PONE-D-21-07064

Conceptualization semicolons

A Comparison Study of Chronic Kidney Disease Biomarkers and Mortality among Older Adults in China and the United States

PLOS ONE

Dear Dr. Ji,

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.

The manuscript presents interesting data and is of potential interest given the scale of the analysis. However, there are several important limitations that preclude to accept the manuscript in its current form. We invite you to submit a revised version of the manuscript that addresses the points below:

Please keep special attention to the Reviewers' suggestions, including:

1. Need to perform analysis with inclusion of the survey weights.

2. Need to report results for each age groups or age-standardization.

3. Better clarification of differences between populations considering age-specific eGFR.

4. Inclusion of additional factors in the model.

5. Enhancement of the "Discussion" section.

Additionally, I suggest to:

1. Rephrase some sentences (for example, the first phrase of the "Introduction" is not fully compliant with the KDIGO definition, the phrase "In CLHLS, the next of kin reported the mortality information in the follow-up surveys in 2014 and 2017/2018." should be changed for clarity) and edit the text in some places for better connection between concepts and paragraphs (the second paragraph of the "Introduction" starting with "China is a middle-income..." would be better to initiate with something like "Previous studies revealed substantial difference between China and USA in the ...").

2. Indicate more details for the Chinese Longitudinal Healthy Longevity Study, and provide after the phrase "The study design and sampling method were described previously (8)" some key information with "In brief, ...". These additional details could better explain the reasons of differences between CLHLS and NHANES. Probably, a table with some core characteristics of both surveys would allow to present them in a clear and concise way.

3. Clearly indicate in the "Methods" whether the determination of serum creatinine measurement procedures has been standardized to isotope dilution mass spectrometry (IDMS).

4. Provide in the "Data sharing statement" information about the data availability (not "additional" but the surveys data).

5. Please use "urinary albumin" instead of "urinary microalbumin".

6. Use IQR instead of range for the description of ACR and other biomarkers in the manuscript.

7. Instead of "Predictors of CKD" that could be revealed in the longitudinal study, the cross-sectional part of the current analysis (related to Table 2) should use the terminology "Factors associated with CKD".

8. The data provided in the "Figure 1" is widely available, and should be moved to the Supplementary.

9. Change legends in figures: instead of "CKD=1 / CKD=0" use "CKD / no CKD", don't use "Strata" in the legend.

10. As you correctly identified in the "Methods", the KDIGO defines CKD based on eGFR and albuminuria. The current analysis merge persons with either low eGFR or increased albuminuria into a single "CKD" group, and presents the data according to presence/absence of CKD. It would be a great advantage if, in addition to this already available analysis, the authors will present a separate analysis for "normal vs low eGFR" and "normal vs increased albuminuria" groups.

11. Please review the tables' titles for clarity (both in the main manuscript and Supplement).

12. Please unify the data representation in tables. In the Supplementary table 2 some cells have no decimal signs, some have (or there is some mistyping): for example in the ACR column for different age groups the values are "8.4 (5.4,17.9)", "10.3 (6,22.7)", etc.

13. Please clarify in "Methods" the phrase "In the logistic regression and the Cox models, missing value of covariates were not excluded, but coded as a categorical variable."

Please submit your revised manuscript by Jul 04 2021 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: http://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,

Boris Bikbov

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.Thank you for providing consent information in the ethics statement of the online submission form. Please also state whether written informed consent was obtained from participants of the CLHLS study.

3. Thank you for providing the date(s) when patient medical information was initially recorded. Please also include the date(s) on which your research team accessed the databases/records to obtain the retrospective data used in your study.

4. Please provide references for the NHANES and CLHLS studies if any exist.

5. Please include your actual numerical p-values in Tables 3, S3, S6, S8, and S9.

6.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

7. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical.

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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?

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: No

Reviewer #2: Yes

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

Reviewer #1: No

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 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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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

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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: 1. Summary

The study summarizes chronic kidney disease biomarkers and mortality among elderly participants in the NHANES survey in the United States and the CLHLS survey in China. It reports on many biomarkers, highlighting a few where they identify differences. The article also reports differences in the mortality among CKD patients in the two surveys and briefly hypothesizes some possible reasons for the differences. However, the authors do not discuss the implications of the overall findings (especially where inconsistencies were found) but rather they summarize tabulated data. More importantly, they overstate the generalizability of the results because they did not incorporate the survey weights into their analyses. This last point is the primary weakness of the study and makes it impossible to accurately assess differences between the two populations. I recommend major revisions before acceptance.

2. Areas for improvement

Major issues:

The authors should repeat the analysis with inclusion of the survey weights of each survey. This current omission prevents comparison and generalizability to the populations these surveys represent. It was briefly noted in the Discussion (lines 474-477) that weights were not used, with no discussion of why or what the implications are. This was a few sentences after the cohort size and representativeness of the samples was incorrectly touted as a strength of the study (lines 467-477). The conclusion (lines 484-487) generalizes to the countries by stating differences were found between “the elderly population in the US” and “in China”, which the study has failed to show.

Also, as the age distributions of the survey participants are quite different between the two samples (lines 246-247), comparison should occur within detailed age groups, or age-standardized across included age groups. This will more accurately highlight real differences in biomarkers or mortality that are not simply due to ageing. For example, reported prevalence of CKD in line 264 could also be reported as age-standardized to better compare the two samples. The age breakdown in lines 267-270 is helpful and better conveys the differences (higher rates in all age groups in US sample than in China sample) than the overall rates in line 264 (higher overall rate in China sample), which is misleading. This is also an issue in the discussion, where line 410 claims that eGFR is lower in the China sample than in NHANES, but line 413 acknowledges that the age-specific eGFR was higher in the Chinese sample for all but the oldest age group. The authors should take care to report and interpret meaningful results.

The conclusion of the abstract supposes that some of the differences may be due to co-morbid conditions (line 53). But this would easily be partially accounted for by at least including indicators for diabetes and hypertension in the adjusted model. Calculating separate results among those with diabetes and/or hypertension is coarse and not very useful, as the authors themselves note that diabetes and hypertension prevalence differs quite a bit between the study populations. Given the known associations between these two conditions and CKD, they should be included in the adjusted models.

In the discussion, differences were repeated but the “why” was not explored. For example, lines 389-394 report that females had higher levels of CKD in the Chinese sample, but there was no association between sex and CKD diagnosis in the US sample. But there was no discussion about why this might be observed. Also, in the US, high household income and low education level were associated with CKD prevalence (lines 392-393) but these two characteristics are typically at odds with each other; usually higher income households have more education. I wish this apparent paradox had been somewhat explored or explained.

Minor issues:

GBD 2019 has been published for a while now and should replace the GBD 2017 source.

What are the implications of the differences in CKD biomarker measurement techniques? This is vaguely included as a limitation (lines 477-478) but not discussed at all in terms of how it affects interpretation of results. The title of the article should be revised to place less emphasis on biomarkers if the authors are not confident about the comparability of biomarker measurement between the samples or able to discuss the potential bias in more detail.

Baseline characteristics of % diabetes and % hypertension among participants should be reported.

The reported in-text results were cumbersome to read and difficult to draw conclusions from as a reader, but I acknowledge that can be difficult when reporting many different variables. (examples: lines 359-360 in particular, and paragraphs that contain lists of CKD prevalences)

It is unclear why the authors also conducted the analysis using the MDRD equation for the NHANES sample. Written justification would have strengthened the decision to include it.

Positive correlations should be assessed for both statistical significance and clinical relevance. The reported OR of 1.000 (1.000, 1.000) in line 351 is apparently statistically significant (with more decimal places?) but is meaningless clinically.

Edit for clarity:

- “bad at self-rated” (line 319)

- “associated with … White, other races…” (line 321)

- “In previous studies…” should be “In a previous study…” (line 416)

A study cited in the discussion found male sex predictive of CKD in a Chinese sample, which the authors claim “is consistent with our results (line 419). But line 389 states that female sex is predictive of CKD in this study’s Chinese sample, which is the opposite of the cited study.

I’m curious if the comparison studies described in the Discussion adjusted their models with the same or similar list of variables, or if differences in variables could account for some of the different results. (for example the study in lines 436-437 that reported different results than this study)

Was prevalence of chronic glomerulonephritis available in either of the surveys? If so, it should have been included in the adjusted models. If not, it would have been helpful to have it stated explicitly (since diabetes and hypertension were available). The one mention of this common primary renal diagnosis, especially in China, was insufficient given its potential importance to some of the differences shown. In renal registries, for example, survival among patients on renal replacement therapy is sometimes reported by primary renal diagnosis (especially diabetes, hypertension, chronic glomerulonephritis, and perhaps other causes), which would have supported the authors’ assertion that underlying comorbidities may account for differences in mortality. I believe from registries, that mortality is higher among patients with ESRD due to diabetes than those with ESRD due to chronic glomerulonephritis. So if more US patients have diabetes than the China samples, and vice versa with chronic glomerulonephritis, then this would be an easy connection to make to support the results.

I wasn’t clear by the end of the article exactly what the purpose of the study was or what conclusions I should draw from it are. The results can certainly be useful, but I wish the Introduction and Discussion had built up more motivation for and implications of the study.

Figures:

- Figure 1 should be a table.

- Figures 2 and 3 should be clearly labeled with CLHLS and NHANES.

Reviewer #2: Thanks for sharing this interesting work. Differences between populations are always a reason for hypothesis for future research regarding their causality (factors, genetic, racial, dietary or others). Very extensive information has been collected and compared, which is difficult to show clearly and is not at times overwhelming and confusing in its presentation.

The study hypothesis is clearly stated, and the population used is adequate.

The methodology is adequate, using population surveys. A problem that will creep into all the results analyzed is the age difference between the two populations. Although multivariate analyzes have been carried out trying to minimize the effect of the age difference between the populations, the use of a matched analysis with more similar populations could have been a useful strategy.

It looks like a comment at least should be done regarding the BMI classification for older adults (aged 65 or older) since a metanalysis published in 2014 by Winter and Al, has shown a different classification for this population (Winter JE, MacInnis RJ, Wattanapenpaiboon N, Nowson CA. BMI and all-cause mortality in older adults: a meta-analysis. Am J Clin Nutr. 2014 Apr;99(4):875-90) suggesting that optimal BMI for those >65 years is likely between 23-30, instead of 18.5 to 25.

Regarding the Results

The two populations studied differ widely in the age of the population, with the Chinese population averaging 13 years older (85 vs. 73 years).

This difference can explain many of the other differences found, even some that seem obvious like practicing physical activity. The fact that the Chinese population is much older than the US population should be discussed, it could be a survivor bias, being a "healthier" population.

In relation to the way of presenting the results, which involve a wealth of information, their presentation would be clearer and easier to read if additional headings were incorporated for the different results to be described., As well as for including headings at the discussion.

A minor commentary: the subtitle of the prevalence chapter would be more adequately described as “Difference in CKD prevalence between the two countries” or “Prevalence of CKD in both countries”.

An additional issue for the mortality analysis may be the loss to follow-up of 321 CLHLS participants (page 13 , line 128, representing 14% of the population. It should be investigated whether these participants were not lost to follow-up due to death, or comment that this was ruled out.

Regarding the limitations of the study, it should be mentioned the differences in the age of both population, that could itself explain many differences between both populations.

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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: Sarah Wulf Hanson

Reviewer #2: Yes: Laura Sola

[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.

PONE-D-21-07064R1

A Comparison Study of Chronic Kidney Disease Biomarkers and Mortality among Older Adults in China and the United States

PLOS ONE

Dear Dr. Ji,

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.

In addition to the Reviewers' comments, please consider the following items:

1. Regarding the extended tables, please consider to use bold style to underline the statistically significant results (this is just a suggestion, not obligatory requirement).

2. Please use 2 decimal signs in OR, i.e. instead of "1.801 (1.054-3.075)" use "1.80 (1.05-3.07)"; except of the cases where more decimal signs are required to demonstrate the 95%CI close to 1 (like "1.0003-1.18").

3. Please revise the manuscript for style describing intervals, and change it to more easier to readers (i.e. avoid technical expressions like "eGFR in [30,45) did not increase mortality risk", and use instead "eGFR 30-45 ml/min/1.73m2")

4. Considering the reviewer's comment "Positive correlations should be assessed for both statistical significance and clinical relevance. The reported OR of 1.000 (1.000, 1.000) in line 351 is apparently statistically significant (with more decimal places?) but is meaningless clinically." and your response "...At a later stage, we will work with the editorial staff to ensure that the reporting guidelines are met....." - Please consider that once the manuscript is accepted for the publication, there will be only minimal grammar/style changes implemented by the Editorial office. Thus, all issues should be resolved during the revision, and this particular reviewer's comment should be addressed properly now, before the "Accepted" decision.

5. The Associate Editor reviewed your manuscript and has indicated "Please assess the reporting of this observational study of clinical data using the STROBE checklist (http://www.strobe-statement.org)"

6. Please use in the "Article summary" the phrases that a reader could understand without reading the manuscript. For example, the phrase "CKD is associated with higher mortality in US study participants, perhaps due to comorbid conditions." would be more clear if changed to something like "CKD is associated with higher mortality in US but not in China study participants, perhaps due to comorbid conditions." Instead of general statement "US study participants had higher concentrations of CKD-related biomarker levels compared with Chinese participants" use the complete list of biomarkers.

The item "Strengths and limitations of this study. Our data was derived from large nationally-

61 representative cohorts in both countries. However, there are challenges in age

62 distribution differences, standardization of CKD biomarker measurement techniques, as

63 well as covariates definitions." should be rephrased for clarity and conciseness.

7. The description of two groups comparison like "The urinary

312 albumin in China was lower than in the US (mean: 25.0 vs. 76.4, median: 5 vs. 11.2, IQR:

313 17.8 vs. 11.2 unit: mg/L)" or "people with lower education (27.2 mg/L of “no formal education” vs 103.9 mg/L of “below high school”)" has limited meaning. Please use plain language and refer to the table with numeric results, or indicate widely accepted measures of central tendency and variability in the text. This also concerns the description at lines 313-339.

8. Some references have no page numbers or eNumber, or ISBN (where appropriate) - like ref 22, 26 and many others. Please check all references and format appropriately.

9. It seems the Table 2 title should be "Odds ratio (95% CI) of factors associated with CKD in CLHLS 2011 participants (China)"

10. In the Supplementary Table 1. Cohorts’ characteristics of this study it is indicated "Older men and women aged 65 or above" for both cohorts. However, the NHANES includes also persons 18-64 years old. Please could you explain?

Please submit your revised manuscript by Oct 07 2021 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: http://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,

Boris Bikbov

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

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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

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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: Yes

Reviewer #2: Partly

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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: The authors' changes have improved the manuscript a great deal. Some light copy-editing is needed. One last change I would recommend is including the limitation of much higher loss to follow-up in the CLHLS sample versus the NHANES sample.

Reviewer #2: As a consequence of correcting the text to the recommendations, the article has greatly improved.

Some minor elements persist, some already mentioned previously.

1. In the Methods chapter, on page 9 when describing "Measurement of biomarkers. In CLHLS, the urine was tested for microalbumin" should refer to albumin and not to microalbumin.

2. The diagnosis of hypertension should include, in addition to the presence of BP <140/90, the intake of antihypertensive medication

3. When describing the prevalence of CKD in both populations, some findings are contrary to the usual occurrence, so must be made some comment. In Chinese participants, those who never smoked and did physical activity, a higher prevalence of CKD was found, this finding should be commented, which is surely more in relation to age than to these characteristics, and is contrary to the effects of smoking and physical activity in general.

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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.

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: Sarah Wulf Hanson

Reviewer #2: Yes: Laura Sola

[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.

PONE-D-21-07064R2A Comparison Study of Chronic Kidney Disease Biomarkers and Mortality among Older Adults in China and the United StatesPLOS ONE

Dear Dr. Ji,

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 Nov 21 2021 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,

Boris Bikbov

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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: (No Response)

Reviewer #2: 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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

Reviewer #2: 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: This manuscript has improved, but a few remaining issues need to be resolved.

1. In the Abstract conclusion, you state that "the association between CKD and mortality was also stronger among the US older adults. This may be due to age difference, biological differences, or co-morbid conditions." However, the statistical models control for age, and so the estimated hazard ratios control for age. So age differences would then not contribute to the difference in strength of association. I suggest removing "age difference" from the last sentence.

2. The last sentence of the Introduction seems states a result rather than a hypothesis. Restate as a hypothesis.

3. Check all references for accuracy (line 94 says "refs", for example, rather than reference numbers).

4. Line 243 states that "age was adjusted for as categorical in the logistic models" but does not state how. Better would be "age was included as four separate age bins (65-69, 70-74, 75-79, 80+) in the logistic models".

5. Line 518-526 discusses the rationale for excluding sample weights from the current analysis. I find this reasoning unconvincing, especially because CLHLS oversampled rural areas and NHANES minorities and lower SES, and the non-weighted results are therefore clearly non-representative. The analysis including sample weights should be in the main text, especially as NHANES has not issued guidance to ignore sample weights in that survey.

Reviewer #2: The questions posed have been answered in an acceptable way. In its new edition the article has been vastly improved, and is fit to be published.

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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.

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: Sarah Wulf Hanson

Reviewer #2: Yes: Laura Sola

[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.

PONE-D-21-07064R3A Comparison Study of Chronic Kidney Disease Biomarkers and Mortality among Older Adults in China and the United StatesPLOS ONE

Dear Dr. Ji,

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 Nov 28 2021 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Boris Bikbov

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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: (No Response)

**********

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

**********

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

**********

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

**********

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: I thank the authors for their quick response. I accept that they will not include sample weights in the main analysis of the paper and am glad the Supplement includes them, and I now suggest two remaining changes:

1. Change statements that assert national representativeness

In the authors' last response, they state "However, we prefer not to include the weights in the main text for reasons stated in the last revision, plus we are not making population at large statements. Treating each participant as an individual allows us to avoid some bias that may be introduced by weights, and since the motivation of our study is to look at epidemiological dose-response relationship, rather make population prevalence estimates, our method is perhaps more robust statistically." In the Results section, the authors are careful to restrict statements to the study samples, but there remain many sentences that do still refer to "the US" or "China" (or similar generalized references), and there are many sentences that do make population prevalence estimates, contrary to the authors' response. Before publication, results need to be changed to refer to the study samples (such as "CLHLS sample" or "US participants", etc) rather than the countries in all of the following lines:

282-285 (example wording change included below), 287, 303, 305, 309, 311, 312, 313, 315-326 ("both countries" change to "both samples"), 332 ("two countries" change to "both samples"), 343, 362, 421, 423, 442, 450, 456.

Original text for lines 282-285: "Among people over 65 years of age, the prevalence of CKD in China and the US were 44.4% (95% CI: 42.2%-46.6%) and 42.3% (95% CI: 40.2%-44.6%), respectively. Besides, the CKD prevalence for the participants without diabetes and hypertension were 37.8% in China and 33% in the US (diabetes/hypertension prevalence: 58% in China vs. 50% in the US)."

Suggested change: "Among people over 65 years of age, the prevalence of CKD in the CLHLS and the NHANES samples were 44.4% (95% CI: 42.2%-46.6%) and 42.3% (95% CI: 40.2%-44.6%), respectively. Besides, the CKD prevalence for the participants without diabetes and hypertension were 37.8% in CLHLS and 33% in NHANES (diabetes/hypertension prevalence: 58% in CLHLS vs. 50% in NHANES)."

2. Clarify that the sample weight limitation applies to both surveys.

Lines 525-526 original text: "We only presented the results considering sample weight as supplementary materials."

Suggested change: "We excluded sample weights from CLHLS for this reason and from NHANES for consistency, and we present results incorporating the sample weights for both studies in the supplementary materials."

I thank the authors for the opportunity to provide feedback on this manuscript, and I look forward to seeing it published soon.

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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.

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: Sarah Wulf Hanson

[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.

Chronic Kidney Disease Biomarkers and Mortality among Older Adults: A Comparison Study of Survey Samples in China and the United States

PONE-D-21-07064R4

Dear Dr. Ji,

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,

Boris Bikbov

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

**********

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

**********

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

**********

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

**********

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: I thank the authors for their final changes and for being willing to go through multiple rounds of revisions. I think this manuscript is now ready for publication.

**********

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: Sarah Wulf Hanson