PONE-D-24-44415Platelet Distribution Width as a Cost-effective Marker for Sepsis-Induced Acute Kidney Injury : a Retrospective Cohort StudyPLOS 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: No

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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: The authors aim to show, in a relatively large retrospective study of

410 sepsis patients, that the platelet distribution width is

predictive of sepsis-associated acute kidney injury. However, the

results do not seem to support their conclusion, as the PDW does not

seem to add a reasonably certain increase in prognostic information

compared to SOFA. Nevertheless, a more careful and detailed analysis

of this promising dataset might provide useful and new insights.

The first question that arises reading the manuscript is: why did they not

also considered the mortality of these patients, and also the timing

of clinical events, as such information, at least for in-hospital mortality,

would be immediately available and also very relevant.

Multivariate logistic analysis is mentioned in the results and the

introduction, and is the main argument of the paper, but is not

mentioned in the statistical methods.

LDH and procalcitonin and other possible indicators of S-AKI

susceptibility, especially, obviously, chronic renal disease, should

have been included in the logistic regression. While some are included

in the overall scores, elements of the scores could be more specific

for a specific prognosis, while using the scores themselves would blur

this association.

The timing between admission--when the PDW and other indices were

measured, and the AKI diagnosis should also be considered in the

analysis (possibly with a Cox model) and so should the comorbidities

that make the groups very heterogenous.

The correlation analysis should be accompanied by graphics showing the primary

data. Correlations below 0.3 are in fact very weak and also the

Pearson correlation coefficient is very sensitive to outliers,

especially if the variables do not have a Gaussian distribution.

Also, the issue of variable independence should be taken into

account. For example, the number of platelets is part of the SOFA

score, but it should be expected to be also correlated to the PDW. A

more careful examination of the individual components of the scores

and their correlation matrix could be revealing. Also, using also more

robust correlation indices, such as Spearman, might be helpful.

On page 6. the AUC for the SOFA-PDW seems to be given as 0.795 and

then, in the next paragraph, 0.799. The confidence limits also differ.

If we compare the AUC for SOFA and SOFA-PDW, that is relevant for the

supposed contribution of the PDW as a new diagnostic criterion, we see

that the difference is small (0.771 vs 0.795 or 0.799). The

confidence intervals are also mostly overlapping. The lack of an

obvious difference, that would be necessary in order to claim a

supplementary diagnostic value, is also visible in figure 1.

Thus, what the results actually seems to indicate is that the PDW does

not add significantly more prognostic information compared to SOFA,

for S-AKI, contrary to the conclusion.

At page 7, in the discussion, the authors propose a chain of

causality, sepsis -> platelet consumption -> increased PDW as an

explanation for the supposed diagnostic value of the increased

PDW for the pathologic impact of sepsis. However, a low platelet count

and increased PDW have many other causes independent of sepsis,

especially in a sample with multiple comorbidities.

Minor observations.

Page 3. `Patients with malignant tumor patients'

Page 5. `a mean age of 78.8±13.6 years' [this is the distribution not the mean]

Page 6. I think the term 'cohort' is usually employed for longer follow-up studies.

Page 8. ``ensuring data accuracy and minimal missing.''

Figure 1.

Colors in the figure are difficult to distinguish, even for a person

who does not have color visual deficiency, like myself.

Reviewer #2: Sepsis is a condition usually linked to increased risk of mortality, especially when renal failure is noticed. It is important to determine the best and adequate methods to evaluate on-time the risk of sepsis development, therefore the current work can improve the current diagnosis management and therapy response. The study was well presented, including a comprehensive description of the methodology and results. The conclusions were in accordance with the assessed data. A minor comment: the figure presenting the ROC curve should be resized (visually, it not clear enough), and considering a previous work focused on the correlation between PDW and sepsis in AKI patients which highlighted that PDW > 17.7% can associate a higher risk for AKI (including the severity of AKI), it would be nice if you could also underline (in the discussions or conclusions) the PDW value from which the risk of AKI was noticed in your patients.

Reviewer #3: I read the manuscript with great interest. This is a single-center retrospective study analyzing a potential correlation between platelet distribution width (PDW) and AKI in sepsis. The authors established well-defined study parameters, most notably exclusion criteria, clear definition of S-AKI and a specific time window of within 24 hours of admission. Statistical analysis appears sound. The correlation with several clinical severity scores was particularly interesting. There are a few opportunities for clarification/edits as outlined below.

- The overall age skewed on the high side (78+/- 13.6 years). Did the correlation between PDW and AKI differ across different age groups?

- For the exclusion criteria “individuals with acute kidney injury induced by causes other than sepsis”: how did the authors clearly and consistently delineate whether sepsis was or was not the inciting cause of AKI?

- If the inference is that increased PDW is a marker for sepsis-induced AKI, how do we know that AKI alone is not the driver for increased PDW? i.e., would we expect to see the same correlation between PDW and AKI in non-septic patients?

- Increased PDW can be caused by multiple other conditions, including respiratory and cardiovascular/cerebrovascular disorders, DM, etc. Table 1 lists comparable percentages of several such conditions for S-AKI and non-AKI groups. I would explicitly draw attention to this within the discussion section.

- Was there a sub-analysis performed to differentiate between sepsis, severe sepsis and septic shock and whether correlation between PDW and AKI was comparable or different across these categories?

- Page 8, last paragraph: “Strengths and limitations” should be a separate section.

- Page 8, last paragraph: “Large cohort “ is listed as one of the strengths, though 410 (written as 401 in that paragraph) is a medium-size study. Could the authors comment on the barriers for not including more patients?

- I agree with the authors that a seven-year study span and potential advances in sepsis diagnosis and treatment might have introduced some confounding variables. It would have been interesting to see whether PDW and AKI correlation was comparable during the first half vs second half of the study period.

- I concur that the study needs to be prospectively validated. Until then, calling PDW a marker for sepsis-induced AKI might be premature. I would reword as “potential marker” throughout the paper.

- Table 1: “Chronic kidney disease” needs a qualifier “stage 1-3”.

- There are several grammatical errors and incorrect sentence structures throughout the manuscript. E.g., Abstract, Results section, p.1: “positively correlation with the SOFA”; p.7, paragraph 2, sentence 3: “numerous microthrombi”; p.7, paragraph 2, last sentence: not grammatically correct, plus brackets with “[Error! Bookmark not defined.];” p.8, sentence 3: end of sentence missing a few words.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Platelet  Distribution Width as a Cost-effective Marker for  Sepsis- associated  Ac ute Kidney Injury:  a Retrospective  Cross-section  Study

PONE-D-24-44415R1

Dear Dr. Du,

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,

Ennio Polilli

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 #2: All comments have been addressed

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

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

Reviewer #2: Yes

Reviewer #3: 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 #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: You have responded to all the comments and the manuscript has been improved - it is more clearly presented the potential role of PDW in assessing S-AKI patients, and, consequently, the benefits of performing this test in clinical practice.

Reviewer #3: Thank you for your response to the reviewers' comments. The answers are satisfactory and all feedback has been addressed.

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Reviewer #2: No

Reviewer #3: No

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