Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy

Kensuke Joh; Takashi Nakazato; Akinori Hashiguchi; Akira Shimizu; Ritsuko Katafuchi; Hideo Okonogi; Kentaro Koike; Keita Hirano; Nobuo Tsuboi; Tetsuya Kawamura; Takashi Yokoo; Ichiei Narita; Yusuke Suzuki

doi:10.1371/journal.pone.0268731

Peer Review History

Original SubmissionMay 7, 2022
9 Jun 2022 Decision Letter - Zhanjun Jia, Editor PONE-D-22-13403Structural modeling for Oxford histological classifications of immunoglobulin A nephropathyPLOS ONE Dear Dr. Joh, 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 Jul 24 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, Zhanjun Jia 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. Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, all author-generated code must be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse. 3. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. If you are reporting a retrospective study of medical records or archived samples, 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. 4. Thank you for stating the following financial disclosure: "This study was supported in part by a Grant-in-Aid for Progressive Renal Diseases Research, Research on Rare and Intractable Disease, from the Ministry of Health, Labour and Welfare of Japan. This research was supported by AMED under Grant Number JP19ek0109261." Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 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. Additional Editor Comments: Some comments from the experts need to be well addressed. [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: Partly Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A Reviewer #3: 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: No Reviewer #3: 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 Reviewer #3: No ****** 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: Previous studies have identified risk factors for IgA nephropathy progression: eGFR and macrohematuria at the time of renal biopsy (Shu, D., Xu, F., Su, Z. et al. Risk factors of progressive IgA nephropathy which progress to end stage renal disease within ten years: a case–control study. BMC Nephrol 18, 11 (2017). This study from Kensuke Joh et al evaluates the diagnostic approach for the treatment of IgA Nephropathy. The number of renal biopsies, the duration of follow-up and the quality of the statistical analysis permit the novelty of these useful and interesting conclusions: Only tubular atrophy/interstitial fibrosis had an accelerative direct effect on renal function decline, while endocapillary hypercellularity and active crescents had an attenuating indirect effect via steroid treatment. This message is very important. A renal biopsy must be performed as soon as possible in order to initiate treatment for endocapillary hypercellularity and active crescent. This study satisfies all the criteria to be accepted by PLOS One I have only very few comments to this article: there are some acronyms in the abstract that are not identified and difficult the complete understanding of the message. line 43 S and M line 44 UPE line 46 eGFR0c Reviewer #2: The present study was a prospective clinical study for patients with IgAN among 44 kidney centers across Japan. By using the Oxford classification, the pathological variables were defined in the research and analysis. The authors applied structural equation modeling (SEM) to evaluate structural correlations associated with the change in eGFR, predicting the systemic path links between renal functional decline (RFD) and histological variables vis clinical or treatment variables. This is the only systematic research that proposes the correlation between histological, clinical, and treatment variables. Overall, it is an exciting study, and most of the conclusions may provide some information for IgAN patients using personalized medicine. However, I have some concerns about this study. 1. It is hard to catch the data and analysis process in the manuscript. A flow chart will help in this regard. 2. Figure 1 shows those variables for the SEM. The authors should outline the possible relationships between those variables but not just indicate the paths in the single image. 3. After removing non-significant paths is not clear. How to remove it? What is the difference without removal? 4. Can the authors simply the models? So complicated with the variables and sub-variables in this study. Making a table for results and conclusions will be much easier to follow. 5. The description for figure 2 is confusing. Reviewer #3: This an paper dealing with finding of independent prognostic variables for renal functional decline in IgA nephropathy. Although the subject is of great interest, overall the article is not clear, with to many abbreviation within the text. Therefore, the manuscript is difficult to read. Some abbreviations are unnecessary – eg. UPE could be replaced with proteinuria (1 word), ST- steroids etc . Some of the abbreviations found in abstract must be spelled out completely on initial appearance in text (S,M,C, MEST…) In table 1 The period of follow up overlaps with Treatment choice. Please clarify. The authors should explain the raison for choosing different parameters like square root eGFR0 instead of eGFR; furthermore, it is not clear what does represent the values UPE0c, SReGFR0c and MAPc- why not MAP0c? …and the confusion continues with C0, C1 etc …. The square root GFR could not be considered a predictor of SLOPE since GFR slopes depends on the eGFR. The authors should also emphasize on the clinical values of their findings. A limitation section should be added as well. ****** 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: Yes: Teresa Adragao Reviewer #2: No Reviewer #3: 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.0268731.r001
Revision 1
1 Aug 2022 Author Response Dear Editor-in-Chief, PLOS ONE Thank you for the thoughtful and constructive feedback you provided regarding our manuscript, entitled “Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy.” We agree with you and have incorporated these suggestions throughout our paper. With these changes to our final manuscript, we hereby resubmit our manuscript for a secondary evaluation. Thank you once again for your consideration of our paper. Answers for the reviewer’s comments Reviewer #1: Previous studies have identified risk factors for IgA nephropathy progression: eGFR and macrohematuria at the time of renal biopsy (Shu, D., Xu, F., Su, Z. et al. Risk factors of progressive IgA nephropathy which progress to end stage renal disease within ten years: a case–control study. BMC Nephrol 18, 11 (2017). Thank you for introducing an interesting paper. For the present study, we have selected clinical variables according to the study by Barbour et al., who selected amount of proteinuria, eGFR, and MAP but not macrohematuria (JAMA Intern Med. 2019;179: 942-52). The information on macrohematuria was unfortunately not collected in the national-wide prospective study and therefore not used in the present study. This study from Kensuke Joh et al evaluates the diagnostic approach for the treatment of IgA Nephropathy. The number of renal biopsies, the duration of follow-up and the quality of the statistical analysis permit the novelty of these useful and interesting conclusions: Only tubular atrophy/interstitial fibrosis had an accelerative direct effect on renal function decline, while endocapillary hypercellularity and active crescents had an attenuating indirect effect via steroid treatment. This message is very important. A renal biopsy must be performed as soon as possible in order to initiate treatment for endocapillary hypercellularity and active crescent. This study satisfies all the criteria to be accepted by PLOS One I have only very few comments to this article: there are some acronyms in the abstract that are not identified and difficult the complete understanding of the message. Line 43 S and Line 44 M line 44 UPE line 46 eGFR0c We have changed some acronyms to their expanded terms in the abstract section. Reviewer #2: The present study was a prospective clinical study for patients with IgAN among 44 kidney centers across Japan. By using the Oxford classification, the pathological variables were defined in the research and analysis. The authors applied structural equation modeling (SEM) to evaluate structural correlations associated with the change in eGFR, predicting the systemic path links between renal functional decline (RFD) and histological variables vis clinical or treatment variables. This is the only systematic research that proposes the correlation between histological, clinical, and treatment variables. Overall, it is an exciting study, and most of the conclusions may provide some information for IgAN patients using personalized medicine. However, I have some concerns about this study. 1. It is hard to catch the data and analysis process in the manuscript. A flow chart will help in this regard. Thank you for your valuable suggestion. We have created a flow chart and added the text as Supplementary Material 1 (Page 14; Line 262). 2. Figure 1 shows those variables for the SEM. The authors should outline the possible relationships between those variables but not just indicate the paths in the single image. After removing non-significant paths is not clear. How to remove it? What is the difference without removal? The final relationship was illustrated in Fig. 2 corresponding with yellow as clinical variables and green as treatment variables, among which all significant relationships were connected by the arrows. Blue lines show a direct relationship with the slope. All histological variables showed additional indirect effects on SLOPE via clinical variables or ST (red arrows). An analyzing process was shown in a flow chart (Supplementary Material 1), indicating the results of linear regression analysis among nonsignificant histological, clinical, and treatment variables (see Step 3 in Supplementary Material 1). We selected the significant paths from the result of Step 3 by removing nonsignificant paths (P > 0.05). SEM was performed again to attest to the goodness of fit for an appropriately fitting model (see Step 4 in Supplementary Material 1). 2. Can the authors simply the models? So complicated with the variables and sub-variables in this study. Making a table for results and conclusions will be much easier to follow. An analyzing process was shown in a flow chart (Supplementary Material 1). The final result was shown in Table 3, showing the direct and indirect effects of Oxford histological variables (M, E, S, T, and C) on changes in the estimated glomerular filtration rate (SLOPE). To introduce Table 3, direct and/or indirect effects of histological variables on SLOPE were calculated as total coefficients, which were the total of direct and indirect coefficients, where each indirect coefficient of M, E, S, T, or C in Table 3 indicated the integration of each coefficient of the clinical and treatment variables in Table 2 according to the paths shown in Fig. 2. The description for figure 2 is confusing. Figure 2 showed an appropriately fitting structural modeling. Using this model, Table 3 was made as the conclusion showing direct and indirect effects of Oxford histological variables on changes in the estimated glomerular filtration rate (SLOPE). Reviewer #3: This paper dealing with finding of independent prognostic variables for renal functional decline in IgA nephropathy. Although the subject is of great interest, overall, the article is not clear, with too many abbreviations within the text. Therefore, the manuscript is difficult to read. Some abbreviations are unnecessary – eg. UPE could be replaced with proteinuria (1 word), ST- steroids etc. We agree that several abbreviations are found within the text; therefore, we should avoid some unnecessary abbreviations. However, each abbreviation has its original meaning, e.g., UPEc0 (centralized urine protein excretion (UPE), SReGFR0c centralized square root estimated glomerular filtration rate (eGFR), MAPc01: centralized mean arterial pressure (MAP) dichotomized with negative MAPc as MAPc0 and positive MAPc as MAPc1. ST not only means steroid therapy but also steroid therapy with/without tonsillectomy. Therefore, we believe that it is better to use abbreviations than to spell out on an initial appearance in the text. Please let us know if you still need the abbreviations to be defined at some places. Some of the abbreviations found in abstract must be spelled out completely on initial appearance in text (S,M,C, MEST…) In the abstract, we have spelled out the initial appearance of S and M. We used proteinuria instead of UPE in the text (Page 3; Lines 34–46). In table 1 The period of follow up overlaps with Treatment choice. Please clarify. In Table 1, the follow-up period was separately indicated from the treatment choice as ST and RASB. The authors should explain the raison for choosing different parameters like square root eGFR0 instead of eGFR; furthermore, it is not clear what does represent the values UPE0c, SReGFR0c and MAPc- why not MAP0c? …and the confusion continues with C0, C1 etc …. To obtain the goodness of fit for an appropriately fitting model, we changed the clinical variables respecting the variable normality, such as UPEc0 (centralized urine protein excretion (UPE), SReGFR0c centralized square root estimated glomerular filtration rate (eGFR), MAPc01: centralized mean arterial pressure (MAP) dichotomized with negative MAPc as MAPc0 and positive MAPc as MAPc1. The final choice of centralization (UPEc0), square root (centralized square root eGFR), or dichotomized MAPc01 was the best choice to obtain the most appropriate fitting model. The square root GFR could not be considered a predictor of SLOPE since GFR slopes depends on the eGFR. We believe that eGFR at biopsy was high, and subsequently, SLOPE declined strongly, whereas when it was low, there was a weaker decline. This is also true in normal kidneys. Therefore, according to our understanding, eGFR at the time of biopsy can influence SLOPE. The authors should also emphasize on the clinical values of their findings. A limitation section should be added as well. Thank you for your valuable comments. We added the following sentence in the conclusion (Page 21; Lines 390–393). “We focused not only on direct effect but also on the indirect effect of histological variables on RFD, where direct effects of clinical variables on RFD, such as SReGFR0c, UPE0c, and ST, were influenced by histological variables.” We added the following information to the limitation section (Page 21; Lines 398–401). “As a limitation, this prospective study using SEM could not predict the prognosis of renal function via Cox regression analysis because the goodness of fit could not be applied to the survival analysis model. Obtaining a more apparent eGFR slope needs longer follow-up.” Sincerely, Kensuke Joh, MD, PhD Department of Pathology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan Tel: 81-3-3433-1111, Fax: 81-3-5472-0700 E-mail: johken@med.tohoku.ac.jp Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0268731.r002
17 Aug 2022 Decision Letter - Zhanjun Jia, Editor Structural modeling for Oxford histological classification s of immunoglobulin A nephropathy PONE-D-22-13403R1 Dear Dr. Joh, 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, Zhanjun Jia 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 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: N/A ****** 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: This study from Kensuke Joh et al evaluates the diagnostic approach for the treatment of IgA Nephropathy. The number of renal biopsies, the duration of follow-up and the quality of the statistical analysis permit the novelty of useful and interesting conclusions. It is possible to change the decline of renal function based on the results of renal biopsy. The final review of this article answers my previous comments Reviewer #2: The authors have addressed all the questions, and the current version of the manuscript has dramatically improved and become more readable. ****** 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: Teresa Adragao MD PhD Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0268731.r003
Formally Accepted
31 Aug 2022 Acceptance Letter - Zhanjun Jia, Editor PONE-D-22-13403R1 Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy Dear Dr. Joh: 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 Dr. Zhanjun Jia Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0268731.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 .