Osteopontin, kidney injury molecule-1, and fetuin-A as prognostic markers of end-stage renal disease: A systematic review and meta-analysis

Yongki Welliam; Bendix Samarta Witarto; Visuddho Visuddho; Citrawati Dyah Kencono Wungu; Raden Mohammad Budiarto; Hendri Susilo; Chaq El Chaq Zamzam Multazam

doi:10.1371/journal.pone.0320804

Peer Review History

Original SubmissionAugust 14, 2024
14 Aug 2024 Author Response https://doi.org/10.1371/journal.pone.0320804.r001
16 Oct 2024 Decision Letter - Wisit Kaewput, Editor PONE-D-24-34763OSTEOPONTIN, KIDNEY INJURY MOLECULE-1, AND FETUIN-A AS PROGNOSTIC MARKERS OF END-STAGE RENAL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSISPLOS ONE Dear Dr. Wungu, 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 30 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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If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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. 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 Reviewer #3: Partly Reviewer #4: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Yes ****** 3. 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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 Reviewer #3: Yes Reviewer #4: 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: The manuscript by Welliam et al. “Osteopontin, kidney injury molecule-1, and Fetuin-A as prognostic markers of end-stage renal disease: a systematic review and meta-analysis” looks interesting. This article aims to evaluate the potential and predictive ability of Osteopontin (OPN), Kidney injury molecule-1 (KIM-1), and Fetuin-A on the incidence of ESRD in CKD patients. This review and Meta-analysis showed that the increased KIM-1 in urine or blood was strongly associated with ESRD, and decreased Fetuin-A levels in Asians had a significant association with the incidence of ESRD. The authors concluded that Osteopontin, KIM-1, and Fetuin-A significantly reflect ESRD in CKD patients, making them potential prognostic indicators. The manuscript is well written and provides enough strategies to fulfill its aims, though language may need some polishing for better flow. In conclusion, I support publication of this work and believe that it would be interesting for researchers working in the field. Reviewer #2: This manuscript written thoroughly and vigorously strengthens the review's question. Reviewer assist your manuscript based on PRISMA 2020 Expanded checklist, and most of the points are all elaborated in your manuscript. However, some minor revisions are needed, please access the pdf file attached. Reviewer #3: This is a remarkable paper. There are a few minor points that need to be checked. 1.The effects of diabetes and hypertension were not taken into account: This study did not take into account the effects of comorbidities such as diabetes and hypertension on the progression of CKD and the onset of ESRD. Patients with comorbidities may have different conditions, so the fact that this was not adjusted for could be a source of bias. 2.The effectiveness of subgroup analysis by age and geographical location: The subgroup analysis examines the distribution of results by age and geographical location, but the age groups may not be appropriate (e.g., broad categories such as “under 60” and “over 60”). In addition, the geographical location analysis does not consider differences between countries or cultural and social backgrounds, and does not adequately explain why significant results were obtained only in the Asian region. 3.The effect of using different types of samples: Some of the included studies measured the concentrations of OPN, KIM-1 and fetuin-A using different samples, such as urine or blood, which may have caused the variation in results. The concentrations of markers in urine and blood may reflect different biological processes, and this must be taken into account in the analysis. 4.Uncertainty over cut-off values for clinical application: There is a problem with clinical application because there is no clear cut-off value for predicting the risk of developing ESRD based on the level of each biomarker. The cut-off value for biomarkers is an important indicator for predicting prognosis, so this point needs to be further investigated. Reviewer #4: The manuscript titled "OSTEOPONTIN, KIDNEY INJURY MOLECULE-1, AND FETUIN-A AS PROGNOSTIC MARKERS OF END-STAGE RENAL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS" by Welliam et al., is clearly written and their claims are fully supported by well-designed study and proper statistical analysis. So, I recommend the publication of this manuscript in the esteemed journal PLOS ONE. ****** 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 . 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Attachments Attachment Submitted filename: PONE-D-24-34763 REVIEW - PRISMA_2020_checklist.pdf https://doi.org/10.1371/journal.pone.0320804.r002
Revision 1
16 Jan 2025 Author Response Point-by-point responses to Reviewers’ comments We sincerely thank the reviewers for their valuable feedback and the Editorial Team of PLOS ONE for the opportunity to revise our manuscript. This response letter outlines the corrections made based on the reviewers’ comments to enhance clarity and improve the presentation of our findings. We hope our revised manuscript provides valuable insights into the OPN, KIM-1, and Fetuin- as prognostic markers of end-stage renal disease. Thank you for considering our work. Reviewer 1 1. The manuscript by Welliam et al. “Osteopontin, kidney injury molecule-1, and Fetuin-A as prognostic markers of end-stage renal disease: a systematic review and meta-analysis” looks interesting. This article aims to evaluate the potential and predictive ability of Osteopontin (OPN), Kidney injury molecule-1 (KIM-1), and Fetuin-A on the incidence of ESRD in CKD patients. This review and Meta-analysis showed that the increased KIM-1 in urine or blood was strongly associated with ESRD, and decreased Fetuin-A levels in Asians had a significant association with the incidence of ESRD. The authors concluded that Osteopontin, KIM-1, and Fetuin-A significantly reflect ESRD in CKD patients, making them potential prognostic indicators. The manuscript is well written and provides enough strategies to fulfill its aims, though language may need some polishing for better flow. In conclusion, I support publication of this work and believe that it would be interesting for researchers working in the field. R : We thank the reviewer for the positive feedbacks. Reviewer 2 1. This manuscript written thoroughly and vigorously strengthens the review's question. Reviewer assist your manuscript based on PRISMA 2020 Expanded checklist, and most of the points are all elaborated in your manuscript. However, some minor revisions are needed, please access the pdf file attached. R : We thank the reviewer for the suggestion. We have stated the date on when the data search was conducted as well as our financial support for this manuscript in Revised Manuscript file. Reviewer 3 1. The effects of diabetes and hypertension were not taken into account: This study did not take into account the effects of comorbidities such as diabetes and hypertension on the progression of CKD and the onset of ESRD. Patients with comorbidities may have different conditions, so the fact that this was not adjusted for could be a source of bias. R : We thank the reviewer for the suggestion. We agree that these comorbidities can affect study outcomes. However, our study primarily aimed to evaluate the potential and predictive ability of Osteopontin (OPN), Kidney injury molecule-1 (KIM-1), and Fetuin-A on the incidence of ESRD in CKD patients without stratifying for comorbid conditions to maintain the broader applicability of the findings. Moreover, while diabetes and hypertension are significant contributors to CKD progression, there are additional underlying factors such as genetic predisposition, dietary habits, medication adherence, or socioeconomic status that also play critical roles and were not adjusted for in this study. These factors can introduce variability in CKD progression independent of the presence of diabetes or hypertension. To mitigate these potential biases, our methodology involved some adjustment or statistical methods including the use of random-effects models and sensitivity analyses. These approaches account for heterogeneity across studies, including variations in the prevalence of comorbidities like diabetes. We acknowledge this as a limitation and recommend further studies incorporating detailed stratification or multivariate adjustment for comorbid conditions are warranted to further elucidate their specific contributions. 2. The effectiveness of subgroup analysis by age and geographical location: The subgroup analysis examines the distribution of results by age and geographical location, but the age groups may not be appropriate (e.g., broad categories such as “under 60” and “over 60”). In addition, the geographical location analysis does not consider differences between countries or cultural and social backgrounds, and does not adequately explain why significant results were obtained only in the Asian region. R : We thank the reviewer for the suggestion. The age categories ("under 60" and "over 60") were chosen to reflect a general distinction between younger and older populations, which is often used in studies related to chronic diseases, including CKD. This cutoff aligns with established clinical observations where individuals over 60 years old generally have a higher prevalence of CKD due to age-related decline in kidney function and increased comorbidities, as supported by studies like Coresh et al., 2007. We acknowledge that narrower age groups could provide more granular insights, but such stratification was limited by the data reported in the included studies. The significant results observed in the Asian region may be attributable to higher prevalence rates of CKD risk factors such as diabetes and hypertension in certain Asian populations and it has been already stated in our discussion (Hill et al., 2016). Additionally, genetic predispositions, dietary patterns, and healthcare access likely contribute to these findings. While we recognize that cultural and social differences between countries can influence outcomes, the meta-analysis aggregated data at the regional level due to inconsistent reporting of country-specific details in the included studies. Reference : • Hill, N.R., Fatoba, S.T., Oke, J.L., Hirst, J.A., O’Callaghan, C.A., Lasserson, D.S. and Hobbs, F.R., 2016. Global prevalence of chronic kidney disease–a systematic review and meta-analysis. PloS one, 11(7), p.e0158765. • Coresh, J., Selvin, E., Stevens, L.A., Manzi, J., Kusek, J.W., Eggers, P., Van Lente, F. and Levey, A.S., 2007. Prevalence of chronic kidney disease in the United States. Jama, 298(17), pp.2038-2047. 3. The effect of using different types of samples: Some of the included studies measured the concentrations of OPN, KIM-1 and fetuin-A using different samples, such as urine or blood, which may have caused the variation in results. The concentrations of markers in urine and blood may reflect different biological processes, and this must be taken into account in the analysis. R : We thank the reviewer for the suggestion. We agree that OPN, KIM-1, and Fetuin-A concentrations in urine and blood may reflect distinct biological processes, which could contribute to variability in the results. We also have added some points related to different samples and their relation to our result. OPN, KIM-1, and Fetuin-A exhibit different physiological roles depending on the sample type. For instance, urinary concentrations of KIM-1 primarily indicate tubular injury and localized renal processes, whereas its presence in blood may reflect systemic inflammation or broader kidney dysfunction (Han et al., 2008). To address this variation, we conducted subgroup analyses stratified by sample type where possible. This allows us to explore whether the type of sample influenced the prognostic utility of these markers. However, after conducting sensitivity analysis, either urine or blood samples provide a comprehensive view of kidney status. Studies suggest that both samples can be used independently or together to enhance the accuracy of ESRD prediction. Reference : • Han, W.K., Waikar, S.S., Johnson, A., Betensky, R.A., Dent, C.L., Devarajan, P. and Bonventre, J.V., 2008. Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney international, 73(7), pp.863-869. 4. Uncertainty over cut-off values for clinical application: There is a problem with clinical application because there is no clear cut-off value for predicting the risk of developing ESRD based on the level of each biomarker. The cut-off value for biomarkers is an important indicator for predicting prognosis, so this point needs to be further investigated. R : We appreciate the reviewer’s emphasis on the importance of establishing cut-off values for biomarkers in clinical practice. We acknowledge that determining precise cut-off values is critical for clinical application and prognosis prediction. However, we would like to clarify the limitations of the current study design and the availability of data in the included studies. Most of the included studies evaluated the association between biomarker levels and the risk of ESRD by comparing the mean concentrations of biomarkers, such as OPN, KIM-1, and Fetuin-A, between patients who progressed to ESRD and those who did not. This approach provides valuable insights into the general relationship between biomarker levels and ESRD risk but does not allow for the determination of specific thresholds at which risk significantly increases. To define cut-off values, studies would need to stratify patients into multiple subgroups based on biomarker concentration intervals. For example, patients could be categorized into ranges of low, medium, and high biomarker levels, and the corresponding rates of ESRD within each group would need to be reported. Such data would allow researchers to identify the concentration level at which the risk of ESRD becomes significantly elevated, thus establishing a clinically actionable threshold. Unfortunately, studies employing this design are currently limited in the available literature. Most studies report mean differences or use continuous data without stratification, leaving a gap in the specific analysis required to determine cut-off values. Additionally, there are inherent challenges in conducting such analyses. These include the need for large patient cohorts to ensure adequate representation across biomarker concentration intervals, as well as standardization in biomarker measurement methods and reporting. The lack of uniformity across studies further complicates efforts to extract or calculate meaningful cut-off values from existing data. Given these limitations, our study focuses on synthesizing the available evidence to highlight the general prognostic value of these biomarkers while acknowledging the need for future research specifically designed to address cut-off determination. Reviewer 4 : 1. The manuscript titled "OSTEOPONTIN, KIDNEY INJURY MOLECULE-1, AND FETUIN-A AS PROGNOSTIC MARKERS OF END-STAGE RENAL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS" by Welliam et al., is clearly written and their claims are fully supported by well-designed study and proper statistical analysis. R : We thank the reviewer for the positive feedbacks. Attachments Attachment Submitted filename: Response to Reviewers and editor.docx https://doi.org/10.1371/journal.pone.0320804.r003
25 Feb 2025 Decision Letter - Wisit Kaewput, Editor OSTEOPONTIN, KIDNEY INJURY MOLECULE-1, AND FETUIN-A AS PROGNOSTIC MARKERS OF END-STAGE RENAL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS PONE-D-24-34763R1 Dear Dr. Wungu, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. 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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 manuscript looks good. I do not have any further comments and support the publication of the manuscript. Reviewer #2: This systematic review & meta-analysis study has conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 thoroughly, and thus meet the standard to be publish on PLOS One journal. ****** 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: Yes: Fachira Rachel Agfata ******** https://doi.org/10.1371/journal.pone.0320804.r004
Formally Accepted
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