PONE-D-21-22096

Association between predialysis creatinine and mortality in acute kidney injury patients requiring dialysis

PLOS ONE

Dear Dr. Chang,

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. The study, however, has some shortcomings that should be addressed. In particular,  to mention  some of them, i) need to provide additional nutrition parameters (i.e. BMI), if available, and include them on the analysis; ii) need to provide in the survival analysis (Kaplan-Meier curves) in Figure 2A, the evaluation by albumin level and, if available, by BMI; iii) need to add also in Figure 2B albumin and BMI, and perform further analyses; iv) need to clarify in both the abstract (Results section) and in the Results section itself (page 12), the sentence about the sensitivity analysis which showed that low creatinine patients with fluid overload had worse survival; v) please comment the issue that dichotomising patients according to serum creatinine is relatively simplistic way to evaluate renal function given that creatinine can be insensitive measure of renal function in the critically ill, as many dynamic changes occur concomitantly in the acute setting that can affect this; vi) need to clarify on page 11 whether there is a statistically significant difference in SOFA/non-renal SOFA scores between the low and high creatinine groups, and add the relevant P-value to this section.

Please submit your revised manuscript by Apr 02 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:

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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: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

********** 

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

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: 1.Some review of the way it is written (background) that can be easily corrected by the authors.

2.The authors presented evidence of low creatinine as a risk factor for mortality, if possible to extract from the database more nutritional parameters need to be included i.e BMI .Also if in the table 2 BMI can be included because the low creatinine may reflect a compromised nutritional status (reason for which BMI and other nutritional factors could be included).

3.In the survival analysis (Kaplan Meir curves) in figure 2A analysis by albumin level can be done and may give some answers also BMI can be used if available.Figure2B is it possible to add albumin and BMI and analyze and see if similar results are obtained.

Reviewer #2: This is a well-written paper on an important topic using two large international ICU datasets (eICU and MIMIC) for analysis followed by external validation using a separate cohort that differed significantly in many ways from the original study population; increasing the potential generalisability of the results. I found the introduction, discussion, statistical methodology and presentation of results to be robust and thought-provoking with regard to generation of further hypotheses in this field. One criticism is that in both the Abstract (Results section) and the Results section itself (page 12), the sentence about the sensitivity analysis which showed that low creatinine patients with fluid overload had worse survival is very poorly and unclearly phrased: "In sensitivity analyses, the low-creatinine group was associated with higher mortality rate in patients as the degree of fluid overload". Please make this phrasing more clear e.g. "In the low-creatinine group, fluid overloaded patients were associated with a significantly worse survival". In terms of the research methodology, dichotomising patients according to serum creatinine is a relatively simplistic way to evaluate renal function, given that creatinine can be an insensitive measure of renal function in the critically ill as many dynamic changes occur concomitantly in the acute setting that can affect this. Nevertheless, the methodology used and results presented are interesting and worthy of attention; particularly given that they were generated from and validated in very large ICU population epidemiological datasets. In the Results section, I note that the "Predialysis creatinine and SOFA/nonrenal SOFA scores" section on page 11 does not clarify whether there is a statistically significant difference in SOFA/non-renal SOFA scores between the low and high creatinine groups. Please add the relevant P-value to this section, as per Figure 3. The discussion is well-written and nuanced with regard to the reasons why low creatinine may be associated with these outcomes in critically ill patients; as well as appropriately acknowledging the relevant limitations to this retrospective observational study, albeit large and robustly conducted. It is particularly important to note that the precise cause of death was not routinely documented in these datasets; which may in some cases affect the degree to which it can be reasonably associated with the low creatinine status of the patient. Overall, however, I think this is a very well-constructed and thought-provoking paper that adds important information to the field of AKI outcomes in the critically ill.

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Reviewer #1: Yes: Luis A Concepcion

Reviewer #2: No

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PONE-D-21-22096R1Association between predialysis creatinine and mortality in acute kidney injury patients requiring dialysisPLOS ONE

Dear Dr. Chang,

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 minor points remain to be addressed. In particular, i) suggestion for including the results of BMI in table 1; ii) clarify how the BMI groups were separated to do the analysis of survival; iii) clarify what percentage of patients were fluid overload in each group (low/high creatinine) and include the number in table 1; iv) need to mention in page 23 that in the group with a creatinine level >4 there were more male and black race patients that usually have higher baseline creatinine levels; v) need to mention that the patients with lower creatinine have more days in the ICU before the RRT initiation; vi) please comment that the creatinine level in these patients may not be the “real” one due to fluid overload and dilution. Did the authors consider to adjust creatinine values to compensate for fluid overload? vi) it may be worth adding a sentence to the limitation section about the limitation associated with dichotomizing creatinine as a continuous predictor variable.

Please submit your revised manuscript by Jul 25 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

**********

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: Review comments to the author:

1.Minor corrections to consider,in page 2 :”creatinine is not practical” probably will chose a different word i.e reliable to reflect the renal function.It is practical because it can be done easily even at the bedside.

2.Minor correction to consider page 3:”low creatinine group had a higher 30 day mortality with regard to the BMI or albumin level” do you mean independent of the BMI or albumin level?.

Same page in conclusion:”mortality rate was substantially higher in patients with lower predialysis creatinine with concomitant elevation of fluid overload” ,do you mean lower predialysis creatinine and fluid overload?.

3.Page 12:we requested analysis using BMI.Is it possible to include the results of the BMI in table 1

What is the BMI between the groups studies (low or high creatinine level)?

How do you separate the BMI groups to do the analysis of survival? By the median distribution?.or using the criteria of low BMI as a reflection of malnutrition i.e BMI<18.5 that indicates underweight?

Same applies for fluid overload:

What percentage of patient were fluid overload in each group (low/high creatinine) include the numbers in table 1 for clarity.

4.page 23:

Consider mention that in the group with a creatinine level >4 there were more males and black race patients that usually have higher baseline creatinine levels.

Also important to mention that the patients with lower creatinine have more days in the ICU before the RRT initiation this could also reflect that they receive more fluid (that is why is important to include the % of patients in this group that were fluid overloaded).

Final comment is that the creatinine level in this patients may not be the “real” one due to fluid overload and dilution (Macedo et al Critical Care 14,R82 (2010) in this paper they have a adjusted creatinine to compensate for fluid overload.

Adjusted creatinine= serum creatinine x( 1+ cumulative fluid balance in L/admission weight (kg) x 0.6)

Will the authors consider using this in their paper?.

Reviewer #2: Thank you for addressing the issues that were previously raised in the original manuscript draft. This revision reads very well and is much more clear. Again it may be worth adding a sentence to the limitations section about the limitation associated with dichotomising creatinine as a continuous predictor variable and I would again ensure that your phrasing is clear in the sentence which addresses mortality being higher in fluid overloaded patients with low pre-dialysis creatinine, as this remains a little unclear in how it is phrased in the results section. Otherwise this is a very well-written revision of a well-conducted, statistically robust and interesting 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 #1: Yes: Luis A Concepcion

Reviewer #2: No

**********

[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.

PONE-D-21-22096R2Association between predialysis creatinine and mortality in acute kidney injury patients requiring dialysisPLOS ONE

Dear Dr. Chang,

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 re-revised manuscript is further improved. However, minor points are still pending to be addressed, namely, i) BMI data important to be presented for each group in Table 1; ii) need to be presented in Table 1 also the percentage of patients with fluid overload in each group.

Please submit your revised manuscript by Sep 15 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.

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

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

**********

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

**********

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 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

**********

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

**********

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 reviewed the authors response.

Still believe that BMI data will be important to be presented for each group in table 1.

Also the percentage of patients with fluid overload in each group to be presented in table 1.

Both data will enhance the differences between the groups.

**********

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: Yes: Luis A Concepcion

**********

[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.

Association between predialysis creatinine and mortality in acute kidney injury patients requiring dialysis

PONE-D-21-22096R3

Dear Dr. Chang,

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 new version of the manuscript is definitely improved. The authors have now adequately addressed the few remaining issues raised by the reviewers.

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,

Giuseppe Remuzzi

Academic Editor

PLOS ONE

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