Efficacy of combining acetazolamide with loop diuretics versus double dose loop diuretics for decongestion in patients with chronic kidney disease: a randomized controlled trial

Abstract

The combination of acetazolamide and loop diuretics in hospitalized heart failure patients has demonstrated positive results in improving diuresis and decongestion. However, the effectiveness of this combination in chronic kidney disease (CKD) patients with volume overload remains to be determined. CKD patients with fluid overload confirmed by bioimpedance spectroscopy were randomized to receive oral acetazolamide 250 mg/day plus furosemide or a doubled dose of furosemide. Volume status, body fluid compartments (assessed by body composition monitoring), and urinary sodium were evaluated at baseline and 2 weeks. The primary endpoint was the change in body weight at 2 weeks. Categorical weight reduction thresholds (≥ 2 kg or > 5%) were analyzed as exploratory outcomes. Fifty-two patients with a mean estimated glomerular filtration rate of 38 ml/min/1.73 m² were included. The combination group achieved a greater reduction in body weight compared with the double-dose group, with a mean between-group difference of − 1.37 kg (95% CI − 2.50 to − 0.24). Exploratory analyses showed a higher proportion of patients achieving ≥ 2 kg weight loss (40.7% vs. 12%; RR 3.39, 95% CI 1.06–10.7) and > 5% weight loss (25.9% vs. 0%; RR 2.25, 95% CI 1.62–3.12) in the combination group. No serious adverse events were observed. Adding acetazolamide to loop diuretics improves decongestion in CKD patients, as reflected by greater weight reduction, without significant safety concerns.

Clinical trial registration: Registration code TCTR20240329006 approved on 29 March 2024.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-50753-2.

Background

Heart failure and chronic kidney disease (CKD) are closely interconnected conditions that frequently coexist and contribute to adverse clinical outcomes¹. In CKD patients, volume overload refers to excess body fluid accumulation, typically identified by clinical findings such as peripheral edema, while congestion reflects the hemodynamic and clinical consequences of this fluid excess. Volume overload is common in CKD and is associated with disease progression and cardiovascular complications^2,3. Although fluid retention and congestion have been linked to worse outcomes, it remains uncertain whether congestion is a direct mediator of risk or a marker of underlying cardiac dysfunction.

Loop diuretics are the cornerstone of therapy for volume management and decongestion⁴. Evidence from the DOSE-AHF trial suggests that greater decongestion, reflected by a body weight reduction of at least 2 kg, is associated with improved clinical outcomes⁵. However, strategies that rely on increasing loop diuretic doses provide only modest additional efficacy and are associated with a higher risk of adverse effects, including electrolyte disturbances, metabolic alkalosis, and worsening kidney function⁶. Furthermore, observational data in heart failure populations have suggested an association between higher loop diuretic doses and adverse cardiovascular outcomes⁷.

Acetazolamide, a carbonic anhydrase inhibitor, is a diuretic that greatly enhances decongestion when combined with loop diuretics, without increasing rates of hypokalemia and acute kidney injury, and with a lower rate of metabolic alkalosis compared to standard treatment⁸. In a multicenter, randomized, placebo-controlled trial, the combination of acetazolamide and loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion⁹. Whether the addition of acetazolamide to loop-diuretic therapy for decongestion in CKD patients with volume overload is beneficial remains unclear. In our study, we examined whether adding acetazolamide to standardized oral loop-diuretic therapy would improve the incidence of successful decongestion among CKD patients with volume overload in the outpatient clinic setting.

Methods

We conducted a single-center, randomized, open-label, investigator-initiated, controlled clinical trial. The protocol was approved by the Ethics Committee and Institutional Review Board of the Royal Thai Army Medical Department (Approval number R020h/66) and registered with the Thai Clinical Trials Registry (TCTR20240329006). The study adhered to the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all participants.

CKD patients were screened at the nephrology clinic of Phramongkutklao Hospital. Eligible participants were adults aged > 20 years with CKD stage 3–4 who had been receiving a stable dose of furosemide for at least 2 weeks and demonstrated clinical evidence of volume overload, defined primarily by peripheral edema on physical examination. Bioimpedance spectroscopy using a Body Composition Monitor (BCM; Fresenius Medical Care, Germany) was used as a supportive, objective tool to quantify fluid status, and an overhydration level > 1 L was applied as a standardized inclusion criterion to ensure consistent baseline volume expansion across participants, rather than as a sole diagnostic definition¹⁰. Exclusion criteria included prior acetazolamide use within 12 weeks, sulfa allergy, systolic blood pressure < 90 mmHg, organ transplantation, pregnancy, nephrotic-range proteinuria (> 3.5 g/day), recent hospitalization within 12 weeks, and significant electrolyte disturbances (hypokalemia, hyperkalemia, metabolic acidosis, or metabolic alkalosis).

The sample size was calculated based on the randomized controlled trial by Imiela et al., which showed mean fluid balance after acetazolamide and loop diuretics as − 666 ± 1,194 ml and 332 ± 705 ml in the control arm, respectively¹¹. The sample size was set to 21 patients per group, with a p-value < 0.05 to detect statistical significance and a power of 90%. Considering a 25% possibility of loss to follow-up, the total sample size was increased to 53.

Participants were randomized in a 1:1 ratio using block randomization (block size of 4) to receive either oral acetazolamide 250 mg once daily added to their baseline loop diuretic regimen or doubling of their individual baseline furosemide dose. This design reflects real-world clinical practice, where diuretic intensification is individualized based on prior exposure. Treatment was initiated immediately after randomization and continued for 2 weeks, as illustrated in Fig. 1.

Fig. 1.

Study Protocol.

Baseline and follow-up data included demographics, comorbidities, medication use, and laboratory parameters. Clinical assessment consisted of blood pressure, body weight, and standardized physical examination findings. Volume status was evaluated using a combination of clinical assessment and BCM measurements. Clinical decongestion was assessed using a pre-specified, standardized congestion scoring system that includes evaluation of peripheral edema, jugular venous distension, and pulmonary rales.

All clinical assessments were performed by trained nephrologists who were not involved in treatment allocation, effectively blinding the evaluators to the intervention and minimizing potential bias. Body weight and body composition measurements were obtained using calibrated instruments under standardized conditions. Laboratory tests included serum electrolytes, blood urea nitrogen, creatinine, and urinary electrolytes. Medication adherence was assessed by pill count, and adverse events were monitored throughout the study.

The primary endpoint was the change in body weight from baseline to 2 weeks, analyzed as a continuous variable to assess the degree of decongestion without escalation of decongestive therapy. This approach was selected to provide an objective and sensitive measure capable of detecting clinically meaningful differences between groups. Secondary endpoints included changes in blood pressure, kidney function, electrolyte parameters, and the incidence of adverse events. Categorical outcomes of body weight reduction (≥ 2 kg or > 5% from baseline) were analyzed as exploratory endpoints.

Statistical analysis

Categorical variables are presented as frequencies, and continuous variables are expressed as mean with standard deviation (SD) if normally distributed, or as median with interquartile range (IQR) if not normally distributed. Differences between groups were assessed using independent samples t-tests or Mann–Whitney U tests for continuous variables, and chi-squared tests and Fisher’s exact tests for categorical variables, as appropriate. Differences within groups were assessed using paired t-tests. Results were reported as differences in mean change with 95% confidence intervals (95% CI). A two-sided p-value of 0.05 was used as the threshold for statistical significance in all analyses. Data analysis was performed using SPSS for Windows, Version 12 (SPSS, Chicago, IL, USA).

Results

The study was conducted from July 2023 to December 2023. A total of 109 patients were screened, and 53 patients were randomized. During the run-in period, one patient withdrew consent (Fig. 2). The mean age of participants was 71.2 ± 11.9 years, and 73% were male. The mean estimated glomerular filtration rate (eGFR) was 37.9 ± 11.2 ml/min/1.73 m². The average furosemide dose was 29.2 mg/day, and mean overhydration, as measured by bioimpedance spectroscopy (BCM), was 2.7 ± 2.0 L.

Fig. 2.

CONSORT Flow Chart.

Underlying kidney diseases included hypertensive nephropathy in 30.7% of patients and diabetic nephropathy in 67.3%. Concomitant medications that could affect hemodynamics included renin–angiotensin–aldosterone system inhibitors (57.5%), calcium channel blockers (63.5%), and beta-blockers (44.2%). Baseline demographic characteristics, blood pressure, renal function, serum electrolytes, urinary sodium, and body fluid composition were well balanced between groups (Table 1). Adherence to the study medication, assessed by pill count, ranged from 92 to 96% in both groups. Regarding cardiac status, 16 patients (30%) had a history of heart failure (Table 1). None had been hospitalized for heart failure 12 weeks prior to enrollment, and all patients completed follow-up in the outpatient setting over the 2-week study period.

Table 1.

Baseline Characteristics:.

Variables	Combination group (N = 27)	Double furosemide group (N = 25)	P value
Male (N, %)	22 (81.5%)	17 (68%)	0.262
Age (years)	71.0 ± 14.2	71.4 ± 9.2	0.905
Body weight (kg)	68.9 ± 11.6	72.0 ± 9.8	0.301
Systolic blood pressure (mmHg)	134.7 ± 18.5	136.1 ± 21.9	0.802
Diastolic blood pressure (mmHg)	65.5 ± 14.3	67.7 ± 11.9	0.551
Causes of CKD (N, %)
- Diabetes	18 (66.7%)	17 (68%)	0.548
- Hypertension	9 (33.3%)	7 (28%)	0.677
History of heart failure (N, %)	9 (33.3%)	7 (28%)	0.677
Anti-hypertensive agents (N, %)
- ACEI/ARBs	15 (55.6%)	15 (60%)	0.746
- Calcium channel blockers	18 (66.7%)	15 (60%)	0.618
- Beta-blockers	11 (40.7%)	12 (48%)	0.598
Furosemide dose (mg/d)	34.8 ± 18.8	24.3 ± 7.5	0.616
eGFR (ml/min/1.73 m²)	37.6 ± 10.7	38.9 ± 11.7	0.676
Blood urea nitrogen (mg/dL)	25.5 ± 11.9	22.1 ± 9.0	0.247
Serum sodium (mmol/L)	139.4 ± 2.6	140.2 ± 3.1	0.327
Serum potassium (mmol/L)	4.2 ± 0.4	4.3 ± 0.5	0.332
Serum chloride (mmol/L)	103.1 ± 2.7	104.2 ± 2.8	0.150
Serum bicarbonate (mmol/L)	25.7 ± 2.6	25.4 ± 3.2	0.718
Serum NT-proBNP (pg/mL)*	450 (149–929)	295.5 (135.25–1566.25.25.25)	0.825
Urine sodium (mmol/L)	70.0 ± 39.7	69.5 ± 28.8	0.971
Overhydration (L)	2.7 ± 1.5	2.7 ± 2.5	0.961
Extracellular water (L)	17.1 ± 3.0	17.6 ± 2.8	0.545
Total body water (L)	31.5 ± 5.7	31.8 ± 4.7	0.799

All data are expressed as mean ± SD except *serum NT-proBNP, which is expressed as median (IQR). BCM: body composition monitoring; eGFR: estimated glomerular filtration rate; ACEI: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blockers; NT-proBNP: N-terminal pro B-type natriuretic peptide.

Change in body weight or fluid overload during the study

The median change in body weight from baseline to 2 weeks was − 1.64 kg (IQR − 4.25 to 0.97; P = 0.003) in the combination group and − 0.27 kg (IQR − 1.32 to 0.78; P = 0.181) in the double-dose group. The between-group mean difference in body weight change was − 1.37 kg (95% CI − 2.50 to − 0.24; P = 0.018) (Fig. 3). Exploratory analyses showed a higher proportion of patients achieving ≥ 2 kg weight reduction (40.7% vs. 12%; RR 3.39, 95% CI 1.06–10.7) and > 5% weight loss (25.9% vs. 0%; RR 2.25, 95% CI 1.62–3.12) in the combination group compared with the double-dose group (Fig. 4). Changes in body composition parameters, including overhydration, extracellular water, and total body water, were not significantly different between groups (Table 2).

Fig. 3.

Change in Body Weight at 2 Weeks. Change in body weight from baseline to week 2 in each treatment group. Within-group p-values indicate changes over time for each group. The mean difference and corresponding p-value represent the comparison between groups at week 2.

Fig. 4.

Proportion of Patients Achieving Weight Reduction at 2 Weeks. Proportion of patients in each treatment group achieving body weight reduction of > 2 kg and > 5% at week 2. Bars show within-group proportions. P-values indicate comparisons between groups for each outcome.

Table 2.

Changes in Body Fluid Compartment and Clinical Parameters at 2 Weeks:.

Variables	Combination group (N = 27)	Double furosemide group (N = 25)	P value
Body fluid compartment
Overhydration (L)	−0.7 (−1.3, −0.03)*	−0.7 (−1.7, 0.4)	0.939
Extracellular water (L)	−0.8 (−2.4, 0.8)	−0.4 (−1.9, 1.1)	0.269
Total body water (L)	−1.2 (−4.4, 2.1)	0.3 (−2.4, 2.9)	0.260
Clinical parameters
Systolic blood pressure (mmHg)	−6.8 (−16.2, 2.5)	−3.5 (−13.6, 6.5)	0.326
Diastolic blood pressure (mmHg)	−1.6 (−9.3, 5.6)	2.2 (−4.1, 8.4)	0.096
Serum NT-proBNP (pg/mL)	−438.2 (−1650.2, 773.8)	−450.0 (−4172.9, 3272.9)	0.454
Estimated GFR (ml/min/1.73 m²)	−5.1 (−10.8, 0.7)	−0.4 (−7.6, 6.8)	0.090
Blood urea nitrogen (mg/dL)	6.1 (−0.5, 12.6)	4.33 (−2.0, 10.7)	0.167
Serum creatinine (mg/dL)	0.2 (−0.1, 0.5)	0.1 (−0.3, 0.5)	0.355
Serum sodium (mmol/L)	−0.6 (−2.1, 0.9)	0.2 (−1.4, 1.7)	0.085
Serum potassium (mmol/L)	−0.1 (−0.4, 0.1)	−0.3 (−0.6, 0)	0.842
Serum chloride (mmol/L)	3.5 (1.4, 5.6)*	−1.8 (−3.6, −0.1)*	< 0.001
Serum bicarbonate (mmol/L)	−4.3 (−6.0, −2.6)*	1.4 (−0.2, 3.0)	< 0.001
Urine sodium (mmol/L)	1.74 (−23.2, 26.7)	−17.6 (−35.6, 0.3)	0.074

All data are expressed as mean with 95% CI.

P < 0.05 compared to baseline.

Change in blood pressure, serum electrolytes, and kidney function during the study

At the 2-week period, changes in blood pressure, kidney function, serum sodium, serum potassium, and urine sodium did not significantly differ between the two groups (Table 2). In contrast, the change in serum bicarbonate from baseline was − 4.3 mmol/L (95% CI −6.0 to −2.6) in the combination group and − 1.4 mmol/L (95% CI −0.2 to 3.0) in the double-dose group, with a significant difference between the two groups (P < 0.001).

Adverse events after treatment

No serious adverse events, including severe hypotension or the need for renal replacement therapy, were observed in either group during the study period. No patients discontinued treatment due to adverse effects. The incidences of hyponatremia, hypokalemia, and severe metabolic acidosis were low and did not differ significantly between groups. Two cases of severe metabolic acidosis occurred in the combination therapy group. Both patients had advanced CKD (stage G4), with baseline eGFR of 21 and 28 ml/min/1.73 m² and baseline serum bicarbonate levels of 22 mEq/L, which may have predisposed them to this complication. In both cases, metabolic acidosis improved after discontinuation of acetazolamide without the need for hospitalization. The incidence of acute kidney injury, defined as an increase in serum creatinine > 0.3 mg/dL from baseline, was 26.2% in the combination group and 24% in the double-dose group, with no significant difference between groups (Table 3).

Table 3.

Adverse events.

Variables	Combination group (N = 27)	Double furosemide group (N = 25)	P value
Hyponatremia (< 135 mmol/L)	1 (3.8%)	0	0.322
Hypokalemia (< 3.5 mmol/L)	1 (3.8%)	1 (4%)	0.977
Severe metabolic acidosis (HCO3−< 16 mmol/L)	2 (7.6%)	0	0.157
Acute kidney injury (Serum creatinine > 0.3 mg/dL from baseline)	7 (26.2%)	6 (24%)	0.811

Discussion

This open-label randomized controlled trial further demonstrates that adding acetazolamide to loop diuretics enhances diuretic efficacy in CKD patients with volume overload receiving chronic diuretic therapy in the outpatient setting. This effect was reflected by a significantly greater reduction in body weight compared with a strategy of doubling the loop diuretic dose, without an increase in serious adverse events.

Acetazolamide, a carbonic anhydrase inhibitor, impedes the catalysis of the chemical reaction converting carbonic acid to carbon dioxide and water in the proximal convoluted tubules, which are responsible for approximately 65% of total tubular sodium reabsorption under normal circumstances—a proportion that may increase in CKD settings. Therefore, to achieve a potent natriuretic response, acetazolamide should be used together with a loop diuretic that works more distally¹². A larger randomized controlled trial indicated that adding acetazolamide to standardized intravenous loop-diuretic therapy in patients with acute decompensated heart failure led to a higher incidence of successful decongestion⁹. A recent meta-analysis similarly demonstrated that acetazolamide, as an adjunctive diuretic, significantly improves global surrogate endpoints for decongestion therapy in patients with acute decompensated heart failure, although not all individual signs and symptoms of volume overload¹³. Our study involving CKD patients with overhydration of more than 1 L from BCM, which correlates well with the gold standard method^10,14, showed that oral acetazolamide 250 mg once daily added to loop-diuretic therapy resulted in greater decongestion and significantly greater body weight reduction of at least 2 kg by week 2. This reduction in body weight correlated well with a composite outcome at 60 days of reduced rehospitalization rates, emergency department visits, or death⁵. Further studies with larger sample sizes are needed to elucidate the complex relationships among degree of decongestion, body weight reduction, and cardiovascular and renal outcomes in CKD patients. Our study did not show statistically significant differences in body composition, particularly overhydration measured by BCM, between groups. This may be due to several factors: first, although the extracellular water (ECW) compartment comprises ~ 40% of total body water, BCM may have limited sensitivity for detecting small, short-term changes, especially in elderly CKD patients with altered body composition or reduced muscle mass¹⁵. Second, the observed changes in body weight and fluid status were modest, and the small sample size may have limited statistical power. Third, the sample size was calculated based on clinical endpoints rather than BCM measurements, further reducing the ability to detect subtle changes. These factors highlight BCM’s limitations for assessing short-term fluid shifts and emphasize the complementary interpretation of body weight and BCM data.

The combination of acetazolamide and loop diuretics did not result in a higher overall incidence of adverse events compared with dose-adjusted loop diuretics alone. Two cases of severe metabolic acidosis occurred in the acetazolamide group, highlighting a known safety concern, particularly in patients with impaired renal function. Given the small sample size and reporting of adverse events as categorical variables, these findings should be interpreted descriptively, and no definitive conclusions regarding comparative safety can be drawn. Short-term worsening of renal function occurred in approximately 25% of both groups, consistent with findings from previous studies^8,9,16. Patients who achieved euvolemia by 2 weeks had their diuretics withdrawn, after which their renal function returned to baseline levels, indicating transient kidney injury or pseudo-worsening renal function—a term frequently mentioned in heart failure settings to describe insignificant rises in creatinine without long-term renal consequences^17,18. In terms of electrolyte abnormalities, both groups exhibited similar trends except for a significant difference in serum bicarbonate change, which was expected due to greater chloride loss from loop diuretics¹⁹. Metabolic alkalosis induced by loop diuretics is one mechanism contributing to diuretic resistance, which may explain why acetazolamide improves diuretic efficacy²⁰. Combination therapy could be beneficial in CKD patients with loop diuretics and subclinical volume overload, especially in high-risk situations such as metabolic alkalosis.

There were several limitations in our study. First, the sample size was relatively small, limiting the power to detect differences in clinical outcomes, particularly in body composition parameters. Second, the short follow-up duration precludes conclusions regarding sustained decongestion and long-term renal outcomes. Third, as the study was conducted before the widespread use of sodium–glucose cotransporter 2 inhibitors (SGLT2i), with only a small proportion of patients receiving these agents, generalizability to current practice may be limited^21,22. Fourth, the use of clinical examination in combination with BCM for inclusion has inherent limitations. Although the > 1 L overhydration threshold was applied to standardize baseline volume status, it should be considered a supportive rather than definitive criterion. Misclassification remains possible, and some normovolemic patients may have been included, potentially leading to inappropriate diuretic exposure and confounding of treatment effects. In addition, BCM may be less sensitive to small, short-term changes in fluid status, particularly in elderly CKD patients with altered body composition, while body weight may reflect both fluid and non-fluid components. Notably, BCM was used primarily for baseline standardization, whereas clinical assessment guided volume evaluation. Moreover, the relatively advanced age of our cohort may influence both efficacy and safety due to age-related physiological changes, limiting applicability to younger populations. Although randomization balanced baseline diuretic doses, the pragmatic dose-doubling strategy may still introduce variability in treatment effect size across individuals. Finally, our original protocol’s composite primary endpoint was modified post-hoc to a single continuous outcome (mean body weight change at 2 weeks) for greater objectivity in our small cohort (n = 52). The study was powered only for this revised primary endpoint (n = 21/group, 90% power, α = 0.05 per Imiela et al.), not multiple endpoints. Secondary/exploratory outcomes thus represent hypothesis-generating findings requiring cautious interpretation due to multiplicity and limited power.

Furthermore, our population consisted of CKD patients receiving chronic outpatient loop diuretic therapy; therefore, the findings may not be generalizable to diuretic-naïve patients. Cardiac function was not systematically assessed and may have influenced decongestion outcomes, although this reflects the pragmatic outpatient design. The observed decrease in serum bicarbonate in both groups may relate to the relatively mild degree of congestion and limited efficacy of loop diuretic dose escalation. Finally, the open-label design may introduce bias; however, most outcomes were objectively measured (e.g., body weight, body composition, and laboratory parameters), and data collection was performed by personnel not involved in treatment allocation.

Conclusion

Our study suggests that adding acetazolamide to standardized loop-diuretic therapy in CKD patients with volume overload improves body weight reduction and decongestion without significant adverse effects. However, as our cohort was predominantly elderly, these findings are most applicable to older CKD populations, and caution is warranted when extrapolating to younger or less advanced CKD patients. Further studies are needed to confirm the effectiveness and safety of this strategy across broader and more diverse patient population.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Author contributions

J.S. and B.S. wrote the main manuscript text. O.S. and A.C. provided statistical analysis. All authors reviewed the manuscript.

Data availability

Data supporting this study is available upon request.

Declarations

Competing interests

The authors declare no competing interests.

Date of first registration

29/3/2024.

Submission ID

466e6e75-277b-4a98-a711-9fafd97af6fd.

Ethics approval

The study was approved by the Ethics Committee of the Institute Review Board at the Royal Thai Army Medical Department and was conducted according to the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all participants.