Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4-5 KDIGO without renal replacement therapy: a double-blind randomized HEBE-CKD trial

Abstract

Background: The co-administration of loop diuretics with thiazide diuretics is a therapeutic strategy in patients with hypertension and volume overload. The aim of this study was to assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4-5 KDIGO.

Methods: A double-blind randomized study was conducted. Patients were randomized into two groups: bumetanide plus chlorthalidone group (intervention) and the bumetanide plus placebo group (control) to evaluate differences in TBW, ECW and ECW/TBW between baseline and 30 Days of follow-up. Volume overload was defined as 'bioelectrical impedance analysis as fluid volume above the 90th percentile of a presumed healthy reference population. The study's registration number was NCT03923933.

Results: Thirty-two patients with a mean age of 57.2 ± 9.34 years and a median estimated glomerular filtration rate (eGFR) of 16.7 ml/min/1.73 m2 (2.2-29) were included. There was decreased volume overload in the liters of total body water (TBW) on Day 7 (intervention: -2.5 vs. control: -0.59, p = 0.003) and Day 30 (intervention: -5.3 vs. control: -0.07, p = 0.016); and in liters of extracellular water (ECW) on Day 7 (intervention: -1.58 vs. control: -0.43, p < 0.001) and Day 30 (intervention: -3.05 vs. control: -0.15, p < 0.000). There was also a decrease in systolic blood pressure on Day 7 (intervention: -18 vs. control: -7.5, p = 0.073) and Day 30 (intervention: -26.1 vs. control: -10, p = 0.028) and in diastolic blood pressure on Day 7 (intervention: -8.5 vs. control: -2.25, p = 0.059) and Day 30 (intervention: -13.5 vs. control: -3.4, p = 0.018).

Conclusion: In CKD stage 4-5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.

Keywords: Bumetanide; CKD stage 4–5 KDIGO; Chlorthalidone.

Conflict of interest statement

None of the authors have conflicts of interest to carry out this study.

© 2022. The Author(s).

Figures

Fig. 1

CONSORT 2010 flow diagram

Fig. 2

Total body water analysis by bioimpedance vectors. The bumetanide plus placebo group is shown in blue (control group), and the bumetanide plus chlorthalidone group is shown in red (intervention group). A There was decreased volume overload in liters of TBW on Day 7 [intervention: -2.5 (95% CI, -3.6 to -1.5) vs. control: -0.59 (95% CI, -1.8 to 0.67), p = 0.003] and Day 30 [intervention: -5.3 (95% CI, -8.6 to -1.95) vs. control: -0.07 (95% CI, -1.02 to 0.87) p = 0.016]. B There was a decrease in ECW on Day 7 [intervention: -1.58 (95% CI, -1.95 to -1.2) vs. control: -0.43 (95% CI, -1.2 to 0.31) p < 0.001] and Day 30 [intervention: -3.05 (95% CI, -4.47 to –1.62) vs. control: -0.15 (95% CI, -0.8 to -0.5), p < 0.000]. C There was a reduction in the ECW/TBW ratio on Day 7 [intervention: -1.29 (95% CI, -2.32 to -0.25) vs. control: -0.72 (95% CI, -1.64 to 0.20), p = 0.384] and Day 30 [intervention: -4.38 (95% CI, -7.8 to -0.92) vs. control: -0.24 (95% CI, -1 to 0.52), p = 0.018]

Fig. 3

Effects on blood pressure. The bumetanide plus placebo group is shown in blue (control group), and the bumetanide plus chlorthalidone group is shown in red (intervention group). A There was a decrease in SBP on Day 7 [intervention: -18 (95% CI, -25.2 to -10.5) vs. control: -7.5 (95% CI, -17 to 2), p = 0.073] and Day 30 [intervention: -26.1, 95% CI, -34.3 to -18.1, vs. control: -10 95% CI, -34.3 to -18.1; p = 0.028]. B There was a reduction in DBP on Day 7 (intervention: -8.5, 95% CI, -13.4 to -3.5, vs. control: -2.25, 95% CI, -6.8 to 2.3, p = 0.059) and Day 30 [intervention: -13.5 (95% CI, -19.2 to -7.7) vs. control: -3.4 (95% CI, -9.7 to -2.9), p = 0.018]. C There was a decrease in MAP on Day 7 (intervention: -11.7, 95% CI, -16.4 to -7.1, vs. control: -3.9, 95% CI, -9.4 to 1.5, p = 0.029) and Day 30 (intervention: -18.1, 95% CI, -22.8 to -13.4, vs. control: -5.4 95% CI, -13 to 2.2, p = 0.005)

Fig. 4

Effect on fractional sodium excretion (FENa) and brain natriuretic peptide (BNP). The bumetanide plus placebo group is shown in blue (control group), and the bumetanide plus chlorthalidone group is shown in red (intervention group). A Analysis of FENA revealed that during the first week after the intervention, the bumetanide plus chlorthalidone group showed a decrease in FENA from 0.78 (95% CI, 0.35 to 1.22) to 0.59 (95% CI, -0.62 to 1.81) without intragroup statistical significance (p = 0.104), while the bumetanide plus placebo group had a change from baseline to day 30 of -0.34 (95% CI, -2.2 to -1.51; p = 0.605). B At the start of follow-up, the bumetanide plus placebo group showed an increase in BNP on Day 7 of 33.6 (95% CI, -61.5 to 128.8 pg/dL) and on Day 30 of 213.5 (95% CI, -143.4 to -570.5 pg/dL) without statistical significance (p = 0.175). The intervention group showed a decrease on Day 7 of -39.3 (95% CI, 19.3 to -25 pg/dL) and on Day 30 of -0.64 (95% CI, -78.7 to 77.4 pg/dL) without a significant difference (p = 0.221). Similarly, intergroup analysis did not reveal any significant differences

Fig. 5

Effect of treatment on renal function. The bumetanide plus placebo group is shown in blue (control group), and the bumetanide plus chlorthalidone group is shown in red (intervention group). A Regarding serum creatinine, the intervention group showed a significant increase at Day 7 (p = 0.001) and Day 30 (p < 0.000). B Regarding GFR, a significant decrease in the intervention group was observed at Day 7 (p = 0.004) and Day 30 (p = 0.003). C Serum urea levels in both groups showed significant increases when comparing baseline versus Days 7 and 30 (control group, p = 0.02 and p < 0.000, respectively, and intervention group, p = 0.008 and p < 0.000, respectively)