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Additional Editor Comments:

Please address all comments raised by Reviewers.

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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?

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: 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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: This study provides an important, data-driven overview of the growing burden of DKD attributable to high BMI, especially in the context of the global obesity epidemic. Its integration of long-term trends, predictive modeling, and socioeconomic analysis makes it valuable for policymakers and researchers. It provides a valuable and comprehensive assessment of the global and Chinese burden of diabetic kidney disease (DKD) attributable to high BMI over three decades, with forecasts to 2045. Strengths include the use of extensive GBD 2021 data, long-term trend analysis with joinpoint regression, predictive modeling via NORDPRED, and stratification by age, sex, and sociodemographic index. These features enhance the study’s policy relevance, particularly for high-burden regions such as China. However, limitations include reliance on modeled data with variable quality across countries, the narrow focus on high BMI without considering interactions with other risk factors. It focuses solely on DKD attributable to high BMI, excluding other major contributors (e.g., hypertension, hyperglycemia, dyslipidemia) and it does not explore interactions between high BMI and other metabolic risk factors.

I suggest to the authors to amplifythe discussion on integrating technological, pharmacological, and mechanistic advances which may help to reduce the rising DKD burden linked to high BMI. Digital tools such as the AWARE web application can facilitate early cardiovascular—and potentially renal—risk identification in high-BMI patients (Berra et al., 2023). Real-world evidence shows that combining GLP-1 receptor agonists with SGLT2 inhibitors improves glycemic and weight control in obese, high-risk individuals (Berra et al., 2024), while intensive cardiometabolic management can also induce atherosclerotic plaque regression (Bucciarelli et al., 2025). Moreover, GLP-1 receptor activation may provide immunomodulatory benefits relevant to DKD pathophysiology (Ben Nasr et al., 2024).

New references to add

1. Berra C, Manfrini R, Mirani M, et al. AWARE: A novel web application to rapidly assess cardiovascular risk in type 2 diabetes mellitus. Acta Diabetol. 2023;60(9):1257-1266.

2. Berra C, Manfrini R, Bifari F, et al. Improved glycemic and weight control with dulaglutide addition in SGLT2 inhibitor-treated obese type 2 diabetic patients at high cardiovascular risk in a real-world setting: The AWARE-2 study. Pharmacol Res. 2024;210:107517.

3. Bucciarelli L, Andreini D, Stefanini G, et al. Pharmacological regression of atherosclerotic plaque in patients with type 2 diabetes. Pharmacol Res. 2025;213:107635.

4. Ben Nasr M, Usuelli V, Dellepiane S, Seelam A, et al. Glucagon-like peptide-1 receptor is a T cell-negative costimulatory molecule. Cell Metab. 2024;36(6):551-566.e8.

Reviewer #2: Authors of the manuscript titled “Charting novel cellular subpopulations in the renal cortex of diabetic nephropathy in a mouse model through single-cell RNA sequencing” performed single cell-RNA sequencing of renal cortexes of STZ-treated mice as a model of type1 diabetes. Gene expression was compared to untreated animals and in-depth analysis revealed interesting changes in distal convoluted tubule and immune cell populations. The manuscript is well written and presented. However, I suggest a major revision before publication. Here my comments:

1) Methods - Authors should better explain immunofluorescence methods.

2) Methods - Authors should include methods for H&E and Masson’s trichrome staining.

3) Methods - Authors should add a paragraph of methods for statistical analysis.

4) Experimental results and analysis - Authors should avoid in this section comments such as the following “GABARAPL1 was implicated in diabetic kidney disease through machine learning methods, and our findings further validated this”. These comments should be placed in the discussion section.

5) Experimental results and analysis - Authors should quantify the immunofluorescence staining using 3 mice per group and at least 10 images per mouse.

6) Experimental results and analysis - Authors should specify in the figure legends the number of biological replicates used for the experiments.

7) Experimental results and analysis - Authors should add higher magnification images for H&E and Masson’s trichrome.

8) Experimental results and analysis - Authors should add a quantification of Masson’s trichrome stained images.

9) The manuscript could benefit from the additional analysis of hub transcription factors controlling gene expression changes observed in T1D model vs. control animals.

10) Authors should cite the following manuscripts: PMID 36871895 PMID 35947673.

Reviewer #3: The paper “Analysis and prediction of the burden of diabetic kidney disease attributable to high body mass index in global and Chinese populations from 1990 to 2021” summarize publicly available data from the Global Burden of Disease study 2021 (GBD 2021) and makes a prediction of high BMI-related- DKD incidence for 2022-2045 in global and Chinese populations. Analysis and prediction of the burden of DKD attributable to high body mass index in global population are not new and were published by different groups during recent years (Ying J, et al; Global, regional, and national burdens of chronic kidney disease attributable to high body mass index from 1990 to 2021, with future forecasts up to 2050: a systematic analysis for the global burden of disease study 2021. Front Public Health. 2025 Jul 9;13:1612300. doi: 10.3389/fpubh.2025.1612300. PMID: 40703164; PMCID: PMC12283729; Tan H, et al; Global burden and trends of high BMI-attributable chronic kidney disease: a comprehensive analysis from 1990 to 2021 and projections to 2035. Front Nutr. 2025 Jul 22;12:1611227. doi: 10.3389/fnut.2025.1611227. PMID: 40777172; PMCID: PMC12330218). Figures 4 and 5 are very similar to the ones presented in these papers. Moreover, the paper is too descriptive and does not properly highlight authors results and predictions. Below all the flaws that must be addressed before the paper could be considered for publication.

Major

- The all paper must focus on the analyses of data on Chinese population. Global data should be used just as comparison and should not be presented as new data. As consequences also figures should be modified (in particular figure 4 and 5).

- Titles of results chapters should not describe the analysis but highlight the general finding.

- Discussion is too general and descriptive and does not focus on authors findings, making hard to understand results and their novelty. Please stress your results novelty and relevance.

- Materials and methods, line 71: which are the criteria used to define high BMI? If official WHO criteria were used, please add reference to them and not to a paper made on Ethiopian population.

Minor

- Figures legends should be moved after references

- Introduction, line 48: please add a sentence briefly describing DKD You could refer to Petrazzuolo A, et al; Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease. Pharmacol Res. 2023 Apr;190:106710. doi: 10.1016/j.phrs.2023.106710. Epub 2023 Mar 4. PMID: 36871895.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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High BMI-Attributed Diabetic Kidney Disease in China Versus Globally, 1990-2021, with Projections to 2045: Divergent Trends and an Accelerating Burden

PONE-D-25-36429R1

Dear Dr. Chen,

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,

Francesca D'Addio, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #1: The authors responded to all the comments and the manuscript in this new version is now ready for publication

Reviewer #3: (No Response)

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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 #3: No

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