The incidence of and risk factors for late presentation of childhood chronic kidney disease: A systematic review and meta-analysis

Lucy Plumb; Emily J. Boother; Fergus J. Caskey; Manish D. Sinha; Yoav Ben-Shlomo

doi:10.1371/journal.pone.0244709

Peer Review History

Original SubmissionSeptember 21, 2020
10 Nov 2020 Decision Letter - Jennifer A Hirst, Editor PONE-D-20-29742 The incidence of and risk factors for late presentation of childhood chronic kidney disease: a systematic review and meta-analysis PLOS ONE Dear Dr. Plumb, 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 25 2020 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 We look forward to receiving your revised manuscript. Kind regards, Jennifer A Hirst, DPhil 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. We note that the original search was performed in 10 September 2019. Please discuss whether relevant literature has been published in the interim that would be expected to affect the results of the meta-analysis. 3. At this time, we ask that you please provide the full search strategy and search terms for at least one database used as Supplementary Information. 4. Thank you for stating the following in the Competing Interests section: "L.P reports grants from National Institute for Health Research and grants from Kidney Research UK during the conduct of the study. F.J.C reports grants from NIHR, grants from Kidney Research UK, and personal fees from Baxter outside the submitted work. M.D.S acknowledges financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre and Clinical Research Facilities awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. Y.B-S is partly funded by National Institute for Health Research Applied Research Collaboration West (NIHR ARC West) at University Hospitals Bristol NHS Foundation Trust. " Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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: I thoroughly enjoyed reviewing this paper and commend the author group on their hard work. Some comments: The conclusion that there is a higher proportion of late presentation in studies of hospitals compared to studies of specialist services is expected given a more dilute population of patients would present to paediatric nephrology services with stable CKD whereas patients with critical illness are far more likely to be admitted to hospital. Nonetheless, discussion of the factors around timely recognition of CKD and appropriate access to healthcare as factors that contribute to late presentation is important. It would be important to see how socio-economic factors surrounding caregivers of children with CKD impact on late presentation - I accept that extracting these individual factors would be difficult, however, I also believe that it would make your conclusions more powerful (as per statement on Page 21 “country income and age of the study cohort represent aggregate data and may not reflect true associations on an individual level.". This is touched upon in some detail, linked to other factors like geographic remoteness and LMIC/HIC countries. Studies like Francis et al (https://link.springer.com/article/10.1007/s00467-015-3279-z) would strengthen this discussion to explore the individual factors further - after all, having caregivers in the middle SES quintile in a LIC vs caregivers in the middle SES quintile of a HIC would impact differently on the child. The other concern of note is the delineation of the included studies into five main categories of ‘late presentation’. In some instances, groups 1-3 are very similar. The authors even refer to “Another definition noted in a prospective Nigerian single-centre study describes[ing] (sic) LP as the development of kidney failure within 6 months of first presentation” - this definition sounds like it would be included in Group 2? It was unclear to me why only publications from 1990 would be included? While this would increase the amount of single-centre studies, it is important to be inclusive and complete in the original search. One could run a sensitivity analysis on studies pre- and post-1990 to delineate potential differences in bias. Otherwise, a thorough search strategy. Overall, a well-executed, technically sound systematic review and meta-analysis. I would recommend minor revisions. Reviewer #2: The authors of this manuscript conducted a systematic review and meta-analysis to determine the incidence of late presentation of chronic kidney disease (CKD) in children and its associated risk factors. After an in-depth and a well-researched review with good statistical analysis, they found a median incidence of 2.1 per million age-related population (pmrap), with non-congenital kidney diseases and older age as related risk factors. Undoubtedly, late stage of CKD, especially end-stage renal failure (ESRF) or end-stage kidney disease (ESKD), contributes to the global health burden in children. This underscores the need for a comprehensive data which reports the extent of this non-communicable disease. However, there are few specific concerns that should be addressed by the authors to improve the manuscript. Specific comments 1. Abstract- Under Background, I think the term ‘kidney failure’ in line 25 should read ‘end-stage renal failure’ or ‘end-stage kidney disease’ since CKD progresses from stages 1 to 4 CKD and ends up in stage 5 CKD or end-stage renal failure. This observation also applies for ‘kidney failure’ mentioned in line 35 (under Results), although you stated in Table 2 that both terms are synonymous.. 2. Introduction- Similarly, I suggest you replace the term ‘kidney failure’ in line 57 (and elsewhere in the manuscript) with ‘end-stage renal failure’ or ‘end-stage kidney disease’ and ‘kidney replacement therapy’ (KRT) with ‘renal replacement therapy’ (RRT). In lines 69 and 74 (and elsewhere in the manuscript), using the abbreviation ‘LP’ for late presentation is unnecessary and could be deleted more so when the same abbreviation also refers to one of the authors! (Line 115). 3. Materials and Methods- Table 1 on the systematic review criteria appears redundant and could be deleted. Presenting the information in prose form may suffice. 4. Discussion- In line 354, do you mean ‘guidance’ or ‘guideline’? Clarify and correct. ****** 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: Yes:** Samuel Uwaezuoke [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. Attachments Attachment Submitted filename: Reviewers comments for PLOS ONE (3).docx https://doi.org/10.1371/journal.pone.0244709.r001
Revision 1
9 Dec 2020 Author Response We would like to thank the editors for consideration of our manuscript and the reviewers for their insightful and detailed comments. In response to editorial comments: - We have checked that our manuscript aligns with PLOS ONE’s style requirements. Please do let us know if there are any further modifications to make. - We have repeated our searches, restricted to published data available in 2020 and have not found any studies that may alter our findings. - We highlight that an example MEDLINE search strategy is included as supplemental figure 1, in accordance with the PRISMA checklist. - We have added a comment about competing interests to our revision cover letter. Below are responses to each reviewer point raised, which we hope are satisfactory. The main body of the manuscript is now 3580 words long. Reviewer #1: I thoroughly enjoyed reviewing this paper and commend the author group on their hard work. Some comments: The conclusion that there is a higher proportion of late presentation in studies of hospitals compared to studies of specialist services is expected given a more dilute population of patients would present to paediatric nephrology services with stable CKD whereas patients with critical illness are far more likely to be admitted to hospital. Nonetheless, discussion of the factors around timely recognition of CKD and appropriate access to healthcare as factors that contribute to late presentation is important. It would be important to see how socio-economic factors surrounding caregivers of children with CKD impact on late presentation - I accept that extracting these individual factors would be difficult, however, I also believe that it would make your conclusions more powerful (as per statement on Page 21 “country income and age of the study cohort represent aggregate data and may not reflect true associations on an individual level.". This is touched upon in some detail, linked to other factors like geographic remoteness and LMIC/HIC countries. Studies like Francis et al (https://link.springer.com/article/10.1007/s00467-015-3279-z) would strengthen this discussion to explore the individual factors further - after all, having caregivers in the middle SES quintile in a LIC vs caregivers in the middle SES quintile of a HIC would impact differently on the child. We thank the reviewer for this comment and agree that socioeconomic factors of the family may be implicated in late presentation of childhood chronic kidney disease. We attempted to extract these data however in many cases these data were not available stratified by late presentation status or stage at presentation. We identified one study that quantified low socioeconomic status although the measure used was not included within the study methodology: [Lines 268-271] “Two studies provided unadjusted data for other risk factors including low socio-economic status (SES) and geographical remoteness respectively. Michael and Gabreil[32] described a cohort of children all presenting with an eGFR of <25ml/min/1.73m2 of which 87.5% were of low SES, although the definition and measure of SES used was unavailable.” Within our data extraction proforma, we included a free text field whereby any comments regarding factors associated with late presentation/referral that were not substantiated were included. We have now included a comment about this qualitative analysis within the manuscript: [Lines 273-277] “Qualitative text analysis was undertaken to identify features described but not substantiated that may be linked to late presentation; these included low socioeconomic status and costs associated with healthcare[21,35,38,46] living in remote areas[35], delayed referral to tertiary care [47], ‘traditional habits’ of first seeking healthcare from traditional healers and a lack of specialist education in local hospitals[39]”. The other concern of note is the delineation of the included studies into five main categories of ‘late presentation’. In some instances, groups 1-3 are very similar. The authors even refer to “Another definition noted in a prospective Nigerian single-centre study describes[ing] (sic) LP as the development of kidney failure within 6 months of first presentation” - this definition sounds like it would be included in Group 2? We thank the reviewer for this observation. The study contained within definition 6, does describe all children presenting to nephrology care who develop kidney failure within a short time-frame, and therefore is comparable to studies within group 2. We have rectified this and re-run analyses that include group 2 studies. The descriptive text for group two has also been updated. We apologise for the confusion. It was unclear to me why only publications from 1990 would be included? While this would increase the amount of single-centre studies, it is important to be inclusive and complete in the original search. One could run a sensitivity analysis on studies pre- and post-1990 to delineate potential differences in bias. Otherwise, a thorough search strategy. We thank the reviewer for their suggestion. We chose not to commence our search prior to 1990 for two reasons. Firstly, we anticipated a large number of studies describing cohorts of children attending specialist nephrology care and therefore sought to limit the search time-frame so as to conduct a thorough yet manageable search. Secondly, many paediatric nephrology units and respective training programmes were in their infancy or being established prior to 1990, as described in this article (https://www.nature.com/articles/pr2002256.pdf?origin=ppub) – we therefore aimed to focus our search on studies from a relatively recent time-period, to reflect modern specialist healthcare access globally. We have added now added a rationale for our search time-frame to our methods: [Lines 101-104] “Studies published between 1 January 1990 and 10 September 2019 which were available in paper or electronic form were included: this time-frame was chosen to adequately capture studies from established paediatric nephrology centres and reflect modern specialist healthcare access globally.“ We also performed a sensitivity analysis, using only the most recent data from a centre or region where older study data had also been published. This did not significantly alter the overall proportion of children presenting late or associations noted within the meta-regression. We have now incorporated these findings into the manuscript. [Lines 245-246] “Additionally, restricting data to the most recent study from each centre or region did not significantly alter findings.” [Lines 299-300] “Similarly, restricting analysis to most recent published data by centre or region did not change associations seen.” Overall, a well-executed, technically sound systematic review and meta-analysis. I would recommend minor revisions. Reviewer #2: The authors of this manuscript conducted a systematic review and meta-analysis to determine the incidence of late presentation of chronic kidney disease (CKD) in children and its associated risk factors. After an in-depth and a well-researched review with good statistical analysis, they found a median incidence of 2.1 per million age-related population (pmrap), with non-congenital kidney diseases and older age as related risk factors. Undoubtedly, late stage of CKD, especially end-stage renal failure (ESRF) or end-stage kidney disease (ESKD), contributes to the global health burden in children. This underscores the need for a comprehensive data which reports the extent of this non-communicable disease. However, there are few specific concerns that should be addressed by the authors to improve the manuscript. Specific comments 1. Abstract- Under Background, I think the term ‘kidney failure’ in line 25 should read ‘end-stage renal failure’ or ‘end-stage kidney disease’ since CKD progresses from stages 1 to 4 CKD and ends up in stage 5 CKD or end-stage renal failure. This observation also applies for ‘kidney failure’ mentioned in line 35 (under Results), although you stated in Table 2 that both terms are synonymous. This manuscript has been written using recommendations from the Kidney Diseases Improving Global Outcomes (KDIGO) 2020 consensus conference (https://www.nature.com/articles/s41581-020-0290-9), which advocates use of the term ‘kidney failure’ in place of ‘end-stage kidney disease’. For this reason, kidney failure and kidney replacement therapy are used throughout the manuscript. We have now referenced this within the methodology and hope this will be acceptable. We have also checked the manuscript to ensure all kidney-related terms align where possible to these recommendations. [Lines 124-126] “The terminology contained within this report aligns with recommendations from Kidney Disease Improving Global Outcomes (KDIGO) consensus conference on nomenclature for kidney function and disease[16], although reference to study-specific terminology is made.” 2. Introduction- Similarly, I suggest you replace the term ‘kidney failure’ in line 57 (and elsewhere in the manuscript) with ‘end-stage renal failure’ or ‘end-stage kidney disease’ and ‘kidney replacement therapy’ (KRT) with ‘renal replacement therapy’ (RRT). In lines 69 and 74 (and elsewhere in the manuscript), using the abbreviation ‘LP’ for late presentation is unnecessary and could be deleted more so when the same abbreviation also refers to one of the authors! (Line 115). Please see the comment above regarding nomenclature used – we hope our rationale for this is acceptable to the reviewer and editorial team. We thank you also for the comment regarding the abbreviation of late presentation. We have now removed this from the manuscript. 3. Materials and Methods- Table 1 on the systematic review criteria appears redundant and could be deleted. Presenting the information in prose form may suffice. We have now removed this table from the manuscript and added information to the text. 4. Discussion- In line 354, do you mean ‘guidance’ or ‘guideline’? Clarify and correct. Our apologies for this error- this has now been corrected to ‘guideline’. Attachments Attachment Submitted filename: PONE-D-20-29742 Response to reviewers.docx https://doi.org/10.1371/journal.pone.0244709.r002
16 Dec 2020 Decision Letter - Jennifer A Hirst, Editor The incidence of and risk factors for late presentation of childhood chronic kidney disease: a systematic review and meta-analysis PONE-D-20-29742R1 Dear Dr. Plumb, 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, Jennifer A Hirst, DPhil Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0244709.r003
Formally Accepted
21 Dec 2020 Acceptance Letter - Jennifer A Hirst, Editor PONE-D-20-29742R1 The incidence of and risk factors for late presentation of childhood chronic kidney disease: a systematic review and meta-analysis Dear Dr. Plumb: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Jennifer A Hirst Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0244709.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .