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

59 Hypertens Res Vol.31 (2008) No.1 p.57-65 Original Article 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 Yoshiyuki FURUMATSU1),2), Yasuyuki NAGASAWA2), Kodo TOMIDA1),2), Satoshi MIKAMI1),2), Tetsuya KANEKO1), Noriyuki OKADA1), Yoshiharu TSUBAKIHARA1), Enyu IMAI2), and Tatsuya SHOJI1) 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 wellestablished 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. (Hypertens Res 2008; 31: 59–67) Key Words: spironolactone, aldosterone, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, proteinuria From the 1)Department of Kidney Disease and Hypertension, Osaka General Medical Center, Osaka, Japan; 2)Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan. Address for Reprints: Enyu Imai, M.D., Department of Nephrology, Osaka University Graduate School of Medicine, 2–2 Yamadaoka (A8), Suita 565– 0871, Japan. E-mail: ; Tatsuya Shoji, M.D., Department of Kidney Disease and Hypertension, Osaka General Medical Center, 3–1–56 Bandai-Higashi, Sumiyoshi, Osaka 558–8558, Japan. E-mail: Received February 14, 2007; Accepted in revised form August 3, 2007. 60 Hypertens Res Vol. 31, No. 1 (2008) Run-in Period Introduction The renin-angiotensin-aldosterone system (RAAS), and particularly angiotensin II (AII), is recognized to be a major contributor to the progression of kidney disease. Solid evidence has established the effectiveness of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II receptor blockers (ARBs) in lessening the contribution of the AII and thereby ameliorating kidney disease. Furthermore, dual blockade with an ACE-I and ARB has been reported to be superior to single blockade both in reducing proteinuria and in slowing the progression of renal disease (1–3). However, some patients do not respond adequately to the conventional renin-angiotensin system (RAS) blockade, raising a clinical problem that remains to be solved. This therapeutic inadequacy might be attributable to such putative mechanisms as non-RAAS stimulators (4, 5), aldosterone breakthrough (6– 9), or a vicious cycle within the RAAS in which aldosterone perpetuates both the expression of ACE and that of AII type 1 receptor (10–12). Recently, not only AII but also aldosterone has been recognized as playing a key role in the RAAS (5, 13). In fact, several clinical studies have demonstrated that monotherapy with an aldosterone blocker (14–16) or combination therapy with an aldosterone blocker plus an ACE-I or ARB reduced proteinuria in patients with chronic kidney disease (CKD) (17– 21). However, Chrysostomou, who first reported the antiproteinuric effect of spironolactone (17), could not prove the efficacy of triple blockade with spironolactone plus an ACE-I and ARB in a later report (22). To date, therefore, the efficacy of aldosterone blockade, especially in conjunction with an ACE-I and ARB, has not been confirmed in patients with CKD. We hypothesized that triple blockade of the RAAS with an aldosterone blocker plus an ACE-I and ARB might be more effective than the dual blockade both in reducing proteinuria and in slowing the progression of renal disease, especially in patients whose proteinuria did not respond sufficiently to the dual blockade. Accordingly, we conducted a 1-year randomized study to assess the efficacy of an aldosterone blocker; spironolactone, administered in conjunction with an ACE-I and ARB on proteinuria and renal function in comparison with the additive use of thiazide or loop diuretics along with an ACE-I and ARB. Methods Patients A randomized, open-label, multicenter, prospective, controlled study was conducted at the Osaka General Medical Center and Osaka University Hospital from 2002 to 2004. Japanese patients who had been treated with the combination of an ACE-I and ARB were screened according to the inclu- 0W -12 W 52 W Triple Blockade group Dual Blockade Enalapril 5 mg + Losartan 50 mg +Spironolactone 25 mg Control group Cr<1.8 : +Trichlormethiazide 1 mg Cr 1.8 : +Furosemide 10 mg Fig. 1. Study protocol. W, weeks. sion and exclusion criteria defined below. Inclusion criteria were an age of 20–70 years; controlled blood pressure (BP) below 130/80 mmHg; chronic nephropathy, as defined by serum creatinine concentration below 3.0 mg/dL or calculated creatinine clearance of more than 30 mL/ min/1.73 m2; daily treatment with 5 mg enalapril and 50 mg losartan for 12 weeks or longer; and persistent proteinuria, defined as urinary protein excretion exceeding 0.5 g/day. Exclusion criteria were diabetes mellitus (HbA1c 5.8% or more); urinary-tract infection; severe renal failure, defined as a serum creatinine concentration more than 3.0 mg/dL; uncontrolled hyperkalemia, defined as a serum potassium concentration more than 5.0 mEq/L; treatment-resistant edema; requirement of treatment with corticosteroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive drugs; prote (...truncated)