Assessment of drug utilization and potentially inappropriate medications in hemodialysis patients with end-stage renal dysfunction: A study in a tertiary care hospital in Bahrain

Abstract

BACKGROUND:

Patients undergoing dialysis pose therapeutic challenges in terms of polypharmacy, administration of potentially inappropriate drugs, and drugs with the potential risk of toxicity.

OBJECTIVE:

This study evaluated the use of drugs, potentially inappropriate medicines (PIM), drugs with risk of Torsades de Pointes (TdP), and the complexity of the prescribed regimen using the medication regimen complexity index scale in patients undergoing hemodialysis.

METHODS:

A retrospective cohort study was carried out amongst patients receiving hemodialysis. Drugs were classified into one of four classes: (i) drugs used in managing renal complications, (ii) cardiovascular drugs, (iii) anti-diabetic drugs, (iv) drugs for symptomatic management, and (v) others. Drugs were considered as PIM according to the Can-SOLVE CKD working group from a network of Canadian nephrology health professionals. The study adhered to the CredibleMeds classification of drugs with known, possible, and conditional risk of TdP and the complexity of prescribed medicines was evaluated based on the pre-validated medication regimen complexity index scale based on form/route, frequency of dosing, and requirement of special instructions.

RESULTS:

Sixty-three participants were included in the study (49 males and 14 females) with the median (range) age of 45 (21–66) years. Cardiovascular drugs followed by drugs used for managing renal complications were the most common classes administered. Notably, 12 (19.1%) patients received one of the non-steroidal anti-inflammatory drugs, 21 (33.3%) received a proton pump inhibitor, three (4.8%) received pregabalin, two (3.2%) received opioid drugs, and one (1.6%) was administered celecoxib. Atorvastatin, furosemide, omeprazole, and allopurinol were the most common PIM drugs administered to the study participants followed by others. Drugs used for symptomatic management had significantly more PIM compared to other classes (p < 0.0001). Six (9.5%) patients received drugs with known TdP risk, one with possible TdP risk, and 61 with conditional risk. Median (range) medical regimen complexity index score was 26.5 (2–62.5).

CONCLUSION:

A huge burden of drug therapy was observed in the hemodialysis patients in terms of higher proportions of PIM, complex medical regimen, and prescription of drugs with risk of TdP. Implementation of clinical decision support tools enhancing rational prescription and identification of drugs with TdP risk, introducing antimicrobial stewardship, and stepwise deprescription of the drugs with the least benefit-risk ratio are warranted.

Keywords

DUS ESRD chronic kidney disease dialysis

1. Background

Unique barriers and challenges remain regarding drug therapy in hemodialysis patients due to the complexity of the advanced renal disease, and additional clearance of drugs due to dialysis procedure [1]. Dialysis patients often receive several medicines long-term resulting in polypharmacy. A study revealed that an average of 10–12 drugs were prescribed along with an average of 4.7 over-the-counter drugs accounting for an average of 19 pills per day [2]. In addition to polypharmacy, the complexity of the medication regimen is a determining factor for compliance [3]. A potentially inappropriate prescription is prescribing drugs with a high risk of adverse effects compared to the potential benefits [4]. Recently, a group of expert Canadian Nephrology health care professionals categorized certain drugs/drug classes as potentially inappropriate medicines (PIM) [5]. A recent study identified that the use of drugs with a known risk of Torsades de Pointes (TdP) was around 2.5 times higher in patients with ESRD than those without ESRD [6]. This is one reason attributed to the increased incidence of death due to cardiovascular disorders and sudden cardiac death in hemodialysis patients (owing to pro-arrhythmic triggers) [7]. Drug utilization studies have a crucial place considering the potential for facilitating rational drug use, cost-efficient utilization of healthcare resources, and recommendations for changes in local, national, and international policies [8]. Patients with chronic kidney disease (CKD) receiving 2 or more potentially inappropriate medicines (PIM) were observed with an increased risk of 30% eGFR decline (odds ratio: 1.71) [9]. Hence, it is extremely challenging to meet the intended therapeutic objectives with a high risk of toxicity. Considering the dearth of data regarding the use of PIM in CKD patients undergoing hemodialysis, we carried out the present drug utilization study. Additionally, we also evaluated the complexity of the prescribed regimen and the extent of drugs with known risk of TdP in our population.

2. Materials and methods

2.1. Study ethics, design and participants

This was a retrospective cohort study carried out from June 2021 to August 2022 in the Department of Nephrology, Salmaniya Medical Complex, Kingdom of Bahrain. We included patients diagnosed with end-stage renal dysfunction and receiving hemodialysis at the dedicated for at least 3 months. Patients with incomplete medication records were excluded. Approval was obtained from the Institutional Ethics Committee (approval number: E05-PI-5/21) and we complied with the latest Declaration of Helsinki guidelines. The following details were retrieved from the study participants: demographics (age, and sex), duration of dialysis, and drug-related details.

2.2. Drug classification

Drugs taken by study participants were classified into five classes: (i) drugs used in managing renal complications, (ii) cardiovascular drugs, (iii) anti-diabetic drugs, (iv) drugs for symptomatic management, and (v) others (Supplementary Table S1) [10]. The following drugs were considered as PIM according to Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) working group from a network of Canadian nephrology health professionals: antiplatelet drugs, anticoagulants, digoxin, diuretics, statins, ezetimibe, niacin, fibrates, metformin, allopurinol, alpha-1 blocker, antacids, antidepressants, antihistamines, antipsychotics, benzodiazepines, cannabinoids, dimenhydrinate, dopamine agonists, gabapentin, hypnotics, laxatives, levodopa, anti-muscarinic drugs, non-steroidal anti-inflammatory drugs, opioids, proton pump inhibitors, gastro-intestinal motility drugs, quinine, bisphosphonates [10]. We adhered to the CredibleMeds classification of drugs with a known, possible, and conditional risk of TdP [11]. The definition stated for the classification of TdP risk is mentioned in Supplementary Table S2. We assessed the complexity of prescribed medicines based on the pre-validated medication regimen complexity index scale [12] which has three components: Component A – Form/route, component B – frequency of dosing, and component C – requirement of special instructions (Table 1).

Table 1
Medical regimen complexity index scale

Component A: Form/route Component B: Frequency of dosing Component C: Requirement of special instructions

Form Route Weight Frequency Weight Direction Weight

Tablet Oral 1 As needed/Once a week/Fortnightly 0.5 To be taken at specified time 1

Syrup Oral 1 Once a day 1 In relation to food intake 1

Ampoule pen Subcutaneous 3 At bedtime 1

Ampoule Subcutaneous 4 Alternate days 2

Vial Intravenous 3 Twice a day 2

Thrice a day 3

Four times a day 4

Component A: Form/route	Component B: Frequency of dosing	Component C: Requirement of special instructions
Tablet	Oral	1	As needed/Once a week/Fortnightly	0.5	To be taken at specified time	1
Syrup	Oral	1	Once a day	1	In relation to food intake	1
Ampoule pen	Subcutaneous	3	At bedtime	1
Ampoule	Subcutaneous	4	Alternate days	2
Vial	Intravenous	3	Twice a day	2
			Thrice a day	3
			Four times a day	4

2.3. Statistical analysis

Descriptive statistics were used to represent the demographic variables. The age of the study participants was classified as follows: young adults – 18 to < 40 years; middle-aged – 40 to < 65 years; and older adults - ≥ 65 years [13]. Linear regression test was carried out with the number of PIM drugs as dependent variable and age group, sex, and as independent variables. Mann-Whitney U test was used for evaluating the statistical differences between sex and medical regimen complexity index, while Kruskal-Wallis H test was used for analyzing the same between various age groups. A p-value of ≤ 0.05 was considered significant. SPSS version 27.0 for Windows (IBM Corp., Armonk, NY, USA) was used for statistical analysis.

3. Results

3.1. Demographics

Sixty-three patients were recruited of which 49 were males, and 14 were females. The median (range) age of study participants was 45 (21–66) years. Twenty-three were young adults, 38 were middle-aged and two were older adults. Twenty-two had concomitant diabetes, and all the study participants had comorbid cardiovascular disorders.

3.2. Drugs used by the study population

Median (range) number of medications used in the study participants was 6 (4–9). The list of drugs used by the patients undergoing hemodialysis can be found in Table 2. Cardiovascular drugs followed by drugs used for managing renal complications were the most common classes administered (Fig. 1). The various classes of drugs administered to the study participants were mentioned in Supplementary Table S3. Notably, 12 (19.1%) patients received one of the non-steroidal anti-inflammatory drugs, 21 (33.3%) received a proton pump inhibitor, three (4.8%) received pregabalin, two (3.2%) received opioid drugs, and one (1.6%) was administered celecoxib.

Table 2
Details of drugs used by study participants

Drugs Median (range) Dose/administration (mg) Median (range) Dose/day (mg)

Acetaminophen (n = 20) 1000 (500-1000) 2000 (1000–4000)

Acetylsalicylic acid (n = 10) 81 81

Alfacalcidol (n = 1) 1 1

Allopurinol (n = 17) 100 (30–300) 100 (30–300)

Alpha methyldopa (n = 4) 500 (250–500) 1250 (250–2000)

Alprazolam (n = 1) 0.5 1

Aluminium hydroxide/Magnesium hydroxide (n = 4) 1215/315 3645/945

Amlodipine (n = 32) 10 (5–10) 10 (5–10)

Amoxicillin/Clavulanic acid (n = 10) 500/125 1000 (500–2000)/250 (125–500)

Atenolol (n = 2) 50 50

Atorvastatin (n = 27) 20 (10–40) 20 (10–40)

Azithromycin (n = 1) 500 500

Betahistine (n = 2) 16 40 (32–48)

Bezafibrate (n = 1) 400 400

Bisacodyl (n = 7) 10 (5–10) 10 (5–30)

Bisoprolol (n = 16) 5 (2.5–10) 5 (2.5–10)

Bromhexine (n = 3) 24 (16–24) 24 (24–32)

Budesonide (n = 1) 0.5 0.5

Calcitriol (n = 30) 0.25 (0.25–1.25) 0.25 (0.125–1.25)

Calcium carbonate (n = 21) 600 1800 (600-1800)

Captopril (n = 3) 12.5 12.5

Carbimazole (n = 1) 10 20

Carvedilol (n = 6) 25 (12.5–25) 50 (25–50)

Ceftriaxone (n = 4) 2000 (1000–2000) 2000 (1000–2000)

Cefuroxime axetil (n = 8) 250 (250–750) 500 (500–1500)

Celecoxib (n = 1) 200 400

Cephalexin (n = 2) 500 2000

Cetirizine (n = 14) 10 10

Chlordiazepoxide/Clidinium bromide (n = 1) 5/2.5 5/2.5

Chlorpheniramine maleate/ 3 (2–4)/33.75 (22.5–45) 3 (2–4)/33.75 (22.5–45)

Pseudoephedrine (n = 2)

Cinacalcet (n = 6) 30 (30–60) 30 (30–60)

Ciprofloxacin (n = 2) 500 1000

Clarithromycin (n = 2) 375 (250–500) 375 (250–500)

Clonazepam (n = 2) 0.5 0.5

Clopidogrel (n = 5) 75 75

Darbepoetin alpha (n = 14)^a 40 (20–100) 40 (10–100)

Diazepam (n = 1) 7 7

Diclofenac sodium (n = 4) 87.5 (75–100) 87.5 (75–100)

Diltiazem (n = 2) 60 120 (60–180)

Diosmin (n = 3) 500 1000 (1000–1500)

Escitalopram (n = 1) 10 10

Esomeprazole (n = 8) 20 20 (20–40)

Ezetimibe (n = 2) 10 10

Drugs	Median (range) Dose/administration (mg)	Median (range) Dose/day (mg)
Acetaminophen (n = 20)	1000 (500-1000)	2000 (1000–4000)
Acetylsalicylic acid (n = 10)	81	81
Alfacalcidol (n = 1)	1	1
Allopurinol (n = 17)	100 (30–300)	100 (30–300)
Alpha methyldopa (n = 4)	500 (250–500)	1250 (250–2000)
Alprazolam (n = 1)	0.5	1
Aluminium hydroxide/Magnesium hydroxide (n = 4)	1215/315	3645/945
Amlodipine (n = 32)	10 (5–10)	10 (5–10)
Amoxicillin/Clavulanic acid (n = 10)	500/125	1000 (500–2000)/250 (125–500)
Atenolol (n = 2)	50	50
Atorvastatin (n = 27)	20 (10–40)	20 (10–40)
Azithromycin (n = 1)	500	500
Betahistine (n = 2)	16	40 (32–48)
Bezafibrate (n = 1)	400	400
Bisacodyl (n = 7)	10 (5–10)	10 (5–30)
Bisoprolol (n = 16)	5 (2.5–10)	5 (2.5–10)
Bromhexine (n = 3)	24 (16–24)	24 (24–32)
Budesonide (n = 1)	0.5	0.5
Calcitriol (n = 30)	0.25 (0.25–1.25)	0.25 (0.125–1.25)
Calcium carbonate (n = 21)	600	1800 (600-1800)
Captopril (n = 3)	12.5	12.5
Carbimazole (n = 1)	10	20
Carvedilol (n = 6)	25 (12.5–25)	50 (25–50)
Ceftriaxone (n = 4)	2000 (1000–2000)	2000 (1000–2000)
Cefuroxime axetil (n = 8)	250 (250–750)	500 (500–1500)
Celecoxib (n = 1)	200	400
Cephalexin (n = 2)	500	2000
Cetirizine (n = 14)	10	10
Chlordiazepoxide/Clidinium bromide (n = 1)	5/2.5	5/2.5
Chlorpheniramine maleate/	3 (2–4)/33.75 (22.5–45)	3 (2–4)/33.75 (22.5–45)
Pseudoephedrine (n = 2)
Cinacalcet (n = 6)	30 (30–60)	30 (30–60)
Ciprofloxacin (n = 2)	500	1000
Clarithromycin (n = 2)	375 (250–500)	375 (250–500)
Clonazepam (n = 2)	0.5	0.5
Clopidogrel (n = 5)	75	75
Darbepoetin alpha (n = 14)^a	40 (20–100)	40 (10–100)
Diazepam (n = 1)	7	7
Diclofenac sodium (n = 4)	87.5 (75–100)	87.5 (75–100)
Diltiazem (n = 2)	60	120 (60–180)
Diosmin (n = 3)	500	1000 (1000–1500)
Escitalopram (n = 1)	10	10
Esomeprazole (n = 8)	20	20 (20–40)
Ezetimibe (n = 2)	10	10

Table 2 (Continued)

Drugs	Median (range) Dose/administration (mg)	Median (range) Dose/day (mg)
Felodipine (n = 1)	5	5
Ferrous gluconate (n = 1)	300	600
Ferrous sulphate (n = 16)	80 (80–190)	160 (80–570)
Folic acid (n = 5)	5	5
Furosemide (n = 22)	40 (40–120)	80 (40–240)
Glyceryl trinitrate (n = 4)	0.5	0.5
Goserelin (n =1)	3.6	3.6
Hydralazine (n = 14)	37.5 (25–50)	87.5 (25–200)
Hydroxychloroquine (n = 1)	200	200
Hyoscine (n = 4)	20 (10–20)	20 (10–20)
Ibuprofen (n = 4)	400 (400–600)	800 (800–1800)
Indapamide (n = 1)	1.5	1.5
Insulin aspart (n = 11)^b	14 (4–30)	42 (10–90)
Insulin glargine (n = 9)^b	20 (15–40)	20 (15–40)
Insulin NPH (n = 1)	5	5
Irbesartan (n = 1)	300	300
Isosorbide mononitrate (n = 2)	45 (30–60)	45 (30–60)
Labetalol (n = 5)	20 (5–20)	20 (5–20)
Lactulose (n = 1)	20000	20000
Levothyroxine (n = 3)	0.05 (0.05–0.1)	0.05 (0.05–0.1)
Linagliptin (n = 1)	5	5
Loperamide (n = 1)	2	2
Loratidine (n = 1)	10	10
Magnesium oxide (n = 8)	250 (250–500)	625 (250–1500)
Mefenamic acid (n = 1)	500	1500
Metoclopramide (n = 7)	10	10
Metoprolol (n = 4)	100 (50–100)	100 (50–100)
Metronidazole (n = 2)	400	1000 (800–1200)
Mirtazapine (n = 1)	30	30
Morphine (n = 1)	6	6
Naproxen (n = 4)	250	500 (250–500)
Nifedipine (n = 8)	75 (60–90)	75 (60–90)
Omega-3 fatty acids (n = 3)	1000	1000
Omeprazole (n = 18)	20 (20–80)	40 (20–80)
Perindopril (n = 1)	10	10
Perindopril/Amlodipine (n = 2)	3.5/2.5	3.5/2.5
Perindopril/Indapamide (n = 3)	5/1.25	5/1.25
Phenytoin (n = 1)	100	100
Piperacillin/Tazobactam (n = 2)	4.5	9
Prednisolone (n = 15)	5 (1–40)	5 (1–40)
Pregabalin (n = 3)	75	75
Promethazine (n = 2)	12.5	12.5
Quetiapine (n = 1)	25	25
Rabeprazole (n = 3)	20	40
Ranitidine (n = 16)	150	300 (150–300)
Rosuvastatin (n = 4)	20 (10–20)	20 (10–20)
Sevelamer carbonate (n = 30)	800 (800–2400)	2400 (800–7200)

Table 2 (Continued)

Drugs	Median (range) Dose/administration (mg)	Median (range) Dose/day (mg)
Silicone dioxide/Dimethyl polysiloxane (n = 2)	4/80	4/80
Sodium bicarbonate (n = 7)	650 (650–850)	1300 (650–1950)
Sodium polystyrene (n = 5)	15	15 (7.5–45)
Tamsulosin (n = 1)	0.5	0.5
Tramadol (n = 1)	80	80
Trimethoprim/Sulfamethoxazole (n = 3)	160/800	80/400
Valacyclovir (n =1)	900	900
Valganciclovir (n = 3)	450 (450–900)	450 (450–900)
Valsartan (n = 5)	80 (80–160)	80 (80–160)
Valsartan/Hydrochlorothiazide (n = 1)	160/12.5	160/12.5
Vitamin B12 (n = 1)	1	1
Vitamin D (n = 8)	800 (400–800)	800 (400–800)
Warfarin (n = 1)	3	3

The values are mentioned in median (range) unless specified; a – Administered on weekly basis; b – Expressed in international units.

Fig. 1.

Drug classes used in the study participants. The vertical bar charts represent the number of study participants receiving drugs of various classes.

3.3. Potentially inappropriate medicines

Atorvastatin, furosemide, omeprazole, and allopurinol were the most common PIM drugs administered to the study participants followed by others (Fig. 2). Drugs used for symptomatic management had significantly more PIM compared to other classes (Fig. 3) and were statistically significant (p < 0.0001). No significant differences in the total number of PIM were observed between age groups and sex.

Fig. 2.

PIM drugs used in the study participants. This Pareto chart represents the distribution of number of patients receiving PIM drugs.

Fig. 3.

PIM according to drug classes. The bar chart represents the number of drugs according to drug classes.

3.4. Drugs with risk of TdP

Six (9.5%) patients received one of the drugs with known TdP risk as follows: Azithromycin (n = 1), ciprofloxacin (n = 2), clarithromycin (n = 2), and escitalopram (n = 1); one with possible TdP risk that received tramadol; and 61 patients received one of the drugs with conditional risk: esomeprazole (n = 8), furosemide (n = 22), indapamide (n = 1), loperamide (n = 1), metoclopramide (n = 7), metronidazole (n = 2), omeprazole (n = 18), hydroxychloroquine (n = 1), and quetiapine (n = 1).

3.5. Medical regimen complexity index assessment

Median (range) medical regimen complexity index score was 26.5 (2–62.5). No significant differences were observed between the age groups (p = 0.8) and sex (p = 0.2).

4. Discussion

Dialysis is associated with muscle cramps, abdominal distension, and paraesthesia, which often are associated with pain episodes [14]. Pain is the greatest symptom of concern and has been shown to impact hugely all the domains of health-related quality of life in ESRD patients [15]. Acetaminophen is the safest analgesic in CKD patients undergoing dialysis as it is predominantly metabolized by the liver and the metabolites are inactive and renally eliminated [16]. We observed that among the analgesics, the majority received acetaminophen. Acetaminophen is also largely dialyzable, and hemodialysis is one of the recommended therapeutic modalities in acetaminophen overdose [17]. Similarly, ibuprofen was not observed to accumulate and was found to be safe in dialysis patients [18]. Amongst the opioid drugs, morphine and codeine are best to be avoided in ESRD and dialysis patients; and methadone, and fentanyl/sufentanil are safer [19]. Morphine and tramadol are significantly removed during hemodialysis [20,21]. Furthermore, the accumulation of morphine metabolites in ESRD has been shown to result in neurotoxicity [22]. In the present study, only one patient received morphine and tramadol each. ESRD and dialysis patients often have autonomic neuropathy due to uremia, and due to microvascular complications of diabetes [23]. Pregabalin is the preferred analgesic for neuropathic pain, and we observed three patients in the present study receiving the drug. However, despite a low molecular weight, low volume of distribution and poor plasma-protein binding, pregabalin-induced myoclonus was observed in hemodialysis patients [24]. Only one patient received celecoxib in the present study. Selective cyclooxygenase-2 inhibitors increase the risk of acute myocardial infarction [25]. Cardiovascular disorders account for almost 40-50% of deaths in ESRD patients [26]. In addition to the well-recognized co-morbid diseases that increase the risk of acute myocardial infarction, the uremic environment and the dialysis mode are additional risk factors among dialysis patients [27]. Hemodialysis is associated with an increased risk of CVD due to the accumulation of dialytic fluid, larger changes in the circulation, and arteriovenous fistula-enhanced circulation [28]. The incidence of acute myocardial infarction was observed to be significantly higher in patients with hemodialysis compared to peritoneal dialysis (9.71 versus 8.35 per 1000 patient-years) [29]. Similarly, the risk of congestive cardiac failure is significantly higher with hemodialysis [30]. Hemodialysis is associated with 61.4% higher risk for subdural hematoma [31].

We observed that many hemodialysis patients received at least one drug with a risk of TdP. Chronic kidney disease particularly ESRD is associated with an increased risk of sudden cardiac death owing to TdP [32]. We used CredibleMeds.org list where drugs are classified into three categories of which the risk of out-of-hospital cardiac arrest for category 1 was 1.7 compared to 1.4 with category 2 drugs [33]. In the present study, seven patients had received drugs belonging to one of these two classes, the majority being the antimicrobial class of drugs. Hemodialysis patients are at high risk of infections and sepsis, and therefore the use of appropriate antimicrobial drugs is necessary [34]. Implementation of an antimicrobial stewardship program in dialysis units is critical considering that nearly one-third of antimicrobial prescriptions may not be indicated [35]. A clinical decision support tool alerting the prescriber about the drugs prolonging QT interval has been shown to significantly reduce the proportion of such high-risk drugs [36].

We observed that our patients on hemodialysis are receiving a complex medical regimen like what was observed in hypertensive patients (median: 17.8; range: 3–46), diabetes (median: 22.98; range: 4–65.5), Human Immunodeficiency Virus syndrome (median: 21.76; range: 2–67.5) and older adults with major depression (median: 25.4; range: 6-64) [37]. This necessitates simplification of the prescribed regimen either by using polypills or fixed-dose combinations of drugs. Recent studies indicate “Drug deprescription” where drugs with a lower benefit-risk ratio are omitted/ removed stepwise from a prescription, have been shown to reduce treatment burden [38]. Medication reconciliation should be implemented in dialysis patients for optimal use of drugs, effective control of medication-related problems, improving medication adherence, and improving the cost-effectiveness of drugs used in hemodialysis patients.

The present study comprehensively evaluated drug use in hemodialysis patients in terms of various safety dimensions. However, the present study is limited by retrospective design, where we could not evaluate the intake of drugs by the patients, compliance to the prescription, consumption of over-the-counter medicines, and duration of dialysis and concomitant disorders. Further, we could not evaluate the association between the prescription of inappropriate medicines, complexity of medical regimen, drugs with risk of TdP, and clinical outcomes.

5. Conclusion

A huge burden of drug therapy was observed in the hemodialysis patients in terms of higher proportions of PIM, complex medical regimen, and prescription of drugs with risk of TdP. Particularly, more concern is required incorporating various clinical decision support tools that enhance rational prescription keeping in mind the potential risk of TdP and should also consider stepwise deprescription of drugs starting with the least benefit-risk ratio.

Footnotes

Ethics approval

The study was approved by the Institutional Ethics Committee (approval number: E05-PI-5/21).

Conflict of interest

None to report.

Data availability statement

The data is available from the corresponding author upon reasonable request.

Funding

None to report.

Supplementary materials

The supplementary material is available in the electronic version of this article: https://dx-doi-org-s.web.bisu.edu.cn/ 10.3233/JRS-230004.

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