A multicentral prospective cohort trial of a pharmacist-led nutritional intervention on serum potassium levels in outpatients with chronic kidney disease: The MieYaku-Chronic Kidney Disease project

Yuki Asai; Asami Muramatsu; Tatsuya Kobayashi; Ikuhiro Takasaki; Toshiki Murasaka; Ai Izukawa; Kahori Miyada; Takahiro Okazaki; Tatsuki Yanagawa; Yasuharu Abe; Yasushi Takai; Takuya Iwamoto

doi:10.1371/journal.pone.0304479

Peer Review History

Original SubmissionNovember 10, 2023
2 Feb 2024 Decision Letter - Chadia Beaini, Editor PONE-D-23-33112A multicentral prospective cohort trial of a pharmacist-led nutritional intervention on serum potassium levels in outpatients with chronic kidney disease: The MieYaku-Chronic Kidney Disease projectPLOS ONE Dear Dr. Asai, 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. ============================== It is a very interesting study. Working on hyperkalemia by diet education is so important in patients with CKD. I will ask you to review the article, and these are my comments: Introduction: 1- First paragraph: the hyperkalemia in CKD can be elaborated in better way 2- Second paragraph: Diet restrictions in CKD: discus more the challenges faced Study design: 1- Why the nephrologist didn’t participate to this study: Cardiologists, registered dieticians, and pharmacists from the National Hospital Organization Mie-Chuo Medical Center participated in this study. 2- What does this mean: those who received a refill prescription, in the exclusion criteria? 3- the patients who developed acute kidney injury during the 12 weeks of follow up, should also be excluded from the study or at least mentioned during the follow up, independently of the creatinine at 0 then 12 weeks Outcomes: 1- Blood urine nitrogen levels should not be used as indicator of hydration 2- How they validate the questionnaire used. Validation is an important aspect in relation to the use of questionnaire/survey form. 3- Potassium level is affected by acidosis: this should also be studied/mentioned The statistical analysis: Correction of the t-test in the sample size The estimated percentage dropouts (attrition rates) are to be stated. Wilcoxon signed-rank test and McNemar test are not clear. More information is to be provided. One or two-sided p value is to be mentioned. Review the figures. ============================== Please submit your revised manuscript by Mar 17 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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The PLOS 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 ****** 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 ****** 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: Line 98, to assess the secondary outcome ‘change in patients’ attitudes toward potassium restriction at 12 weeks’ using 2 questions (Q3 & Q4) and understanding of hyperkalemia and potassium restrictions respectively (Q1 & Q2) is insufficient. To measure these outcomes usually requires a series of questions. Line 127, information on whether the questionnaire/questions was/were validated or piloted is to be mentioned. Validation is an important aspect in relation to the use of questionnaire/survey form. Line 139, alpha and beta figures are incorrectly cited. It should be alpha = 0.05, beta=0.20 (or power= 80%) Line 140, the estimated percentage dropouts (attrition rates) are to be stated. Line 144, the sentence is incomplete and requires revision. Line 145, the use of McNemar is not clear. More information is to be provided. Line 147, one or two-sided p value is to be mentioned. For percentage figures in the text and tables, at least one decimal point is to be provided. Figure 3, 4, 5, S2 Fig, the statistical test is to be denoted in the figure footnote. n to be stated. Line 110, the sentence ‘This is the Fig 1 legend.' is to be omitted. Likewise with the sentence in Line 176, Line 178, Line 207, Line, 211, Line 213. Effect size index and confidence interval could be reported. Figure 1, the word ‘Questionary survey’ to be revised. ****** 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. 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Revision 1
14 Feb 2024 Author Response Response to Reviewers We thank the reviewer for evaluating our manuscript and providing valuable suggestions. We have revised the manuscript in response to the comments. Guest Editor: Introduction: 【Comment1】 1- First paragraph: the hyperkalemia in CKD can be elaborated in better way 【Answer1】 According to your suggestion, we have added the following sentences about hyperkalemia in CKD. Lines 27-41 Hyperkalemia is a life-threatening metabolic problem that can lead to cardiac arrest in extreme cases [1]. Patients with chronic kidney disease (CKD) often acquire this condition, with an incidence rate of 14¬–20% in patients with CKD [2]. Serum potassium levels ≥ 5.5 mEq/L in CKD may be associated with increases in acute- [3] and long-term [4] mortality. Therefore, hyperkalemia is the most important adverse event that shortens lifetime in patients with CKD. The mechanism of developing hyperkalemia is attributed to be reduced kidney function because serum potassium is primarily extracted via urine. In fact, during CKD stage 3b [5], urinary excretion rate is substantially reduced, and the occurrence of hyperkalemia events is elevated [3]. While the prevalence of hyperkalemia in patients with CKD has recently increased due to increased prescription of renin-angiotensin system inhibitors (RASi) [6,7], discontinuation of RASi [8] or mineralocorticoid receptor antagonists [9] due to hyperkalemia may be associated with a higher risk of death and major adverse cardiovascular events; therefore, even drugs that cause hyperkalemia should be continued for the long-term prognosis of patients with CKD. Reference list 2. Gilligan S, Raphael KL. Hyperkalemia and Hypokalemia in CKD: Prevalence, Risk Factors, and Clinical Outcomes. Adv Chronic Kidney Dis. 2017; 24: 315-318. 4. Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int. 1996; 49: 800-805. 【Comment2】 2- Second paragraph: Diet restrictions in CKD: discus more the challenges faced 【Answer2】 We have inserted the following sentences. Lines 42-58 Dietary potassium restriction is a reasonable approach for preventing hyperkalemia and has been advised for patients with CKD worldwide [10]. A meta-analysis revealed that dietary potassium restriction can lower serum potassium levels [11]. However, because of influencing factors that alter serum potassium levels, such as hydration level, acid-base status, glycemic management, and gastrointestinal complications, it is challenging to identify the appropriate potassium intake for specific patients with CKD [12]. Further complicating potassium restriction is the fact that different foods have different potassium content [13], and severe potassium restriction in the diet (restricting vegetable and fruit intake) has been associated with death regardless of CKD stage [14]. Various lifestyle habits (cigarette smoking, infrequent alcohol consumption, and low physical activity) and characteristics (younger age, higher body mass index, male gender, and lower educational attainment) may be involved in low-adherence to CKD-specific dietary recommendations, including potassium restriction [15], indicating that guidance regarding potassium restriction needs to be individualized to fit the patient's lifestyle and characteristics. Therefore, it is crucial that dietary potassium restriction be managed by healthcare workers in conjunction with patients with CKD. Reference list 15. Kaesler N, Baid-Agrawal S, Grams S, Nadal J, Schmid M, Schneider MP, Eckardt KU, Floege J, Bergmann MM, Schlieper G, Saritas T. Low adherence to CKD-specific dietary recommendations associates with impaired kidney function, dyslipidemia, and inflammation. Eur J Clin Nutr. 2021; 75: 1389-1397. Study design: 【Comment3】 1- Why the nephrologist didn’t participate to this study: Cardiologists, registered dieticians, and pharmacists from the National Hospital Organization Mie-Chuo Medical Center participated in this study. 【Answer3】 As you mentioned, the quality of the intervention method may be elevated with the participation of nephrologists. However, the National Hospital Organization Mie Chuo Medical Center did not have a staff nephrologist. Therefore, it was considered necessary to construct a project with the participation of nephrologists in the future investigation. According to your suggestion, we have inserted the following sentences. Lines 304-308 Fifth, although the quality of the intervention method may be elevated with the participation of nephrologists, the National Hospital Organization Mie Chuo Medical Center did not have staff nephrologists. Therefore, it was considered necessary to construct a project with the participation of nephrologists in future investigations. 【Comment4】 2- What does this mean: those who received a refill prescription, in the exclusion criteria? 【Answer4】 If the patient brought a refill prescription, serum potassium level cannot be evaluated because there is no need to visit the Mie Chuo Medical center during or after the 12-week follow-up period and. Therefore, “those who received a refill prescription” was set as an exclusion criterion. According to your indication, we have added the following sentences. Lines 91-95 If the patient brought a refill prescription, serum potassium level could not be evaluated because there is no need to visit the Mie Chuo Medical center during or after the 12-week follow-up period. Therefore, “those who received a refill prescription” was set as an exclusion criterion. 【Comment5】 3- the patients who developed acute kidney injury during the 12 weeks of follow up, should also be excluded from the study or at least mentioned during the follow up, independently of the creatinine at 0 then 12 weeks 【Answer5】 We conducted the additional survey to clarify the incidence of acute kidney injury (AKI) during the 12 weeks of follow up. An AKI was defined as an increase in creatinine of at least 0.3 mg/dL within 48 hours or a 1.5-fold increase in creatinine, which is known or presumed to have occurred within 7 days [KDIGO Clinical Practice Guideline for Acute Kidney Injury]. No patient developed AKI during the 12-week follow-up period, suggesting that AKI would not affect the serum potassium levels during 12-week follow-up periods. According to your suggestion, we have included the following sentences and the baseline of serum creatinine (Table 1). Materials and Methods section Lines 106-109 The development of acute kidney injury (AKI) was elucidated during the 12-week follow-up period. An AKI was defined as an increase of at least 0.3 mg/dL in creatinine within 48 h or a 1.5-fold increase in creatinine, which is known or presumed to have occurred within 7 days [19]. Result section Lines 216-217 In addition, the developed AKI was not observed during the 12-week follow-up period. Discussion section Lines 260-261 In the present study, serum potassium levels decreased without any changes in hydration levels, kidney function, or developing AKI. Reference list 19. Kidney Disease Improving Global Outcomes: KDIGO Clinical Practice Guideline for Acute Kidney Injury. Section 2: AKI Definition. 2012. [Cited 2024 Feb 10]. Available from: https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf. Outcomes: 【Comment6】 1- Blood urine nitrogen levels should not be used as indicator of hydration 【Answer6】 Blood urine nitrogen (BUN) and serum creatinine ratio have been used as indicators of hydration [18]. Therefore, we evaluated the hydration status by changes in BUN/creatinine ratio. The significance differences were not observed between pre- and post-intervention (p = 0.904, 95% confidence interval (CI): -1.793 – 1.214). According to your suggestion, we have revised the following sentences and Figure 3C. In addition, the baseline of BUN/creatinine ratio was added in Table 1. Abstract section Lines 16-17 blood urine nitrogen/serum creatinine ratio (p = 0.38, 95% CI: -1.793–1.214) Materials and methods section Lines 104-106 eGFR and blood urine nitrogen (BUN)/serum creatinine ratio were assessed as indicators of renal function and hydration [18], respectively. Result section Lines 214-216 In contrast, eGFR (p = 0.563, 95%CI: -2.427 – 2.555) (Fig 3B) and BUN/creatinine ratio (p = 0.904, 95%CI: -1.793–1.214) (Fig 3C) did not change. Lines 235-239 Fig. 3. Effect of nutritional intervention on (A) serum potassium levels, (B) eGFR, and (C) BUN/creatinine ratio. The number of patients included in the analysis of each parameter was 25. BUN, blood urine nitrogen. eGFR, estimated glomerular filtration rate. CI, confidence interval. The differences in respective variables between pre- and post-intervention were compared by the Wilcoxon signed-rank test. Reference list 18.　Robinson BE, Weber H. Dehydration despite drinking: beyond the BUN/Creatinine ratio. J Am Med Dir Assoc. 2004; 5: S67–S71. 【Comment7】 2- How they validate the questionnaire used. Validation is an important aspect in relation to the use of questionnaire/survey form. 【Answer7】 The questionnaire used in the present study was not validated because we originally developed it. The relationship between changes in awareness/knowledge and specific dietary changes through questionnaires should be evaluated, but has not been done. Therefore, the extent to which the patients' diets have changed by the present form of questionnaire would not be fully evaluated. According to your suggestion, we have added the following sentence in limitation. Lines 308-312 Sixth, because the questionnaire used in the present study was developed originally, the relationship between changes in awareness/knowledge and specific dietary changes through questionnaires was not validated. Therefore, the extent to which the patients' diets have changed by the present questionnaire would not be fully evaluated. 【Comment8】 3- Potassium level is affected by acidosis: this should also be studied/mentioned. 【Answer8】 In this study, blood gas test was not available because the study was conducted on outpatients. Alternately, the difference between sodium and chloride levels (Na-Cl) mEq/L as a surrogate marker of metabolic acidosis in the present study [20]. There was no significant difference in the value of Na-Cl between pre- and post-intervention, therefore changes in status of acidosis might not be associated with the potassium level alteration. According to your suggestion, we have added the following sentences. In addition, the baseline value of Na-Cl was added in Table 1. Materials and Methods section Lines 109-111 Additionally, the difference between sodium and chloride levels (Na–Cl) mEq/L as a surrogate marker of metabolic acidosis in the present study [20]. Result section Lines 217-218 There was no significant difference in the value of Na-Cl between pre- and post-intervention (p = 0.377, 95%CI: -1.324–0.444). The statistical analysis: 【Comment9】 Correction of the t-test in the sample size 【Answer9】 There was a typographical error in the sample size calculation from study protocol. Thank you for your understanding. It has been corrected as follows. Sample size section Lines 158-163 With a standard deviation of serum potassium levels of 1.0 mEq/L, and a mean difference of 0.5 mEq/L due to intervention, using a corresponding t-test (α = 0.05 and β = 0.20), the number of cases necessary for the trial was calculated to be n = 34. Although similar reports have not existed, the estimated percentage dropouts over the observation period were set as 15.0% [22], the target number of registered patients was established as 40. Moreover, the following sentences has been revised. Lines 297-299 Second, because the sample size was limited, and required sample size could not be reached, there could be unexplained confounding factors, such as patient selection bias. 【Comment10】 The estimated percentage dropouts (attrition rates) are to be stated. 【Answer10】 We have revised the following sentences. Lines 161-163 Although similar reports have not existed, the estimated percentage dropouts over the observation period were set as 15.0% [22], the target number of registered patients was established at 40. Reference list 22. Sedgwick P. Randomised controlled trials: the importance of sample size. BMJ. 2015; 350: h1586. doi: 10.1136/bmj.h1586. 【Comment11】 Wilcoxon signed-rank test and McNemar test are not clear. More information is to be provided. 【Answer11】 According to your suggestion, we have revised the following sentences. Lines 166-170 The Wilcoxon signed-rank test was used to examine differences in continuous variables, such as serum potassium, eGFR, BUN/creatinine ratio, Na-Cl, SBP, and DBP between pre- and post-intervention because respective variables followed a non-normal distribution. In the questionnaire survey, the rate of responses on the 4-point scale were compared pre- and post-intervention for questions 1 to 4, using the McNemar test. 【Comment12】 One or two-sided p value is to be mentioned. 【Answer12】 As you indicated, we have revised the following sentence. Lines 172-173 All statistical analyses were performed using SPSS Statistics version 27 (IBM Japan, Tokyo, Japan), and the significance level was set at two-sided p < 0.05. Response to Reviewers We thank the reviewer for evaluating our manuscript and providing valuable suggestions. We have revised the manuscript in response to the comments. Reviewer #1: 【Comment1】 Line 98, to assess the secondary outcome ‘change in patients’ attitudes toward potassium restriction at 12 weeks’ using 2 questions (Q3 & Q4) and understanding of hyperkalemia and potassium restrictions respectively (Q1 & Q2) is insufficient. To measure these outcomes usually requires a series of questions. 【Comment2】 Line 127, information on whether the questionnaire/questions was/were validated or piloted is to be mentioned. Validation is an important aspect in relation to the use of questionnaire/survey form. 【Answer 1 and 2】 As you indicated, these were the only questions that could not adequately elucidate the changes in patient knowledge/awareness. The questionnaire used in the present study was developed originally, therefore, the relationship between changes in awareness/knowledge and specific dietary changes through questionnaires was not validated. Therefore, the extent to which the patients' diets have changed by the present form of questionnaire would not be fully evaluated. According to your suggestion, we have added the following sentence in limitation. Lines 308-312 Sixth, because the questionnaire used in the present study was developed originally, the relationship between changes in awareness/knowledge and specific dietary changes through questionnaires was not validated. Therefore, the extent to which the patients' diets have changed by the present questionnaire would not be fully evaluated. 【Comment3】 Line 139, alpha and beta figures are incorrectly cited. It should be alpha = 0.05, beta=0.20 (or power= 80%) 【Answer3】 As you indicated, we have corrected the transcription error. Lines 158-161 With a standard deviation of serum potassium levels of 1.0 mEq/L, and a mean difference of 0.5 mEq/L due to intervention, using a corresponding t-test (α = 0.05 and β = 0.20), the number of cases necessary for the trial was calculated to be n = 34. 【Comment4】 Line 140, the estimated percentage dropouts (attrition rates) are to be stated. 【Answer4】 As you indicated, we have inserted the following sentences. Lines 161-163 Although similar reports have not existed, the estimated percentage dropouts over the observation period were set as 15% [22], the target number of registered patients was established at 40. Reference list 22. Sedgwick P. Randomised controlled trials: the importance of sample size. BMJ. 2015; 350: h1586. 【Comment5】 Line 144, the sentence is incomplete and requires revision. 【Comment6】 Line 145, the use of McNemar is not clear. More information is to be provided. 【Answer 5 and 6】 According to your suggestion, we have revised the following sentences. Lines 166-170 The Wilcoxon signed-rank test was used to examine differences in continuous variables https://doi.org/10.1371/journal.pone.0304479.r002
14 May 2024 Decision Letter - Amir Hossein Behnoush, Editor A multicentral prospective cohort trial of a pharmacist-led nutritional intervention on serum potassium levels in outpatients with chronic kidney disease: The MieYaku-Chronic Kidney Disease project PONE-D-23-33112R1 Dear Dr. Asai, 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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If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: The study titled "A multicentral prospective cohort trial of a pharmacist-led nutritional intervention on serum potassium levels in outpatients with chronic kidney disease: The MieYaku-Chronic Kidney Disease project" is well-written with accurate methodology and presentation of the results. I reviewed previous comments and the response of the authors to the comments. I have no other comments for improvement. Congratulations! ****** 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 ******** https://doi.org/10.1371/journal.pone.0304479.r003
Formally Accepted
22 May 2024 Acceptance Letter - Amir Hossein Behnoush, Editor PONE-D-23-33112R1 PLOS ONE Dear Dr. Asai, 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. Amir Hossein Behnoush Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0304479.r004

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