Risk factors, predictions, and progression of acute kidney injury in hospitalized COVID-19 patients: An observational retrospective cohort study

Maryam N. Naser; Rana Al-Ghatam; Abdulla H. Darwish; Manaf M. Alqahtani; Hajar A. Alahmadi; Khalifa A. Mohamed; Nahed K. Hasan; Nuria S. Perez

doi:10.1371/journal.pone.0257253

Peer Review History

Original SubmissionMay 11, 2021
14 Jul 2021 Decision Letter - Giuseppe Remuzzi, Editor PONE-D-21-15637 Risk factors, predictions, and progression of acute kidney injury in hospitalized COVID-19 patients: An observational retrospective cohort study PLOS ONE Dear Dr. Naser, 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 addresses a timely and potentially relevant topic. However, the study has several shortcomings that should be addressed to reach robust conclusions. To mention some of them, i) need to provide information with regard of prior immunosuppression; ii) need to include serum albumin in the data analysis; iii) need to quote and properly discuss the recent literature on the role of hypoalbuminemia as independent risk factor for COVID-19 AKI and severity; iv) need to perform further analysis including survival analysis for length of ICU stay, length of hospitalization and mortality; v) need to include and discuss the relevant papers on renal tropism of SARS-CoV-2 and AKI development. Please submit your revised manuscript by Aug 28 2021 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: http://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: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In your ethics statement in the Methods section and in the online submission form, please provide additional information about the data used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. 3. Thank you for providing the date(s) when patient medical information was initially recorded. Please also include the date(s) on which your research team accessed the databases/records to obtain the retrospective data used in your study. 4. "Please revise your tables to replace p-values of "n.s." to their actual numerical value. 5. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 6. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ 7. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary) [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: In the present study, Naser et al. present data from a retrospective single-center cohort study identifying risk factors for AKI related to COVID-19. This is a timely and important topic in this pandemic. However, the following comments should be addressed to further improve the strength of this study: 1. Information with regard of prior immunosuppression should be included since this might also influence COVID-19 and AKI severity (e.g. B cell depletion). 2. In the data analysis, serum albumin should be included because hypalbuminemia has previously been described as independent risk factor for COVID-19 AKI and severity. In addition, the literature should be cited accordingly (Huang J et al. Hypoalbuminemiapredicts the outcome of COVID-19 independent of age and co-morbidity. J Med Virol. 2020, Aziz M et al. The association of lowserum albumin level with severe COVID-19: a systematic review andmeta-analysis. Crit Care. 2020, Paliogiannis P et al. Serumalbumin concentrations are associated with disease severity andoutcomes incoronavirus 19 disease (COVID-19): a systematic review and meta-analysis. Clin Exp Med. 2021, Tampe D et al. Urinary Levels of SARS-CoV-2 Nucleocapsid Protein Associate With Risk of AKI and COVID-19 Severity: A Single-Center Observational Study. Front Med. 2021). 3. Since AKI has been associated with COVID-19 severity and mortality, data analysis should also include survival analysis for ICU stay of length, length of hospitalization and mortality. 4. Since renal tropism of SARS-CoV-2 has been linked to AKI in COVID-19, the relevant literature should be discussed and included (Puelles et al. NEJM 2020, Braun et al. Lancet 2020). ****** 6. 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 [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. https://doi.org/10.1371/journal.pone.0257253.r001
Revision 1
5 Aug 2021 Author Response The authors thank the reviewer(s) for addressing very important points. Therefore, in the revised version, we addressed all the points (highlighted in red). i) need to provide information with regard of prior immunosuppression; In the revised version (page 6), a statement is included stating “Furthermore, none of the patients had a history of immunodeficiency disorders.” ii) need to include serum albumin in the data analysis; In the revised version of the manuscript, a detailed analysis of serum albumin in AKI and non-AKI patients was included (Table 2, Table 3, Fig. 1C, Table 5) and also in page (2, 11, 12, 15). iii) need to quote and properly discuss the recent literature on the role of hypoalbuminemia as independent risk factor for COVID-19 AKI and severity; In the revised version of the manuscript, a detailed discussion on the role of hypoalbuminemia is discussed (page 18). “In the present study, however, and following age adjustment, only serum albumin, D-Dimer, Troponin I, and ProBNP high values were associated with AKI development. One of the recent studies showed that hypoalbuminemia predicts the outcome of COVID-19 independent of age and co-morbidity [24]. In that study, however, the authors did not look into AKI as a reason for hypoalbuminemia but related that to inflammatory cascades and capillary permeability in severe cases of COVID-19 [24]. In contrast, other studies related hypoalbuminemia to nutritional index [25]. In our study, 21 patients (11%) who did not develop AKI, had hypoalbuminemia, and 2 of these patients died (p>0.05). On the contrary, death was correlated to the severity of hypoalbuminemia during AKI development (p<0.001). Since during AKI development, kidneys start excreting albumin in urine as seen herein, hypoalbuminemia becomes more evident and also a predictor of severity and death of COVID-19.” iv) need to perform further analysis including survival analysis for length of ICU stay, length of hospitalization and mortality; Firstly, it has to be mentioned that all patients were admitted to the intensive care/isolation unit for COVID-19. Therefore, the length of hospitalization mentioned in the original manuscript refers to the length of stay in the ICU/isolation unit (see page 6 in the revised version). Secondly, survival analysis with Kaplan Meier plot is introduced in the revised version showing % survival versus time (days) following admission (page 14 & Fig 3A). “The Kaplan-Meier survival curve showed that 50% of patients with AKI died within 33 days of admission to the ICU/isolation unit (Fig 3a). It must be mentioned that there were 21 transferred patients, whom 6 out of 7 of them died (~7% of the death within AKI patients) within 2-28 days. This indicates that median survival time of 33 days is slightly underestimated. “ v) need to include and discuss the relevant papers on renal tropism of SARS-CoV-2 and AKI development. In the revised version (page 19), we addressed this point. “Besides, in a post-mortem study of COVID-19 patients, SARS-CoV-2 RNA was found in 60% of COVID-19 patients, and the presence of RNA was associated with older age and accelerated deaths [28]. However, in the latter study, patients with SARS-CoV-2 negative RNA in their kidneys also died but had a longer survival time. These data suggest that SARS-CoV-2 renal tropism is not the only reason for AKI injury.” https://doi.org/10.1371/journal.pone.0257253.r002
27 Aug 2021 Decision Letter - Giuseppe Remuzzi, Editor Risk factors, predictions, and progression of acute kidney injury in hospitalized COVID-19 patients: An observational retrospective cohort study PONE-D-21-15637R1 Dear Dr. Naser, 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 revised manuscript has improved. The authors have properly addressed all the comments raised by the reviewer. 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 ******** 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: The authors adequately addressed all comments as suggested. Therefore, I recommend acceptance of the manuscript. ****** 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 https://doi.org/10.1371/journal.pone.0257253.r003
Formally Accepted
20 Sep 2021 Acceptance Letter - Giuseppe Remuzzi, Editor PONE-D-21-15637R1 Risk factors, predictions, and progression of acute kidney injury in hospitalized COVID-19 patients: An observational retrospective cohort study Dear Dr. Naser: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Giuseppe Remuzzi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0257253.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .