Effect of spironolactone on survival in patients undergoing maintenance hemodialysis

Seok Hui Kang; Bo Yeon Kim; Eun Jung Son; Gui Ok Kim; Jun Young Do

doi:10.1371/journal.pone.0301458

Peer Review History

Original SubmissionMay 24, 2023
18 Sep 2023 Decision Letter - Satoshi Higuchi, Editor PONE-D-23-13967Effect of spironolactone on survival in patients undergoing maintenance hemodialysisPLOS ONE Dear Dr. Do, 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 02 2023 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, Satoshi Higuchi 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 noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: - https://www.mdpi.com/2077-0383/12/2/625 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. 3. Thank you for stating in your Funding Statement: "This work was supported by the Medical Research Center Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT, and Future Planning (2022R1A5A2018865, SHK), the Basic Science Research Program through the NRF of Korea, funded by the Ministry of Education (2022R1I1A3072966, SHK), and the NRF grant funded by the Korea government (MSIT) (2022R1F1A1076151, JYD)." Please provide an amended statement that declares all the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement. Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf. 4. Thank you for stating the following in the Acknowledgments Section of your manuscript: "This research was supported by a grant from the Joint Project on Quality Assessment Research, Republic of Korea. The epidemiologic data used in this study were obtained from Periodic Hemodialysis Quality Assessment by HIRA. The requirement for informed consent was waived due to the retrospective nature of the study. De-identifcation was performed, and data usage was permitted by the National Health Information Data Request Review Committee of HIRA." We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: "This work was supported by the Medical Research Center Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT, and Future Planning (2022R1A5A2018865, SHK), the Basic Science Research Program through the NRF of Korea, funded by the Ministry of Education (2022R1I1A3072966, SHK), and the NRF grant funded by the Korea government (MSIT) (2022R1F1A1076151, JYD). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results." Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 6. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. Additional Editor Comments: Thank you for this opportunity to review your work. There are some comments from the Editor. How did the authors determine each variable of CCI score? Please clarify in the Method section and quote any manuscripts referring to CCI score. Please indicate any rationales for selection of variables in the multivariate analysis. CCI score contains renal impairment, congestive heart failure, and so on; therefore, it is inappropriate to include CCI score, serum creatinine, and congestive heart failure. In Figure 1, please describe patient number at risk. Also, please demonstrate lost follow-up rate in the Result section. [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: 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: 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: 1) Is it possible to analyze the determinants of spironolactone prescription? 2) Is it possible to mention the differences in patient background from previous studies investigating the impact of spironolactone on patients with HD? 3) In line 195, "This indicates that many clinicians hesitate about prescribing spironolactone in patients undergoing HD although it has some beneficial effects." The benefit of spironolactone administration in patients with HD has been shown in small RCTs, but there is not sufficient evidence. Therefore, I believe that many physicians are not hesitant to prescribe spironolactone, but rather think that 'there is no need to prescribe it. Reviewer #2: In the present work the authors present data on the impact of MRA intake on survival in patients undergoing chronic hemodialysis (HD). Even though being associated with higher mortality in a univariate analysis, the effect did not remain significant in the multivariate regression. Please find attached my comments. 1) Please provide a Table showing results of both the uni- and multivariate Cox regression model. This important to understand which parameters eliminated MRAs in the multivariate regression. 2) Can the authors provide information regarding the cause of death? Especially cardiovascular death would be of high interest. 3) Can the authors provide information on the LVEF of each group? 4) Did the patients receive other heart failure medication besides MRAs? 5) The Kaplan Meier Chart is visually not appealing. Maybe the authors could improve the design of this figure? 6) Please provide information on follow-up completeness 7) Was hyperkalemia more prevalent in the MRA cohort? 8) How did the authors deal with patients who received MRAs later during follow-up ****** 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.0301458.r001
Revision 1
24 Nov 2023 Author Response Reviewer #1: 1) Is it possible to analyze the determinants of spironolactone prescription? Answer: Thank you for your comment. We have performed a logistic regression using the prescription of spironolactone as a dependent variable (Table 2). The added Table 2 is as follows: Table 2. Logistic regression analyses for the use of spironolactone Univariate Multivariate OR (SE) P OR (SE) P Age (years) 0.011 (0.004) 0.013 -0.022 (0.007) 0.014 HD vintage (days) -0.000 (0.000) <0.001 -0.000 (0.000) <0.001 CCI score 0.163 (0.018) <0.001 0.072 (0.029) 0.011 Ultrafiltration volume (L/session) -0.305 (0.050) <0.001 -0.175 (0.076) 0.021 Hemoglobin (g/dL) -0.146 (0.072) 0.042 -0.074 (0.090) 0.411 Serum albumin (g/dL) -1.017 (0.153) <0.001 -0.895 (0.203) <0.001 Serum phosphorus (mg/dL) -0.214 (0.045) <0.001 -0.040 (0.064) 0.534 Serum calcium (mg/dL) -0.164 (0.063) 0.009 0.043 (0.098) 0.659 Systolic blood pressure (mmHg) -0.018 (0.004) <0.001 -0.022 (0.006) <0.001 Diastolic blood pressure (mmHg) -0.030 (0.007) <0.001 -0.002 (0.009) 0.848 Serum creatinine (mg/dL) -0.251 (0.022) <0.001 -0.186 (0.035) <0.001 Use of antihypertensive drug 0.650 (0.143) <0.001 0.196 (0.235) 0.402 Use of β-blockers 0.742 (0.114) <0.001 0.737 (0.184) <0.001 Use of statin 0.674 (0.114) <0.001 0.490 (0.149) 0.001 The presence of angina 0.578 (0.114) <0.001 0.032 (0.161) 0.841 The presence of MI 0.774 (0.155) <0.001 0.574 (0.200) 0.004 The presence of HF 0.753 (0.115) <0.001 0.469 (0.163) 0.004 P-values are tested using Student’s t-test for continuous variables and Pearson’s χ2 test for categorical variables. Multivariate analysis is adjusted for age, HD vintage, ultrafiltration volume, hemoglobin, serum albumin, serum phosphorus, serum calcium, systolic blood pressure, diastolic blood pressure, serum creatinine, use of antihypertensive drug, β-blockers, or statin, the presence of angina, MI, or HF. Control group, patients without spironolactone use; SPR group, patients with spironolactone use. Abbreviations: CCI, Charlson comorbidity index; HD, hemodialysis HF, heart failure; MI, myocardial infarction; OR, odds ratio; SE, standard error. Multivariate logistic regression analysis showed that age, HD vintage, ultrafiltration volume, serum albumin, systolic blood pressure, and serum creatinine were inversely associated with the use of spironolactone. The CCI score, the use of β-blocker or statin, or the presence of MI of HF were positively associated with the use of spironolactone. These revealed that patients with underlying heart diseases were prone to taking spironolactone. We have included these variables as covariates in multivariate analyses for mortality. We have added these comments and a Table in the Results section. 2) Is it possible to mention the differences in patient background from previous studies investigating the impact of spironolactone on patients with HD? Answer: Thank you for your comment. Most studies for association between the use of spironolactone and outcomes were performed as randomized trials and most baseline characteristics were similar between the users and non-users. To identify differences in baseline characteristics between the users and non-users, retrospective cross-sectional or observational studies would be more useful than randomized controlled trials. Lin et al. analyzed the nationwide population-based study and evaluated the use of spironolactone and clinical outcomes in patients with advanced chronic kidney disease. In their study, users had a higher the prevalence of heart diseases, CCI scores, the use of statins or aspirin, and erythropoietin doses than non-users [1]. The results of our study showed similar trends to those of Lin’s study. In our study, the use of spironolactone was inversely associated with age, HD vintage, ultrafiltration volume, serum albumin, systolic blood pressure, and serum creatinine, and positively associated with CCI scores, the use of β-blocker or statin, or the presence of MI of HF. Ours and Lin’s studies reveal that patients with underlying heart diseases were prone to taking spironolactone and factors associated with malnutrition or volume overload were also associated with the use of spironolactone. However, due to limitations in sample size of the SPR group, caution is needed in drawing definitive information. Added reference [1] Tseng WC, Liu JS, Hung SC, Kuo KL, Chen YH, Tarng DC, Hsu CC. Effect of spironolactone on the risks of mortality and hospitalization for heart failure in pre-dialysis advanced chronic kidney disease: A nationwide population-based study. Int J Cardiol. 2017 Jul 1;238:72-78. 3) In line 195, "This indicates that many clinicians hesitate about prescribing spironolactone in patients undergoing HD although it has some beneficial effects." The benefit of spironolactone administration in patients with HD has been shown in small RCTs, but there is not sufficient evidence. Therefore, I believe that many physicians are not hesitant to prescribe spironolactone, but rather think that 'there is no need to prescribe it. Answer: Thank you for your comment. As the reviewer suggested, we have revised the relevant sentence as follows: Recent meta-analyses and some randomized controlled trials showed favorable results of spironolactone on clinical outcomes. However, most randomized studies had small sample sizes and some studies showed a high risk of complications for gynecomastia, hyperkalemia, or arrhythmia by spironolactone. Consequently, there was insufficient evidence regarding the clinical efficacy of spironolactone on cardiovascular outcomes or mortality beyond the hazard effect. Therefore, many clinicians may consider the use of spironolactone unnecessary. Reviewer #2: In the present work the authors present data on the impact of MRA intake on survival in patients undergoing chronic hemodialysis (HD). Even though being associated with higher mortality in a univariate analysis, the effect did not remain significant in the multivariate regression. Please find attached my comments. 1) Please provide a Table showing results of both the uni- and multivariate Cox regression model. This important to understand which parameters eliminated MRAs in the multivariate regression. Answer: Thank you for your comment. We have added Table 3 with data for covariate and univariate and multivariate analyses. Table 3 is as follows: Table 3. Cox regression analyses for patient survival. Univariate Multivariate HR (95% CI) P HR (95% CI) P Group (ref: control) 1.34 (1.14–1.58) <0.001 1.06 (0.87–1.30) 0.588 Age (increase per 1 year) 1.06 (1.06–1.06) <0.001 1.06 (1.06–1.06) <0.001 Hemodialysis vintage (increase per 1 day) 1.00 (1.00–1.01) <0.001 1.00 (1.00–1.01) <0.001 CCI score (increase per 1 score) 1.14 (1.13–1.14) <0.001 1.07 (1.07–1.07) <0.001 Ultrafiltration volume (increase per 1 kg/session) 0.92 (0.90–0.93) <0.001 1.09 (1.07–1.11) <0.001 KtVurea (increase per 1 unit) 0.91 (0.87–0.97) <0.001 0.64 (0.60–0.68) <0.001 Hemoglobin (increase per 1 g/dL) 0.86 (0.85–0.88) <0.001 0.92 (0.90–0.94) <0.001 Serum albumin (increase per 1 g/dL) 0.37 (0.36–0.39) <0.001 0.63 (0.60–0.66) <0.001 Serum creatinine (increase per 1 mg/dL) 0.87 (0.86–0.87) <0.001 0.95 (0.94–0.95) <0.001 Serum phosphorus (increase per 1 mg/dL) 0.85 (0.84–0.86) <0.001 1.02 (1.01–1.04) 0.001 Serum calcium (increase per 1 mg/dL) 0.94 (0.92–0.95) <0.001 1.05 (1.02–1.07) <0.001 Systolic blood pressure (increase per 1 mmHg) 1.01 (1.01–1.01) <0.001 1.01 (1.01–1.01) <0.001 Diastolic blood pressure (increase per 1 mmHg) 0.98 (0.98–0.99) <0.001 1.00 (0.99–1.00) 0.347 Use of antihypertensive drug 1.12 (1.09–1.15) <0.001 0.94 (0.90–0.98) 0.006 Use of β-blockers 1.07 (1.04–1.10) <0.001 1.07 (1.03–1.12) <0.001 Use of statin 1.10 (1.07–1.14) <0.001 0.93 (0.90–0.97) <0.001 Presence of angina 1.57 (1.53–1.62) <0.001 1.09 (1.05–1.13) <0.001 Presence of myocardial infarction 1.90 (1.82–1.98) <0.001 1.20 (1.14–1.27) <0.001 Presence of heart failure 1.43 (1.39–1.47) <0.001 1.01 (0.97–1.05) 0.576 Multivariate analysis is adjusted for age, hemodialysis vintage, CCI score, ultrafiltration volume, Kt/Vurea, hemoglobin, serum albumin, serum creatinine, serum phosphorus, serum calcium, systolic blood pressure, diastolic blood pressure, use of antihypertensive drug, β-blockers, or statin, the presence of angina of myocardial infarction or heart failure, and was performed using enter mode. Abbreviations: CCI, Charlson comorbidity index; CI, confidence interval; HR, hazard ratio. 2) Can the authors provide information regarding the cause of death? Especially cardiovascular death would be of high interest. Answer: Thank you for your comment. As the reviewer pointed out, the benefits of spironolactone mainly originate from the cardiovascular system. In our study, the outcome was all-cause mortality, and analyses using death by cardiovascular disease might show different results. Furthermore, information, such as ejection fraction, cardiac mass, or the presence of hypertrophy using echocardiography are very useful to identify the cause-relationship between the use of spironolactone and clinical outcomes beyond simple death. Moreover, left ventricular ejection fraction is very important information for classifying heart failure. Heart failure can be divided into reduced, mildly reduced, or preserved ejection fractions. The effect of spironolactone may be different according to the three groups. However, our study collected from data the HD quality assessment program and claims. HD quality assessment program only collected essential data directly regarding HD quality, such as dialysis adequacy, hemoglobin, or phosphorus levels regardless of the patient status or risk factors associated with prognosis. In addition, the death data was collected using claims data, which included data for survivor or death, but not for cause of death. These are inherent limitations of our study, but our study as a pilot study may be valuable in providing preliminary information to design future studies. We have added these comments in the Discussion section. 3) Can the authors provide information on the LVEF of each group? Answer: Thank you for your comment. We have added some comments for this issue. Detailed explanations are presented in the answer to the previous comment. 4) Did the patients receive other heart failure medication besides MRAs? Answer: Thank you for your comment. We have added the data for β-blockers and renin-angiotensin system blockers (RASB). Patients with β-blockers and RASB were 21370 (39.1%) and 16714 (30.6%) in the control group and 181 (57.4%) and 97 (30.8%) in the SPR group, respectively. The proportion of patients using β-blockers was higher in the SPR group than in the control group (P < 0.001). There was no significant difference in RASB use between the two groups (P = 0.995). We have added these data in the Results section. 5) The Kaplan Meier Chart is visually not appealing. Maybe the authors could improve the design of this figure? Answer: Thank you for your comment. We have revised Figure 1 to a new figure with a 95% confidence interval, P-value, and numbers at risk as follows; Figure 1. Kaplan–Meier curves of patient survival in the two study groups. SRP: patients with a prescription of spironolactone. 6) Please provide information on follow-up completeness Answer: Thank you for your comment. In our study, data during follow-up were collected using claims data and all patients were completely followed up to the end-point. If the patient followed up did not die by the index date (April 2022), they were defined as survivors. If the patient died before the index date, they were defined as non-survivors at the time of death. If the patients performed peritoneal dialysis or kidney transplantation before the index date, we defined the date of the first prescription for peritoneal dialysis or kidney transplantation to the end-point of follow-up and were considered survivors to the date. In addition, we have added numbers at risk in Figure 1 and the data would be useful to identify follow-up status. We have added these data in the Methods section. 7) Was hyperkalemia more prevalent in the MRA cohort? Answer: Thank you for your comment. Our dataset did not include the prevalence of hyperkalemia or serum potassium levels. Hyperkalemia can be developed by various factors such as diet, nutritional status, or the use of many medications. In addition, the ICD-10 code was not added despite hyperkalemia. Therefore, our study did not evaluate the effect of spironolactone on hyperkalemia. Nevertheless, we evaluated the dose of polystyrene sulfonate calcium (PSC), which indirectly revealed the risk of hyperkalemia or serum potassium levels. The dose of PSC was not different between the two groups. Generally, the use of spironolactone is associated with hyperkalemia. Non-difference in the use of PSC between the two groups would be caused by some factors. First, the use of PCS did not directly reveal the hyperkalemia or serum potassium level. Serum potassium level or prevalence of hyperkalemia may be higher in the SPR group than in the control despite of same dose of PCS. The actual use of medication did not match the prescribed doses. Second, considering the risk of hyperkalemia in the SPR group, stricter diet control may be performed. Third, the SPR group had greater comorbidities, and these may be poor nutritional status. The SPR group had lower serum albumin and phosphorus levels compared to the control group. We have added these comments in the Discussion section. 8) How did the authors deal with patients who received MRAs later during follow-up Answer: Thank you for your comment. In our study, 1659 and 3% of the control group were without spironolactone during the HD quality assessment program and with spironolactone after the program. We compared the patient survival according to patients without spironolactone during the program and follow-up, those with spironolactone during the program, and those with spironolactone during follow-up without the drug during the program. Multivariate analysis showed that hazard ratio (95% CI) was 1.08 (95% CI, 0.99-1.18; P = 0.073) for patients with spironolactone during follow-up without the drug during the program and 1.06 (95% CI, 0.86-1.31, P = 0.563) for those with spironolactone during the program compared to patients without spironolactone during program and follow-up. The small proportions of control may not influence the overall trend. We have added these comments in the Results section. Attachments Attachment Submitted filename: Responses for reviewer comments-complete.docx https://doi.org/10.1371/journal.pone.0301458.r002
23 Jan 2024 Decision Letter - Satoshi Higuchi, Editor PONE-D-23-13967R1Effect of spironolactone on survival in patients undergoing maintenance hemodialysisPLOS ONE Dear Dr. Do, 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 Mar 08 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. 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, Satoshi Higuchi Academic Editor PLOS ONE [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: (No Response) Reviewer #2: 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 Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No 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: If CCI (Charlson comorbidity index) is selected as a covariate when performing multivariate analysis, serum creatinine and the presence of HF or MI should not be included. This is because these items are included in the CCI. CCI should be excluded if serum creatinine and HF or MI are more preferred items. The OR of the logistic analysis in Table 2 should not normally be negative. Is this result the slope of the regression equation? Reviewer #2: Thank you very much for answering my and the others reviewers questions. The manuscript significantly improved. ****** 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.0301458.r003
Revision 2
28 Feb 2024 Author Response Reviewer #1 If CCI (Charlson comorbidity index) is selected as a covariate when performing multivariate analysis, serum creatinine and the presence of HF or MI should not be included. This is because these items are included in the CCI. CCI should be excluded if serum creatinine and HF or MI are more preferred items. Answer: Thank you for your comments. As reviewer pointed out, we have excluded serum creatinine, myocardial infarction, and congestive heart failure as covariates in the multivariate analysis. The revised results were similar with those obtained when including these variables. We have revised the results for multivariate analyses. The OR of the logistic analysis in Table 2 should not normally be negative. Is this result the slope of the regression equation? Answer: Thank you for your comments. In Table 2, the odd ratio (SE) are presented as regression coefficients and standard errors in logistic regression analysis. We have converted these values to more easily interpretable odds ratio with 95% confidence interval. The revised Table 2 is as follows: Table 2. Logistic regression analyses for the use of spironolactone Univariate Multivariate OR (95% CI) P OR (95% CI) P Age (years) 1.01 (1.00–1.02) 0.013 0.98 (0.97–0.99) 0.029 HD vintage (days) 1.00 (1.00–1.01) <0.001 1.00 (1.00–1.01) 0.015 CCI score 1.18 (1.14–1.22) <0.001 1.16 (1.09–1.22) <0.001 Ultrafiltration volume (L/session) 0.74 (0.67–0.81) <0.001 0.76 (0.66–0.88) <0.001 Kt/Vurea 0.84 (0.54–1.32) 0.446 0.66 (0.36–1.22) 0.187 Hemoglobin (g/dL) 0.86 (0.75–0.99) 0.042 0.88 (0.72–1.06) 0.177 Serum albumin (g/dL) 0.36 (0.27–0.49) <0.001 0.39 (0.25–0.59) <0.001 Serum phosphorus (mg/dL) 0.81 (0.74–0.88) <0.001 0.91 (0.80–1.03) 0.133 Serum calcium (mg/dL) 0.85 (0.75–0.96) 0.009 1.02 (0.82–1.25) 0.878 Systolic blood pressure (mmHg) 0.98 (0.97–0.99) <0.001 0.98 (0.96–0.99) <0.001 Diastolic blood pressure (mmHg) 0.97 (0.96–0.98) <0.001 1.00 (0.99–1.02) 0.663 Use of antihypertensive drug 1.91 (1.45–2.53) <0.001 0.96 (0.58–1.58) 0.874 Use of β-blockers 2.10 (1.68–2.63) <0.001 2.20 (1.48–3.28) <0.001 Use of statin 1.96 (1.57–2.45) <0.001 1.88 (1.37–2.58) <0.001 The presence of angina 1.78 (1.43–2.23) <0.001 1.12 (0.80–1.55) 0.517 Multivariate analysis was adjusted for age, HD vintage, ultrafiltration volume, Kt/Vurea, hemoglobin, serum albumin, serum phosphorus, serum calcium, systolic blood pressure, diastolic blood pressure, use of antihypertensive drug, β-blockers, or statin. Control group, patients without spironolactone use; SPR group, patients with spironolactone use. Abbreviations: CCI, Charlson comorbidity index; CI, confidence interval; HD, hemodialysis; OR, odds ratio. Attachments Attachment Submitted filename: Responses for reviewer comments.docx https://doi.org/10.1371/journal.pone.0301458.r004
18 Mar 2024 Decision Letter - Satoshi Higuchi, Editor Effect of spironolactone on survival in patients undergoing maintenance hemodialysis PONE-D-23-13967R2 Dear Dr. Do, 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. Please make sure your user information is up-to-date by logging into Editorial Manager at http://www.editorialmanager.com/pone/ and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Satoshi Higuchi 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (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: (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: (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: (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 ******** https://doi.org/10.1371/journal.pone.0301458.r005
Formally Accepted
21 Mar 2024 Acceptance Letter - Satoshi Higuchi, Editor PONE-D-23-13967R2 PLOS ONE Dear Dr. Do, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Satoshi Higuchi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0301458.r006

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 .