The diagnostic value of native kidney biopsy in low grade, subnephrotic, and nephrotic range proteinuria: A retrospective cohort study

Jonathan de Fallois; Soeren Schenk; Jan Kowald; Tom H. Lindner; Marie Engesser; Johannes Münch; Christof Meigen; Jan Halbritter

doi:10.1371/journal.pone.0273671

Peer Review History

Original SubmissionMay 7, 2022
23 Jun 2022 Decision Letter - Xianwu Cheng, Editor PONE-D-22-13404The diagnostic value of native kidney biopsy in low grade, subnephrotic, and nephrotic range proteinuria: a retrospective cohort studyPLOS ONE Dear Dr. de Fallois 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. Please submit your revised manuscript by August 7, 2022. 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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Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Additional Editor Comments: Both reviewers have concerned the statistical analysis. [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 Reviewer #2: Yes ******** 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 ****** 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 ****** 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 conducted a retrospective analysis of all native kidney biopsies for comparison of histological diagnoses and clinical outcomes stratified by amount of proteinuria at the time of kidney biopsy. They concluded that frequency of primary glomerulopathies supports to perform kidney biopsy in patients with subnephrotic proteinuria. The study is interesting and important. The results of this study are convincing. The manuscript is well written and easy to follow. Concerns: 1) In the abstract, results section, one of 37.7 should be 34.4. 2) The authors should indicate what the results of the genetic analysis were in this study cohort and how they relate to the data already presented in this study. 3) As a limitation of this study, the authors point out that the observation period is short, and they should also discuss what impact this may have. Reviewer #2: In this retrospective study authors tried to evaluate the utility of kidney biopsy in patients with low grade or subnephrotic proteinuria in comparison to the established value of biopsy in patients with nephrotic range proteinuria. The results presented in this manuscript are based on original research and the whole article is well written and intelligible. The statistics and the overall design of the study are appropriate and are described in sufficient detail. The conclusions are presented appropriately and are supported by the analysis. Nevertheless, in table 1 authors must show the p value for any statistically significant differences between the presented variables. Authors may opt to present patients with eGFR < 15 ml/min/1.73 m2 as CKD-5ND (not on dialysis). Authors describe increased all cause mortality for patients with nephrotic range proteinuria. Are there any data on specific causes of mortality (i.e. cardiovascular disease, cancer etc.)? Can authors describe which are the specific causes of this increased mortality? As the observational period is limited, can authors include in their analyses the decrease of eGFR by 50% as an end point? This way it will be possible to detect the probability of kidney function deterioration even in patients with low grade proteinuria. ****** 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 Reviewer #2: Yes: Marios Papasotiriou MD, PhD ******** [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. 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Revision 1
6 Jul 2022 Author Response July 2022 POINT-TO-POINT RESPONSE – Manuscript PONE-D-22-13404 Review Comments to the Author Reviewer #1: The authors conducted a retrospective analysis of all native kidney biopsies for comparison of histological diagnoses and clinical outcomes stratified by amount of proteinuria at the time of kidney biopsy. They concluded that frequency of primary glomerulopathies supports to perform kidney biopsy in patients with subnephrotic proteinuria. The study is interesting and important. The results of this study are convincing. The manuscript is well written and easy to follow. RESPONSE: We thank the Reviewer for the appreciation. Concerns: 1) In the abstract, results section, one of 37.7 should be 34.4. RESPONSE: Thank you for pointing that out. We corrected accordingly. 2) The authors should indicate what the results of the genetic analysis were in this study cohort and how they relate to the data already presented in this study. RESPONSE: Although genetic testing was performed in 45/573 (7.9%) of the total cohort, genetic analysis was not systematically performed as part of the study protocol. Therefore, obtained genetic diagnoses were not reported and statistically associated with kidney biopsy results and degree of proteinuria. However, this comparison would be an interesting follow-up investigation beyond the current manuscript. 3) As a limitation of this study, the authors point out that the observation period is short, and they should also discuss what impact this may have. RESPONSE: We fully agree and added the following paragraph to the Discussion: “Additionally, the relatively short observational period of about 700 days on average limits statements on long-term patient outcome and potential attenuation by therapeutic efforts. Clinical endpoints in mildly and moderately progressive disease would have only been captured upon long-term observation.“ Reviewer #2: In this retrospective study authors tried to evaluate the utility of kidney biopsy in patients with low grade or subnephrotic proteinuria in comparison to the established value of biopsy in patients with nephrotic range proteinuria. The results presented in this manuscript are based on original research and the whole article is well written and intelligible. The statistics and the overall design of the study are appropriate and are described in sufficient detail. The conclusions are presented appropriately and are supported by the analysis. RESPONSE: We thank the Reviewer for the appreciation. Nevertheless, in table 1 authors must show the p value for any statistically significant differences between the presented variables. RESPONSE: As suggested, we added the p-values in Table 1. Authors may opt to present patients with eGFR < 15 ml/min/1.73 m2 as CKD-5ND (not on dialysis). RESPONSE: We agree and adapted the proposed terminology in Tab. 2 and throughout the manuscript. Authors describe increased all-cause mortality for patients with nephrotic range proteinuria. Are there any data on specific causes of mortality (i.e. cardiovascular disease, cancer etc.)? Can authors describe which are the specific causes of this increased mortality? RESPONSE: We now provide supplementary information about specific causes of mortality in a new supplementary Table (Suppl. Table 3). In all study groups infectious complications predominated. Interestingly, cardiovascular disease was most frequent in the nephrotic group. We added the following sentence to the Results section: “Accounting for about 40% of all cases, infectious complications were the leading specific cause of death in all study groups; followed by cardiovascular disease, especially in the nephrotic group (Suppl. Tab. 3).” As the observational period is limited, can authors include in their analyses the decrease of eGFR by 50% as an end point? This way it will be possible to detect the probability of kidney function deterioration even in patients with low grade proteinuria. RESPONSE: We thank the Reviewer for this valuable suggestion. Accordingly, we now calculated a new composite outcome including decrease of >50% from baseline eGFR, all-cause mortality and ESKD (revised Table 2 and revised Figure 3). Interestingly, we observed new events (n=2) exclusively among patients in the subnephrotic group. Additional Editor Comments: Both reviewers have concerned the statistical analysis. RESPONSE: By adding p-values to Table 1 and calculating outcomes for an additional end-point (eGFR decrease by 50%), we address the points raised by both Reviewers and make up for the limited observational period. Attachments Attachment Submitted filename: PONE-D-22-13404_Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0273671.r002
12 Aug 2022 Decision Letter - Xianwu Cheng, Editor The diagnostic value of native kidney biopsy in low grade, subnephrotic, and nephrotic range proteinuria: a retrospective cohort study PONE-D-22-13404R1 Dear Dr. de Fallois 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. 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, Xianwu Cheng, M.D., Ph.D., FAHA Academic Editor PLOS ONE Additional Editor Comments (optional): All oroginal conerns have been addressed by the authors. 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 ******** 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: (No Response) Reviewer #2: (No Response) ****** 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 Reviewer #2: Yes: Marios Papasotiriou MD, PhD ******** https://doi.org/10.1371/journal.pone.0273671.r003
Formally Accepted
24 Aug 2022 Acceptance Letter - Xianwu Cheng, Editor PONE-D-22-13404R1 The diagnostic value of native kidney biopsy in low grade, subnephrotic, and nephrotic range proteinuria: a retrospective cohort study Dear Dr. de Fallois: 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 Associate Prof. Xianwu Cheng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0273671.r004

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