonitis had not occurred within the period when PPI had been prescribed.

The authors should clarify whether the patients were suffered from peritonitis during the period of taking PPI.

Reviewer #2: Dr. Maeda S et al. reported the association between proton pump inhibitor (PPI) use and the risk of peritonitis in peritoneal dialysis patients in the retrospective single center cohort. In general, the work is interesting, although there are several deficiencies that need to be addressed before it would be suitable for publication, including:

1. The authors had defined patients who took any PPI for at least 1 week as the PPI group. How many patients had taken any PPI at onset of peritonitis? The authors should show the Kaplan-Meier curve of patients who took any PPI at onset of peritonitis.

2. The authors should describe the usage of previous/ongoing immunosuppression in Table 1.

3. The observational, nonrandomized design does not permit to establish a causality link between treatment with PPI and outcomes. The authors should well describe the possibility that PPI use may just be a confounding factor for other, unknown variables.in limitation.

Reviewer #3: In this manuscript, the authors evaluated the association of PPI use and peritonitis, and they found that PPI use was associated with increased risk of peritonitis. This paper must be the first one showing the risk of PPI for peritonitis as the authors say and might be very important information in clinical practice for the PD patients, however there seems to be several points should be revised.

1. The authors defined the PPI group as the patients who took any PPI for at least 1 week and did not define the timing of taking the medicine. Please explain why the authors defined the period of prescription as 1 week and if you have some articles you used as reference, please specify them.

2. Patients taking steroid or immunosuppressant are vulnerable to infection. Please describe the number of patients taking steroid or immunosuppressant, if you have data.

3. The reason why the association between H2-receptor antagonist (H2RA) use and peritonitis was not significant might be due to the small sample size. Please clarify the number of the patients taking H2RA in Table 1.

Reviewer #4: In the manuscript entitled “Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients”, authors conducted a retrospective PD patient study to assess the risk of using PPI against peritonitis. The study is well designed and provides good recommendation for the nephrologists. There are some issues that need to be addressed before publishing.

1) It is not clear where the H2RA patient cohort is coming from? Please make it clear and include the data in Figure 1

2) In the table 2 make it clear that Peritonitis, peritoneal disfunction etc are the reasons for PD retrieval. Because of the way the table is structured, it took some effort to understand. Make some font changes, or tab difference to make it easy to follow

3) In this study, baseline data from the patients show that serum albumin from PPI and non-PPI groups are comparable. It is known that inflammation can cause hypoalbuminemia. In other studies where they predicted serum albumin as risk factor, the base serum level at admission was lower. In the current study, it is not clear the low serum albumin is really a predictor or the effect of inflammation, please comment and clarify.

4) A minimum treatment of 1 week with PPI was included in the PPI group. Was the treatment continuous, or intermittent?

5) Authors often compared with another meta analysis and commented that the current work has more sample number. It is not true. Please correct the facts contextually.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients

PONE-D-19-22245R1

Dear Dr. Ito,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Hideharu Abe, M.D., Ph. D.

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

Reviewer #3: All comments have been addressed

Reviewer #4: 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: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

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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 #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

Reviewer #4: 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: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

Reviewer #4: 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: I believe that the authors have completely revised their manuscript R1. I have no more queries or comments about it.

Reviewer #2: (No Response)

Reviewer #3: The issues I pointed out were addressed appropriately. The reason why H2RA use was not identified as a risk factor of peritonitis might be due to the small number of patients using H2RA (n=36). I think this manuscript is acceptable in this form.

Reviewer #4: The Authors have satisfactorily addressed all the comments and made necessary changes in the manuscript.

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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.

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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

Reviewer #3: No

Reviewer #4: No