INTRODUCTION:

The kidneys play a role in metabolism, filtration, excretion, and maintenance of fluid and electrolyte balance in the blood¹. However, pathological disorders, such as chronic kidney disease (CKD), can impair their functions. CKD is a structural abnormality of the kidneys and takes place progressively over three months or more. Renal structure and function abnormalities are characterized by kidney damage and a decrease in glomerular filtration rate (GFR) that is lower than 60 mL/minute/1.73 m2²^,³. The prevalence of this disease is 13.4% and ranks 17^th among the causes of death in the world⁴, and based on the Global Burden of Disease (2015), it has been increasing by 18.4% since 2005⁵^,⁶.

CKD causes an increase in serum potassium levels (hyperkalemia). The kidneys excrete approximately 90-95% of the daily potassium diet, and only 5-10% is removed by the intestine. Hyperkalemia is a condition of serum potassium above the normal limits, >5.0, >5.5, or >6.0 mmol/L⁷. However, CKD patients are at high risk when GFR is below 15 mL/min. In addition, other predisposing factors cause serum potassium levels to increase. These include abnormal cellular redistribution, increased intake, and reduced ability to excrete potassium⁸.

Since potassium plays a vital role in myocardial contraction, hyperkalemia causes electrophysiological disorders of the heart, which include decreased myocardial resting membrane potential, increased depolarization, myocardial instability, and abnormalities of the conduction system that ultimately lead to arrhythmias, and in the heart, it can trigger sudden cardiac death⁴^,⁸^,⁹^,¹⁰. The prevalence of hyperkalemia is higher in CKD patients (40-50%) than in the general population (2-3%). In addition, its prevalence among CKD patients increases the probability of death, which is why adequate treatment is necessary⁷^,¹¹.

Although hyperkalemia management in healthcare facilities always uses drug combinations, there has not been many data regarding the effectiveness of the drug combinations. Therefore, this study aimed to determine the use and effectiveness of drug combinations based on the improvement of serum potassium levels in CKD patients with hyperkalemia.

MATERIAL AND METHODS:

Research design:

This study was observational with retrospective and prospective data collection methods conducted at Dr. Saiful Anwar and Lavalette Hospitals in Malang, Indonesia. The data were obtained from the medical records of CKD patients with hyperkalemia from 2017-2019. A simple random sampling method was used to monitor serum potassium levels before and after the administration of hyperkalemia drug combinations. The inclusion criteria were inpatients with pre-hemodialysis hyperkalemia, aged ≥15 years, and receiving hyperkalemia drug combination therapy. Meanwhile, the exclusion criteria were hyperkalemia patients not attributable to CKD. Patients who met the inclusion and exclusion criteria through medical tracing and direct monitoring in the inpatient room were included as the study sample.

Ethical clearance:

The ethical approvals were obtained from the Medical Research Ethics Commission of the Regional General Hospital Dr. Saiful Anwar (No. 400/039/K.3/302/2019) and the Health Research Ethics Commission of the Faculty of Medicine, Universitas Brawijaya Malang (No. 91/EC/KEPK-S1-FARM/03/2019).

Data analysis:

The paired T-test and one-way ANOVA data analysis methods were used. The paired T-test was used to determine the effectiveness of each drug group by examining the differences in potassium levels before and after the administration of the drug combinations. The one-way ANOVA test was used to determine which group of drugs was most effective in reducing the serum potassium level. The data were considered statistically significant when the p-value was <0.05.

RESULTS:

Demographic data:

Data were obtained from 47 medical records of 21 male patients (44.7%) and 26 female (55.3%). They were divided into six age categories: 4 (8.5%), 10 (21.3%), 13 (27.7%), 13 (27.7%), 6 (12.8%) and 1 (2.1%) patients in the age range of 26-35, 36-45, 46-55, 56-65, 66-75, and 76-85 years, respectively (Table 1). The pattern of drug combination therapy used for hyperkalemia was categorized into four groups: A, B, C, and D. The commonly used therapy was group A (60.2%), while the least was D (5.1%) (Table 1).

Table 1: Patient Distribution.

Gender		n	Percentage (%)
	Male	21	44.7
	Female	26	55.3
	Total	47	100.0
Age
	26-35	4	8.5
	36-45	10	21.3
	46-55	13	27.7
	56-65	13	27.7
	66-75	6	12.8
	76-85	1	2.1
	Total	47	100.0
Drug Combination
	Group A	47	60.2
	Group B	19	24.4
	Group C	8	10.3
	Group D	4	5.1
	Total	78*	100.0

*From 47 patients with CKD stage V or End-Stage Renal Disease (ESRD), 78 hyperkalemia correction data were obtained because one patient received more than one therapy for hyperkalemia correction in the same or different hyperkalemia drug combination group.

Mean change in patient’s serum potassium levels:

The effectiveness of drug combinations for hyperkalemia is indicated by changes in the serum potassium levels and its mean difference in patients before and after administration. Mean changes (∆p) of serum potassium levels show its extent of decline at each group of drug combinations in a single treatment (Table 2).

Comparison of serum potassium levels before and after hyperkalemia correction:

The paired T-test results (Table 3) showed a statistically significant decrease in serum potassium levels after hyperkalemia correction (p < 0.05) in the drug combination group A, B, and C. Similarly, there was a decrease in group D after hyperkalemia correction, although not statistically significant (p > 0.05).

Table 3: Paired T-test Results with Serum Potassium Levels before and after Administration of Hyperkalemia Drug Combination.

Variables		n	Mean ± s.d (mmol/L)	Mean Difference ± s.d (mmol/L)	p
Group A	Pre	47	6.56 ± 0.59	0.62 ± 0.58	0.000
	Post	47	5.93 ± 0.80
Group B	Pre	19	6.89 ± 0.74	0.72 ± 0.61	0.000
	Post	19	6.18 ± 1.00
Group C	Pre	8	6.92 ± 0.95	1.03 ± 0.52	0.001
	Post	8	5.89 ± 1.06
Group D	Pre	4	7.20 ± 0.21	0.84 ± 0.73	0.106
	Post	4	6.36 ± 0.90

Comparison of changes in serum potassium levels among groups of hyperkalemia drug combinations:

The one-way ANOVA test (Table 4) was performed on all four groups of drug combinations that can reduce serum potassium levels. The test results showed a p-value of 0.336, meaning there is no significant difference (p > 0.05). Therefore, the effectiveness of drug combination group A, B, C, and D in reducing serum potassium levels is the same.

Table 4: Results of The One-Way ANOVA Test for Changes in Serum Potassium Levels between The Hyperkalemia Drug Combination Groups.

Variables		n	Mean ± s.d (mmol/L)	p
Drug Group	A	47	0.62 ± 0.58	0.336
	B	19	0.72 ± 0.61
	C	8	1.03 ± 0.53
	D	4	0.84 ± 0.73

DISCUSSION:

The distribution by gender shows a higher number of female patients than males. A higher prevalence of women experiencing CKD is due to a more significant factor in decreasing GFR and increasing albuminuria incidence¹²^,¹¹. Further, this disease is a risk factor for hyperkalemia emergence resulting from decreased GFR. The risk increases up to 5.5 times in patients with kidney disease and 2 times in females¹³.

Most CKD patients with hyperkalemia are between 46-55 and 56-65 years old. Structural and functional changes in the kidneys occur with age¹⁴, causing potassium imbalance. In addition, the risk of this disease increases in elderly patients compared to younger ones. Besides kidney disease, the elderly suffers from several comorbidities, such as heart disease¹⁵ and hypertension, which trigger renal tubular dysfunction. They also suffer from decreased glomerular filtration rate, which causes reduced potassium excretion by the kidneys¹³.

Drugs used in the management of hyperkalemia include calcium gluconate, Actrapid-HM®, NovoRapid®, Humulin-R®, D40%, and Ventolin® Nebules. The therapeutic dose was similar among groups. Calcium gluconate dose of 100 mg/mL was administered up to 10 mL, up to 10 IU insulin with 50 mL D40%, and 2.5 mg up to 10 mg Ventolin® Nebules. Drug combinations were used by the two hospitals in managing this disease. Therefore, a single drug administration needs to be discouraged as therapy.

The drug combination is generally used to treat hyperkalemia since there are several therapeutic goals to achieve. The four groups and the administered dosages followed hyperkalemia management according to the National Kidney Foundation (2015)¹². The four groups further showed changes in serum potassium levels after therapy administration. The mean changes in A, B, C, and D groups were 0.62, 0.72, 1.03, and 0.84 mmol/L, respectively. They indicated the magnitude of the decrease in serum potassium levels in each group of drug combinations.

This study examined the reduction in patients’ serum potassium levels after drug combination administration to determine the effectiveness of the treatment. The drug combinations of group A, B, C, and D were calcium gluconate, insulin, and D40%. However, the difference among the four groups was the type of insulin used and the addition of Ventolin® Nebules. The effectiveness was supported by the drug’s mechanism of actions in achieving the goals of hyperkalemia therapy. According to the American Family Physician, managing hyperkalemia has three goals, namely 1) stabilizing myocardia in preventing arrhythmias, 2) shifting extracellular potassium to enter the cell, and 3) removing the excess from the body¹⁶.

Calcium neutralizes the cardiotoxicity of hyperkalemia by stabilizing cardiac cell membranes to prevent unwanted depolarization. Stabilizing the cardiac cell membranes is conducted by increasing the threshold potential of the heart. Therefore, it returns the normal gradient between the threshold and the resting membrane potentials. Calcium does not affect a decreased serum potassium level and can be administered as 10% calcium gluconate (100 mg/mL) with a dose of 10 mL⁸^,¹⁷.

In the body, about 98% of potassium is stored in intracellular matrix, while the remaining 2% is stored in extracellular. It plays an important role in myocardial contraction, and its upsurge in hyperkalemia triggers heart rhythm disorders (arrhythmia), a dangerous condition as it causes cardiac arrest and results in death¹⁸.

Insulin activates Na⁺/K⁺-ATPase pumps in skeletal muscle¹⁹ and causes a shift in potassium to the intracellular. The most recommended type is short-acting at a dose of 10 units²⁰. Actrapid-HM® and Humulin-R® are short-acting insulin²¹, while NovoRapid® is rapid-acting. Their effects are determined within 15-30 minutes after the provision with action duration ≥2 hours and are expected to reduce serum potassium levels by 0.7-1.0 mmol/L¹⁶.

Furthermore, insulin binds to its receptors when glucose is accessible¹⁹, and its absorption triggers an increase in the ability of adenosine triphosphate (ATP) for Na⁺/K⁺-ATPase activity. Similarly, this binding increases Na⁺/K⁺-ATPase activity in skeletal muscle by increasing pumping expression in the plasma membrane. It directly stimulates the pump by signaling phosphatidylinositol 3-kinases (PI3Ks) and atypical protein kinase C (PKC)²². The binding subsequently causes phosphorylation of the insulin receptor substrate 1 protein (IRS-1) that binds to PI3Ks. However, the interaction between IRS-1 and PI3Ks activates phosphoinositide-dependent kinase-1. After that, atypical PKC activation occurs and causes Na⁺/K⁺-ATPase pump activation²³.

The insulin supply in hyperkalemia management needs to be accompanied by dextrose²⁴, which is intended to increase insulin activity by lowering serum potassium levels. Dextrose administration aims to prevent the occurrence of hypoglycemia in patients¹⁶^,²⁵^,²⁶. Hypoglycemia significantly affects the length of stay and mortality, and the risk increases from 8.7 to 13%, even when the patient has received insulin and dextrose²⁷^,²⁸. Further, dextrose is required to support the Na⁺/K⁺-ATPase activity since it undergoes the glycolysis pathway in the cells. Pyruvate kinase catalyzes ATP formation in the glycolysis process by converting phosphoenolpyruvate to pyruvate. ATP formation by pyruvate kinase further energizes Na⁺/K⁺-ATPase²⁹.

In this study, the use of insulin to treat hyperkalemia was marked as an off-label drug, meaning that the drug use has not been reviewed or approved by the authorized body or outside the indications. However, the legal authority recognizes the doctor’s policy to administer such drugs³⁰. Insulin indications approved by the FDA or Indonesian Food and Drug Administration and listed on the label are considered therapies for type 1 and 2 diabetes mellitus and diabetic ketoacidosis³¹^,³². In addition, off-label insulin has been accepted by medical practitioners in hyperkalemia management³³^,³⁴.

Ventolin® Nebules containing salbutamol (albuterol) treat hyperkalemia by inducing potassium shift from extracellular to the intracellular matrix. Salbutamol increases Na⁺/K⁺-ATPase activity in skeletal muscle through different cellular lines with insulin. Therefore, the addition of β2 agonist therapy, such as salbutamol at a dose of 10-20 mg, is insulin additive in reducing potassium levels²⁰. Its effect in lowering serum potassium level by 0.5-1.0 mmol/L can be observed within 30 minutes with a duration of ≥2 hours¹⁶.

Drug group combinations of A, B, C, and D in this study reduced serum potassium levels since they met the hyperkalemia therapy goal. Therefore, the result of the therapy evaluation in hyperkalemia also indicates the use of drug combinations. It shows that extracellular potassium is transported into the cells using intravenous insulin and β2 agonists when administered together³⁵.

In addition, it is known that no drug combination is superior to others in lowering the serum potassium level. The drug’s addition does not increase the significant effect of decreasing serum potassium level. However, the combined use of calcium gluconate, insulin, and D40% reduces the level. Hyperkalemia treatment is very diverse and complex. The addition of several different drugs may increase the effect of decreasing serum potassium level, but no randomized controlled trials data support this therapeutic approach³⁶. Therefore, more studies and evaluations are needed for hyperkalemia management. By considering treatment’s effectiveness and cost efficiency, pharmacists can suggest using the most minimal combination of anti-hyperkalemia. Pharmacists can also encourage the use of drugs that are effective, efficient, and safe in hospitals. In addition to assisting in determining the therapy, pharmacists can monitor the patient’s serum potassium level and other laboratory data as a reference to discontinue or repeat the therapy for hyperkalemia management and monitor the drug side effects. The limitation of this study is that this study did not observe data on the patients’ blood glucose levels. These data are needed because patients receive insulin that potentially causes hypoglycemia. Even though the patients received D40%, the patients’ blood glucose levels were best observed and recorded to minimize the risk of hypoglycemia.

CONCLUSION:

From this study, it can be concluded that the mostly used drug combination therapy for hyperkalemia in CKD patients is calcium gluconate, Actrapid® HM, and D40%. Drug combinations of calcium gluconate, Actrapid® HM, D40%; calcium gluconate, Actrapid® HM, D40%, Ventolin® Nebules; and calcium gluconate, NovoRapid®, D40%® are able to reduce serum potassium levels significantly. Therefore, the effectiveness of all drug combination groups for hyperkalemia management is similar.

FUNDING:

This research was funded by PNBP 2017 FMUB under the Contract Number: 19/SK/UN10.7/PN/BPPM/2017.

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

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Received on 03.08.2020 Modified on 19.03.2021

Research J. Pharm. and Tech 2022; 15(1):6-10.

DOI: 10.52711/0974-360X.2022.00002

No.	Group	Drug’s Name	∆p (mmol/L)	n
1.	A	Calcium gluconate, Actrapid-HM®, D40%	0.62	47
2.	B	Calcium gluconate, Actrapid-HM®, D40%, Ventolin® Nebules	0.72	19
3.	C	Calcium gluconate, NovoRapid®, D40%	1.03	8
4.	D	Calcium gluconate, Humulin-R®, D40%	0.84	4
Total				78