-->PONE-D-25-66090-->-->Incidence and risk factors for recurrent IgA nephropathy after kidney transplantation: a multicenter cohort study from Denmark-->-->PLOS One

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ACADEMIC EDITOR: -->-->The manuscript is novel and provides new insights to the field. However, there are major concerns as raised by the reviewers. Hence, i request to revise the MS based on the reviewers comments and resubmit for further consideration. -->-->==============================

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Please revise your MS based on the reviewers' comments and resubmit.

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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?

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Reviewer #1: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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Reviewer #1: Yes

Reviewer #2: 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: Thank you for the opportunity to review this manuscript regarding the incidence and risk factors for recurrent IgA nephropathy after kidney transplantation in a multicenter cohort study from Denmark. This is an interesting small retrospective multicenter analysis about recurrent IgA nephropathy after kidney transplantation in 120 recipients between 1990 and 2020. Seventeen of 120 patients had IgA nephropathy recurrence on for cause biopsies. I suggest that the analysis raises some issues in its present form and request some modifications to improve its impact and generalizability.

1. Can you show the changes in the Oxford classification between the first biopsy and the recurrence? It is unclear whether treatment was changed after the IgA nephropathy recurrence, and the possible impact of that in terms of time to graft failure and death.

2. Four out of ten who developed graft failure presented IgA nephropathy recurrence in combination with infection and rejection. How many of them have graft loss due to IgA or rejection/infection? It would be more appropriate to perform an analysis excluding these patients if the primary cause was not IgA recurrence. Additionally, in Uffing et al. (ref#18, 10.2215/CJN.00910121), IgA nephropathy recurrence rates were higher in patients with de novo DSA and pre-emptive. Can the authors comment on that and report their data about DSAs in their population?

3. Data about IgA recurrence treatment should at least be presented in supplementary material and commented on.

4. Complement activation is acquiring greater importance in IgA nephropathy, and some new drugs targeting complement pathways (e.g., iptacopan, pegcetacoplan) showed promising results. Recent findings suggest that complement deposition could be abrogated in post-treatment biopsies (see 10.1016/j.ajt.2025.08.015). Could complement deposition (at least C3, ideally C5b-9) be evaluated in the patient and commented on the eventual differences or changes between the steroid-free group and the steroid group?

5. I do not fully understand if the differences among patients with recurrent IgAN (younger at time of IgAN diagnosis, younger at KF, faster progression from primary diagnosis to KF were significant or only trends. Please include the p-value in the text and tables.

6. Other induction therapy refers to no induction, steroids only, or alemtuzumab? Please specify.

7. Minor point: Correct typos in table 1 (e.g., Immunodeposits on electron microscopy 74(120) 62%)

Reviewer #2: Major comments

1. Disease definition and potential misclassification (IgA nephropathy)

The definition of IgA nephropathy requires clarification. In addition to cases with predominant mesangial IgA deposition on immunofluorescence, the manuscript includes patients described as having “mesangioproliferative glomerulonephritis where IgAN was most likely.” As mesangioproliferative GN represents a histopathological pattern rather than a specific diagnosis, this definition may lack specificity. In particular, other conditions such as fibrillary glomerulonephritis can present with a mesangioproliferative pattern and may occasionally show IgA or mixed immunoglobulin deposition. The use of the term “most likely IgAN” is subjective and may reduce reproducibility, especially when the same criteria are applied to define recurrent disease in allograft biopsies, where mesangioproliferative changes are often non-specific.

The authors are encouraged to clarify the exact histopathological criteria used to define both primary and recurrent IgAN, including whether electron microscopy was systematically performed and whether fibrillary or other non-IgA immune complex glomerulopathies were explicitly excluded. Clarifying these points would strengthen confidence in the reported recurrence rates and subsequent risk factor analyses.

2. Interpretation of steroid analysis and statistical considerations

The analysis of maintenance steroid use is limited by the small number of recurrence events, resulting in wide confidence intervals and limited statistical precision. Although the lack of statistical significance is appropriately reported, the discussion currently presents the steroid findings in a relatively definitive manner. Given the imprecision of the estimates, the absence of a statistically significant association should be interpreted with caution and should not be equated with evidence of no effect.

This issue would benefit from being addressed explicitly in the discussion, rather than only as a general limitation, by emphasizing limited power and uncertainty in the effect estimates. A more cautious wording would better reflect the statistical constraints of the dataset.

Minor comments

Figure 1 contains a labeling error in which the recurrent and non-recurrent IgAN groups appear to be inverted, which conflicts with the text and Table 1 and should be corrected. Figure 2 is of suboptimal visual quality and appears blurred; higher-resolution images would improve readability. In addition, the tables contain a small number of typographical and formatting issues that should be corrected for clarity and consistency.

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Reviewer #1: No

Reviewer #2: No

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Incidence and risk factors for recurrent IgA nephropathy after kidney transplantation: a multicenter cohort study from Denmark

PONE-D-25-66090R1

Dear Dr. Øhrstrøm,

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,

Nasar Alwahaibi, PhD

Academic Editor

PLOS One

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

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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 #1: Partly

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-->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

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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 #1: 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 #1: No further revisions are required. However, the manuscript's overall impact is low due to intrinsic limitations (i.e., no evaluation of the Oxford classification and complement deposition on kidney biopsies).

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-->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.

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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

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