PONE-D-24-23392The Relationship Between Acetaminophen Administration and Acute Kidney Injury in Critically Ill Patients with Clostridium difficile Infection: A Cohort StudyPLOS ONE

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Additional Editor Comments :

This title looks like the Acetaminophen increased Acute Kidney Injury otherwise after we reread the manuscript the result showed the Acetaminophen lower the risk of Acute Kidney Injury.

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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: Yes

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

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

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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: I wish if the authors can briefly state the proposed possible mechanisms of action of acetaminophen in their manuscript, although the full detailed mechanisms are not fully understood according to the FDA and to try to explain the study results in the light of these mechanisms (e.g how the selectivity of acetaminophen towards COX-1, COX-2 and COX-3 variants can justify the observed results)

Reviewer #2: 1). How does the dosage of acetaminophen affect the risk of acute kidney injury (AKI) in critically ill patients with Clostridium difficile infection (CDI) as observed in the study?

2). What confounding factors were identified in the study, and how did adjusting for these factors influence the results regarding the association between acetaminophen dosage and AKI risk?

3). What are the potential clinical implications of the study's findings on acetaminophen administration and AKI risk in patients with CDI, and how might these findings influence future practices in the management of critically ill patients?

Reviewer #3: Dear Editor and Authors,

I would like to start by commending the authors on their important contribution to understanding the relationship between acetaminophen administration and the risk of acute kidney injury (AKI) in critically ill patients with Clostridioides difficile infection (CDI). The use of a large and well-validated dataset like MIMIC-IV adds strength to the findings, and the statistical methods used are robust and appropriate for the study design. The work is both timely and clinically relevant, given the ongoing challenge of AKI management in critically ill populations. I believe this study has the potential to impact clinical practice, and with some revisions, it will be even stronger.

Overall, this is a strong manuscript with valuable clinical insights. I hope the suggestions provided will help enhance its clarity and impact. Thank you again for your hard work and contribution to this important area of research.

Overall, this is a strong manuscript with valuable clinical insights. I hope the suggestions provided will help enhance its clarity and impact. Thank you again for your hard work and contribution to this important area of research.

I have provided detailed feedback on various sections of the manuscript to help enhance its clarity and scientific rigor.

Abstract

The abstract concisely summarizes the study but could benefit from some modifications for clarity:

* Background: The sentence "However, the correlation between its administration and acute kidney injury (AKI) among critically ill patients remains controversial" should be more specific. Adding the phrase “particularly in patients with Clostridioides difficile infection (CDI)” will provide clearer context earlier on.

* Methods: The term "multivariate logistic regression" should be pluralized to "multivariate logistic regression models." Additionally, consider briefly mentioning how confounders were selected or adjusted for, to provide a more complete picture.

* Results: The phrase "we found that acetaminophen administration was associated with 32% lower risk" could be more smoothly expressed as "acetaminophen administration was associated with a 32% reduction in the risk of AKI." Furthermore, specifying "95% CI" instead of "CI" is more standard.

* Conclusion: To emphasize clinical relevance, you could rephrase the conclusion as: "Our study suggests that early acetaminophen administration may offer renal protection by reducing the risk of AKI in critically ill patients with CDI."

Introduction

The introduction is well-written, but there are opportunities to strengthen the framing of the problem and the study's hypothesis:

* Clarity of Concepts: While the background on AKI and CDI is solid, the introduction could benefit from a more explicit explanation of the mechanism by which CDI might increase the risk of AKI. Discussing the toxins produced by Clostridioides difficile and how they exacerbate renal injury would help justify the study's focus.

* Mechanistic Hypothesis: The potential mechanisms by which acetaminophen might protect against AKI (e.g., by reducing oxidative stress or inflammation) could be further elaborated. This would better support the rationale for the study and provide a clearer connection between the drug's properties and the expected outcomes.

* Literature Gap: While you highlight that prior studies have shown inconsistent results regarding acetaminophen and AKI, it would be beneficial to explore why these inconsistencies might exist (e.g., differences in patient populations, timing of administration, or methodological limitations of previous studies). This will strengthen the justification for your study.

Methods

The methods section is detailed, but a few areas could use additional clarification or elaboration:

* Study Design and Data Source: It would be helpful to include more details about why MIMIC-IV was chosen as the data source for this study. Highlighting the database's strengths, such as its large size, diversity of patient populations, and detailed clinical variables, would justify its use.

* Outcome Definitions: The use of KDIGO criteria to define AKI is appropriate, but a brief explanation of why this definition was selected (in comparison to other criteria) would provide additional context for readers who may not be as familiar with this classification.

* Covariates: The covariates are thoroughly described, but it would be helpful to explain the rationale for including specific variables like heart rate and blood pressure as potential confounders. This can clarify how you aimed to control for factors that may influence AKI risk.

* Statistical Analysis: While the use of multiple imputation for handling missing data is appropriate, a brief justification for this method would be beneficial. Additionally, mention if any sensitivity analyses were conducted to assess the robustness of your findings in the face of imputed data.

Results

The results section is generally well-presented but could benefit from additional explanations and some restructuring:

* Clarity in Data Presentation: Although you refer to the tables for detailed results, it would be helpful to provide a more thorough narrative summary of key findings. For instance, instead of just directing readers to "See Table 1," briefly describe the most relevant characteristics, such as significant differences in age or baseline health between groups.

* Subgroup Analysis: The interaction effects from the subgroup analysis (Figure 2) are interesting but would benefit from further discussion. For example, why was there no significant interaction effect in certain subgroups? Offering potential explanations (e.g., sample size limitations, differences in baseline characteristics) would provide a more nuanced interpretation.

* Visuals: The inclusion of a patient flow diagram (Figure 1) is helpful. Just ensure that it is clearly referenced in the text and consider briefly summarizing the patient selection process to help readers follow along more easily.

Discussion

The discussion is thoughtful and connects the findings to existing literature, but it could be expanded in certain areas:

* Comparison with Previous Studies: While you effectively compare your findings with previous studies, it would be useful to delve deeper into why your results may differ from those of Patanwala et al. or Hiragi et al. For instance, were there differences in study design, patient populations, or AKI definitions that could explain the discrepancies? Offering potential reasons for these differences will show a critical engagement with the existing body of research.

* Mechanistic Insights: A more detailed discussion of the potential mechanisms by which acetaminophen might reduce AKI would add depth to the paper. Consider expanding on the role of oxidative stress and lipid peroxidation in AKI and how acetaminophen’s pharmacologic properties may counteract these processes.

* Limitations: You mention some limitations, but it would be beneficial to explicitly address additional potential weaknesses of the study. For example, since this is an observational study, residual confounding may still be present despite adjustments. Similarly, the use of retrospective data from MIMIC-IV could introduce bias related to selection or unmeasured variables. Discussing these limitations will add transparency and strengthen the validity of your findings.

* Clinical Implications: Your findings have clear clinical implications, but they could be emphasized further. For instance, should acetaminophen now be recommended as a preventive measure for AKI in CDI patients? While this study provides evidence in favor of its use, you could mention the need for randomized controlled trials to definitively establish causality.

Additional Comments

* Formatting and Writing Style: Ensure that the formatting is consistent throughout, particularly in the use of citations and the presentation of numerical data. For instance, there are some minor issues like misplaced periods in "consequences1–4." or "infection3,5" that should be corrected for consistency.

* Conclusion: Both the abstract and main text conclusions could be strengthened by suggesting future research directions. For example, while acetaminophen shows promise in reducing AKI risk, a call for randomized controlled trials would make the conclusion more forward-looking.

Reviewer #4: Thank you for the opportunity to review the manuscript titled, "The Relationship Between Acetaminophen Administration and Acute Kidney Injury in Critically Ill Patients with Clostridium difficile Infection: A Cohort Study". The manuscript presents a comprehensive analysis of the relationship between early acetaminophen administration and acute kidney injury (AKI) in critically ill patients with Clostridium difficile infection (CDI) admitted into intensive care unit (ICU). While the study addresses a relevant clinical research problem and has strong potential to improve clinical practice, there are some issues and recommendations the authors needs to address to enhance the robustness and quality of their study.

The following are my comments describing the issues and recommendations:

Comments:

1. Title page

I. The corresponding author should provide an ORCID iD in line with PLOS submission guidelines.

2. Introduction

I. The authors cited previous studies with conflicting results but did not provide a thorough analysis of why these discrepancies exist or how their study aims to resolve them. They should provide additional literature review on the mechanism by which acetaminophene is hypothesized to have a protective effect on the kidneys in CDI patients. This would further strengthen the rationale for this study.

3. Material and methods: The study adheres to general scientific principles, but some areas require more clarity and justification.

I. The definition of acetaminophen exposure as administration within the first day of ICU admission is a somewhat narrow definition, as longer durations of exposure might influence outcomes. The authors should clarify the rationale behind this cutoff and why those who were commenced after 24 hours of ICU admission were excluded

II. The authors did not provide information regarding the use of opiods and nonsteroidal anti-imflammatory, which are associated with an increased risk of AKI in the study population. This should be included as part of limitations of this study if the data cannot be extracted from the MIMIC IV version 2.2 database.

III. They should explain why adverse events of acetaminophen administration such hypersensitivity reactions, acute liver failure, etc were not investigated as one of the secondary outcome measures?

4. Data analysis

The statistical analysis is generally sound and adheres to standard practices for cohort studies.

I. Although the subgroup analyses of the covariates including comorbid conditions were done , the interaction terms are not well-explained, and the justification for specific subgroups analysis is also not clear. The authors need to provide more rationale for the subgroups used in the analysis.

II. Excluding patients with renal diseases would have simplified the analysis by reducing the need to adjust for this significant confounder. The effects of acetaminophen would have been clearer in patient without pre-existing kidney problems.

III. There is a heavy reliance on odds ratios, but a computation of the absolute risk differences would help to contextualize the findings of a decrease in incidence of AKI by 32%.

IV. In addition to the logistic regression analysis, the use of cox regression and hazard ratio analysis would have enhanced the robutness of the study findings, especially by providing insights into the timing of AKI onset relative to acetaminophen administration.

5. Results:

I. The unit of measurement for age in this statement ''The age of all participants was 66.8 ± 16.5" was not stated.

II. Each table should be placed in the manuscript file directly after the paragraph in which it was first cited.

6. Reference

I. The authors did not comply with PLOS recommendation of using Vancouver reference style as outlined by the International Committee of Medical Journal Editors (ICMJE).

7. Writing

I. The manuscript did not include page and line numbers in accordance with PLOS submission guidelines.

II. Some typographical and grammatical errors need to be addressed: For eamples 'our aim is to' was use instead of 'our aim was to" in the abstract, adults was spelt as adluts in the result section, "After adjusted for potential confounders" should written as " After adjusting for confounders" in the abstracts. The appropriate use of indefinite and definite articles through out the manuscript.

III. The were numerous use of single spacing between words and

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Reviewer #1: Yes: Ahmed Ibrahim Mohamed Ibrahim

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: Abbas Lawal Ibrahim

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Acetaminophen administration reduces acute kidney injury risk in critically ill patients with Clostridium difficile infection: a cohort study

PONE-D-24-23392R1

Dear Dr. Qiu

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Kind regards,

Diana Laila Ramatillah, PhD

Academic Editor

PLOS ONE

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