What is the clinical evidence from this study?

Study design: RCT. Population: Non-diabetic nephropathy (n=32). Intervention: Spironolactone (triple blockade) vs. Trichlormethiazide (1 mg) or furosemide (20 mg). Primary outcome: Change in urinary protein level (p=<0.05).

January 1, 2008Open Access

Effect of Renin-Angiotensin-Aldosterone System Triple Blockade on Non-Diabetic Renal Disease: Addition of an Aldosterone Blocker, Spironolactone, to Combination Treatment with an Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker

Q: What are the key findings of this study?

Adding spironolactone to ACE-I and ARB therapy decreased urinary protein levels by 58% (p<0.05) in patients with non-diabetic nephropathy, compared to no change in the control group.

YFYoshiyuki FurumatsuMiyoshi Kasei (Japan)YNYasuyuki NagasawaHyogo Medical University KTKodo TomidaYodogawa Christian Hospital

Key Result

Adding spironolactone to ACE-I and ARB therapy decreased urinary protein levels by 58% (p<0.05) in patients with non-diabetic nephropathy, compared to no change in the control group.

Study Design

Type

RCT (n=32)

Blinding

Open-label

Randomization

randomized

Multicenter

Yes

Structured PICO

Does the addition of spironolactone to ACE-I and ARB therapy reduce proteinuria in patients with non-diabetic nephropathy?

Population

32 Japanese adults (age 20-70 years) with non-diabetic chronic nephropathy and persistent proteinuria (>0.5 g/day) despite >12 weeks of dual RAAS blockade (enalapril 5 mg and losartan 50 mg). Key exclusions: diabetes mellitus (HbA1c ≥5.8%), severe renal failure (serum creatinine >3.0 mg/dL), and uncontrolled hyperkalemia (serum potassium >5.0 mEq/L).

Intervention

Spironolactone 25 mg oral once daily added to ongoing ACE-I (enalapril 5 mg) and ARB (losartan 50 mg) combination treatment for 1 year.

Comparator

Trichlormethiazide 1 mg or furosemide 10 mg (depending on serum creatinine level) added to ongoing ACE-I (enalapril 5 mg) and ARB (losartan 50 mg) combination treatment for 1 year.

Outcome

Reduction in proteinuria (urinary protein excretion) at 1 year.surrogate

Adding spironolactone to dual RAAS blockade significantly reduces proteinuria in non-diabetic nephropathy patients who do not respond adequately to ACE-I and ARB therapy alone.

Main Result

Absolute Event Rate: -58% vs 0%

p-value: p=<0.05

Abstract

Although dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) is generally well-established as a treatment for nephropathy, this treatment is not fully effective in some patients. Based on the recent evidence implicating aldosterone in renal disease progression, this study was conducted to examine the efficacy of blockade with three different mechanisms by adding an aldosterone blocker in patients who do not respond adequately to the dual blockade. A 1-year randomized, open-label, multicenter, prospective controlled study was conducted, in which 32 non-diabetic nephropathy patients with proteinuria exceeding 0.5 g/day were enrolled after more than 12 weeks of ACE-I (5 mg enalapril) and ARB (50 mg losartan) combination treatment. These patients were allocated into two groups of 16 patients each: a triple blockade group in which 25 mg of spironolactone daily was added to the ACE-I and ARB combination treatment, and a control group in which 1 mg of trichlormethiazide or 20 mg of furosemide was added to the combination treatment instead of spironolactone depending upon the creatinine level. After 1 year of treatment, the urinary protein level decreased by 58% (p<0.05) with the triple blockade but was unchanged in the controls. Furthermore, urinary type IV collagen level decreased by 40% (p<0.05) with the triple blockade but was unchanged in the controls. The decreases in urinary protein and urinary type IV collagen were not accompanied by a decrease in blood pressure. Mean serum creatinine, potassium and blood pressure did not change significantly by either treatment. In conclusion, triple blockade of the RAAS was effective for the treatment of proteinuria in patients with non-diabetic nephropathy whose increased urinary protein had not responded sufficiently to a dual blockade.

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