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. (Hypertens Res 2008; 31: 59−67)
Similar content being viewed by others
Article PDF
References
Russo D, Pisani A, Balletta MM, et al : Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 1999; 33: 851–856.
Russo D, Minutolo R, Pisani A, et al : Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis 2001; 38: 18–25.
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T : Combination treatment of angiotensin-II receptor blocker and angiotensin-converting−enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–124.
Okubo S, Niimura F, Nishimura H, et al : Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest 1997; 99: 855–860.
Epstein M : Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am J Kidney Dis 2001; 37: 677–688.
Borghi C, Boschi S, Ambrosioni E, Melandri G, Branzi A, Magnani B : Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors. J Clin Pharmacol 1993; 33: 40–45.
Pitt B : “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995; 9: 145–149.
Sato A, Saruta T : Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 2001; 29: 13–21.
Naruse M, Tanabe A, Sato A, et al : Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension 2002; 40: 28–33.
Robert V, Heymes C, Silvestre JS, Sabri A, Swynghedauw B, Delcayre C : Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt−induced fibrosis. Hypertension 1999; 33: 981–986.
Harada E, Yoshimura M, Yasue H, et al : Aldosterone induces angiotensin-converting−enzyme gene expression in cultured neonatal rat cardiocytes. Circulation 2001; 104: 137–139.
Sugiyama T, Yoshimoto T, Tsuchiya K, et al : Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. Endocrinology 2005; 146: 3900–3906.
Epstein M : Aldosterone as a mediator of progressive renal dysfunction: evolving perspectives. Intern Med 2001; 40: 573–583.
Pitt B, Reichek N, Willenbrock R, et al : Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 2003; 108: 1831–1838.
White WB, Duprez D, St Hillaire R, et al : Effects of the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic hypertension. Hypertension 2003; 41: 1021–1026.
Takeda Y : Pleiotropic actions of aldosterone and the effects of eplerenone, a selective mineralocorticoid receptor antagonist. Hypertens Res 2004; 27: 781–789.
Chrysostomou A, Becker G : Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med 2001; 345: 925–926.
Bianchi S, Bigazzi R, Campese VM : Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study. Am J Kidney Dis 2005; 46: 45–51.
Schjoedt KJ, Rossing K, Juhl TR, et al : Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 2005; 68: 2829–2836.
Bianchi S, Bigazzi R, Campese VM : Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 2006; 70: 2116–2123.
Schjoedt KJ, Rossing K, Juhl TR, et al : Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 2006; 70: 536–542.
Chrysostomou A, Pedagogos E, MacGregor L, Becker G : Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or wihtout an angiotensin II receptor blocker. Clin J Am Soc Nephrol 2006; 1: 256–262.
Pitt B, Zannad F, Remme WJ, et al, Randomized Aldactone Evaluation Study Investigators : The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–717.
Sato A, Hayashi K, Naruse M, Saruta T : Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003; 41: 64–68.
Bakris GL, Williams M, Dworkin L, et al : Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000; 36: 646–661.
Buter H, Hemmelder MH, Navis G, de Jong PE, de Zeeuw D : The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 1998; 13: 1682–1685.
Shimizu N, Miyashita H, Koide K, Yoshikawa J : Antipressor effect of spironolactone or thyazide diuretics for essential hypertension: double blind comparative study. Horumon To Rinsho 1977; 25: 167–174 ( in Japanese).
Ginsberg JM, Chang BS, Matarese RA, Garella S : Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983; 309: 1543–1546.
Schwab SJ, Christensen RL, Dougherty K, Klahr S : Quantitation of proteinuria by the use of protein-to-creatinine ratios in single urine samples. Arch Intern Med 1987; 147: 943–944.
Kawasaki T, Ueno M, Uezono K, et al : Average urinary excretion of sodium in 24 hours can be estimated from a spot-urine specimen. Jpn Circ J 1982; 46: 948–953.
Kawamura M, Kusano Y, Takahashi T, Owada M, Sugawara T : Effectiveness of a spot urine method in evaluating daily salt intake in hypertensive patients taking oral antihypertensive drugs. Hypertens Res 2006; 29: 397–402.
Obata K, Iwata K, Ichida T, et al : One step sandwich enzyme immunoassay for human type IV collagen using monoclonal antibodies. Clin Chim Acta 1989; 181: 293–303.
Donovan KL, Coles GA, Williams JD : An ELISA for the detection of type IV collagen in human urine—application to patients with glomerulonephritis. Kidney Int 1994; 46: 1431–1437.
Cameron JS, Blandford G : The simple assessment of selectivity in heavy proteinuria. Lancet 1966; 2: 242–247.
Sato A, Hayashi K, Saruta T : Antiproteinuric effects of mineralocorticoid receptor blockade in patients with chronic renal disease. Am J Hypertens 2005; 18: 44–49.
Han KH, Kang YS, Han SY, et al : Spironolactone ameliorates renal injury and connective tissue growth factor expression in type II diabetic rats. Kidney Int 2006; 70: 111–120.
Sawathiparnich P, Kumar S, Vaughan DE, Brown NJ : Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab 2002; 87: 448–452.
Brown NJ, Vaughan DE, Fogo AB : The renin-angiotensin-aldosterone system and fibrinolysis in progressive renal disease. Semin Nephrol 2002; 22: 399–406.
Goumenos DS, Tsakas S, El Nahas AM, et al : Transforming growth factor-beta(1) in the kidney and urine of patients with glomerular disease and proteinuria. Nephrol Dial Transplant 2002; 17: 2145–2152.
Agarwal R, Siva S, Dunn SR, Sharma K : Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-beta levels. Am J Kidney Dis 2002; 39: 486–492.
Sato A, Suzuki Y, Saruta T : Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension. Hypertens Res 1999; 22: 17–22.
Asai M, Monkawa T, Marumo T, et al : Spironolactone in combination with cilazapril ameliorates proteinuria and renal interstitial fibrosis in rats with anti-Thy-1 irreversible nephritis. Hypertens Res 2004; 27: 971–978.
Sato A, Saruta T, Funder JW : Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection. Hypertens Res 2006; 29: 211–216.
McKelvie RS, Yusuf S, Pericak D, et al : Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999; 100: 1056–1064.
Tang WH, Vagelos RH, Yee YG, et al : Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure. J Am Coll Cardiol 2002; 39: 70–78.
Price DA, Porter LE, Gordon M, et al : The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol 1999; 10: 2382–2391.
Hollenberg NK, Price DA, Fisher ND, et al : Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus. Kidney Int 2003; 63: 172–178.
Watanabe H, Sanada H, Shigetomi S, Katoh T, Watanabe T : Urinary excretion of type IV collagen as a specific indicator of the progression of diabetic nephropathy. Nephron 2000; 86: 27–35.
Okonogi H, Nishimura M, Utsunomiya Y, et al : Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus. Clin Nephrol 2001; 55: 357–364.
Tomino Y, Suzuki S, Azushima C, et al : Asian multicenter trials on urinary type IV collagen in patients with diabetic nephropathy. J Clin Lab Anal 2001; 15: 188–192.
Nishimura M, Sasaki T, Ohishi A, et al : Angiotensin-converting enzyme inhibitors and probucol suppress the time-dependent increase in urinary Type IV collagen excretion of Type II diabetes mellitus patients with early diabetic nephropathy. Clin Nephrol 2001; 56: 96–103.
Goodfield NE, Newby DE, Ludlam CA, Flapan AD : Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999; 99: 2983–2985.
Fogari R, Zoppi A, Preti P, Fogari E, Malamani G, Mugellini A : Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive postmenopausal women. Am J Hypertens 2001; 14: 921–926.
Uzu T, Harada T, Namba T, et al : Thiazide diuretics enhance nocturnal blood pressure fall and reduce proteinuria in immunoglobulin A nephropathy treated with angiotensin II modulators. J Hypertens 2005; 23: 861–865.
Sato A, Saruta T : Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res 2004; 27: 303–310.
Pitt B, Williams G, Remme W, et al : The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 2001; 15: 79–87.
Juurlink DN, Mamdani MM, Lee DS, et al : Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351: 543–551.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Furumatsu, Y., Nagasawa, Y., Tomida, K. et al. 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. Hypertens Res 31, 59–67 (2008). https://doi.org/10.1291/hypres.31.59
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.31.59
Keywords
This article is cited by
-
Efficacy and safety of a low-sodium diet and spironolactone in patients with stage 1-3a chronic kidney disease: a pilot study
BMC Nephrology (2022)
-
Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone
Hypertension Research (2021)
-
Mineralocorticoid Antagonism and Diabetic Kidney Disease
Current Diabetes Reports (2019)
-
Combination antihypertensive therapy in clinical practice. The analysis of 1254 consecutive patients with uncontrolled hypertension
Journal of Human Hypertension (2016)
-
Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial
Clinical and Experimental Nephrology (2015)