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 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 losar- tan) 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 treat- ment, 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 treat- ment, 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 Univer- sity 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: [email protected]; 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: [email protected] Received February 14, 2007; Accepted in revised form August 3, 2007. 60 Hypertens Res Vol. 31, No. 1 (2008) Run-in Period Introduction -12 W 0 W 52 W The renin-angiotensin-aldosterone system (RAAS), and par- Triple Blockade group Dual Blockade ticularly angiotensin II (AII), is recognized to be a major con- +Spironolactone 25 mg tributor to the progression of kidney disease. Solid evidence Enalapril 5 mg + has established the effectiveness of angiotensin-converting Losartan 50 mg Control group enzyme inhibitors (ACE-Is) or angiotensin II receptor block- Cr<1.8 : +Trichlormethiazide 1 mg ers (ARBs) in lessening the contribution of the AII and Cr 1.8 : +Furosemide 10 mg thereby ameliorating kidney disease. Furthermore, dual blockade with an ACE-I and ARB has been reported to be Fig. 1. Study protocol. W, weeks. 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 sion and exclusion criteria defined below. renin-angiotensin system (RAS) blockade, raising a clinical Inclusion criteria were an age of 20–70 years; controlled problem that remains to be solved. This therapeutic inade- blood pressure (BP) below 130/80 mmHg; chronic nephropa- quacy might be attributable to such putative mechanisms as thy, as defined by serum creatinine concentration below 3.0 non-RAAS stimulators (4, 5), aldosterone breakthrough (6– mg/dL or calculated creatinine clearance of more than 30 mL/ 9), or a vicious cycle within the RAAS in which aldosterone min/1.73 m2; daily treatment with 5 mg enalapril and 50 mg perpetuates both the expression of ACE and that of AII type 1 losartan for 12 weeks or longer; and persistent proteinuria, receptor (10–12). defined as urinary protein excretion exceeding 0.5 g/day. Recently, not only AII but also aldosterone has been recog- Exclusion criteria were diabetes mellitus (HbA1c 5.8% or nized as playing a key role in the RAAS (5, 13). In fact, sev- more); urinary-tract infection; severe renal failure, defined as eral clinical studies have demonstrated that monotherapy with a serum creatinine concentration more than 3.0 mg/dL; an aldosterone blocker (14–16) or combination therapy with uncontrolled hyperkalemia, defined as a serum potassium an aldosterone blocker plus an ACE-I or ARB reduced pro- concentration more than 5.0 mEq/L; treatment-resistant teinuria in patients with chronic kidney disease (CKD) (17– edema; requirement of treatment with corticosteroids, non- 21). However, Chrysostomou, who first reported the antipro- steroidal anti-inflammatory drugs, or immunosuppressive teinuric effect of spironolactone (17), could not prove the effi- drugs; proteinuria greater than 5.0 g/g·Cr; hypoalbuminemia cacy of triple blockade with spironolactone plus an ACE-I less than 2.8 g/dL; renovascular hypertension; malignant and ARB in a later report (22). To date, therefore, the efficacy hypertension; myocardial infarction; cerebrovascular acci- of aldosterone blockade, especially in conjunction with an dent; peripheral vascular disease; heart failure; chronic ACE-I and ARB, has not been confirmed in patients with hepatic disease (rise of serum aminotransferase concentra- CKD. tion); connective-tissue disease; obstructive uropathy; cancer; We hypothesized that triple blockade of the RAAS with an chronic pulmonary disease; drug or alcohol misuse; preg- aldosterone blocker plus an ACE-I and ARB might be more nancy; breast-feeding; and history of allergic reaction to effective than the dual blockade both in reducing proteinuria drugs, especially ACE-Is or ARBs. and in slowing the progression of renal disease, especially in patients whose proteinuria did not respond sufficiently to the Protocol dual blockade. Accordingly, we conducted a 1-year random- ized study to assess the efficacy of an aldosterone blocker; Among the 38 eligible patients, 6 were excluded because they spironolactone, administered in conjunction with an ACE-I did not excrete urinary protein of more than 0.5 g/day after and ARB on proteinuria and renal function in comparison the dual blockade with an ACE-I and ARB. The remaining 32 with the additive use of thiazide or loop diuretics along with subjects were randomly divided into two groups: a triple an ACE-I and ARB. blockade group (n=16) and a control group (n=16). In the triple blockade group, we added 25 mg spironolactone to the Methods ongoing treatment with the ACE-I (5 mg enalapril) and ARB (50 mg losartan). Though it has not been clarified whether 25 mg of spironolactone is sufficient for reducing proteinuria, 25 Patients mg was effective in former trials (17, 20, 21, 23, 24). Thus, in A randomized, open-label, multicenter, prospective, con- this study, we set the dosage of spironolactone to 25 mg. In trolled study was conducted at the Osaka General Medical the control group, we added 1 mg trichlormethiazide or 10 mg Center and Osaka University Hospital from 2002 to 2004. furosemide according to the patient’s serum creatinine level Japanese patients who had been treated with the combination (trichlormethiazide for subjects whose creatinine was less of an ACE-I and ARB were screened according to the inclu- than 1.8 mg/dL or furosemide for those whose creatinine level Furumatsu et al: Triple Blockade with ACE-I, ARB and Spironolactone 61 Table 1. Baseline Characteristics of 30 Patients U-Prot/g Cr (g/g Cr) Triple Control 0.6 blockade p (n=15) (n=15) 0.4 ± ± Age (years) 49.8 2.7 53.9 2.7 0.29 0.2 Gender (male/female) 10/5 9/6 0.70 0 4 8 12 week 1 year Height (cm) 166.1±2.1 162.6±1.8 0.22 0 Body weight (kg) 70.2±2.8 64.9±2.4 0.16 BMI (kg/m2) 26.3±1.4 24.4±0.7 0.25 -0.2 Systolic BP (mmHg) 126.4±2.8 129.6±2.5 0.40 -0.4 *p <0.05 Diastolic BP (mmHg) 79.1±2.2 79.4±2.2 0.92 vs. Control Mean BP (mmHg) 94.9±2.2 96.1±2.1 0.69 -0.6 # Cr (mg/dL) 1.07±0.11 1.22±0.10 0.33 Ccr (mL/min/1.73 m2) 91.8±11.8 68.9±7.8 0.12 -0.8 # K (mEq/L) 4.28±0.12 4.28±0.08 0.97 -1.0 ± ± # Albumin (mg/dL) 3.73 0.08 3.64 0.09 0.48 p<0.05 vs. 0 week (Dunnett) T-Cho (mg/dL) 197.0±16.3 172.7±14.7 0.28 -1.2 Ht (%) 40.3±1.2 39.1±1.3 0.48 Fig. 2. Changes in proteinuria.