Skip to main content
PMC home page
PLOS ONE logoLink to PLOS ONE
. 2024 May 31;19(5):e0304479. doi: 10.1371/journal.pone.0304479

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 1,2,*, Asami Muramatsu 3, Tatsuya Kobayashi 4, Ikuhiro Takasaki 5, Toshiki Murasaka 6, Ai Izukawa 7, Kahori Miyada 8, Takahiro Okazaki 9, Tatsuki Yanagawa 2, Yasuharu Abe 10, Yasushi Takai 11, Takuya Iwamoto 1
Editor: Amir Hossein Behnoush12
PMCID: PMC11142692  PMID: 38820514

Abstract

Although dietary potassium restriction is an acceptable approach to hyperkalemia prevention, it may be insufficient for outpatients with chronic kidney disease (CKD). Most outpatients with CKD use community pharmacies owing to the free access scheme in Japan. The MieYaku-CKD project included a community pharmacist-led nutritional intervention for dietary potassium restriction, with the goal of determining its efficacy for patients’ awareness of potassium restriction and serum potassium levels in outpatients with CKD. This was a five-community pharmacy multicenter prospective cohort study with an open-label, before-and-after comparison design. Eligible patients (n = 25) with an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 received nutritional guidance from community pharmacists. The primary outcome was a change in serum potassium levels at 12 weeks post-intervention. The eligible patients’ knowledge, awareness, and implementation of potassium restriction were evaluated using a questionnaire. The median value of serum potassium was significantly reduced from 4.7 mEq/L before to 4.4 mEq/L after the intervention [p < 0.001, 95% confidence interval (CI): 0.156–0.500], with no changes in eGFR (p = 0.563, 95% CI: -2.427–2.555) and blood urine nitrogen/serum creatinine ratio (p = 0.904, 95% CI: -1.793–1.214). The value of serum potassium had a tendency of attenuation from 5.3 to 4.6 mEq/L (p = 0.046, 95% CI: 0.272–1.114) in the eGFR < 30 mL/min/1.73 m2 group. A questionnaire revealed that after the intervention, knowledge and attitudes regarding dietary potassium restriction were much greater than before, suggesting that the decrease in serum potassium levels may be related to this nutritional guidance. Our findings indicate that implementing a dietary potassium restriction guidance program in community pharmacies is feasible and may result in lower serum potassium levels in outpatients with CKD.

1 Introduction

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.

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 contents [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.

The role of the pharmacist extends beyond dispensing medications and plays an essential role in health promotion and screening [16]. There are 61,715 community pharmacies in United States, and 48.1% people live within 1 mile of any pharmacy [17]. Therefore, it goes without saying that community pharmacies are highly accessible healthcare locations for many outpatients with CKD. Hyperkalemia episodes occurred in 47.3% of the outpatients [3], indicating that community pharmacists can help outpatients with CKD in restricting their potassium intake. To the best of our knowledge, no information exists on the effects of community pharmacist-led nutritional interventions on serum potassium levels in outpatients with CKD, therefore, we hypothesized that the nutritional guidance provided by community pharmacists for outpatients with CKD may be a useful technique for dietary potassium restriction.

The present study aims to investigate the influence of community pharmacist-led nutritional guidance about dietary potassium restriction on the patient awareness and serum potassium levels in outpatients with CKD in a community setting (MieYaku Chronic Kidney [MY-CKD] Project).

2 Martials and methods

2.1 Study design

This was a multicenter prospective cohort study with an open-label, before-and-after comparison design. This study was conducted in five community pharmacies belonging to the Tsu Pharmaceutical Association. Cardiologists, registered dieticians, and pharmacists from the National Hospital Organization Mie Chuo Medical Center (Mie, Japan) participated in this study.

2.2 Participants

Urinary potassium excretion decreases estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 in the Japanese population [5], therefore, the cut-off value for eligible patients with CKD was set at eGFR < 45 mL/min/1.73 m2. The inclusion criterion was adult outpatients (age ≥18 years old) at Mie Chuo Medical Center with eGFR < 45 mL/min/1.73 m2. As a result, the following patients were excluded from the study: patients (a) below the age of 18, (b) with communication difficulties, (c) with hypokalemia (serum potassium level < 4.0 mEq/L), (d) undergoing hemodialysis, (e) taking potassium preparations, and (f) who received a refill prescription 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.

2.3 Outcomes

All registered patients were followed up for 12 weeks. The following patients were excluded from the outcome evaluation during the observation period: those with (1) changes in the dosage of drugs affecting serum potassium levels, such as RASi, mineralocorticoid receptor antagonists, loop diuretics, or potassium-binding agents; (2) hemodialysis introduction; and (3) failure to complete the questionnaires at 12 weeks.

The primary outcome was the change in serum potassium levels from baseline (pre-intervention, day 1) to 12 weeks (post-intervention, day 84). eGFR and blood urine nitrogen (BUN)/serum creatinine ratio were assessed as indicators of renal function and hydration [18], respectively. 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]. Additionally, the difference between sodium and chloride levels (Na-Cl) mEq/L as a surrogate marker of metabolic acidosis in the present study [20]. In a subgroup study, the reduction of serum potassium levels was compared between eGFR < 30 and eGFR ≥ 30 mL/min/1.73 m2. Laboratory data were collected from Mie Chuo Medical Center’s elective medical records.

The secondary outcome was the change in patients’ attitudes toward potassium restriction at 12 weeks. Information about the questionnaire survey were listed in the S1 Methods. Questions 1 and 2 inquired about their understanding of hyperkalemia and potassium restrictions, respectively. Questions 3 and 4 were designed to address attitudes toward potassium restriction. Changes in the ratio between pre- and post-intervention were evaluated from questions 1 to 4. In the post-intervention period, questions 5 and 6 were meant to assess future awareness of potassium restriction.

2.4 Adverse event

The systolic and diastolic blood pressures (SBP and DBP) were monitored before and after the intervention. Cases of hypokalemia that required treatment were also collected.

2.5 Pharmacist intervention strategy

The intervention scheme is shown in Fig 1.

Fig 1. Schematic illustrating the MieYaku-Chronic Kidney Disease (MY-CKD) project.

Fig 1

Open in a new tab

CKD, chronic kidney disease. DBP, diastolic blood pressure. SBP, systolic blood pressure.

2.5.1 Training

On November 1, 2022, a cardiologist (TO), registered dietician (AM), and pharmacist (YA) gave a seminar to community pharmacists on potassium control in CKD. This educational program included a 60-min classroom session as well as a web-based component. Thirty-six community pharmacists attended the lectures and discussed their participation in the MY-CKD project. The purpose of this training was to standardize the quality of pharmacist interventions and eliminate study bias. Details of the lecture contents are provided in S1 Table.

2.5.2 Intervention

All the following interventions were implemented at each community pharmacy:

On the first intervention day (day 1), community pharmacists met with patients to describe the goals of the MY-CKD project, how to gather laboratory data, and lifestyle adjustments to avoid dialysis. Using a nutritional guidance sheet, community pharmacists lectured on dietary techniques for potassium restriction (S1 Fig). These nutritional guidance documents were mostly prepared by a registered dietician (AM) in consultation with healthcare workers. Following the lecture, a questionnaire was used to assess baseline awareness of potassium restriction, and SBP and DBP were measured at rest. Adherence was assessed if the patient was taking potassium-binding agents.

We continued to monitor the patient for dietary changes, kidney function, and serum potassium levels during the follow-up period.

A questionnaire survey to evaluate the awareness of potassium restriction was conducted 12 weeks after the intervention. SBP and DBP were measured at rest.

2.6 Sample size

In a prior study, nutritional advice for a potassium-restricted diet resulted in a decrease of up to 0.5 mEq/L in serum potassium levels [11]. The maximum standard deviation for serum potassium levels among individuals has been reported to be 0.8 mmol/L [21]. 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.

2.7 Statistical analysis

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. The effect size of changes in serum potassium level mediated by this intervention was calculated. 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.

2.8 Ethics approval statement

This study was conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The study protocol was approved by the National Hospital Organization, Mie Chuo Medical Center (approval ref. MCERB-202238) and Mie Pharmaceutical Association (approval ref. 2022–3). When community pharmacists referred to the value of eGFR on the prescription issued by Mie Chuo Medical Center, if they met the inclusion criteria, consent to participate in this study was obtained from the patients by each community pharmacist using a written consent document. All data were analyzed anonymously. We registered the protocol for this study in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000049814).

3 Results

3.1 Characteristics of the participants

Enrolment in the MY-CKD project began on December 28, 2022, with five community pharmacies, and terminated on March 28, 2023. A total of 35 patients with CKD were resistant to treatment. Fig 2 shows that during the observation period, 25 patients were eligible for outcome evaluation based on the exclusion criteria, and the required number of patients was reached.

Fig 2. Flowchart showing the selection of eligible patients.

Fig 2

Open in a new tab

CKD, chronic kidney disease. RASi, renin-angiotensin system inhibitors.

The baseline patient characteristics are presented in Table 1. There were 19 patients (64.0%) who were men, with a median age of 78 and a body mass index of 22.6 kg/m2. The median eGFR was 35.0 mL/min/1.73 m2 (range: 30.5–36.7 mL/min/1.73 m2), which corresponds to the G3b stage. The baseline serum potassium level was 4.7 mEq/L (range: 4.3–5.1 mEq/L), which was close to the upper reference limit. While all patients cooked largely for themselves, only 8.0% (n = 2) requested advice from registered dietitians. Medication was self-managed by 80.0% of respondents. Only 12.0% (n = 3) of patients were taking potassium-binding agents.

Table 1. Baseline characteristics of eligible patients.

Factors n = 25
Basic property
 Male/Female, (Male, %) 19/6 (76.0)
 Age 78 (70, 83) a
 Body mass index (kg/m2) 22.6 (21.8, 24.9) a
Comorbidity
 Diabetes mellitus, n (%) 17 (68.0)
 Heart failure, n (%) 13 (52.0)
 Hypertension, n (%) 22 (88.0)
  Systolic blood pressure (mmHg) 133 (125, 142) a
  Diastolic blood pressure (mmHg) 72 (65, 79) a
Laboratory data
 Na (mEq/L) 139 (138, 140) a
 Cl (mEq/L) 106 (104, 107) a
 Na-Cl (mEq/L) 33 (32, 35) a
 K (mEq/L) 4.7 (4.3, 5.1) a
 AST (IU/L) 22 (21, 25) a
 ALT (IU/L) 16 (13, 22) a
 Serum creatinine (mg/dL) 1.5 (1.3, 1.7) a
 eGFR (mL/min/1.73 m2) 35.0 (30.5, 36.7) a
 BUN (mg/dL) 27.7 (22.0, 30.4) a
 BUN/creatinine ratio 17.0 (13.6, 21.5) a
 Hemoglobin (g/dL) 12.9 (11.6, 13.6) a
Lifestyle
 Primary meal format at home
  Cooking by themselves, n (%) 25 (100.0)
 Required advice from registered dietitians, n (%) 2 (8.0)
Medications
 Manage medicine
  Self-management, n (%) 20 (80.0)
  Family-management, n (%) 5 (20.0)
 RAS inhibitors, n (%) 17 (68.0)
 MRA, n (%) 5 (20.0)
 Loop diuretics, n (%) 7 (28.0)
 Potassium-binding agents, n (%) 3 (12.0)
 SGLT2 inhibitors, n (%) 5 (20.0)
Open in a new tab

ALT: alanine aminotransferase. AST: aspartate aminotransferase. BUN: blood urea nitrogen. eGFR: estimated glomerular filtration rate. MRA: mineralocorticoid receptor antagonist. RAS: renin-angiotensin system. SGLT2: sodium–glucose cotransporter 2. aEach value represents the median (25th, 75th percentile).

3.2 Outcomes

Fig 3A shows that the median value of serum potassium significantly decreased from 4.7 mEq/L before intervention to 4.4 mEq/L post-intervention [p < 0.001, 95% confidence interval (CI): 0.156–0.500], and its effect size was -0.67. 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. In addition, the developed AKI was not observed during the 12-week follow-up period. 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). In subgroup analysis, serum potassium levels had a tendency of attenuation in the eGFR < 30 mL/min/1.73 m2 group (n = 6), from 5.3 mEq/L to 4.6 mEq/L (p = 0.046, 95%CI: 0.272–1.114) (Fig 4A). On the other hand, patients with eGFR ≥ 30 mL/min/1.73 m2 showed a significant decrease in serum potassium levels (p = 0.009, 95%CI: 0.057–0.364) (Fig 4B).

Fig 3.

Fig 3

Open in a new tab

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. The differences in respective variables between pre- and post-intervention were compared using the Wilcoxon signed-rank test.

Fig 4.

Fig 4

Open in a new tab

Changes in serum potassium levels in (A) eGFR < 30 mL/min/1.73 m2 and (B) eGFR ≥ 30 mL/min/1.73 m2. The number of patients in eGFR < 30 mL/min/1.73 m2 and eGFR ≥ 30 mL/min/1.73 m2 were six and 19, respectively. eGFR, estimated glomerular filtration rate. The differences in respective variables between pre- and post-intervention were compared using the Wilcoxon signed-rank test.

The percentage of responses changed significantly for all questions (Fig 5). For questions 1 and 2, no patients answered "Not at all" when asked about their understanding of the risk of hyperkalemia and potassium-rich foods (p < 0.001). Concerning routine potassium restriction awareness (question 3), the percentage of “Every time” increased (p = 0.143), while the percentage of “Not at all” decreased (p = 0.008). For question 4, “Is it bothersome to be aware of your potassium intake?” the percentages who replied “Not at all” (p < 0.001) and “Not much” (p = 0.012) decreased, while the percentage who answered “Slightly” (p = 0.136) and “Extremely” increased (p = 0.122). "Frequently" was the most prevalent response to the question “Has this guidance made you more careful about your intake of foods containing potassium?”, (56.0%, 14/25), followed by “Not that much,” “Sometimes,” and “Not at all.” Finally, 68.0% (17/25) of respondents claimed they will continue to avoid consuming potassium-containing foods in the future.

Fig 5. Evaluation of changes in understanding and attitude regarding dietary potassium restriction obtained using a questionnaire survey.

Fig 5

Open in a new tab

The number of patients that responded to each question of the questionnaire was 25. The rate of responses on the 4-point scale were compared pre- and post-intervention for question 1 to 4, respectively, using the McNemar test.

3.3 Adverse event

Although the SBP and DBP of the six patients could not be followed in post-intervention, there were no significant changes in the median values of SBP or DBP following intervention (S2 Fig). Furthermore, there were no cases of hypokalemia requiring potassium supplementation.

4 Discussion

In the present study, serum potassium levels decreased without any changes in hydration levels, kidney function, or developing AKI. Furthermore, patients who underwent dose modification with concomitant drugs that affected serum potassium levels were excluded, suggesting that the decrease in serum potassium levels could be attributed to nutritional guidance. The results of our questionnaire survey also support this hypothesis.

Although hyperkalemia is commonly defined as serum potassium levels ≥ 5.5 mEq/L, levels > 5.0 mEq/L have been linked to an increased risk of mortality in CKD stages 4–5 [23]. The reduction of serum potassium levels to less than 5.0 mEq/L in patients with eGFR < 30 mL/min/1.73 m2 may help improve the prognosis of CKD patients; therefore, stricter control of serum potassium levels is required in the CKD stage of the patients in this study.

Patient knowledge of CKD is often minimal, with only 26.5% of patients with an eGFR < 60 mL/min/1.73 m2 reporting awareness [24]. Moreover, even among hemodialysis patients, the level of knowledge acquisition regarding potassium restriction was poor [25]. Following the current nutritional intervention, 0.0% of patients answered "Not at all" when asked about the risk of hyperkalemia and foods with high potassium content (Fig 5), indicating increased knowledge among patients with CKD. Terlizzi et al. [26] found that multidisciplinary team support could help patients maintain a healthy nutritional status while delaying dialysis. The MY-CKD project’s strengths were that community pharmacists learned the basics through lectures from cardiologists, registered dietitians, and hospital pharmacists (S1 Table), and community pharmacists then passed on their knowledge to patients with CKD. Additionally, community pharmacists shared the goal of lowering serum potassium levels in patients with CKD, and constant follow-up on cooking procedures for potassium reduction was deemed important during the observation period. As all patients enrolled in this trial cooked for themselves (Table 1), this intervention strategy may result in a change in attitude toward routine potassium restriction. However, the percentage of patients with problematic potassium restriction increased (Fig 5). The MY-CKD project is thought to have provided the patient with information about the pathogenesis of CKD and potassium restriction. However, this may lead to patients needing nutritional management.

It is well-known that potassium intake is responsible for the dose-dependent reduction of blood pressure [27]. However, severe potassium restriction may cause blood pressure fluctuation in patients with CKD [28]. Therefore, the effect of dietary potassium restriction on SBP and DBP was classified as a negative event in this study. Neither SBP nor DBP changed significantly after the intervention (S2 Fig), suggesting that the degree of potassium restriction had no effect on blood pressure.

Our study had several limitations. First, the long-term persistence of the dietary potassium restriction could not be determined. 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. Third, in patients with eGFR < 60 mL/min/1.73 m2 in Japan, the frequency of hyperkalemia was considerably higher in the winter (December–February) than that in the summer (June–August) [29]. Seasonal changes may have had an impact on 52.0% (13/25) of patients whose observation end date was in summer, indicating that seasonal variations cannot be ruled out. Fourth, the efficiency of this intervention strategy in patients undergoing hemodialysis remains unknown. 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. 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. Finally, because this study only included patients with CKD who were outpatients at a secondary hospital in Japan, the impact on patients who attended hospitals with different characteristics, such as tertiary hospitals or clinics, is unknown. A cluster-randomized controlled study in Japan found that a lifestyle advising program in community pharmacies can lower SBP [30] and hemoglobin A1c [31]. Given these limitations and evidence, a cluster-randomized controlled design with long-term follow-up of potassium restriction is needed to evaluate the variability in serum potassium levels when patients are supported by community pharmacists.

CKD is one of the most important global public health problems that shortens the lifetime by increasing the requirement for dialysis treatment and risk of cardiovascular events [32]. The number of community pharmacies in Japan is comparable to those in the United States [17, 33], therefore, the evidence from the MY-CKD project of dietary potassium restriction by community pharmacist will provide great benefit for patients with CKD. Therefore, the present intervention strategy may serve as a model case in the world for nutritional guidance provided to CKD patients by community pharmacists.

5 Conclusion

This is the first study to show that a community pharmacist-led nutritional intervention mediated through the MY-CKD project improves dietary potassium restriction attitudes and lowers serum potassium levels in patients with CKD. Although few studies have demonstrated the benefits of community pharmacist activities in practice, the implementation of nutritional interventions, such as potassium restriction, for patients with CKD by educated community pharmacists certainly contributes directly to the improvement of community populations’ health.

Supporting information

S1 Checklist. CONSORT checklist.

(DOC)

pone.0304479.s001.doc (218.5KB, doc)
S2 Checklist. STROBE statement—checklist of items that should be included in reports of cohort studies.

(DOCX)

pone.0304479.s002.docx (33.5KB, docx)
S1 File. Study protocol in English.

(DOCX)

pone.0304479.s003.docx (147.1KB, docx)
S2 File. Study protocol in Japanese.

(DOCX)

pone.0304479.s004.docx (150.2KB, docx)
S1 Methods. The questionnaire contents in MY-CKD project.

(DOCX)

pone.0304479.s005.docx (21.8KB, docx)
S1 Table. Lecture contents in the MY-CKD project.

(DOCX)

pone.0304479.s006.docx (28.2KB, docx)
S1 Fig. The nutritional guidance document of MY-CKD project.

(PPTX)

pone.0304479.s007.pptx (787.5KB, pptx)
S2 Fig

Changes in (A) SBP and (B) DBP by dietary potassium restriction. The number of patients in pre-intervention and in post-intervention were 25 and 19, respectively. DBP, diastolic blood pressure. SBP, systolic blood pressure. CI, confidence interval. The differences in respective variables between pre- and post-intervention were compared using the Wilcoxon signed-rank test.

(PPTX)

pone.0304479.s008.pptx (130.2KB, pptx)

Acknowledgments

We thank Tomoharu Hasebe, Hiroya Inui, Chie Suezawa, Zyun Niato, Akira Sato, Yuji Nakagawa, Yuko Niimi, Yasuki Ogino, Hiroki Sugino, Ryota Kobayashi, Yoshihiro Kinoshita, Takahiro Fukuyama, Koji Terada, Shinichi Maegawa, Kosuke Miyachi, Tomohiko Aoki, Taisuke Matsumuro, and Nobuyuki Nakagawa for their institutional enrollment in the MY-CKD project.

Data Availability

The raw laboratory data supporting the findings of this study are openly available in repository Mendeley Data at https://data.mendeley.com/datasets/c9kydmj6c2/1. DOI is 10.17632/c9kydmj6c2.1.

Funding Statement

This work was supported by grant of Japan Pharmaceutical Association "Yakuzaishi shokuno shinko kenkyu josei jigyo"(grant for research and studies which seek to develop pharmacy profession and function in healthcare and pharmaceutical affairs) (Grant No. jpa2022-03). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Pun PH, Lehrich RW, Honeycutt EF, Herzog CA, Middleton JP. Modifiable risk factors associated with sudden cardiac arrest within hemodialysis clinics. Kidney Int. 2011; 79: 218–227. doi: 10.1038/ki.2010.315 [DOI] [PubMed] [Google Scholar]
  • 2.Gilligan S, Raphael KL. Hyperkalemia and Hypokalemia in CKD: Prevalence, risk factors, and clinical outcomes. Adv Chronic Kidney Dis. 2017; 24: 315–318. doi: 10.1053/j.ackd.2017.06.004 [DOI] [PubMed] [Google Scholar]
  • 3.Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009; 169: 1156–1162. doi: 10.1001/archinternmed.2009.132 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1038/ki.1996.111 [DOI] [PubMed] [Google Scholar]
  • 5.Ueda Y, Ookawara S, Ito K, Miyazawa H, Kaku Y, Hoshino T, et al. Changes in urinary potassium excretion in patients with chronic kidney disease. Kidney Res. Clin Pract. 2016; 35: 78–83. doi: 10.1016/j.krcp.2016.02.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004; 351: 543–551. doi: 10.1056/NEJMoa040135 [DOI] [PubMed] [Google Scholar]
  • 7.Saito Y, Yamamoto H, Nakajima H, Takahashi O, Komatsu Y. Incidence of and risk factors for newly diagnosed hyperkalemia after hospital discharge in non-dialysis-dependent CKD patients treated with RAS inhibitors. PLoS One. 2017; 12: e0184402. doi: 10.1371/journal.pone.0184402 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Xu Y, Fu EL, Trevisan M, Jernberg T, Sjölander A, Clase CM, et al. Stopping renin-angiotensin system inhibitors after hyperkalemia and risk of adverse outcomes. Am eart J. 2022; 243: 177–186. doi: 10.1016/j.ahj.2021.09.014 [DOI] [PubMed] [Google Scholar]
  • 9.Trevisan M, Fu EL, Xu Y, Savarese G, Dekker FW, Lund LH, et al. Stopping mineralocorticoid receptor antagonists after hyperkalaemia: trial emulation in data from routine care. Eur J Heart Fail. 2021; 23: 1698–1707. doi: 10.1002/ejhf.2287 [DOI] [PubMed] [Google Scholar]
  • 10.Turakhia MP, Blankestijn PJ, Carrero JJ, Clase CM, Deo R, Herzog CA, et al. Chronic kidney disease and arrhythmias: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Eur Heart J. 2018; 39: 2314–2325. doi: 10.1093/eurheartj/ehy060 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Morris A, Krishnan N, Kimani PK, Lycett D. Effect of dietary potassium restriction on serum potassium, disease progression, and mortality in chronic kidney disease: a systematic review and meta-analysis. J Ren Nutr. 2020; 30: 276–285. doi: 10.1053/j.jrn.2019.09.009 [DOI] [PubMed] [Google Scholar]
  • 12.Naber T, Purohit S. Chronic kidney disease: role of diet for a reduction in the severity of the disease. Nutrients. 2021; 13: 3277. doi: 10.3390/nu13093277 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Cupisti A, Kovesdy CP, D’Alessandro C, Kalantar-Zadeh K. Dietary approach to recurrent or chronic hyperkalaemia in patients with decreased kidney function. nutrients. 2018; 10: 261. doi: 10.3390/nu10030261 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Wakasugi M, Yokoseki A, Wada M, Momotsu T, Sato K, Kawashima H, et al. Vegetable and fruit intake frequency and mortality in patients with and without chronic kidney disease: a hospital-based cohort study. J Ren Nutr. 2023; 33: 566–574. [DOI] [PubMed] [Google Scholar]
  • 15.Kaesler N, Baid-Agrawal S, Grams S, Nadal J, Schmid M, Schneider MP, et al. Low adherence to CKD-specific dietary recommendations associates with impaired kidney function, dyslipidemia, and inflammation. Eur J Clin Nutr. 2021; 75: 1389–1397. doi: 10.1038/s41430-020-00849-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Eades CE, Ferguson JS, O’Carroll RE. Public health in community pharmacy: a systematic review of pharmacist and consumer views. BMC Public Health. 2011; 11: 582. doi: 10.1186/1471-2458-11-582 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Berenbrok LA, Tang S, Gabriel N, Guo J, Sharareh N, Patel N, et al. Access to community pharmacies: A nationwide geographic information systems cross-sectional analysis. J Am Pharm Assoc (2003). 2022; 62: 1816–1822.e2. doi: 10.1016/j.japh.2022.07.003 [DOI] [PubMed] [Google Scholar]
  • 18.Robinson BE, Weber H. Dehydration despite drinking: beyond the BUN/Creatinine ratio. J Am Med Dir Assoc. 2004; 5: S67–S71. doi: 10.1097/01.JAM.0000035860.71185.39 [DOI] [PubMed] [Google Scholar]
  • 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.
  • 20.Nihon Jinzo Gakkai. [Special issue: Evidence-based practice guideline for the treatment of CKD]. Nihon Jinzo Gakkai Shi. 2013; 55: 585–860. [PubMed] [Google Scholar]
  • 21.Kurita N, Wakita T, Ishibashi Y, Fujimoto S, Yazawa M, Suzuki T, et al.: Association between health-related hope and adherence to prescribed treatment in CKD patients: multicenter cross-sectional study. BMC Nephrol. 2020; 21: 453. doi: 10.1186/s12882-020-02120-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Sedgwick P. Randomised controlled trials: the importance of sample size. BMJ. 2015; 350: h1586. doi: 10.1136/bmj.h1586 [DOI] [PubMed] [Google Scholar]
  • 23.de Rooij ENM, de Fijter JW, Le Cessie S, Hoorn EJ, Jager KJ, Chesnaye NC, et al.: Serum potassium and risk of death or kidney replacement therapy in older people with CKD stages 4–5: eight-year follow-up. Am J Kidney Dis. 2023; 82: 257–266.e1. doi: 10.1053/j.ajkd.2023.03.008 [DOI] [PubMed] [Google Scholar]
  • 24.Chu CD, Chen MH, McCulloch CE, Powe NR, Estrella MM, Shlipak MG, et al. Patient awareness of CKD: a systematic review and meta-analysis of patient-oriented questions and study setting. Kidney Med. 2021; 3: 576–585.e1. = doi: 10.1016/j.xkme.2021.03.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Montazeri RS, Sharifi N. Evaluation of nutritional knowledge in terms of dietary sources of protein, phosphorous, potassium and fluids restriction in hemodialysis patients. Jentashapir J Health Res. 2014; 5: e21878. [Google Scholar]
  • 26.Terlizzi V, Sandrini M, Vizzardi V, Tonoli M, Facchini A, Manili L, et al.: Ten-year experience of an outpatient clinic for CKD-5 patients with multidisciplinary team and educational support. Int Urol Nephrol. 2022; 54: 949–957 doi: 10.1007/s11255-021-02963-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Filippini T, Naska A, Kasdagli MI, Torres D, Lopes C, Carvalho C, et al. Potassium intake and blood pressure: a dose-response meta-analysis of randomized controlled trials. J Am Heart Assoc. 2020; 9: e015719. doi: 10.1161/JAHA.119.015719 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Suh SH, Song SH, Oh TR, Choi HS, Kim CS, Bae EH, et al. Association of urinary potassium excretion with blood pressure variability and cardiovascular outcomes in patients with pre-dialysis chronic kidney disease. Nutrients. 2021; 13: 4443. doi: 10.3390/nu13124443 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Koyama T, Makinouchi R, Machida S, Matsui K, Shibagaki Y, Imai N. Seasonal changes in the prevalence of hyperkalemia in the emergency department: a single center study. Medicina (Kaunas). 2022; 58: 282. doi: 10.3390/medicina58020282 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Okada H, Onda M, Shoji M, Sakane N, Nakagawa Y, Sozu T, et al. Effects of lifestyle advice provided by pharmacists on blood pressure: The COMmunity Pharmacists ASSist for Blood Pressure (COMPASS-BP) randomized trial. Biosci Trends. 2018; 11: 632–639. doi: 10.5582/bst.2017.01256 [DOI] [PubMed] [Google Scholar]
  • 31.Okada H, Onda M, Shoji M, Sakane N, Nakagawa Y, Sozu T, et al. Effects of lifestyle intervention performed by community pharmacists on glycemic control in patients with type 2 diabetes: the community pharmacists assist (compass) project, a pragmatic cluster randomized trial. Pharmacology & Pharmacy 2016; 7: 124–132. [Google Scholar]
  • 32.Collins AJ, Foley RN, Gilbertson DT, Chen SC. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl (2011). 2015; 5: 2–7. doi: 10.1038/kisup.2015.2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Ministry of Health, Labour and Welfare. First Working Group on the Work of Pharmacy Pharmacists and the Functions of Pharmacies. [Cited 2023 Oct 7]. Available from: https://www.mhlw.go.jp/content/11121000/000896856.pdf

Decision Letter 0

Chadia Beaini

2 Feb 2024

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.

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,

Chadia Beaini, M.D.

Guest 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. Please provide a completed TREND checklist (http://www.cdc.gov/trendstatement/)

3. Thank you for stating the following financial disclosure:"This work was supported by grant of Japan Pharmaceutical Association "Yakuzaishi shokuno shinko kenkyu josei jigyo"(grant for research and studies which seek to develop pharmacy profession and function in healthcare and pharmaceutical affairs) (Grant No. jpa2022-03)."

Please state what role the funders took in the study.  If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.""

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: 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

**********

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.

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

**********

[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.

PLoS One. 2024 May 31;19(5):e0304479. doi: 10.1371/journal.pone.0304479.r002

Author response to Decision Letter 0

14 Feb 2024

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

Decision Letter 1

Amir Hossein Behnoush

14 May 2024

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. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® 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,

Amir Hossein Behnoush

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

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

**********

Acceptance letter

Amir Hossein Behnoush

22 May 2024

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

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. CONSORT checklist.

    (DOC)

    pone.0304479.s001.doc (218.5KB, doc)
    S2 Checklist. STROBE statement—checklist of items that should be included in reports of cohort studies.

    (DOCX)

    pone.0304479.s002.docx (33.5KB, docx)
    S1 File. Study protocol in English.

    (DOCX)

    pone.0304479.s003.docx (147.1KB, docx)
    S2 File. Study protocol in Japanese.

    (DOCX)

    pone.0304479.s004.docx (150.2KB, docx)
    S1 Methods. The questionnaire contents in MY-CKD project.

    (DOCX)

    pone.0304479.s005.docx (21.8KB, docx)
    S1 Table. Lecture contents in the MY-CKD project.

    (DOCX)

    pone.0304479.s006.docx (28.2KB, docx)
    S1 Fig. The nutritional guidance document of MY-CKD project.

    (PPTX)

    pone.0304479.s007.pptx (787.5KB, pptx)
    S2 Fig

    Changes in (A) SBP and (B) DBP by dietary potassium restriction. The number of patients in pre-intervention and in post-intervention were 25 and 19, respectively. DBP, diastolic blood pressure. SBP, systolic blood pressure. CI, confidence interval. The differences in respective variables between pre- and post-intervention were compared using the Wilcoxon signed-rank test.

    (PPTX)

    pone.0304479.s008.pptx (130.2KB, pptx)

    Data Availability Statement

    The raw laboratory data supporting the findings of this study are openly available in repository Mendeley Data at https://data.mendeley.com/datasets/c9kydmj6c2/1. DOI is 10.17632/c9kydmj6c2.1.

    Articles from PLOS ONE are provided here courtesy of PLOS

    RESOURCES