Acetazolamide and Hydrochlorothiazide Followed by Furosemide Versus Furosemide and Hydrochlorothiazide Followed by Furosemide for the Treatment of Adults With Nephrotic Edema: A Randomized Trial

Background: Nephrotic edema is considered refractory if it does not respond to maximum or near maximum doses of loop diuretics. This condition can be treated with loop diuretics and thiazides. However, animal studies show that the simultaneous downregulation of pendrin with acetazolamide and inhibition of the sodium-chloride cotransporter with hydrochlorothiazide generates significant diuresis, and furosemide administration following a pendrin inhibitor potentiates furosemide's diuretic effect. Therefore, we performed this study to compare the efficacy of acetazolamide and hydrochlorothiazide followed by furosemide versus furosemide and hydrochlorothiazide followed by furosemide for treatment of refractory nephrotic edema. Study Design: Randomized, double-blind, 2-arm, parallel trial. Setting & Participants: 20 patients with refractory nephrotic edema despite treatment with 80 mg of furosemide daily and creatinine clearance > 60 mL/min. Intervention: Patients were randomly assigned to 2 groups: group 1 (n = 10) received 250 mg of acetazolamide and 50 mg of hydrochlorothiazide daily and group 2 (n = 10) received 40 mg of furosemide and 50 mg of hydrochlorothiazide daily for 1 week in phase 1. In phase 2, both groups received 40 mg of furosemide daily for 2 weeks. Outcomes: The primary outcome was absolute change in weight before and at the end of each phase. Measurements: Weight and 24-hour urine volume at baseline and the end of each phase. Results: The mean weight decrease was of significantly larger magnitude in group 1 compared with group 2 at the end of phase 1 (-1.4 +/- 0.52 [SD] vs 0.65 +/- 0.41 kg; P = 0.001) and phase 2 (-1.6 +/- 0.84 vs 0.5 +/- 0.47 kg; P = 0.005). The increase in 24-hour urine volume was also significantly higher in group 1 at the end of phase 2. Limitations: Small sample size, short follow-up duration, and lack of serum bicarbonate and chloride measurement. Conclusions: Acetazolamide and hydrochlorothiazide followed by furosemide is more effective than furosemide and hydrochlorothiazide followed by furosemide for the treatment of refractory nephrotic edema. (C) 2016 by the National Kidney Foundation, Inc.