Predictors of elevated carotid intima-media thickness as a surrogate marker for cardiovascular disease in pediatric chronic kidney disease

Emi Yulianti; Retno Palupi-Baroto; Sasmito Nugroho; Noormanto Noormanto; Maria Grace Wilianto; Dwi Astuti Dharma Putri; Indah Kartika Murni

doi:10.1371/journal.pone.0329412

Peer Review History

Original SubmissionJune 26, 2024
Decision Letter - Elena Olmastroni, Editor PONE-D-24-25206Predictors of increased vascular thickness in children with chronic kidney diseasePLOS ONE Dear Dr. Murni, 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 Dec 20 2024 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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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 amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical. [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: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: No Reviewer #2: 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 ****** 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 very much for inviting me as a peer reviewer and giving me the opportunity to review. The author studied the predictive factors of increased vascular thickness in children with chronic kidney disease. This research is of great significance for reducing cardiovascular events in children with CKD in the future. The content of the article still needs further modification to arouse more interest from readers. Introduction� There is a lack of connection between the first paragraph and the second paragraph. The first paragraph of this article tells the reason for the high mortality rate of CKD. The second paragraph directly leads to the acceleration of atherosclerosis and cardiovascular disease. The lack of connection of relevant content may confuse readers. Suggest the author to add reasons (such as high CKD mortality rate, which may be caused by factors such as XX, XX, etc., with cardiovascular factors being the main factor). Methods� 1. The sample size of this study is 71 cases. How did the author determine the sample size? It is not provided in the manuscript. 2. Was blinding used in this study? If used, is it single blind or double-blind? Please explain to the author. 3.What is the deadline for measuring CIMT at least three months after CKD diagnosis? Is follow-up conducted after CIMT and echocardiography measurements? If so, how long is the follow-up period? Results� Could the author explain the main outcome measure of this study? Is it CIMT? Please explain and make corresponding modifications to the abstract section. Discussion� What is the possible reason for the statistical difference in the systolic and diastolic function of the heart between the CIMT elevated group and the non elevated group? Please add relevant literature to enhance the persuasiveness of the content. Other parts� Is the relevant data in this article shared? Please indicate at the end of the article that the author. Reviewer #2: Thank you for inviting me to review this manuscript. Overall, the study gets 2 out of 5 points regarding its novelty. I think the manuscript needs a major revision and cannot be considered for publication without addressing the following points: -The title of the study does not accurately reflect its content and should be revised for better alignment. - remove the sentences saying that this study is the first study on this topic. -The authors describe their study as a retrospective cohort; however, the duration of follow-up is unclear. If no follow-up was conducted, please clarify how the relative risk (RR) was calculated. -Line 46: The time period for which this mortality rate applies is missing. Please specify the year. -Methods: It is recommended to include details about the ultrasound device used in the study. -Methods: A reference for the assessment of nutritional status should be cited. -Methods: Please provide details on how height and weight measurements were conducted. -The limitations section should be expanded, as the study has additional limitations that were not fully addressed. ****** 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: No Reviewer #2: 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.0329412.r001
Revision 1
16 Apr 2025 Author Response PONE-D-24-25206 Predictors of increased vascular thickness in children with chronic kidney disease Response to the reviewers Reviewer 1 Comments to the Author Thank you very much for inviting me as a peer reviewer and giving me the opportunity to review. The author studied the predictive factors of increased vascular thickness in children with chronic kidney disease. This research is of great significance for reducing cardiovascular events in children with CKD in the future. The content of the article still needs further modification to arouse more interest from readers. Introduction? There is a lack of connection between the first paragraph and the second paragraph. The first paragraph of this article tells the reason for the high mortality rate of CKD. The second paragraph directly leads to the acceleration of atherosclerosis and cardiovascular disease. The lack of connection of relevant content may confuse readers. Suggest the author to add reasons (such as high CKD mortality rate, which may be caused by factors such as XX, XX, etc., with cardiovascular factors being the main factor). Authors’ response Thank you for the suggestion to revise the wording and flow of the manuscript. We have amended the sentences as suggested. Change made in the manuscript The elevated mortality risk is largely attributed to factors such as accelerated atherosclerosis, vascular calcification, and chronic inflammation, which are common in CKD patients. Among these, cardiovascular disease stands out as a major in individuals with end-stage CKD. (Page 3, line 45 – 47) Methods? 1. The sample size of this study is 71 cases. How did the author determine the sample size? It is not provided in the manuscript. 2. Was blinding used in this study? If used, is it single blind or double-blind? Please explain to the author. 3. What is the deadline for measuring CIMT at least three months after CKD diagnosis? Is follow-up conducted after CIMT and echocardiography measurements? If so, how long is the follow-up period? Authors’ response Thank you for the suggestion to improve the method section. We have modified the related points as suggested. 1. Sample size calculation have been added in the method section. 2. This study is a single blind study who is the trained technicians conducting the echocardiography assessment, we added this information within the manuscript. 3. No follow up period after CIMT measurement was conducted within this study, this limitation was listed within the discussion. Change made in the manuscript 1. The sample size calculation was based on a 74.5% prevalence of elevated CIMT in children with CKD, considering five independent variables. Following the rule of thumb for factor analysis (at least 10 events per predictor), a minimum of 67 patients was required (Page 4, line 78 – 80) 2. As a part of single-blind study design, the measurement was done by trained technicians who were blinded to the participant’s clinical information. (Page 6, line 120-121) 3. None Results? Could the author explain the main outcome measure of this study? Is it CIMT? Please explain and make corresponding modifications to the abstract section. Authors’ response This study aimed to identify predictors of cardiovascular events in pediatric patients with CKD, using CIMT as a surrogate marker. The independent variable was the predictors of elevated CIMT, while the dependent variable (outcome) was CIMT. This outcome has been incorporated into the abstract (last sentence of the background), as well as the introduction and methods sections. Change made in the manuscript Abstract: Carotid intima-media thickness (CIMT) was the outcome measure, assessed at least three months post-diagnosis to evaluate cardiovascular events based on vascular thickness (Page 2, line 24-26). Method section: The independent variable was the predictors of elevated CIMT, while the dependent variable (outcome) was CIMT (Page 7, line 144-145). Discussion? What is the possible reason for the statistical difference in the systolic and diastolic function of the heart between the CIMT elevated group and the non elevated group? Please add relevant literature to enhance the persuasiveness of the content. Authors’ response As provided in the Result section, page 10 line 169-170, this study revealed that systolic and diastolic functions showed no statistical differences between groups with and without elevated CIMT. Change made in the manuscript None Other parts? Is the relevant data in this article shared? Please indicate at the end of the article that the author. Authors’ response Data used in this study is available upon request. Change made in the manuscript Data used in this study is available upon request. (Page 8, line 154) Reviewer 2 Comments to the Author Thank you for inviting me to review this manuscript. Overall, the study gets 2 out of 5 points regarding its novelty. I think the manuscript needs a major revision and cannot be considered for publication without addressing the following points: 1. The title of the study does not accurately reflect its content and should be revised for better alignment. Authors’ response Thank you for the feedback, we have modified the title and replaced it with “Predictors of elevated carotid intima-media thickness as a surrogate marker for cardiovascular disease in pediatric chronic kidney disease” Change made in the manuscript Predictors of elevated carotid intima-media thickness as a surrogate marker for cardiovascular disease in pediatric chronic kidney disease (Page 1, Line 1-2) 2. Remove the sentences saying that this study is the first study on this topic. Authors’ response Thank you for the suggestion to remove the specific sentence, we have modified it as suggested. Change made in the manuscript As far as we are aware, limited studies have explored predictive factors for cardiovascular events in children with CKD in Indonesia (Page 4, Line 66-67). 3. The authors describe their study as a retrospective cohort; however, the duration of follow-up is unclear. If no follow-up was conducted, please clarify how the relative risk (RR) was calculated. Authors’ response Our retrospective cohort study used multivariate logistic regression to identify independent predictors at diagnosis (e.g., age, male sex, obesity, CKD stage, and hypertension) associated with elevated CIMT (outcome), measured at least three months post-diagnosis as a proxy for cardiovascular risk. Adjusted odds ratios (OR) were obtained from the analysis, as stated in the abstract. We have also corrected the RR in Table 3 as suggested. Change made in the manuscript Abstract: We used multivariate logistic regression to identify independent predictors at diagnosis (e.g., age, male sex, obesity, CKD stage, and hypertension) associated with elevated CIMT (outcome), measured at least three months post-diagnosis as a proxy for cardiovascular risk (Page 2, line 24-26). Table 3: OR: Odd Ratio (Page 11, Line 182-183). 4. Line 46: The time period for which this mortality rate applies is missing. Please specify the year. Authors’ response Thank you for the kind correction, we have added the time period of the mortality rate in the manuscript. Change made in the manuscript In 2018, mortality rates for children aged 1-19 years with end-stage CKD in general US pediatric population were reported at 0.31 per 1000 population. (Page 3, Line 49-50) 5. Methods: It is recommended to include details about the ultrasound device used in the study. Authors’ response Thank you for the recommendation, we have added the details of the ultrasound device in the method section. Change made in the manuscript The CIMT measurements were conducted using a common carotid artery B-mode ultrasound with a Phillips HD11 XE ultrasound system, a fully digital imaging platform designed for high-definition vascular imaging. It was equipped with an L12-3 broadband linear array transducer, which operates at frequencies of 3–12 MHz and features a 38 mm aperture for precise assessments of vascular structures. This combination enables detailed imaging and ensures accurate evaluation of CIMT in pediatric patients [14]. (Page 6-7, Line 125-131) 6. Methods: A reference for the assessment of nutritional status should be cited. Authors’ response We have added the citation for nutritional status assessment in the method section as advised. Change made in the manuscript Nutritional status was evaluated using height and weight measurements, applying the WHO Growth Reference 2007 definitions through WHO AnthroPlus software [11] (Page 5, Line 91-92). 7. Methods: Please provide details on how height and weight measurements were conducted. Authors’ response Thank you for the advise, we have added the details of related measurements as suggested. Change made in the manuscript Height measurement in children who can stand were measured using stadiometer with the child stands barefoot with heels, buttocks, shoulders, and head touching the vertical board. For children who were not able to stand, recumbent length is measured using an infantometer, with the child lying flat, and the head and feet aligned to the measurement board. While for weight measurement, a calibrated digital scale were used. Measurements were taken with minimal clothing and no shoes to avoid interference with the reading. The nutritional status classifications used were… (Page 5, Line 92-98). 8. The limitations section should be expanded, as the study has additional limitations that were not fully addressed. Authors’ response Thank you for your review, we have expanded the limitations in the discussion section. Change made in the manuscript Furthermore, the study did not account for other predictors such as dietary habits, physical activity levels, or genetic predisposition, which could influence vascular thickness independently of CKD. These limitations suggest the need for cautious interpretation of the findings regarding generalizability and longitudinal CIMT trends, and the role of external risk factors in pediatric CKD patients. (Page 13, Line 225-229) Attachments Attachment Submitted filename: [PLOS one] Response to the reviewers.docx https://doi.org/10.1371/journal.pone.0329412.r002
Decision Letter - Elena Olmastroni, Editor PONE-D-24-25206R1Predictors of elevated carotid intima-media thickness as a surrogate marker for cardiovascular disease in pediatric chronic kidney diseasePLOS ONE Dear Dr. Murni, 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 Jun 18 2025 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, Elena Olmastroni 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. [Note: HTML markup is below. Please do not edit.] 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: (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 Reviewer #2: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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: Thank you to the author for responding carefully to the first round of review comments and completing the revisions. The article has made significant improvements in methodological description, data presentation, and discussion depth, but there are still the following issues that need further improvement: Discussion section of the article: 1. Need to respond to the latest evidence-based medicine evidence: contradictory conclusions regarding the predictive value of CIMT compared to CKD studies published in 2023 2. Clinical translation suggestion: Provide specific pathways for integrating CIMT testing into the existing cardiovascular risk assessment system for CKD children, such as screening frequency and threshold definition. 3.Given the racial differences in the normal reference values of CIMT in children, it is recommended to supplement the racial composition of the study population in the limitations section. Reference section: Due to some of the references being relatively old, it is recommended that the author update 3-5 relevant references from the past 3 years. Reviewer #2: (No Response) ****** 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: No Reviewer #2: 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.0329412.r003
Revision 2
18 Jun 2025 Author Response PONE-D-24-25206R1 Predictors of elevated carotid intima-media thickness as a surrogate marker for cardiovascular disease in pediatric chronic kidney disease Response to the reviewers Reviewer #1 Comments to the Author Thank you to the author for responding carefully to the first round of review comments and completing the revisions. The article has made significant improvements in methodological description, data presentation, and discussion depth, but there are still the following issues that need further improvement: Discussion section of the article: 1. Need to respond to the latest evidence-based medicine evidence: contradictory conclusions regarding the predictive value of CIMT compared to CKD studies published in 2023 Authors’ response Thank you for the kind suggestion to respond to the latest evidence-based medicine evidence. We have added and cited the article as suggested into the discussion section. Change made in the manuscript A 2023 case-control study involving children with CKD stages 3-4 reported contradictory findings regarding the predictive value of CIMT. The study found no significant differences in CIMT measurements between CKD cases and healthy controls [21]. In contrast, a study in adults with advanced CKD, CIMT was significantly associated with lower estimated glomerular filtration rate (eGFR) and increased cardiovascular risk, supporting its role as a predictive marker [22]. However, in pediatric CKD patients, CIMT showed no significant correlation with CKD stage or cardiovascular risk factors [23]. Meanwhile, findings in predialysis CKD were mixed—some studies supported CIMT as a predictor of cardiovascular events, while others found carotid plaque burden to be more reliable. These inconsistencies highlight the need for population-specific approaches and further research to clarify CIMT’s value in CKD management [24]. (Page 13, line 212 – 221) Discussion section of the article: 2. Clinical translation suggestion: Provide specific pathways for integrating CIMT testing into the existing cardiovascular risk assessment system for CKD children, such as screening frequency and threshold definition. Authors’ response Thank you for the suggestion to enrich the discussion in this article. As recommended, we have added to the manuscript a specific pathway that integrates CIMT examination into the current system for assessing cardiovascular in children with CKD. Change made in the manuscript To support practical clinical integration, CIMT assessment should become part of routine cardiovascular risk evaluation in children with CKD. Annual CIMT screening is recommended for those with CKD stages 3-5, and every two years for stages 1-2. CIMT values at or above the 95th percentile (adjusted for age, sex, and height) are considered abnormal and signal increased cardiovascular risk. An elevated CIMT should trigger further evaluation, including blood pressure monitoring and echocardiographic assessment for cardiac structure and function. Children with both elevated CIMT and other risk factors, such as hypertension, should be prioritized for intensified interventions, including tighter blood pressure control, lifestyle changes, and targeted pharmacologic therapy. This integrated approach supports early identification and management of high-risk patients, aiming to improve long-term cardiovascular outcomes in pediatric CKD. (Page 13, line 223 – 232) Discussion section of the article: 3. Given the racial differences in the normal reference values of CIMT in children, it is recommended to supplement the racial composition of the study population in the limitations section. Authors’ response Thank you for highlighting the importance of considering racial differences in measuring CIMT in children. As suggested, we have included this issue on the limitations section. Change made in the manuscript Our cohort compromised predominantly Southeast Asian children, which may limit generalizability to populations with differing CIMT reference norms. Future multiracial studies might be needed to validate a more universal CIMT thresholds. (Page 14, line 246 – 249) Reference section: Due to some of the references being relatively old, it is recommended that the author update 3-5 relevant references from the past 3 years. Authors’ response Thank you for the suggestion. We have added updated relevant references from the past three years to statements previously supported by relatively older articles. Additional new references have also been included to support Discussion section, as outlined in response #1 to reviewer. Change made in the manuscript Within Introduction section: Chronic kidney disease (CKD), especially in its late stages, has been associated with significant morbidity and mortality, often due to cardiovascular problems. Complications due to cardiovascular events are considered quite significant in children with CKD because they possess a higher rate of mortality compared to the mortality caused by CKD itself [1,2]. (Page 3, line 40) � previously only supported by reference number one from Shulman et al. (1989) The elevated mortality risk is largely attributed to factors such as accelerated atherosclerosis, vascular calcification, and chronic inflammation, which are common in CKD patients. Among these, cardiovascular disease stands out as a major in individuals with end-stage CKD. Both accelerated atherosclerosis and cardiovascular disease are major causes of morbidity and mortality in patients with end-stage CKD [3,4]. (Page 3, line 49) � previously only supported by reference number three from Kumar et al. (2009) CIMT reflects arterial wall thickness, making it a reliable diagnostic tool [8,9]. (Page 4, line 60) � previously only supported by reference number eight from Chen et al. (1999) New added articles within the references list: 2. Li L-C, Tain Y-L, Kuo H-C, Hsu C-N. Cardiovascular diseases morbidity and mortality among children, adolescents and young adults with dialysis therapy. Front Public Health. 2023;11: 1142414. doi:10.3389/fpubh.2023.1142414 4. Marx-Schütt K, Cherney DZI, Jankowski J, Matsushita K, Nardone M, Marx N. Cardiovascular disease in chronic kidney disease. European Heart Journal. 2025; ehaf167. doi:10.1093/eurheartj/ehaf167 9. Akinmolayan A, Papacosta AO, Lennon LT, Ellins EA, Halcox JPJ, Whincup PH, et al. Carotid Intima‐Media Thickness, Carotid Distensibility, and Incident Heart Failure in Older Men: The British Regional Heart Study. JAHA. 2025; e037167. doi:10.1161/JAHA.124.037167 21. Hussain Z, Bajeer I, Khatri S, Mohsin S, Kumar P, Hashmi S. Carotid Intima-Media Thickness in Children with Chronic Kidney Disease as an Early Predictor of Cardiovascular Diseases. PJMHS. 2023;17: 65–68. doi:10.53350/pjmhs02023171265 22. Rizikalo A, Coric S, Matetic A, Vasilj M, Tocilj Z, Bozic J. Association of Glomerular Filtration Rate and Carotid Intima-Media Thickness in Non-Diabetic Chronic Kidney Disease Patients over a 4-Year Follow-Up. Life. 2021;11: 204. doi:10.3390/life11030204 23. Palupi-Baroto R, Hermawan K, Murni IK, Nurlita T, Prihastuti Y, Puspitawati I, et al. Carotid intima-media thickness, fibroblast growth factor 23, and mineral bone disorder in children with chronic kidney disease. BMC Nephrol. 2024;25: 369. doi:10.1186/s12882-024-03771-z 24. Colbert G, Jain N, De Lemos JA, Hedayati SS. Utility of Traditional Circulating and Imaging-Based Cardiac Biomarkers in Patients with Predialysis CKD. Clinical Journal of the American Society of Nephrology. 2015;10: 515–529. doi:10.2215/CJN.03600414 (Page 17 – 18, line 281 – 361) Attachments Attachment Submitted filename: [PLOS_one]_Response_to_the_reviewers_auresp_2.docx https://doi.org/10.1371/journal.pone.0329412.r004
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Formally Accepted
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