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PLOS ONE

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[This work was funded by Travere Therapeutics.]

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[AJ has served on a scientific advisory board for Calliditas Therapeutics. KDJ is a founder and co-president of the American Society of Onco-Nephrology; reports consultancy agreements with Secretome, George Clinicals, PMV pharmaceuticals and Calliditas. KDJ reports honoraria from the American Society of Nephrology, the ISN, and UpToDate.com; reports serving on the editorial boards of American Journal of Kidney Diseases, CJASN, Clinical Kidney Journal, Journal of Onconephrology, Kidney International, and Nephrology Dialysis Transplantation; reports serving as Editor-in-Chief of ASN Kidney News and section editor for onconephrology for Nephrology Dialysis Transplantation. MB is a consultant for Travere Therapeutics, Inc. JAB is an employee, and DMWC was an employee, of Genesis Research Group which received compensation from Travere Therapeutics, Inc. for conducting this study. MEB is a consultant for Travere Therapeutics, Inc. and reports an additional consultancy agreement with Amgen, Inc.].

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Additional Editor Comments:

Please see comments attached by the reviewers.

[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?

Reviewer #1: Partly

Reviewer #2: Yes

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

Reviewer #1: N/A

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: 1. Introduction:

The introduction is well-written, providing adequate background on IgA nephropathy and its clinical significance. However, the paragraph on existing therapies (ACEi, ARBs, corticosteroids) could be expanded to include more discussion on the limitations of these treatments in the context of IgAN, especially in relation to long-term outcomes. This would better set the stage for the need for new therapeutic interventions.

The discussion on the risks of corticosteroid therapy could be more detailed. For example, providing specific data or references on the adverse effects associated with corticosteroids would strengthen the argument for exploring alternative treatments.

2. Methods:

Study Selection: The methods for study selection are clear, and the authors have used appropriate inclusion and exclusion criteria (e.g., randomization, sample size ≥30). However, the protocol for this SLR was not registered. While this is acceptable, it is important to state why this was not done and how the review maintained transparency and rigor in the absence of registration.

Search Strategy: The search strategy is robust, covering key databases and supplementing electronic searches with manual searches of conference abstracts and clinical trial registries. One potential limitation is the restriction to English-language publications. The authors could mention whether non-English studies were considered or excluded, and how this might affect the generalizability of the findings.

Risk of Bias Assessment: The authors mention using NICE guidelines to assess the risk of bias, but the details of this process could be clearer. For instance, a brief summary of the bias assessment results for included studies would be helpful for readers to understand the quality of the evidence synthesized.

3. Results:

Study Characteristics: The results section is well-organized, and the synthesis of the 76 included randomized controlled trials (RCTs) is comprehensive. However, the authors could better highlight the key findings from the Phase 3 trials (NefIgArd and PROTECT) earlier in the results section to draw attention to the most relevant and high-quality evidence.

Data Presentation: The results are presented clearly with appropriate use of tables and figures to summarize study designs, patient characteristics, and key outcomes. However, the text could be improved by making explicit connections between the tables/figures and the narrative. For example, in Table 8 (eGFR outcomes), it would be helpful to briefly summarize the key findings in the text and highlight the clinical significance of the eGFR changes reported.

Study Heterogeneity: While a narrative synthesis is appropriate for the heterogeneity of the included studies, it may be helpful to briefly address the extent of heterogeneity in study designs, patient populations, and interventions. This would provide readers with a clearer sense of the limitations of the review.

4. Discussion:

Interpretation of Findings: The discussion effectively summarizes the key findings and places them in the context of existing literature. The authors highlight the need for further high-quality studies with longer follow-up periods. This is a critical point, and the authors could expand on the potential reasons for the mixed results in the current body of evidence. For example, how might study design, sample size, or bias have contributed to these inconsistent findings?

Implications for Practice: The implications for clinical practice could be more explicitly stated. For instance, what specific recommendations can be made for clinicians based on the findings of this review, especially regarding newer treatments like TRF-B and sparsentan? A brief discussion of the real-world application of these findings would help strengthen the manuscript.

Limitations: The authors acknowledge several limitations of the included studies, such as small sample sizes, risk of bias, and short follow-up periods. However, a more in-depth exploration of the limitations of the review itself (e.g., potential publication bias, exclusion of non-English studies) would enhance the transparency and rigor of the manuscript.

5. Conclusion:

The conclusion summarizes the key points effectively but could be more concise. The call for further randomized controlled trials with longer follow-up periods is appropriate, but it would be helpful to highlight the specific areas in which additional research is most urgently needed (e.g., the long-term efficacy of TRF-B, sparsentan, or combination therapies).

Minor Comments:

Figures and Tables: Ensure that all figures and tables are clearly labeled and referenced in the text. For example, Table 8 on eGFR outcomes could benefit from a more thorough explanation in the main text about how the data were interpreted.

References: Some references are cited more than once in different parts of the manuscript (e.g., references to TRF-B and sparsentan studies). Ensure consistent citation style and check for duplicates in the reference list.

Language: While the manuscript is generally well-written, there are occasional minor grammatical errors and awkward phrasing. Consider a thorough review for clarity and readability.

Reviewer #2: It is with great pleasure that I review the manuscript entitled "Clinical study outcomes in IgA nephropathy: a systematic literature review and narrative synthesis". It is a well-written manuscript that tackles an important topic in IgAN treatment. I have only a few suggestions:

1) I suggest creating subtopics for each treatment modality in the immunosuppressive/immunomodulatory section of the results for better clarity.

2) I suggest adding the statistical test used in each study related to the provided p-values in the tables, when available.

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Reviewer #1: No

Reviewer #2: No

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Clinical study outcomes in IgA nephropathy: a systematic literature review and narrative synthesis

PONE-D-24-42874R1

Dear Dr. Anushya Jayabalan

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,

Rajendra Bhimma, PhD

Academic Editor

PLOS ONE

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