Heart Science Journal 2026.
: 70-75
Contents list available at w.
Original Article Renal function and potassium changes in HFrEF patients treated with ACEI ARNI: A prospective cohort study among Acehnese.
Indonesia Iffah Munawarah1.
Teuku Heriansyah1*.
Maimun Syukri2.
Adi Purnawarman1.
Buchari Buchari3 1 Department of Cardiology and Vascular Medicine.
Faculty of Medicine.
Universitas Syiah Kuala.
Banda Aceh.
Indonesia 2 Department of Internal Medicine.
Faculty of Medicine.
Universitas Syiah Kuala.
Banda Aceh.
Indonesia 3 Department of Clinical pathology.
Faculty of Medicine.
Universitas Syiah Kuala.
Banda Aceh.
Indonesia
ARTICLE INFO
ABSTRACT
Keyword :
ACEI.
ARNI.
Heart Failure.
Potassium.
Renal Function.
Background: Renin-Angiotensin-Aldosterone System (RAAS) acceleration commonly occur in Heart Failure (HF).
Drugs such as Angiotensin-Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor-Neprilysin Inhibitors (ARNI) become essential part of HF treatment.
Long-term consumption may impair kidney function and potassium imbalance, which could potentially limit the therapy, therefore we conducted this study to assess the effects of ACEI and ARNI on renal function and potassium level in Indonesian patients with heart failure with reduced ejection fraction (HFrEF), as no local studies exist.
Method: A prospective cohort was performed in Banda Aceh, which comprise of 40 ACEI and 40 ARNI patients on standard Left ventricular ejection fraction (LVEF), serum creatinine level then converted into estimated Glomerular Filtration Rate .
GFR), and serum potassium level were measured at baseline and after 3 months into the therapy.
Independent t-test was applied to compare groups.
Result: Both ARNI and ACEI groups showed significant improvement in eGFR .
< 0.
The intergroup difference was 11 mg/dL .
= 0.
showed that ACEI had a better outcome in eGFR improvement compare with ARNI.
Potassium rose slightly in both groups, with an intergroup difference of 0.
082 mmol/L .
= 0.
, indicating no meaningful difference.
Conclusion: Both ACEI and ARNI improved eGFR after 3 months, with a modest potassium increase.
Introduction Heart failure (HF) affects over 20 million population worldwide and recognized as a global health problem due to high mortality and poor quality of life.
The incidence of HF rises yearly, with frequent hospital readmissions, making it a major burden.
1 About one in four hospitalized patients are readmitted within 30 days, and almost half within six months.
Khan et al.
reported increase of readmissions .
Ae90 day.
between 2010Ae2017.
2 HF results from impaired systolic and diastolic function, reducing the heartAos ability to provide enough blood for body and meet metabolic needs.
3 Left ventricular ejection fraction (LVEF) is widely used to assess cardiac function and predict outcomes in HF, particularly in reduced ejection fraction (HFrEF).
The Renin-Angiotensin-Aldosterone System (RAAS) regulate sodium and fluid balance, influencing blood pressure through the heart, kidneys, and vessels.
5 In HFrEF.
RAAS activity is elevated.
6 Reduced sodium delivery to the distal tubule causes glomerular hypoperfusion and sympathetic activation, leading to renin release and a cascade of vasoconstriction, fluid retention, and potassium excretion.
5 ACE
inhibitors (ACEI.
block angiotensin I to II conversion, lowering angiotensin II levels and RAAS activation.
6 Those mechanism reduces preload, afterload, improves natriuresis, and lowers vascular pressures, lead to improving clinical outcomes in HF.
7 For this reason.
ACEIs remain a cornerstone in HF therapy.
Angiotensin receptor-neprilysin inhibitors (ARNI.
combine neprilysin inhibition with RAAS blockade .
acubitril/valsarta.
8 They enhance remodeling, diuresis, and natriuresis while reducing vasoconstriction and fluid retention.
Trials show ARNI lowers HF readmission and mortality, particularly in HFrEF.
8 Consequently.
ARNI is now among the four pillars of HFrEF therapy with ACEI, betablockers, mineralocorticoid receptor antagonists (MRA.
, and SGLT2 Despite the benefit.
RAAS inhibitors can impair kidney function which lead to hyperkalemia.
The effect could cause dose adjustments or discontinuation of the therapy.
10 Schmidt et al.
>30% serum creatinine rise in over 120,000 ACEI users, highlighting renal risks.
11 ACEIs may also increase potassium, and both hyperkalemia and hypokalemia raise mortality risk.
10,12,13 Nevertheless.
ACEI benefits often outweigh risks.
ARNI can also affect renal outcomes.
Some studies reported increased urinary albumin-to-creatinine ratioI.
14 Major clinical studies including PARADIGM-HF and PIONEER-HF showed ARNI exceeds ACEI in enhancing survival and lowering morbidity in HFrEF patients.
8Ae15 Most evidence derives from Caucasian cohorts, while Asian populations remain underrepresented.
Genetic, lifestyle, and metabolic differences may influence disease expression and treatment response.
* Corresponding author at: Department of Cardiology and Vascular Medicine.
Faculty of Medicine.
Universitas Syiah Kuala.
Banda Aceh.
Indonesia E-mail address: teuku_hery@usk.
id (T.
Heriansya.
https://doi.
org/10.
21776/ub.
Received 25 December 2025.
Received in revised form 16 March 2026.
Accepted 30 March 2026 Available online 26 April 2026 I.
Munawarah, et al Heart Science Journal 2026.
: 70-75
Figure 1.
Consort flow of the study Hence, this study investigates the outcome of ACEI and ARNI on renal function and potassium level in Indonesian HFrEF patients, focusing on Acehnese ethnicity.
Echocardiography used the Simpson method (GE Vivid E.
, calculating ejection fraction.
Comorbidities such as hypertension (SBP Ou140 mmHg or DBP Ou90 mmH.
and diabetes .
asting glucose Ou126 mg/dL, 2-hour glucose Ou200 mg/dL, or HbA1c Ou6.
5%) were noted.
Smoking history was Blood specimens were taken from the brachial vein at baseline and 3 months to measure creatinine and potassium.
All renal data were converted into eGFR to provide standardized assessment of renal Methods Study design This prospective cohort study was carried out from February to April 2023 at Intensive Coronary Care Unit (ICCU) and Cardiology Ward of Dr.
Zainoel Abidin General Hospital.
Banda Aceh.
Indonesia.
It evaluated the outcomes of ACEIs and ARNIs on renal function and serum potassium in HFrEF patients.
Measure To examining renal function, serum creatinine was first Serum creatinine level was measured using Jaffe kinetic method (Indiko analyze.
Samples were placed in heparin tubes .
voiding EDTA, citrate, fluorid.
Calibration used ScaI calibrators and Nortrol controls, with aliquots stored at Ae20AC.
Values were reported in mg/dL.
The obtained serum creatinine level was then converted to eGFR using the CKD Ae EPI formula.
Results were expressed in mL/min/1.
Ethical approval Following the ethical guidelines of the Declaration of Helsinki's.
The Dr.
Zainoel Abidin General Hospital Ethics Committee granted approval for this study (No.
124/ETIK-RSUDZA/2.
Study population Potassium was analyzed using Ion Selective Electrodes (ISE) on the Nova 5 CRT Electrolyte Analyzer.
Sample preparation was similar to creatinine testing.
Calibration involved replacing reagent tubes and adjusting parameters.
Results were expressed in mmol/L.
Purposive sampling identified HFrEF patients receiving ACEI or ARNI therapy.
Using SlovinAos formula, a minimum of 31 participants was required.
this was increased by 20% to 40 per group.
Inclusion criteria is adults aged 18Ae75 with cardiologist-confirmed HFrEF (LVEF <50%).
With patient with congenital heart disease, severe valvular disease.
COPD, or late-stage chronic kidney disease .
tage IV Ae V or estimated Glomerular Filtration Rate .
GFR) < 30 mL/min/1.
73mA were not included in this study Data analysis Baseline characteristics were presented descriptively.
Continuous data are summarized using mean A SD or median .
inAe ma.
, whereas categorical data were described using frequency and Normality was tested by Shapiro-Wilk.
Paired t-tests were implemented for normally distributed data.
Mann-Whitney U or Wilcoxon tests otherwise.
A p-value <0.
05 indicated significance.
Analysis used SPSS version 25 (SPSS Inc.
Chicago.
IL.
USA).
Data collection Baseline data included demographics, vital signs .
lood pressure, heart rat.
, body mass index (BMI), and LVEF.
Munawarah, et al Heart Science Journal 2026.
: 70-75
Result Table 1.
Characteristics of the heart failure patients with reduced ejection fraction .
N (%) Characteristics ACEI .
ARNI .
Age, meanASD .
56A11
Sex Male 31 .
Female 9 .
Systolic blood pressure (SDP), meanASD .
25A23.
32A23.
Diastolic blood pressure (DBP), meanASD .
83A0.
35A10.
Hypertension Yes 17 .
Type 2 diabetes mellitus Yes 17 .
Smoking Yes 27 .
Body mass index (BMI), .
g/m.
MeanASD 39A2.
97A2.
Normal 10 .
Overweight 27 .
Obese 3 .
Creatinine Pre 05A0.
15A0.
Pottasium Pre 1A0.
08A0.
eGFR Pre 72 .
Ae .
Ae .
Table 2.
Effect of ACEI and ARNI administration on eGFR among HFrEF patients .
mL/min/1.
Groups Pre Post ARNI .
24A21.
05A17.
ACEI .
Oe.
- .
a Analyzed with Paired T-test b Analyzed with Wilcoxon test Table 3.
Comparison of eGFR after ACEI and ARNI administration among HFrEF patients .
Groups Difference Delta (Mean C SD) ARNI 81C22.
ACEI
19,86 C 22.
a Analyzed with Independent sample T-test Table 4.
Effect of ACEI and ARNI administration on potassium levels among HFrEF patients .
Potassium levels .
mol/L) Groups Pre Post ARNI .
0 A 0.
4 A 0.
ACEI .
2Oe5.
2Oe5.
a Analyzed with Independent sample T-test b Analyzed with Wilcoxon test Table 5.
Comparison of potassium levels after ACEI and ARNI administration among HFrEF patients .
Groups Difference Delta (Mean C SD) ARNI 33 C 0.
ACEI
25 C 0.
a Analyzed with Independent sample T-test Table.
6 Metabolic and demographic factors to eGFR changes Cofounding Factors Age
Type 2 Diabetes Hypertension RAAS Inhibitor
Constant
a Analyzed with Linier Regression test
p-valuea
P-Value 0,706 p-value p-valuea
p-valuea
0,036b p-valuea
B CI 95%
058, 1.
600, 12.
363, 4.
935, -3.
Munawarah, et al Heart Science Journal 2026.
: 70-75
Blood pressure Response During 3 months Follow-Up
SBP-ACEI
SBP-ARNI
MAP-ACEI
MAP-ARNI
DBP-ACEI
DBP-ARNI
Pre 1 month 2 month p = 0.
3 month Figure 2.
Blood Pressure Response during 3 months follow up periode.
Patient selection From 110 screened HFrEF patients, 17 excluded and 13 declined, leaving 80 participants.
They were allocated into ACEI .
and ARNI .
Figure 1 outlines the recruitment process.
Baseline characteristics Baseline characteristics illustrated in Table 1.
The ARNI group was older than the ACEI group.
Both groups were predominantly Blood pressure was comparable, though systolic values were slightly higher in ARNI patients .
32A23.
71 vs 122.
25A23.
Hypertension, diabetes, and smoking prevalence were similar.
BMI distribution was also not significantly different.
Baseline characteristics showed a statistically significant difference in age.
therefore, multivariate analysis was subsequently performed (Table 6 and .
Blood pressure changes Monthly blood pressure monitoring is shown in Figure 2.
Wilcoxon analysis revealed significant reductions in systolic, diastolic, and mean arterial pressure (MAP) after 3 months in both groups .
< Main findings A total of 40 ACEI and 40 ARNI groups was enrolled in our Table 2 shows eGFR results.
Both groups demonstrated improvement in eGFR .
< 0.
As shown in Table 4, potassium rose significantly in both groups after 3 months .
< 0.
Seven patients in each group developed mild hyperkalemia .
4 mmol/L).
The intergroup difference in eGFR was 11 mL/min/1.
73mA .
= 0.
ACEI demonstrated greater improvement in eGFR compared with ARNI.
Potassium rose slightly in both groups, with an intergroup difference of 0.
082 mmol/L .
= 0.
, indicating no meaningful difference (Table 3 and Table .
Despite the slight increase in potassium levels, no dangerous symptoms were observed, hence the therapy was continued.
Discussion RAAS inhibitors remain essential in HFrEF therapy, but increase of kidney function level and dyskalemia often leads to 16,17 Making regular monitoring of kidney function and potassium important This study showed ARNI improved patientAos serum creatinine level compared to the baseline, consistent with trials such as PARADIGM-HF.
7 The nephroprotective effect is linked to enhance the natriuretic peptide activity, reducing inflammation, fibrosis, and improving renal perfusion through the decrease of blood pressure and arteriole vasodilation.
18 Furthermore.
ARNI improves renal hemodynamics by inducing systemic blood pressure reduction, dilatation of afferent arterioles, and relative vasoconstriction of efferent arterioles, which collectively enhance renal blood flow 18.
Improved cardiac output may also support renal function, as reported in various study such as PARADIGM-HF.
PARAGON-HF, and PIONEER-HF.
7,14,19
Patients with ACEI also showed improved serum creatinine, contrary to earlier reports of increased levels.
4,20Ae22 Rise of serum creatinine are often considered as Aupre-renal success,Ay reflecting renal 4,22 Increase of serum creatinine level up to 30% which will stabilize within the next four weeks are still acceptable.
Long-term ACEI benefits include reduced intraglomerular pressure, improved filtration, and lower albuminuria.
Usage of ARNI enhance renal flow via natriuretic peptides, dilating afferent arterioles and relaxing mesangial cells, while ACEI dilates efferent arterioles, reducing hyperfiltration but risking transient GFR decline and hyperkalemia.
Hyperkalemia is a concern in patient with RAAS inhibitors, especially in older patients, diabetics, and those with Chronic kidney disease (CKD).
24 Reduced cardiac output decreases renal perfusion, activating RAAS and sympathetic pathways.
While initially adaptive, this contributes to electrolyte imbalance.
ACEI and ARNI both suppress aldosterone, limiting potassium excretion.
Adding MRAs further increases risk by directly blocking aldosterone-driven sodium reabsorption and potassium elimination.
25,26
In this study, potassium rose significantly in both groups, with mild hyperkalemia .
otassium level was > 5 to C 6 mmol/L) found in 14 No difference was found between ACEI and ARNI, consistent with PARADIGM-HF and PIONEER-HF studies where hyperkalemia rates were similar.
7,14,24 Severe hyperkalemia .
otassium level > 7 mmol/L) was rare in both groups.
7 Although Mineralocorticoid Receptor Antagonists (MRA.
increase the risk further.
ARNI may carry a slightly lower risk than ACEI, but close monitoring is essential.
This is the first Indonesian study to compare both ARNI and ACEI on renal function and potassium level as the side effect of the Both groups improved serum creatinine level, with no difference in hyperkalemia or MACE incidence, consistent with Heriansyah et al.
Various factors may explain the differences between the findings of this study and those of earlier research, including variations in patient ethnicity, age, body mass index (BMI), metabolic factors such as hypertension and diabetes mellitus, treatment duration, and medication dosing.
For example.
Desai et al.
conducted their research in a U.
cohort with a mean BMI of 30 kg/mA, and ARNI therapy was I.
Munawarah, et al Heart Science Journal 2026.
: 70-75
escalated to the target dose of 97/103 mg.
Conversely, the current study involved Indonesian participants with an average BMI of 25 kg/mA, and the ARNI dosage remained below the maximum.
Moderation in ARNI dosage is likely due to a more pronounced blood pressure-lowering effect observed in the Indonesian population compared to Caucasians, which may present challenges in achieving full titration.
The Acehnese population has a distinct regional dietary pattern characterized by high intake of sodium, fat, and sugar.
This pattern may affect their metabolic therefore, the changes in eGFR and potassium levels observed in this study were likely influenced not only by medication but also by other factors, including metabolic conditions.
This study has several limitations: .
the sample size was limited and from a single institution.
Future studies are recommended to use a randomized controlled trial (RCT) design to ensure better control of the study population and minimize potential bias, .
the follow-up duration was short.
the influence of dosage variations on outcomes did not evaluate in this study.
information regarding additional heart failure therapies administered to patients was not Momoniat T.
Ilyas D.
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Heart.
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doi:10.
1136/heartjnl-2018-314158 Conclusion Significant improvement in eGFR was observed in HFrEF patients received with both ACEI and ARNI after three months of Additionally, while both therapies demonstrated improved eGFR during the 3 months follow-up period, a slight increase in serum potassium levels was observed in both groups.
Schmidt M.
Mansfield KE.
Bhaskaran K.
Nitsch D.
Sorensen HT.
Smeeth L, et al.
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Declaration 1 Ethics Approval and Consent to participate The Declaration of Helsinki's guiding principles were followed in the conduct of this study.
The Dr.
Zainoel Abidin General Hospital Ethics Committee gave its approval (No.
124/ETIK-RSUDZA/2.
Ferreira JP.
Mogensen UM.
Jhund PS.
Desai AS.
Rouleau JL.
Zile MR, et al.
Serum potassium in the PARADIGM-HF trial.
Eur J Heart Fail.
:2056-2064.
doi:10.
1002/ejhf.
Consent for publication Not applicable.
Rossignol P.
Dobre D.
McMurray JJV.
Swedberg K.
Krum H.
Veldhuisen DJ, et al.
Incidence.
Determinants, and Prognostic Significance of Hyperkalemia and Worsening Renal Function in Patients With Heart Failure Receiving the Mineralocorticoid Receptor Antagonist Eplerenone or Placebo in Addition to Optimal Medical Therapy.
Circ Heart Fail.
:51-58.
doi:10.
1161/CIRCHEARTFAILURE.
3 Availibility of data and materials Data used in our study were presented in the main text.
4 Competing interests Not applicable.
5 Funding Source This research was supported by the Ministry of Higher Education through Universitas Syiah Kuala, under Grant Number 381/UN11.
1/PG.
05/2023.
Voors AA.
Gori M.
Liu LCY.
Claggett B.
Zile MR.
Pieske B, et al.
Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection Eur Heart Fail.
:510-517.
doi:10.
1002/ejhf.
6 Authors contributions Idea/concept: TH.
IM.
Design: TH,IM Control/supervision: TH.
IM.
MS.
AP.
BC.
Data collection/processing: TH.
IM.
Analysis/interpretation:TH.
IM.
MS.
AP.
BC.
Literature review: TH.
IM.
Writing the article: IM.
Critical review: TH.
MS.
AP.
BC.
All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.
Velazquez EJ.
Morrow DA.
DeVore AD.
Duffy CI.
Ambrosy AP.
McCague K, et al.
AngiotensinAeNeprilysin Inhibition in Acute Decompensated Heart Failure.
New England Journal of Medicine.
:539-548.
doi:10.
1056/NEJMoa1812851 Tamargo J.
Kaski JC.
Kimura T.
Barton JC.
Yamamoto K.
Komiyama M, et al.
Racial and ethnic differences in pharmacotherapy to prevent coronary artery disease and thrombotic events.
Eur Heart J Cardiovasc Pharmacother.
:738-751.
doi:10.
1093/ehjcvp/pvac040 7 Acknowledgements Authors express their gratitude to the staffs of cardiac center ward of Dr.
Zainoel Abidin Hospital.
Banda Aceh.
Indonesia.
Seferovic PM.
Ponikowski P.
Anker SD.
Bauersachs J.
Chioncel O.
Cleland.
JGF, et al.
Clinical practice update on heart failure 2019:
pharmacotherapy, procedures, devices and patient management.
An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology.
Eur J Heart Fail.
:1169-1186.
doi:10.
1002/ejhf.
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