Association of Estimated Glomerular Filtration Rate Slopes with Cardiorenal Outcomes in Patients with Chronic Kidney Disease before and after Multidisciplinary Education

Abstract

Introduction

Multidisciplinary education has been shown to slow the progression of chronic kidney disease (CKD) and reduce cardiovascular (CV) risk, although its effects depend partly on patient characteristics. The aim of this study was to assess how patients categorized on the basis of estimated glomerular filtration rate (eGFR) responded to multidisciplinary education in terms of cardiorenal outcomes.

Methods

In this retrospective cohort study, we included 447 CKD patients who received multidisciplinary education between January 1, 2013, and December 31, 2020, at Nara Prefecture General Medical Center. Exposure was four categories according to eGFR slopes before and after multidisciplinary education. The primary outcomes were renal events defined as the composite of dialysis initiation, transplantation, and 30% eGFR decline, and CV events defined as the composite of heart failure requiring hospitalization, coronary or leg revascularization, cardiac sudden death, and stroke.

Results

Multidisciplinary education decreased the median eGFR slope from −5.00 to −0.65 mL/min/1.73 m²/year. In fully adjusted models, the hazard ratios (95% confidence intervals) for total renal events relative to slow-slow eGFR decline were 1.02 (0.50–2.06) for fast-slow decline, 5.30 (2.82–9.97) for slow-fast decline, and 7.53 (4.02–14.1) for fast-fast decline. Only fast-fast eGFR decline was associated with a high risk of CV events. Subgroup analyses showed similar trends. Fast decline after education was independently associated with increased proteinuria and decreased hemoglobin levels.

Conclusions

Fast eGFR decline after but not before multidisciplinary education was significantly associated with renal and CV events in CKD patients. Attention should be paid to CKD patients with limited benefit from multidisciplinary education.

Introduction

The number of patients with chronic kidney disease (CKD) has been increasing worldwide, with the current prevalence in developed countries ranging from 5 to 15% [1–3]. The incidence and progression of CKD are at least partly associated with traditional risk factors such as diabetes, hypertension, dyslipidemia, obesity, smoking, and the use of drugs associated with renal damage, and all of these can lead to overt proteinuria, kidney function decline, and ultimately end-stage kidney disease (ESKD). Multifactorial interventions for these comorbid conditions and diseases play critical roles in CKD management. Among these interventions is multidisciplinary education, which has been shown to contribute significantly to preventing CKD and slowing its progression [4, 5], and to delaying declines in estimated glomerular filtration rate (eGFR) [6, 7]. Multidisciplinary education is an integrative medical care system that includes doctors, nurses, and dietitians who participate in medical treatment, patient education, diet consultation, and behavioral adjustment.

However, there is heterogeneity in the composition of multidisciplinary CKD teams and their interventional strategies [8]. The Chronic Renal Insufficiency Cohort (CRIC) Study reported that prior nephrology care was not associated with slower CKD progression [9]. A randomized control study revealed that multidisciplinary treatment for up to stage 3b CKD slowed its progression 3 months after randomization [10]. These results suggest that CKD is a multifactorial disease in which the degree of effectiveness of multidisciplinary care differs between patients. It remains unknown if specific characteristics of CKD patients are associated with the successful delay of CKD progression, and if changes in renal function resulting from multidisciplinary CKD care are associated with adverse events. In this study, therefore, we aimed to determine the relationship between renal prognosis and annual eGFR slopes before and after multidisciplinary education.

Methods

Patients and Study Design

This hospital-based, retrospective, observational study initially enrolled 1,152 CKD patients who received inpatient multidisciplinary education at Nara Prefecture General Medical Center, Japan, between January 1, 2013, and December 31, 2020. The following patients were excluded: 105 patients with CKD complicated by acute kidney injury; 75 patients with nephrotic syndrome or collagen diseases who were treated with steroids or immunosuppressive agents; and 48 patients with urinary tract malignancies, including those who had undergone surgery for renal cancer. These conditions and treatments are known to substantially influence renal function, thereby precluding accurate estimation of eGFR slopes before and after multidisciplinary education; 427 with missing data; and 50 lost to follow-up. Finally, 447 patients were included in the analysis. Baseline data, including clinical characteristics and laboratory findings, were collected at the beginning of multidisciplinary education. Baseline characteristics of 353 excluded patients and 447 included patients are presented in online supplementary Table; for all online suppl. material, see https://doi.org/10.1159/000550676.

Multidisciplinary education was provided to clinically stable outpatients. Patients with unstable conditions, including acute kidney injury, were excluded. eGFR measurements were obtained during routine outpatient visits under stable clinical conditions. We calculated two eGFR trajectories, one before and one after multidisciplinary education, on the basis of eGFR levels measured at the following time points: 1 year before education, at the beginning of education (baseline), and 1 year after education. The eGFR slopes before and after education (mL/min/1.73 m²/year) were calculated using the following equations, respectively: “eGFR at baseline – eGFR before 1 year of CKD education” and “eGFR after 1 year of CKD education – eGFR at baseline.” Patients were divided into four slope categories according to the medians of the two eGFR slopes before and after education: slow-slow (SS), fast-slow (FS), slow-fast (SF), and fast-fast (FF) eGFR decline.

Multidisciplinary Education

Our multidisciplinary education program is an integrative medical care system that includes doctors, nurses, dietitians, and pharmacists who participate in medical treatment, patient education, diet consultation, and behavioral adjustment. CKD patients who visited our hospital received inpatient and outpatient multidisciplinary education for 1–4 days at the discretion of clinicians. Nurses instructed patients about a series of CKD care-related topics, such as lifestyle and physical activity choices, understanding of kidney disease and risk factors, and if necessary, choice of renal replacement therapy. After evaluating patients’ daily dietary habits, dieticians provided nutritional plans that included sodium and potassium restriction. Pharmacists provided optimal medication management, including dosage adjustments, defined on the basis of CKD stage, to prevent adverse effects. After each of these portions of the education program, all members of the multidisciplinary team discussed patients and provided individualized CKD care to achieve delayed CKD progression.

Study Outcome

The primary outcome was the overall incidence of renal events and cardiovascular (CV) events beginning 1 year after education. Renal events were a composite of ESKD-related outcomes defined as hemodialysis, peritoneal dialysis, transplantation, and a 30% decline from baseline eGFR. CV events were defined as the composite of heart failure requiring hospitalization, coronary or leg revascularization, cardiac sudden death, and stroke. All events were confirmed through medical records.

Statistical Analysis

All variables are expressed as medians (interquartile range). Differences between groups were assessed using the Mann–Whitney U test for continuous variables and the χ² test for categorical variables, as appropriate. Logistic regression model analysis adjusted for demographics (age and sex), comorbidities (primary disease underlying CKD, hypertension, dyslipidemia, smoking, and body mass index), and blood parameters (eGFR, hemoglobin, serum albumin, C-reactive protein, and proteinuria). A restricted spline curve was used to examine the timing and effect of receiving interprofessional education on eGFR, adjusted for the same set of covariates. The cumulative incidence of the primary endpoint was estimated using the Kaplan-Meier method according to the four eGFR slope categories, and differences were assessed using the log-rank test. A Cox regression model was used to determine adjusted associations between eGFR slope categories and the study endpoint. For renal outcomes, the model was adjusted for demographics (age and sex), comorbidities (primary disease underlying CKD, hypertension, dyslipidemia, smoking status, and body mass index), and laboratory parameters (baseline eGFR, hemoglobin, serum albumin, C-reactive protein, and proteinuria). For cardiovascular outcomes, the model was adjusted for age, sex, primary disease underlying CKD, hypertension, dyslipidemia, baseline eGFR, and proteinuria. Patients with SS decline were used as a reference group.

Similar analyses were performed in subgroup and sensitivity analyses. As sensitivity analyses, a fully adjusted model further including renin–angiotensin system inhibitors and statins was applied. We also examined the associations between pre- and post-education eGFR slopes and the risk of cardiorenal events, applying a cutoff value of −3 mL/min/1.73 m²/year for eGFR slope.

Two-sided p values <0.05 were considered statistically significant. JMP 14.3.0 (SAS Institute, Cary, NC, USA) and STATA MP version 17 software (Stata Corp., College Station, TX, USA) were used to perform all statistical analyses.

Results

Baseline Characteristics

This study analyzed 447 CKD patients who underwent a multidisciplinary educational program at our hospital (Fig. 1). Our program was associated with a decrease in the median eGFR slope of −5.00 to −0.56 mL/min/1.73 m²/year. Baseline characteristics were categorized into four groups according to eGFR slopes before and after multidisciplinary education, using cut-off values of −5.00 and −0.56 mL/min/1.73 m²/year to define fast and slow eGFR decline. The four categories were defined as fast-fast, slow-fast, fast-slow, and slow-slow, and the baseline characteristics of each group are listed in Table 1. FF decline was significantly associated with higher prevalences of hypertension and diabetes, increased proteinuria, and decreased eGFR compared to patients in the other three categories. However, multivariable analysis revealed that fast versus slow eGFR slopes after education were significantly associated with decreased hemoglobin and increased proteinuria (Table 2). Restricted spline curve analysis showed lower levels of eGFR at the timing of education was associated with higher odds ratio of faster post-education eGFR decline (Fig. 2).

Fig. 1.

Patient flowchart. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. A total of 1,152 patients with CKD received multidisciplinary education between 2013 and 2020. Of these, 447 patients were ultimately included in the final analysis. These patients were categorized into four groups according to pre- and post-education eGFR slope cutoff values of −5.0 and −0.65 mL/min/1.73 m²/year, respectively: fast-fast (FF, n = 106), slow-fast (SF, n = 118), fast-slow (FS, n = 117), and slow-slow (SS, n = 106).

Table 1.

Baseline characteristics in the four categories

​	Category				p value
	fast-fast (FF)	slow-fast (SF)	fast-slow (FS)	slow-slow (SS)
Participants, n	106	118	117	106	​
Age, years	70 (63–77)	70 (60–77)	72 (63–78)	67 (56–77)	0.18
Sex (male), n (%)	74 (70)	76 (64)	88 (75)	70 (66)	0.28
Etiology of CKD, n (%)
Diabetic kidney disease	48 (45)	30 (25)	33 (28)	26 (34)	0.01
Chronic glomerulonephritis	25 (24)	37 (31)	37 (32)	22 (21)
Nephrosclerosis,	13 (12)	15 (13)	17 (15)	22 (21)
Other	20 (19)	36 (31)	30 (26)	36 (34)
Body mass index, kg/m2	22.6 (20.0–26.0)	23.0 (20.6–25.2)	23.3 (20.8–26.0)	23.5 (21.0–25.8)	0.46
Hypertension, n (%)	89 (84)	83 (70)	86 (74)	70 (66)	0.02
Diabetes, n (%)	53 (50)	39 (33)	42 (36)	31 (29)	0.01
Dyslipidemia, n (%)	42 (40)	52 (44)	47 (40)	43 (41)	0.90
Current smoker, n (%)	35 (33)	34 (29)	42 (36)	32 (30)	0.67
eGFR at education, mL/min/1.73 m2	26 (18–43)	40 (19–50)	35 (25–45)	38 (29–48)	<0.001
Proteinuria, g/gCre	1.2 (0.49–3.6)	0.68 (0.21–1.9)	0.57 (0.14–1.6)	0.31 (0.12–1.01)	<0.001
Hemoglobin, g/dL	12.0 (10.5–13.1)	12.4 (11.1–13.5)	12.7 (11.0–13.8)	12.9 (11.7–14.6)	<0.001
Serum albumin, g/dL	3.8 (3.4–4.1)	3.9 (3.6–4.1)	3.9 (3.5–4.2)	4.0 (3.8–4.2)	0.004
C-reactive protein, mg/dL	0.08 (0.03–0.30)	0.07 (0.03–0.24)	0.13 (0.03–0.43)	0.06 (0.03–0.18)	0.001

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.

Table 2.

Determinants associated with faster eGFR slopes after education

​	β	95% CI	p value
Age	0.0027	−0.13 to 0.019	0.74
Sex (male)	−0.069	−0.54 to 0.40	0.77
Body mass index	0.028	−0.026 to 0.083	0.31
Diabetic kidney disease	−0.13	−0.57 to 0.30	0.55
Hypertension	−0.29	−0.78 to 0.20	0.25
Dyslipidemia	0.044	−0.37 to 0.46	0.83
Current smoker	0.035	−0.40 to 0.47	0.87
eGFR at education	−0.0025	−0.015 to 0.01	0.69
Proteinuria	−0.14	−0.26 to −0.036	0.01
Hemoglobin	0.15	0.02 to 0.29	0.03
Serum albumin	−0.012	−0.45 to 0.42	0.96
C-reactive protein	0.18	−0.13 to 0.51	0.25

CI, confidence interval; eGFR, estimated glomerular filtration rate.

Fig. 2.

Restricted cubic spline curve analysis showing the association between eGFR at education and faster eGFR decline after education. eGFR, estimated glomerular filtration rate. Restricted cubic spline curve showed that lower eGFR values were significantly associated with higher odds of a faster post-education eGFR slope.

Renal Events

During the median follow-up period of 25 months, composite renal events occurred in 156 patients. Crude Kaplan-Meier analysis demonstrated that FF and SF declines were significantly associated with a high incidence of composite renal events (log-rank p < 0.001; Fig. 3a).

Fig. 3.

Kaplan-Meier analysis showing the associations of four categories with renal (a) and cardiovascular events (b). FF, fast-fast; FS, fast-slow; HR, hazard ratio; SF, slow-fast; SS, slow-slow. Kaplan-Meier analyses demonstrated patients with FF or SF decline had a significantly higher incidence of renal events (p < 0.001), whereas the highest incidence of cardiovascular events was observed in FF decline alone (p < 0.001).

Adjusted Cox hazard regression analyses showed that FF and SF declines were associated with a significantly greater risk of total renal events than the reference group of SS decline (Table 3). In adjusted models, hazard ratios (95% confidence intervals) for total renal events were 1.02 (95% CI: 0.50–2.06, p = 0.91) for FS decline, 5.30 (95% CI: 2.82–9.97; p < 0.001) for SF decline, and 7.53 (95% CI: 4.02–14.1; p < 0.001) for FF decline. The four groups had similar trends for each event of 30% eGFR decline and ESKD.

Table 3.

Adjusted risks of renal and cardiovascular events in the four categories

​	SS	FS		SF		FF
		HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value
Renal events
Composite	reference	1.02 (0.50–2.06)	0.91	5.30 (2.82–9.97)	<0.001	7.53 (4.02–14.1)	<0.001
30% eGFR decline	reference	0.95 (0.44–2.05)	0.67	4.59 (2.33–9.05)	<0.001	5.82 (2.94–11.5)	<0.001
ESKD	reference	1.19 (0.39–3.65)	0.89	6.83 (2.47–18.9)	<0.001	13.2 (4.91–35.5)	<0.001
Cardiovascular events
​	reference	2.34 (0.98–5.60)	0.07	2.19 (0.87–5.50)	0.10	4.68 (1.99–11.0)	<0.001

eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FF, fast-fast; FS, fast-slow; SF, slow-fast; SS, slow-slow.

CV Events

A total of 84 CV events occurred during a median follow-up duration of 43 months. In Kaplan-Meier analysis, FF decline was associated with a significantly higher incidence of CV events than the other groups (log-rank p < 0.001; Fig. 3b). In adjusted models, FF decline was associated with a 5.06-fold higher risk of CV events relative to SS decline (p < 0.001), whereas FS or SF decline was associated with an approximately 2.34- and 2.19-fold higher risk than SS decline, respectively, but this difference was not statistically significant (p = 0.07 and p = 0.10, respectively).

Subgroup and Sensitivity Analyses

We investigated the relationships of eGFR decline categories with renal and CV events in subgroup analyses stratified by age, sex, diabetic kidney disease, baseline eGFR, proteinuria, renin-angiotensin system inhibitors and statin (Fig. 4a, b). The relationships between renal events and FF and FS declines after CKD education were consistent in each subgroup, but CV events seemed to be associated with FF decline alone.

Fig. 4.

Adjusted hazard ratios of renal (a) and cardiovascular events (b) for four categories in subgroup analyses. CI, confidence interval; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; FF, fast-fast; FS, fast-slow; HR, hazard ratio; SF, slow-fast; SS, slow-slow. The findings remained consistent across subgroup analyses stratified by age, sex, underlying causes of CKD, eGFR, proteinuria, RAS inhibitor and statin.

In fully adjusted model including renin-angiotensin inhibitors and statin use, the results were similar to those of our main analysis; hazard ratios (95% confidence intervals) for renal and cardiovascular events were 0.79 (95% CI: 0.39–1.61; p = 0.56) and 1.84 (95% CI: 0.72–4.52; p = 0.20) for FS decline, 5.16 (95% CI: 2.79–9.54; p < 0.001) and 1.75 (95% CI: 0.70–4.34; p = 0.23) for SF decline, and 6.20 (95% CI: 3.38–11.4; p < 0.001) and 4.52 (95% CI: 1.98–10.3; p < 0.001) for FF decline.

We additionally evaluated the associations between pre- and post-education eGFR slopes and subsequent renal and cardiovascular outcomes using a cutoff value of −3 mL/min/1.73 m²/year. For composite renal events, adjusted hazard ratios (95% confidence intervals) were 0.97 (95% CI: 0.56–1.69; p = 0.92) for FS decline, 7.30 (95% CI: 3.81–13.9; p < 0.001) for SF decline, and 5.19 (95% CI: 2.93–9.20; p < 0.001) for FF decline. In contrast, we examined adjusted hazard ratios (95% confidence intervals) for cardiovascular events were 1.60 (95% CI: 0.76–3.36; p = 0.22) for FS decline, 1.70 (95% CI: 0.59–4.87; p = 0.32) for SF decline, and 4.60 (95% CI: 2.12–9.97; p < 0.001) for FF decline.

Discussion

The present study found that the post-education eGFR slope emerged as a key determinant of renal and cardiovascular outcomes regardless of whether the pre-education eGFR decline was fast or slow, suggesting focusing on the post-education eGFR slope may help reduce cardiorenal events among CKD patients who have undergone multidisciplinary education. Furthermore, we demonstrated that the clinical benefits of multidisciplinary care in patients with CKD were heterogeneous and appeared to depend on specific patient characteristics including anemia, higher levels of proteinuria and lower eGFR at the time of receiving multidisciplinary education. These observations underscore the need for nephrologists to identify patients who are less responsive to multidisciplinary care and to tailor post-education management strategies accordingly.

Our multidisciplinary team, which consisted of doctors, nurses, dieticians, and pharmacists, was able to achieve a decrease in the median eGFR slope from −5.00 to −0.65 mL/min/1.73 m²/year. The four groups categorized by eGFR slopes exhibited different benefits from CKD education. While patients with SF or FF decline had higher prevalences of diabetes and hypertension and lower eGFR levels, this study identified severe proteinuria, lower eGFR, and anemia, which are common features of advanced CKD, as factors that may reduce the effectiveness of CKD education. There are several plausible mechanisms that may explain why certain patients, particularly those with advanced CKD, fail to derive sufficient benefit from multidisciplinary education. First, substantial and functionally irreversible nephron loss may limit the ability of educational interventions aimed at lifestyle modification and pharmacological optimization to overcome the dominant effects of progressive underlying pathology. Second, patients with advanced CKD often exhibit uremia-related metabolic disturbances, chronic inflammation, and malnutrition, which may attenuate physiological responsiveness to behavioral and nutritional interventions. Anemia and frailty markedly impair physical functioning and activity, and dietary salt restriction may also lead to inadequate energy intake and vitamin deficiencies, potentially resulting in unintended weight loss and an increased risk of cardiovascular mortality [11–13]. Third, Other factors may also indicate which CKD patients will profit from multidisciplinary CKD education; specifically, it has been shown that post-education lack of exercise [14], shorter sleep duration [15], and consistent poor self-management behaviors [16] may lead to adverse renal events. In addition, studies of multidisciplinary interventions outside nephrology have reported socioeconomic status and suboptimal adherence as negative modifiers of intervention effectiveness [17, 18].

Over the years, numerous studies have demonstrated that multidisciplinary education for CKD patients is associated with a reduced risk of renal events. Three randomized controlled studies showed that in comparison with usual care, multidisciplinary education was associated with a slower annual decline in GFR in patients with stage 3–5 CKD [10, 19, 20]. Such outcomes may be the result of education achieving increased self-awareness and medication compliance, reduced protein and salt intake, and better exercise habits [21]. Multidisciplinary education has also been shown to lower the percentage of patients initiating dialysis [22, 23] and to reduce medical expenses [24–26]. Another study found that it decreased the need for using a dialysis catheter and increased the use of peritoneal dialysis [6]. One report indicated that CKD patients who received multidisciplinary education had a 40% reduction in the risk of hospitalization due to infection, and a 51% reduction in patient mortality compared with patients who did not undergo the education [27]. Similar findings regarding the relation between mortality and multidisciplinary education have been reported in a cohort study and a meta-analysis [28, 29].

Of note, our findings revealed that slow eGFR decline after multidisciplinary education was significantly associated with a low incidence of CV events. A retrospective, single-center study in South Korea showed that patients undergoing multidisciplinary education had a 0.24-fold decrease in the risk of CV events [30]. Practice facilitation conducted as part of a multidisciplinary care program was shown to significantly decrease the occurrence of CV diseases in a recent Japanese study [31]. Several mechanisms may underlie the association between declining kidney function and CV events. Steeper eGFR decline may elevate blood pressure and worsen lipid profiles [32], and may reflect the presence of more severe comorbidities [33, 34]. Multidisciplinary education may mitigate CV risk factors and the effects of comorbidities by achieving reduced salt intake and proper medication adjustment, both of which could contribute to attenuating eGFR decline and reducing the incidence of CV events.

This study had several limitations. First, this was a single-center, observational study with a relatively small sample size. In addition, substantial proportions of patients were excluded because of missing data, mainly due to the lack of eGFR measurements 1 year prior to education. These patients likely had more preserved kidney function and may not have undergone regular renal monitoring, potentially introducing selection bias. Second, eGFR slopes were calculated on the basis of only three creatinine measurements (one at the beginning of multidisciplinary education, one beforehand, and one afterward), which may have resulted in marked variability when analyzing the relation between eGFR slopes and study outcomes. Third, patient guidance and education in our multidisciplinary education program were individualized rather than uniform; therefore, the results may not be generalizable to other patients receiving multidisciplinary care. Fourth, although baseline eGFR, proteinuria, medication use, and other relevant covariates were adjusted for in the analyses, changes in these factors over the study period were not systematically assessed, and residual confounding cannot be excluded. Fifth, the number of cardiovascular events was relatively small compared with renal events, potentially limiting the statistical power to assess the association between pre- and post-education eGFR slopes and cardiovascular event risk. In fact, although not statistically significant, the FS and SF groups tended to have an approximately twofold higher risk of cardiovascular events compared with the SS group.

Despite these limitations, this study has several notable strengths. This study has several notable strengths. First, leveraging longitudinal eGFR trajectories before and after multidisciplinary education enabled a dynamic assessment of kidney function and demonstrated that post-education eGFR decline, rather than pre-education decline, is more critical. In addition, severe proteinuria, low eGFR, and anemia identified patients in whom multidisciplinary care may be less effective. These findings have not been reported previously and are therefore considered highly significant in the management of patients with CKD. Second, our findings indicated that a rapid post-education eGFR decline is associated with clinically meaningful composite renal and cardiovascular outcomes renal and cardiovascular events, with the robustness of this association supported by subgroup and sensitivity analyses. Finally, the real-world nature of the study population and care setting strengthens the generalizability and practical applicability of our results to routine clinical practice.

In conclusion, fast eGFR decline after multidisciplinary CKD education, but not before, was significantly associated with renal and CV events in CKD patients. Attention should be paid to CKD patients who may achieve only limited benefit from multidisciplinary education.

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. Opt-out informed consent protocol was used for use or collection of participant data for research purposes. This consent procedure was reviewed and approved by the Ethics Committee of Nara General Medical Center, Approval No. [316], date of decision [12/5/2018]. Information about the study was disclosed on the institution’s website, and participants were given the opportunity to refuse participation (http://www.nara-hp.jp/about/ethics). The requirements of written informed consent was then waived due to the retrospective nature of the study.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding have been received.

Author Contributions

Research idea and study design were done by K.T. and M.M.; data acquisition was done by M.K.; data analysis/interpretation were conducted by M.N., T.K., M.K. and K.T. statistical analysis was performed by M.M.; writing was done by M.M.; supervision or mentorship was done by M.E. and K.S. All authors read the draft and approved the final version of the manuscript.

Funding Statement

No funding have been received.

Data Availability Statement

The datasets that support the findings of the current study are not publicity available due to privacy reasons but are available from the corresponding author on reasonable request.