Figures
Abstract
Objectives
Owing to recent changes in our understanding of the underlying cause of chronic kidney disease (CKD), the importance of lifestyle modification for preventing the progression of kidney dysfunction and complications has become obvious. In addition, effective cooperation between general physicians (GPs) and nephrologists is essential to ensure a better care system for CKD treatment. In this cluster-randomized study, we studied the effect of behavior modification on the outcome of early- to moderate-stage CKD.
Participants
A total of 2,379 patients (1,195 in group A (standard intervention) and 1,184 in group B (advanced intervention)) aged between 40 and 74 years, who had CKD and were under consultation with GPs.
Intervention
All patients were managed in accordance with the current CKD guidelines. The group B clusters received three additional interventions: patients received both educational intervention for lifestyle modification and a CKD status letter, attempting to prevent their withdrawal from treatment, and the group B GPs received data sheets to facilitate reducing the gap between target and practice.
Main outcome measure
The primary outcome measures were 1) the non-adherence rate of accepting continuous medical follow-up of the patients, 2) the collaboration rate between GPs and nephrologists, and 3) the progression of CKD.
Results
The rate of discontinuous clinical visits was significantly lower in group B (16.2% in group A vs. 11.5% in group B, p = 0.01). Significantly higher referral and co-treatment rates were observed in group B (p<0.01). The average eGFR deterioration rate tended to be lower in group B (group A: 2.6±5.8 ml/min/1.73 m2/year, group B: 2.4±5.1 ml/min/1.73 m2/year, p = 0.07). A significant difference in eGFR deterioration rate was observed in subjects with Stage 3 CKD (group A: 2.4±5.9 ml/min/1.73 m2/year, group B: 1.9±4.4 ml/min/1.73 m2/year, p = 0.03).
Conclusion
Our care system achieved behavior modification of CKD patients, namely, significantly lower discontinuous clinical visits, and behavior modification of both GPs and nephrologists, namely significantly higher referral and co-treatment rates, resulting in the retardation of CKD progression, especially in patients with proteinuric Stage 3 CKD.
Trial registration
The University Hospital Medical Information Network clinical trials registry UMIN000001159
Citation: Yamagata K, Makino H, Iseki K, Ito S, Kimura K, Kusano E, et al. (2016) Effect of Behavior Modification on Outcome in Early- to Moderate-Stage Chronic Kidney Disease: A Cluster-Randomized Trial. PLoS ONE 11(3): e0151422. https://doi.org/10.1371/journal.pone.0151422
Editor: Gianpaolo Reboldi, University of Perugia, ITALY
Received: June 10, 2015; Accepted: February 24, 2016; Published: March 21, 2016
Copyright: © 2016 Yamagata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This study was supported by a grant for a strategic outcome study project from the Ministry of Health, Labour and Welfare of Japan and a Grant-in-Aid for Research on Advanced Chronic Kidney Disease, Practical Research Project for Renal Diseases from Japan Agency for Medical Research and development, AMED. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
It is estimated that more than 10% of the general population has chronic kidney disease (CKD) in Japan [1] and other countries, increasing with the aging of the population [2]. Previous studies have suggested that CKD is not only main risk of end-stage kidney disease (ESKD), but one of the most important risk factors for cardiovascular disease among known risk factors of diabetes, hypertension, hyperlipidemia, obesity, smoking, and lifestyle-related diseases [3],[4]. Therefore, early detection and early treatment start are also important in terms of preventing increases in the ESKD population and cardiovascular complications [2]. However, even if early detection of CKD is achieved, effective treatment and care systems are not yet established. At the onset of lifestyle-related diseases such as diabetes, hypertension, dyslipidemia, and CKD, most subjects consult general practitioners (GPs). Furthermore, there is initially a lack of subjective symptoms, until severe organ failure occurs. Owing to the asymptomatic phases of CKD, patients are left untreated until ESKD or advanced symptomatic phases. In a previous study, many subjects did not accept medical follow-up or stopped attending the follow-up even when it was necessary, especially younger and male patients [5]. Consequently, it is important to establish appropriate, consistent, and specific treatment and prevention-based care systems according to the progression of CKD.
In this study, we performed a prospective stratified cluster-randomized trial in order to examine the effectiveness of behavior changes of both patients and GPs, designed to prevent non-adherence of continuous medical follow-up in CKD patients, with appropriate timing of introductions from GPs to nephrologists and co-treatment by GPs and nephrologists in order to reduce the evidence-practice gap in CKD treatment, and with the establishment of a better outcome of CKD patients seen by GPs at local medical associations (LMA) by adding several advanced care systems for CKD patients. Previously, several follow-up studies of CKD patients at annual screening were performed in the general population [6] or at nephrology clinics [7], but no long-term follow-up studies or clinical studies of CKD patients cared for by GPs have been performed. Furthermore, there is little information about the detailed clinical outcomes and treatment patterns at GPs. We compared the effects of lifestyle modification by educational intervention on mainly early-stage CKD patients seen at GPs.
In this study, we show the effect of an advanced CKD care system on early-stage CKD patients seen at GPs, and elucidate their outcomes. A cluster-randomized design that randomized LMA was chosen to avoid within-LMA contamination.
Methods
Study design
The study methods have been reported previously [8]. The detailed study design was developed and implemented by an advisory committee, and all analyses were completed by a coordinating center (for details, see supporting information). This study was a Central Institutional Review Board Program; the Committee on Ethics in Strategic Research of the Kidney Foundation, Japan, and the institutional review board at the University of Tsukuba examined and approved the implementation plans and their revision.
This study was conducted at 15 managing facilities in Japan. Two to four local medical associations (LMAs), which constitute the infrastructure of the Japan Medical Association, located near each managing facility, were selected. In total, 49 LMAs (for details, see supporting information and S1 Fig) participated. The trial was a stratified open cluster-randomized study with two intervention groups of A (standard intervention) and B (advanced intervention). Each LMA was regarded as a cluster. For randomization, we divided the country into four regions as strata because the rate of increase of dialysis patients varies from region to region in Japan [9]. Each LMA recruited 10~58 GPs by whom patients in this study were treated.
The study was sponsored by a grant for a strategic outcome study project from the Ministry of Health, Labour and Welfare of Japan.
Study patients
Each registered GP obtained written informed consent for the study from eligible patients before randomization. Eligible participants were those aged between 40 and 74 years who had Stage 1, 2 4, or 5 CKD, or Stage 3 CKD with proteinuria (ratio of urinary protein/urinary creatinine ≥ 0.3 g/g.cre, or proteinuria ≥ 1+) and diabetes or Stage 3 CKD with proteinuria (ratio of urinary protein/urinary creatinine >0.3 g/g.cre or proteinuria >1+) and hypertension, who were under consultation with GPs. Dialysis patients, renal transplant patients, and those who did not consent were excluded from the study.
Participant recruitment was from April 1, 2008 to October 19, 2008. On October 20, 2008, the LMAs were randomly assigned at a ratio of 1:1 to group A (standard intervention) or group B (advanced intervention) (Fig 1). Randomization was performed centrally by means of a computer-generated random-number sequence. The primary intervention study and follow-up duration lasted from October 20, 2008, to March 31, 2012.
We recruited 49 local medical associations (clusters) in 15 different prefectures, which were classified into four regions (strata) based on the level of increase in the rate of dialysis patients [9]. We recruited 557 GPs and 2,417 patients; 2,379 patients from 489 GPs gave consent. After randomization, 68 patients in group B chose to withdraw, while only 13 patients in group A did so. Most of the patients in group B withdrew just after randomization due to an aversion to the educational intervention. Finally, 1,107 patients in group A and 1,029 patients in group B completed this cluster-randomized trial.
Study assessments
At each consultation, physicians and their certified staff measured patients’ blood pressure, and checked their blood pressure readings recorded at home. Examinations or surveys were performed every six months regarding body weight, smoking status, obtained blood and urine, number of patients referred by nephrologists, number of new dialysis patients, and incidence of cardiovascular events. In group B, physicians sent a list of patients who did not visit their clinics as scheduled to the coordinating center every month.
The standards for referral from GPs to nephrologists were as follows: 1) ratio of urinary protein/urinary creatinine ≥ 0.5 or proteinuria ≥ 2+; 2) both proteinuria and hematuria are positive (≥ 1+); 3) estimated GFR (eGFR) < 50 mL/min/1.73 m2; and 4) when GPs judge that patients should consult a nephrologist.
eGFRs in this study were calculated using the following formula:
Study interventions
Patients in both group A and group B clusters underwent treatment in accordance with the current CKD treatment guide. S1 Table shows a summary of targets for CKD treatment applied to all patients. In patients with CKD, lifestyle modifications to avoid obesity and stop smoking are necessary. In addition, strict blood pressure control (less than 130/80 mmHg), strict blood sugar control (Hba1c <6.9%), and non-HDL cholesterol control (non-HDL-C <150 mg/dl) are targets for CKD treatment.
Lecture meetings about the CKD treatment guidelines were held several times annually at local medical associations, and the coordinating center sent a newsletter about CKD treatment to general practitioners bimonthly.
Patients in the group B clusters received three additional interventions. Firstly, the group B patients received 30-minute educational sessions from dieticians upon visiting their local GP offices every three months. The curricula by the dieticians were developed centrally. In terms of lifestyle and nutritional modification, patients received a 30-minute session from a registered dietician. Prior to every session, the dietician checked the patient’s condition using a checklist as shown in S2 Fig. Every checklist item had a score; the higher the score, the further the treatment target. The dietician decided on the dietary counseling theme depending on the score. Registered dieticians provided lifestyle/dietary advice according to the instructions. They helped patients to achieve their CKD treatment goals (S1 Table), explained the examination results, achievements in CKD care, and their implications to patients. The registered dieticians had received training so that they would be able to provide integrated and consistent advice. Secondly, the group B patients received a CKD treatment report from the coordinating center bimonthly to learn about CKD and their ideal lifestyle to prevent progression. In addition, the patients also received a letter, phone call, or email a week before the consultation day, and those who had not consulted a physician for over two months were encouraged to receive care, as an attempt to prevent their withdrawal from treatment. Thirdly, the group B GPs received comments about their patients’ data, focusing on the gap between target and practice, from the coordinating center. The coordinating center also provided information on the patients scheduled to visit the office, examinations, treatment patients should undergo on their next visitation, patients who did not visit hospitals as scheduled, those who were going to receive lifestyle/dietary advice, and those who met the conditions for referral to nephrologists.
Study outcomes
There were three primary outcomes in this study. The first primary parameter for assessment was the rate of discontinuation of clinical visits. The definition of discontinuation of clinical visits was the absence of a clinical visit for more than 6 months. We compared the rate of discontinuous clinical visits between the groups. The second primary parameter was the proportion of patients under co-treatment between GPs and nephrologists. For calculating the proportion of patients under co-treatment between GPs and nephrologists, we counted the number of patients who reached the criteria for requiring nephrology care, and the number of patients who received an introductory letter to a nephrologist using the standards for referral from GPs to nephrologists. Furthermore, we counted the number of return visits to GPs after referral to nephrologists. The third primary parameter for assessment was the progression of CKD stage. To compare annual changes in the CKD stage between the two groups, we used annual eGFR changes (ml/minute/1.73 m2/year) in total and in each CKD stage.
Secondary parameters were as follows: 1) the proportion of adherence to the complete CKD treatment guide, 2) the rate of achievement of blood pressure goals, 3) the number of subjects with a 50% reduction in urinary protein, 4) the number of subjects with a doubling of serum creatinine or a 50% reduction in eGFR, 5) yearly changes in the number of patients starting renal replacement therapy, and 6) the incidence of cardiovascular events.
Sample size calculation
To determine the sample size, we compared the rate of exacerbation of eGFR between group A and group B interventions. We referred to the epidemiological data in the CKD taskforce, collected by the statistical board of the Japanese Society of Nephrology, in which the worsening velocity was -0.59 (SD 0.04) ml/min/year based on changes in renal function among healthy Japanese people who underwent health checkups [10], and the rate of renal deterioration in patients in Stage 3 CKD with diabetes or hypertension [mean serum creatinine = 1.69 mg/dl (SD = 0.57 mg/dl), annual decrease rate = 5.93 ml/min/year (SD 4.321 ml/min/year), n = 569] [11]. We calculated the sample size by T-test on the assumption of a 15% improvement in the rate of renal deterioration, underα = 0.05, β = 0.2, intracluster GP number = 10. Assuming an intracluster correlation of 0.5 for safety, we obtained a study size of 2,264, estimating the proportion that would withdraw as 10%.
Statistical analysis
Statistical analyses were performed using an intent-to-treat approach. For the proportion of absence from clinical visits of patients, and the co-treatment proportion between GPs and nephrologists, each proportion was analyzed by a generalized mixed-effect model of binary outcomes (binomial model) with intervention group as a fixed effect and clusters as a random effect. The deteriorating velocity of eGFR was analyzed by a linear mixed-effect model with intervention group as a fixed effect, and clusters and intercept of the line as a random effect.
For the analysis of clinical events, each comparison between group A and group B was conducted by a linear mixed-effect model with patient-nested cluster as the random effect. For comparison of the two groups, we adjusted for age, gender, presence of hypertension or diabetes, initial renal function, and geographical region. For comparison of eGFR between groups, to minimize the effect of missing values, we further performed comparisons with samples with more than 4 serum creatinine values. All of the statistical analyses were carried out using R version 3.0.1 software [12].
Results
Study clusters and patients
In the LMAs, 489 GPs recruited 2379 patients and obtained a complete baseline questionnaire and consent. The LMAs were randomly assigned to group A or group B (Fig 1). The characteristics of the patients in the two groups were similar at baseline, except for CKD stage and serum uric acid level. The proportion of cases of CKD stage 1+2 in group A was 49.4%, but it was 43.1% in group B, and the proportion of Stage 3 CKD in group A was 40.7%, but it was 47.4% in group B, while the average eGFR and average serum creatinine levels were identical in the two groups. Uric acid in group B was 6.25±1.67, while it was 6.08±1.48 in group A (Table 1).
CKD treatment target Item changes
During the intervention period, 46% of patients in group B received 12 educational sessions, 73% of patients received more than 10 educational sessions, 11.2% of patients received fewer than 10 sessions, and 15.8% of patients stopped the educational intervention. Table 2 shows medication changes during the study period. In total, group B patients had greater improvements in CKD practice guide target items, except for hemoglobin level (Fig 2). With this intervention, there were gradually increasing differences in average values of each item between group A and group B. The average BMI difference between the 2 groups was significant after 2 years (Fig 2A). In addition, the average glycated hemoglobin difference was significant at 2.5 years (Fig 2B). While the percentage of medication of anti-diabetes drugs among group B decreased, that of group A increased. Although proportion of subject using insulin were increased in both groups, obvious increment was observed in group A (Table 2 and S3 Table). Blood pressure of the two groups was identical at randomization, and remained unchanged during the study (Fig 2C and 2D). The percentages of medication of anti-hypertensives and any class of anti-hypertensive drugs were identical between the groups (Table 2 and S4 Table).
Items were BMI changes (A), HbA1c changes (B), systolic (C) and diastolic blood pressure changes (D), non-HDL cholesterol changes (E), and hemoglobin changes in subjects with Stage 3 CKD or later (F) during the study period. Patients in group B had greater improvements than those in group A in terms of the CKD practice guide targets, except for hemoglobin level. In particular, BMI, HbA1c, and blood pressure differences between group A and group B gradually increased over the time course of the interventions. Average BMI was significantly reduced in group B patients 2 years after starting the advanced intervention, and HbA1c was also significantly reduced in group B patients 2.5 years after starting the advanced intervention. * indicates p<0.05 between group A and group B by Student’s T test.
Primary outcomes
1) Rate of absence of patients from clinical visits.
There were 193 patients in group A and 136 patients in group B who were absent from regular clinical visits for more than 6 months. Table 3 shows the rates of absence from clinical visits among the subjects. A total of 16.2% of group A subjects and 11.5% of group B subjects ceased regular visits for more than 6 months. These figures were significantly different (P = 0.01) after adjustment for age, gender, presence of hypertension or diabetes, initial renal function, and geographical region.
During the study period, an absence from consultation for 2 months or more in group B subjects was observed 1255 times (see S2 Table). A significantly higher cessation rate of regular visits was observed in male subjects in group A (group A: male 18.5%, female 10.5%; group B: male 11.7%, female 11.2%). The main reason for the difference between the groups was the significant improvement of visits by males in group B via support from the coordinating center.
2) Co-treatment rate between GPs and nephrologists.
During the entire period, 976patients in group A and 904 patients in group B reached the criteria for requiring nephrology care, and 165 patients (16.9%) in group A and 289 patients (32.0%) in group B were introduced to nephrologists. A significantly higher referral rate was observed in group B after adjustment for age, gender, presence of hypertension or diabetes, initial renal function, and geographical region (P<0.01). Among 976 patients who reached the criteria for requiring nephrology in Group A, 240 were due to a ratio of urinary protein/urinary creatinine ≥ 0.5 or proteinuria ≥ 2+, 244 patients were due to both proteinuria and hematuria being positive, 130 patients showed estimated GFR (eGFR) < 50 mL/min/1.73 m2, and 171 patients had both urinalysis abnormalities and eGFR exacerbation, Among 904 patients who reached the criteria for requiring nephrology in Group B, 238 patients were due to a ratio of urinary protein/urinary creatinine ≥ 0.5 or proteinuria ≥ 2+, 135 patients were due to both proteinuria and hematuria are positive (≥ 1+), 179 patients showed eGFR < 50 mL/min/1.73 m2, and 138 patients had both urinalysis abnormalities and eGFR exacerbation.
In Group A subjects who reached the criteria for requiring nephrology care, 8.5% of subjects with urinary abnormalities, 13.9% of subjects with eGFR exacerbation and 29.3% having both criteria were introduced to nephrologists. In Group B subjects who reached the criteria for requiring nephrology care, 21.4% of subjects with urinary abnormalities, 42,5% of subjects with eGFR exacerbation and 37.8% with both criteria were introduced to nephrologists. Among the subjects who reached the criteria for requiring nephrology care, there was a significant initial eGFR difference between referred subjects and non-referred ones (group A: referred 44.6±23.5 ml/min/1.73 m2, non-referred 59.5±20.4 ml/min/1.73 m2; group B: 50.4±21.0 ml/min/1.73 m2, 56.6±20.9 ml/min/1.73 m2).
Among the referred subjects, 89 patients in group A and 195 patients in group B were reintroduced to GPs, and a significantly higher co-treatment rate was observed in group B (P<0.01). Comparing the reintroduced subjects with the non-reintroduced ones, initial eGFR was significantly higher in the former group in group A, while this difference was not observed in group B (group A: reintroduced 49.3±25.4 ml/min/1.73 m2, not reintroduced 38.3±18.9 ml/min/1.73 m2; group B: 49.9±20.2 ml/min/1.73 m2, 51.1±22.2 ml/min/1.73 m2).
3) progression of CKD stages.
There was no significant difference between groups in the rate of eGFR deterioration. (group A: 2.6±5.8 ml/min/1.73 m2, group B: 2.4±5.1 ml/min/1.73 m2, p = 0.07). There was a significant difference in the eGFR deterioration rate in subjects with Stage 3 CKD (group A: 2.4±5.9 ml/min/1.73 m2, group B: 1.9±4.4 ml/min/1.73 m2, p = 0.03), while the eGFR deterioration rates were identical for the other CKD stages. Each CKD stage analysis was conducted separately.
We compared eGFR deterioration rates using linear regression, and to minimize sampling bias we further analyzed subjects who had more than 4 records of serum creatinine. As shown in Table 3, the differences in eGFR deterioration rate were the same as in the analysis of total subjects.
Secondary outcomes
There was no significant difference between group A and group B in terms of the cumulative incidence of achieving the CKD treatment guide targets at the end of study (Table 4). However, during the study period, more patients in group B had reached the targets of BMI <25, glycated hemoglobin <6.9%, and other measured risk factors, except for non-HDL cholesterol level and smoking cessation rate, and the differences between group A and B became wider in BMI, HbA1c, and blood pressure with time after the start of the study (Fig 3). The numbers of subjects with a 50% reduction in urinary protein were identical; however, the number of subjects with a doubling of serum creatinine or 50% reduction in eGFR was significantly reduced in group B. The cumulative incidence of a doubling of serum creatinine or 50% reduction in eGFR also showed a gradually increasing difference between groups A and B over the course of the study. Finally, 6.7% of group A subjects and 4.4% of group B subjects showed doubling of serum creatinine (P = 0.02) and 8.1% of group A subjects and 5.8% of group B subjects showed 50% reduction of eGFR (P = 0.01) at 3.5 years, which were significantly different between the groups by the generalized linear mixed model (Table 4 and Fig 4). However, the cumulative incidences of patients starting renal replacement therapy and the incidences of cardiovascular events were identical in the two groups (Table 4).
CKD treatment cumulative achievements for BMI <25 (A), HbA1c <6.9% (B), controlled blood pressure (C), smoking cessation (D), non-HDL-C <150 mg/dl (E), and proportion of hemoglobin concentration controlled to 10–12 g/dl among CKD stages 3, 4, and 5 (F). There was no significant difference between group A and group B in CKD treatment control achievements by generalized linear mixed model. Patients in group B had greater cumulative incidences of achieving the targets of BMI <25, glycated hemoglobin <6.9%, and other measured risk factors, except for non-HDL cholesterol level and smoking cessation rate. In particular, cumulative differences in the rates of achieving BMI, HbA1c, and blood pressure targets between group A and group B gradually widened over the course of the interventions.
Both the number of subjects with a doubling of serum creatinine and the number with a 50% reduction in eGFR significantly decreased in group B. The cumulative incidence of a doubling of serum creatinine or a 50% reduction in eGFR also exhibited a gradually increasing difference between groups A and B over the course of the study. A significant difference was shown between Group A and Group B by generalized linear mixed model.
Discussion
In general, poor adherence to medication is associated with the development of complications, disease progression, avoidable hospitalizations, higher medical costs, premature disability, and death[13],[14]. Discontinuous clinical visit rates are relatively high across disease states, treatment regimens, and age groups in males, with the first several months of therapy characterized by the highest rate of discontinuation [5]. Most CKD patients are asymptomatic, and discontinuous clinical visit is one of the main problems of such patients. In this study, our intervention methods successfully achieved behavior modification of CKD patients by producing significantly more regular clinical visits in Group B. Not only encouragement to make regular clinical visits, but also regular educational sessions by dieticians and entering clinical studies with consent may have had some effect in this study. Meanwhile, the discontinuous clinical visit rates in female subjects were identical between the two groups. For the avoidance of discontinuous clinical visits, this type of intervention was thus not effective in female subjects. There are several explanations for this gender differences. One is that males often received regular educational sessions from dieticians with their family, especially with their wife, while females often received the sessions alone. Males had more chances to hear advice from their families than females. Furthermore, support provided by females was positively related to patients' intention to adhere, whereas support provided by males was slightly negatively related to the intention of their female spouses to adhere [15].
Appropriate timing of referral to nephrologists has been shown to delay the progression of CKD,[16]. In this study, we successfully observed behavior modification of GPs by our group B interventions. On the basis of the Japanese Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney Disease [17], we encouraged referral to a nephrologist at eGFR <50 ml/min/1.73 m2 or upon overt proteinuria. However, most of our subjects were not referred due to overt proteinuria. Proteinuria was shown to be the most important risk factor for the progression of ESRD [6], but there was no evidence of clinical improvement by such early referral to a nephrologist. We will continue to follow-up our subjects and will show the effect of appropriate referral to a nephrologist on the prognosis of early-stage CKD patients in the near future.
Several previous studies showed that concentrated educational interventions in the early period of the trial had a good effect on the rate of renal function deterioration and patient outcome [18] [19]. In this study, the educational interventions in group B were 30-minute sessions every 3 months during the entire intervention period, the effects of which would have appeared gradually. As shown in Figs 2 and 3, except for non-HDL cholesterol concentration and hemoglobin changes, subjects in group B showed gradual improvements of glucose control, and body weight control compared with group A patients. Those changes might be due to the multifactorial intervention in Group B. As a result, significant differences in creatinine doubling and eGFR 50% reduction were observed, and the differences between groups A and B widened over time (Fig 4). In addition, the average rate of eGFR deterioration tended to be lower in group B, while the medication rates of ARB and ACEI were identical between the groups.
A favorable effect in this study was obvious in subjects with Stage 3 CKD. For evaluation of renal function, we used a serum creatinine-based GFR estimation formula for the Japanese. This formula is suitable for predicting renal function of less than GFR <60 ml/min/1.73 m2 [20]. Consequently, estimation of GFR with this eGFR formula had a wide range of potential over- and underestimation in CKD stages 1 and 2. Meanwhile, in stage 3 subjects, a significant improvement of eGFR deterioration rate was observed. Stage 3 CKD is the most prevalent in the CKD population [21],[22], and most such patients were cared for by GPs. Meanwhile, in CKD stage 4 and 5 patients, no favorable effect was observed. Recent trials for advanced CKD patients did not show favorable effects on renal outcome at CKD stages 4 and 5 [23–25]. Several reports suggested that predialysis nephrologist care might have favorable effects on patient outcomes in those stages of CKD upon receiving multidisciplinary treatment [19,26]. We have to determine the ideal treatment methods for CKD stage 4 or 5, in order to effectively delay the progression of renal function deterioration.
Finally, a limitation of this study was that we could not observe any differences in the cumulative incidence of patients starting renal replacement therapy or suffering cardiovascular events between the two groups, but we think this type of intervention would have an effect on the incidences of RRT and CVD events after long-term observation. Several previous studies showed that such educational intervention had a long-term legacy effect [27,28]. We have to obtain longer follow-up results after intervention in the near future. Furthermore, several follow-up studies of CKD patients at annual screening in the general population [29] or in nephrology clinics [30] [31] [32] have been performed, but there was only one report about long-term follow-up studies of CKD patients cared for by GPs [33]. There are few interventional clinical studies of CKD patients cared for by GPs, and there is also little information about the detailed clinical outcome and treatment pattern changes in recent years at GPs. A long-term follow-up of this subject would be also valuable.
In conclusion, an advanced CKD care system could achieve behavior modification of CKD patients, namely, significantly lower discontinuous clinical visit rates, and behavior modification of both GPs and nephrologists, namely, significantly higher referral and co-treatment rates, resulting in the retardation of CKD progression, especially in patients with proteinuric Stage 3 CKD. For the purpose of lifestyle modification for preventing the progression of kidney dysfunction and complications, this type of multifactorial intervention might be one solution.
Supporting Information
S1 Fig. Distribution of clinical sites in Japan.
https://doi.org/10.1371/journal.pone.0151422.s001
(DOCX)
S2 Fig. Comprehensive lifestyle and nutrition education score sheet.
https://doi.org/10.1371/journal.pone.0151422.s002
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S2 Table. Number and detailed contact methods for group B patients who did not receive regular consultation at GPs for 2 months and over.
https://doi.org/10.1371/journal.pone.0151422.s005
(DOCX)
S3 Table. Detail of anti-diabetes drug changes during the study period.
https://doi.org/10.1371/journal.pone.0151422.s006
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S4 Table. Detail of anti-hypertensive drug changes during the study period.
https://doi.org/10.1371/journal.pone.0151422.s007
(DOCX)
Acknowledgments
The statistical analysis in this study was carried out using the Institute of Statistical Mathematics Cooperative Use Registration Program (2013-ISM CRP-0006).
This study was supported by a grant for a strategic outcome study project from the Ministry of Health, Labour and Welfare of Japan, and supported in part by a Grant-in-Aid for Research on Advanced Chronic Kidney Disease (REACH-J), Practical Research Project for Renal Diseases from Japan Agency for Medical Research and development, AMED.
We express our thanks to the doctors and dieticians who participated in this study. We also express our thanks for the continuous support from members of the Japanese Society of Nephrology, the Japan Dietetic Association, and the Japanese Medical Association.
The Study Group for Frontier of Renal Outcome Modifications in Japan (FROM-J) were as follows;
A leading author and the principal investigator of FROM-J is Kunihiro Yamagata, MD, PhD (contact email address: k-yamaga@md.tsukuba.ac.jp)
Coordinating center
University of Tsukuba. Kunihiro Yamagata, Masafumi Okada, Hideto Takahashi, Chie Saito, Hirayasu Kai, Reiko Ohkubo, Yuichi Ishikawa, Kohsuke Yamaga, Mariko Doi, Toshiyuki Imasawa, Shoko Shimizu, Reiko Matsuzawa, Mitsuko Fumoto, Naomi Hirafuji
Hamamatsu Medical University. Akira Hishida, Akihiko Kato,
Japan Kidney Foundation. Osamu Sakai, Toshiyuki Imasaw, Satoshi Morita, Shigeru Takahashi
Committee
Advising Committee. Kunihiro Yamagata, Hirofumi Makino, Tadao Akizawa, Kunitoshi Iseki, Sadayoshi Ito, Kenjiro Kimura, Daisuke Koya, Yoshiharu Tsubakihara, Ichiei Narita, Tetsuya Mitarai, Masanobu Miyazaki, Tsuyoshi Watanabe, Takashi Wada
Nutrition Support Working Group. Kunihiro Yamagata, Yuichi Ishikawa, Toshiyuki Imasawa, Mari Odamaki, Hirayasu Kai, Yoshie Kanazawa, Yoshihiko Kanno, Chie Saito, Atsuko Sakai, Shuichi Tsuruoka, Kazuhiko Tsuruya, Toshiyuki Nakao, Masayoshi Fujiwara, Fumio Mizuno, Kohsuke Yamada
Committee for Assessments of Events. Akira Sato, Yasunobu Nakai, Norio Hanafusa, Junichi Hoshino
Medical economics analyzing working group. Masahide Kondo, Reiko Ohkubo, Shu-ling Hoshi
Clinical sites
University Hospital of the Ryukyus
Kunitoshi Iseki
Chubu Okinawa Medical Association. Higa Seiken, Shinzato Osamu, Shukumine Chiaki, Tamaki Osamu, Ikehara Hiroshi
Urasoe medical association. Nakama Seitaro, Karimata Yoichi, Shimoji Katsuyoshi, Nakamura Hiroshi, Taira Masahiro, Tokuyama Kiyotaka, Hisada Tomoichiro
Naha Medical Association. Tomori Hiroaki, Nakamoto Masakazu, Miyagi Masatake, Iju Morimasa, Yagi Noriharu, Kanashiro Osamu, Gakiya Izuru, Kinjo Yukihiro, Kyan Kunio, Hirata Haruo
Nambu Medical Association. Higa Akira, Tokumura Yasumasa, Kadena Nariyuki, Mori Toshikazu, Tanaka Hideaki, Tamaki Seishu, Shimabukuro Takeshi, Ashitomi So, Matsuoka Mitsuteru
University of Kumamoto
Kimio Tomita, Yukimasa Kohda, Taku Miyoshi.
Kumamoto City Medical Association. Iemura Akihiro, Sakai Koichi, Jinnouchi Hideaki, Kaku Yutaka, Takeshita Seiichi, Katase Tatsuya, Kataoka Koichiro, Inoue Junnosuke, Tabuchi Hirotaka, Shimada Tatsuya, Ogata Ichiro, Honjo Koji, Yoshimura Ryohei
Yatsushiro City Medical Association. Okamura Kenji, Takano Yoshihisa, Ogaki Satoru, Matsuoka Noboru, Ueno Naotsugu, Chirifu Haruaki, Masuda Yoji
University of Nagasaki
Tomoya Nishino, Yoko Obata, Akira Furusu
Nagasaki city medical association. Tsuruta Masako, Tetuo Hirokuni, Yoshimi Kozaburo, Shirahige Yutaka, Migita Reijiroh, Kurobe Katsunori, Matsuzaki Tadaki, Okuno Shinichiro, Oku Yasuhiko, Baba Koreaki, Yamamoto Hidefumi, Isomoto Shojiro
Sasebo Medical Association. Senju Shin, Sakaguchi Yoji, Haraguchi Masuho, Tokunaga Masaki, Matsumoto Takashi
oomura medical association. Izaki Miwa, Oka Hiroyuki, Noguchi Akihiko, Nakamura Masumi, Tomonaga Akimitsu, Tasaki Kenichi, Koga Naruhiko
Isahaya medical association. Takahara Akira, Kusano Shiro, Mori Hiroshi, Inuo Hjime, Gondo Michio, Kiriyama Ken, Tsunoo Naoto, Oosumi Mitsuhiko, Yamaguchi Kunitaro, Nakashima Tsuneyuki, Miyamoto Toshimitsu, Noda Shin, Goto Yoshiki, Takino Hirofumi, Yamasaki Yoshiyuki
University of Okayama
Hirofumi Makino, Yohei Maeshima, Naoki Kashihara (Kawasaki Medical University), Norio Komai (Kawasaki Medical University)
Fuchu Medical Association. Okuno Fumio, Sano Toshiaki, Seo Yasuo, Tani Hideki, Hosoya Shigee, Watanabe Kunitake, Ikeda Jun, Mishima Takateru, Inoue Katsutoshi, Takeda Eiji, Cho Takeshi, Naito Kenichi, Yamamoto Yasuhiro, Kawamura Hideyasu, Sumii Kengo
Mimasaka Medical Association. Ido Kiyohito, Matano Shigeru, Harada Seishi, Usumoto Ryoji, Tago Takuji, Miyashima Hiroto, Matsuzaka Hiroto, Hirai Ryuzo, Sakamoto Taisuke, Osakada Munemichi, Kanchiku Ichiro, Kondo Masanori, Motoyama Yuzo, Fukui Shoji
Okayama Medical Association. Hioka Hiroshi, Shindo Akihisa, Imajo Tamotsu, Nakajima Takanobu, Hisamoto Nobumi, Terami Taketo, Sato Ryosuke, Hirata Hiroshi, Sato Yoshinobu, Kawamura Norio, Matsuyama Masaharu, Adachi Noriko
Kurashiki Medical Association. Kuniyasu Tetsuya, Murakami Mikio, Kunitomi Kimito, Miura Hiroshi, Shirahige Katsuya, Hironaka Kazue, Takaya Yasumasa, Saito Noriaki, Moriyasu Fumiaki, Yoshida Soichiro, Sasaki Tetsuro
University of Nagoya
Seiichi Matsuo, Yoshinari Yasuda, Shoichi Maruyama
Kasugai Medical Association. Ito Yusuke, Ichikawa Atsushi, Komatsubara Kazuo, Sakakibara Kazumoto, Naitou Koutarou, Nojiri Osamu, Mori Kenichi, Yamagiwa Kayo, Akiyama Noboru, Tashiro Yoshiko
Seto-Asahi Medical Association. Ito Takao, Ohashi Mitsuru, Torii Akihito, Nagae Itsuro, Noda Masaharu, Kuroe Koshiro, Machida Hideyuki
Anjo Medical Association. Hirano Yoshika, Fujii Yasuaki, Shimizu Seiji, Ishizaki Seiji
Okazaki City Medical Association. Komori Yasuo, Kanda Hirofumi, Yamamoto Teruyoshi, Koide Nobukiyo
Nagoya Medical Association. Oishi Mutuso, Ogawa Tadashi, Kato Tomoko, Tatematsu Hiroshi, Nishimura Kenji, Miyake Toshiyuki, Soga Taro, Takeuchi Masayuki, Ogawa Takuo, Yamamoto Hiroyasu, Ogata Korechika, Yasui Kenji, Maeda Toshio
Hamamatsu Medical University
Akira Hishida, Yoshihide Fujigaki, Hideo Yasuda, Noriko Mori (Shizuoka prefectural hospital)
Shizuoka City Shizuoka Medical Association. Shibayama Shusuke, Aoyama Shigeo, Oishi Tatsuo, Sugiyama Keiichi, Iimuro Suguru, Fukuchi Yasunori, Hakamada Kouji, Oka Shinichiro, Watanabe Megumi, Takano Satoshi, Teramura Jun
Hamamatsu Medical Association. Goto Yoshinori, Nagasaka Shiro, Mamiya Yasuyoshi, Takinami Minoru, Shiratori Masayuki, Iwata Satoru, Kumagai Junichi, Takahashi Toshiaki, Fujishima Yuriko, Nakajima Takeyuki
Kanazawa University
Takashi Wada, Kiyoki Kitagawa, Akinori Hara, Tadashi Toyama, Hitoshi Yokoyama (Kanazawa Medical University)
Kanazawa Medical Association. Takeda Yasuo, Maekawa Nobumasa, Yokoi Masato, Morita Masato, Kaji Kyosuke, Ohno Hideki, Doniwa Kenichi, Wakasa Yutaka, Kitano Hirotsugu
Toyama City Medical Association. Naito Takero, Asaji Akira, Konishi Keiko, Ejiri Mizuho, Hori Fumi, Noda Takashi, Takahashi Hideo, Yoshiyama Izumi, Horichi Hajime, Ueno Hitoshi, Nakayama Tetsunori, Ota Katsuro, Shibata Osamu, Iwai Hisakazu, Tsuchida Toshihiro, Tanei Masanobu, Koyata Hirohisa, Tsuneda Takakazu, Yamamoto Hideki
Kahokugunshi Medical Association. Kakuda Hirokazu, Kubo Takayuki, Kontani Kazuhiro, Ninomiya Tetsuhiro, Takata Mitsuhiko, Kitatani Hideki, Yamada Tsubara, Okino Soichi, Yoshio Hiroyuki, Nakada Shigeru, Chadani Takashi
Uozu City Medical Association. Masuzaki Shigeki, Miyamoto Hiroshi, Sawaguchi Kiyoshi, Hada Mutsuo
Shimoniikawa Medical Association. Kawase Norio, Bando Toru, Fujioka Teruhiro, Yamamoto Masayasu, Ikeda Ichiro, Koizumi Hisashi, Makino Hiroshi, Takazakura Eisuke, Nakagawa Hikohito
Niigata University
Ichiei Narita, Hiroki Maruyama, Shin Goto
Shibatakitakambara Medical Association. Hanano Masaharu, Sasagawa Yasuo, Kawai Kazuo, Saito Toru, Nakagawa Iwao, Kido Shigeo, Higuchi Kenichi, Shimazu Wakio
Medical Association of Niigata City. Yokota Tatsuya, Adachi Tetsuo, Hayashi Hiroshi, Miyajima Takefumi, Suzuki Masataka, Kikuchi Masatoshi, Igarashi Kenichi, Okada Kiyoshi, Yanagisawa Yoshikazu, Okada Masami, Kobayashi Hiroyuki, Miura Kazumasa, Kiyono Yasuyuki, Hayashi Naoki, Tazawa Yoshihito, Fujita Kazutaka, Wakabayashi Masaya, Tanabe Hajime, Fujita Junji
Kashiwazaki Kariwa Medical Association. Nakazawa Toshiro, Sugimoto Fujio, Sato Toshiro, Homma Tamotsu, Sato Takahisa, Sato Kazuaki, Takagi Akio, Hirano Toru, Takahashi Tadashi
St. Marianna Medical University
Kenjiro Kimura, Takeo Sato, Yusuke Konno
Asao Medical Association. Okazaki Takeomi, Uchida Mitue, Mineki Hitoshi, Yoshimatsu Nobuhiko, Obata Junichi, Shimazaki Minako, Kimura Takashi, Watanabe Yoshiro
Miyamae Medical Association. Onoda Shoichi, Takenaka Kikuo, Kamata Masahiro, Hara Toshio, Morishima Akira, Tamura Takashi, Fukushima Yoshihiko, Murakami Yasufumi, Ito Katsuhiko, Kawakami Satoshi, Takahashi Toshimitsu, Nakada Masahiro
Tama Medical Association. Kou Mototetsu, Suzuki Masayuki, Yamamoto Masaru, Okano Koichi, Ishihara Hiroshi, Doi Yoshiyuki, Sekiguchi Shinya, Nishine Akira, Yoshida Hiromi, Okabe Toshiaki, Tsuchiya Hiroaki, Makino Hideki
Inagi City Medical Association. Kajiwara Takahiro, Takeda Yuko, Watanabe Sumio
Showa University
Tadao Akizawa, Takanori Shibata, Ashio Yoshimura, Eriko Kinugasa, Hiroaki Ogata
Shinagawa Medical Association. Tanaka Tsutomu, Shirai Hiroshi, Kawamura Satoshi, Iwahata Takahiko, Ishii Makoto, Takase Shigeru, Miyahira Tsuneko, Matsuyama Tsuyoshi, Ogawa Hideya
Omori Medical Association. Katagiri Masato, Suzuki Hiroshi, Kawada akinori, Watanabe Sho, Ui Tadahiro, Arai Toshihide, Hirose Chieko, Fujii Daigo, Houjo Minoru
Aoba Medical Association. Fujikura Hisanori, Nishiyama Genyo, Fujita Koki, Kawase Sadao, Ogihara Atsushi, Nishikawa Masato, Oka Keiko, Yoshimoto Midori, Furuta Kaoru, Miyamoto Norio
Tsuzuki Medical Association. Takeda Shigeru, Tada Hiromi, Ono Katsuyuki, Harada Hirofumi, Hironaka Taro, Mitani Hideki
Saitama Medical University
Tetsuya Mitarai, Hajime Hasegawa
Kumagaya medical association. Kakuta Reiko, Nishida Shin, Negoro Takashi, Suzuki Makoto, Shinozawa Takashi, Shibuya Tomoyuki, Kujirai Noboru, Murakami Kazuhiko, Sakamoto Koichi
Urawa Medical Association. Sekiyama Tatsuya, Kitahama Hiroyuki, Abe Riichiro, Tonegawa Yoji, Ashiya Yumiko, Saito Shigeru, Sekine Noriyo, Tosaka Hideaki, Ishida Yusei, Mizutani Motoo
University of Tsukuba
Kunihiro Yamagata, Chie Saito, Hirayasu Kai
Tsukuba Medical Association. Iioka Yukio, Iida Shotaro, Kashimura Hiromasa, Kimura Ikuo, Kurata Shoji, Sato Koichi, Narushima Kiyoshi, Niizawa Gaku, Miyakawa Kenji, Miyamoto Masatoshi, Shibahara Ken
Mito Medical Association. Abe Seijirou, Iitake Kazuhiro, Kuroha Akio, Abe Hiroyuki, Kawachi Shigeto, Takahashi Minoru, Nishimiya Katsuaki, Sumiya Ryoitsu, Kameda Sadahiko, Aoki Kaori, Harada Mahito
Inashiki Medical Association. Kashiwagi Yasutaka, Narushima Katsuhiko, Yuhara Kyoko, Innami Ryuichi, Miyamoto Jiro, Shinotsuka Isao, Sakamoto Shigehito
Suigo Medical Association. Nakazawa Ritsuji, Iijima Fukuo, Ohkubo Yoshihiko, Matsuzaki Hiroaki, Hanawa Kenji, Tseng Chen-Chiang
Jichi Medical University
Eiji Kusano
Utsunomiya medical association. Nakagawa Yoichi, Kase Norio, Kobayashi Kimiya, Okawa Fujio, Inooka Gen, Saito Koshi, Kimura Kenichi, Kuroda Toshio, Takeda Shigeyuki, Watanabe Hironobu, Murayama Naoki
Oyama Area Medical Association. Oohashi Hiroshi, Yamanaka Tsuneo, Kawamura Hajime, Hoshino Satoshi, Inaba Shunzo, Sato Shin, Iino Tomoya, Shinohara Hideki, Kikuchi Hironori, Akazawa Satoshi, Kakuta Hiroshi
Fukushima Medical University
Tsuyoshi Watanabe, Masaaki Nakayama, Koichi Asahi, Tsuneo Konta (University of Yamagata)
Iwaki Medical Association. Shimizu Kazumasa, Nagase Noriko, Taneda Yoshinobu, Nakayama Motoji, Sato Takeshi, Nakano Shonai, Komatsu Masafumi
Yamagata City Medical Association. Komatsu Yoshimasa, Sugiyama Kazuhiko, Kamimura Yuko, Igarashi Hide, Yamaguchi Seiji, Tachibana Hidetada, Yamaguchi Keiko, Kawashima Sukehiko, Shirakabe Masanori, Nemoto Hajime
Fukushima City Medical Association. Miyazaki Yoshihiro, Umetsu Hirotaka, Kitsunai Yoshiichi, Watanabe Takako, Saito Koichi, Machii Kazuo, Miyake Hiroaki, Watanabe Kazuo, Muraoka Ryo, Ishii Hajime
Koriyama Medical Association. Tsuda Fukumi, Yanai Koichi, Hirosaka Akira, Seino Hiroaki, Usami Keiji, Sato Eiichi, Yamasawa Masanori
University of Tohoku
Sadayoshi Ito, Hiroshi Sato, Mariko Miyazak
Sendai Medical Association. Nishiyama Akimitsu, Nagashima Michio, Uchida Noki, Meguro Yuki, Osawa Hirotoshi, Sukegawa Izumi, Mori Ruriko, Akimoto Hiroji, Kaneto Hiroyuki, Kimura Mahito, Hishinuma Tamio
Ishinomaki Medical Association. Kumon Toshikatsu, Kishi Mikio, Chiba Jun, Endo Fumio, Sakurai Tadami, Chiba Yoshiro, Shishido Tomoaki, Narita Mitsuyoshi, Satoh Mitsuo, Ito Kenichi
Author Contributions
Conceived and designed the experiments: KY HM KI SI IN T. Wada T. Watanabe. Performed the experiments: KY HM KI SI KK EK TS KT IN T. Nishino YF TM T. Wada T. Watanabe T. Nakamura SM. Analyzed the data: KY HM KI IN T. Watanabe. Wrote the paper: KY.
References
- 1. Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, et al. Prevalence of chronic kidney disease in the Japanese general population. Clin Exp Nephrol 2009; 13: 621–630. pmid:19513802
- 2. James MT, Hemmelgarn BR, Tonelli M Early recognition and prevention of chronic kidney disease. Lancet 2010; 375: 1296–1309. pmid:20382326
- 3. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001; 134: 629–636. pmid:11304102
- 4. Brugts JJ, Knetsch AM, Mattace-Raso FU, Hofman A, Witteman JC Renal function and risk of myocardial infarction in an elderly population: the Rotterdam Study. Arch Intern Med 2005; 165: 2659–2665. pmid:16344425
- 5. Evans CD, Eurich DT, Remillard AJ, Shevchuk YM, Blackburn D First-fill medication discontinuations and nonadherence to antihypertensive therapy: an observational study. Am J Hypertens 2012; 25: 195–203. pmid:22089108
- 6. Yamagata K, Ishida K, Sairenchi T, Takahashi H, Ohba S, Shiigai T, et al. Risk factors for chronic kidney disease in a community-based population: a 10-year follow-up study. Kidney Int 2007; 71: 159–166. pmid:17136030
- 7. Denker M, Boyle S, Anderson AH, Appel LJ, Chen J, Fink JC, et al. Chronic Renal Insufficiency Cohort Study (CRIC): Overview and Summary of Selected Findings. Clin J Am Soc Nephrol 2015.
- 8. Yamagata K, Makino H, Akizawa T, Iseki K, Itoh S, Kimura K, et al. Design and methods of a strategic outcome study for chronic kidney disease: Frontier of Renal Outcome Modifications in Japan. Clin Exp Nephrol 2010; 14: 144–151. pmid:20020312
- 9. Usami T, Koyama K, Takeuchi O, Morozumi K, Kimura G Regional variations in the incidence of end-stage renal failure in Japan. JAMA 2000; 284: 2622–2624. pmid:11086370
- 10. Imai E, Horio M, Yamagata K, Iseki K, Hara S, Ura N, et al. Slower decline of glomerular filtration rate in the Japanese general population: a longitudinal 10-year follow-up study. Hypertens Res 2008; 31: 433–441. pmid:18497462
- 11. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–860. pmid:11565517
- 12.
Team RC (2013) R: A language and environment for statistical computing. R Foundation for Statistical Computing,. Vienna, Austria: http://www.R-project.org/. pp. http://www.R-project.org/.
- 13. Munger MA, Van Tassell BW, LaFleur J Medication nonadherence: an unrecognized cardiovascular risk factor. MedGenMed 2007; 9: 58.
- 14. Pladevall M, Brotons C, Gabriel R, Arnau A, Suarez C, de la Figuera M, et al. Multicenter cluster-randomized trial of a multifactorial intervention to improve antihypertensive medication adherence and blood pressure control among patients at high cardiovascular risk (the COM99 study). Circulation 2010; 122: 1183–1191. pmid:20823391
- 15. Jungers P Late referral: loss of chance for the patient, loss of money for society. Nephrol Dial Transplant 2002; 17: 371–375. pmid:11865079
- 16. Yamagata K, Nakai S, Masakane I, Hanafusa N, Iseki K, Tsubakihara Y Ideal timing and predialysis nephrology care duration for dialysis initiation: from analysis of Japanese dialysis initiation survey. Ther Aphe Dial 2012; 16: 54–62.
- 17. Yokoyama Y, Yamazaki S, Hasegawa T, Wakita T, Hayashino Y, Takegami M, et al. Impact of early referral to nephrologist on mental health among hemodialysis patients: a Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephron Clinical practice 2009; 113: c191–197. pmid:19672118
- 18. Devins GM, Mendelssohn DC, Barre PE, Binik YM Predialysis psychoeducational intervention and coping styles influence time to dialysis in chronic kidney disease. Am J Kidney Dis 2003; 42: 693–703. pmid:14520619
- 19. Chen YR, Yang Y, Wang SC, Chiu PF, Chou WY, Lin CY, et al. Effectiveness of multidisciplinary care for chronic kidney disease in Taiwan: a 3-year prospective cohort study. Nephrol Dial Transplant 2013; 28: 671–682. pmid:23223224
- 20. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982–992. pmid:19339088
- 21. Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, et al. Prevalence of chronic kidney disease in the Japanese general population. Clin Exp Nephrol 2009; 13: 621–630. pmid:19513802
- 22. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007; 298: 2038–2047. pmid:17986697
- 23. Imai E, Chan JC, Ito S, Yamasaki T, Kobayashi F, Haneda M, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia 2011; 54: 2978–2986. pmid:21993710
- 24. Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363: 1146–1155. pmid:20843249
- 25. Akizawa T, Asano Y, Morita S, Wakita T, Onishi Y, Fukuhara S, et al. Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial. Am J Kidney Dis 2009; 54: 459–467. pmid:19615804
- 26. Peeters MJ, van Zuilen AD, van den Brand JA, Bots ML, van Buren M, Ten Dam MA, et al. Nurse Practitioner Care Improves Renal Outcome in Patients with CKD. J Am Soc Nephrol 2014; 25: 390–398. pmid:24158983
- 27. Devins GM, Mendelssohn DC, Barre PE, Taub K, Binik YM Predialysis psychoeducational intervention extends survival in CKD: a 20-year follow-up. Am J Kidney Dis 2005; 46: 1088–1098. pmid:16310575
- 28. Gaede P, Lund-Andersen H, Parving HH, Pedersen O Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–591. pmid:18256393
- 29. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073–2081. pmid:20483451
- 30. Feldman HI, Appel LJ, Chertow GM, Cifelli D, Cizman B, Daugirdas J, et al. The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods. J Am Soc Nephrol 2003; 14: S148–153. pmid:12819321
- 31. Okubo R, Kai H, Kondo M, Saito C, Yoh K, Morito N, et al. Health-related quality of life and prognosis in patients with chronic kidney disease: a 3-year follow-up study. Clin Exp Nephrol 2014; 18: 697–703. pmid:24198050
- 32. Nakayama M, Sato T, Sato H, Yamaguchi Y, Obara K, Kurihara I, et al. Different clinical outcomes for cardiovascular events and mortality in chronic kidney disease according to underlying renal disease: the Gonryo study. Clin Exp Nephrol 2010; 14: 333–339. pmid:20556461
- 33. Minutolo R, Lapi F, Chiodini P, Simonetti M, Bianchini E, Pecchioli S, et al. Risk of ESRD and death in patients with CKD not referred to a nephrologist: a 7-year prospective study. Clin J Am Soc Nephrol 2014; 9: 1586–1593. pmid:25074838