American Journal of Kidney Diseases

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

Published:December 31, 2016DOI:


      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.


      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.


      The primary outcome was absolute change in weight before and at the end of each phase.


      Weight and 24-hour urine volume at baseline and the end of each phase.


      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.


      Small sample size, short follow-up duration, and lack of serum bicarbonate and chloride measurement.


      Acetazolamide and hydrochlorothiazide followed by furosemide is more effective than furosemide and hydrochlorothiazide followed by furosemide for the treatment of refractory nephrotic edema.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Deschenes G.
        • Feraille E.
        • Doucet A.
        Mechanisms of oedema in nephrotic syndrome: old theories and new ideas.
        Nephrol Dial Transplant. 2003; 18: 454-456
        • Doucet A.
        • Favre G.
        • Deschênes G.
        Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications.
        Pediatr Nephrol. 2007; 22: 1983-1990
        • Bockenhauer D.
        Over- or underfill: not all nephrotic states are created equal.
        Pediatr Nephrol. 2013; 28: 1153-1156
        • Hamm L.L.
        • Batuman V.
        Edema in the nephrotic syndrome: new aspect of an old enigma.
        J Am Soc Nephrol. 2003; 14: 3288-3289
        • Duffy M.
        • Jain S.
        • Harrell N.
        • Kothari N.
        • Reddi A.S.
        Albumin and furosemide combination for management of edema in nephrotic syndrome: a review of clinical studies.
        Cells. 2015; 4: 622-630
        • Qavi A.H.
        • Kamal R.
        • Schrier R.W.
        Clinical use of diuretics in heart failure, cirrhosis, and nephrotic syndrome.
        Int J Nephrol. 2015; 2015: 975934
        • Vasudevan A.
        • Mantan M.
        • Bagga A.
        Management of edema in nephrotic syndrome.
        Indian Pediatr. 2004; 41: 787-795
        • De Bruyne L.K.M.
        Mechanisms and management of diuretic resistance in congestive heart failure.
        Postgrad Med J. 2003; 79: 268-271
        • Wilcox C.S.
        New insights into diuretic use in patients with chronic renal disease.
        J Am Soc Nephrol. 2002; 13: 798-805
        • Soleimani M.
        A novel target for diuretic therapy.
        Iran J Kidney Dis. 2012; 6: 419-425
        • Sinning A.
        • Radionov N.
        • Trepiccione F.
        • et al.
        Double knockout of the Na+-driven Cl-/HCO3- exchanger and Na+/Cl- cotransporter induces hypokalemia and volume depletion.
        J Am Soc Nephrol. 2017; 28: 130-139
        • Wall S.M.
        • Lazo-Fernandez Y.
        The role of pendrin in renal physiology.
        Annu Rev Physiol. 2015; 77: 363-378
        • Patel-Chamberlin M.
        • Varasteh Kia M.
        • Xu J.
        • Barone S.
        • Zahedi K.
        • Soleimani M.
        The role of epithelial sodium channel ENaC and the apical Cl(-)/HCO(3)(-) exchanger pendrin in compensatory salt reabsorption in the setting of Na-Cl cotransporter (NCC) inactivation.
        PLoS One. 2016; 11: e0150918
        • Zahedi K.
        • Barone S.
        • Xu J.
        • Soleimani M.
        Potentiation of the effect of thiazide derivatives by carbonic anhydrase inhibitors: molecular mechanisms and potential clinical implications.
        PLoS One. 2013; 8: e79327
        • Cil O.
        • Haggie P.M.
        • Phuan P.W.
        • Tan J.A.
        • Verkman A.S.
        Small-molecule inhibitors of pendrin potentiate the diuretic action of furosemide.
        J Am Soc Nephrol. 2016; 27: 3706-3714
        • Knauf H.
        • Mutschler E.
        Functional state of the nephron and diuretic dose-response–rationale for low-dose combination therapy.
        Cardiology. 1994; 84: 18-26
        • Saghaei M.
        Random allocation software for parallel group randomized trials.
        BMC Med Res Methodol. 2004; 4: 26
        • Jones G.R.D.
        • Lim E.-M.
        The National Kidney Foundation guideline on estimation of the glomerular filtration rate.
        Clin Biochem Rev. 2003; 24: 95-98
        • Soleimani M.
        • Barone S.
        • Xu J.
        • et al.
        Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure.
        Proc Natl Acad Sci U S A. 2012; 109: 13368-13373
        • Soleimani M.
        The multiple roles of pendrin in the kidney.
        Nephrol Dial Transplant. 2015; 30: 1257-1266
        • Jentzer J.C.
        • DeWald T.A.
        • Hernandez A.F.
        Combination of loop diuretics with thiazide-type diuretics in heart failure.
        J Am Coll Cardiol. 2010; 56: 1527-1534
        • Wall S.M.
        • Kim Y.H.
        • Stanley L.
        • et al.
        NaCl restriction upregulates renal Slc26a4 through subcellular redistribution: role in Cl- conservation.
        Hypertension. 2004; 44: 982-987
        • Bagnis C.
        • Marshansky V.
        • Breton S.
        • Brown D.
        Remodeling the cellular profile of collecting ducts by chronic carbonic anhydrase inhibition.
        Am J Physiol Renal Physiol. 2001; 280: F437-F448
        • Galla J.H.
        Metabolic alkalosis.
        J Am Soc Nephrol. 2000; 11: 369-375
        • Haque S.K.
        • Ariceta G.
        • Batlle D.
        Proximal renal tubular acidosis: a not so rare disorder of multiple etiologies.
        Nephrol Dial Transplant. 2012; 27: 4273-4287
        • Ellison D.H.
        • Loffing J.
        Thiazide effects and side effects: insights from molecular genetics.
        Hypertension. 2009; 54: 196-202
        • Mount D.B.
        Causes of hypokalemia in adults.
        in: Post T.W. UpToDate. UpToDate, Waltham, MAJune 4, 2016
        • Papademetriou V.
        Diuretics, hypokalemia, and cardiac arrhythmia: a 20-year controversy.
        J Clin Hypertens (Greenwich). 2006; 8: 86-92
        • Wilson T.W.
        • Falk K.J.
        • Labelle J.L.
        • Nguyen K.B.
        Effect of dosage regimen on natriuretic response to furosemide.
        Clin Pharmacol Ther. 1975; 18: 165-169

      Linked Article