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

Furumatsu, Yoshiyuki; Nagasawa, Yasuyuki; Tomida, Kodo; Mikami, Satoshi; Kaneko, Tetsuya; Okada, Noriyuki; Tsubakihara, Yoshiharu; Imai, Enyu; Tanaka, Shōji

doi:10.1291/hypres.31.59

Cited by 89 publications

(69 citation statements)

References 59 publications

(60 reference statements)

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“…Blockade of the MR has been demonstrated to have a general renoprotective effect in patients with diabetes mellitus (27,28,29,30) and with chronic kidney disease (31,32,33) as indicated by a reduction of proteinuria. Although aldosterone excess as in PA is known to cause additional deleterious effects on the kidney (34), there are only a few studies investigating effectiveness of PA therapy on renal function.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Fourkiotis

Vonend²,

Diederich³

et al. 2013

European Journal of Endocrinology

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Objective: Primary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce. Design and methods: This prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; nZ86); spironolactone (nZ65); and eplerenone (nZ18)). Results: GFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross-sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications. Conclusions: Renal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given.

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Section: Discussionmentioning

confidence: 99%

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Fourkiotis

Vonend²,

Diederich³

et al. 2013

European Journal of Endocrinology

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“…In an open-label, multicenter, prospective controlled study involving 32 patients with nondiabetic CKD and persistent proteinuria, Furumatsu et al 33 compared the treatment of SPL to trichlormethiazide or furosemide. After 1 year of treatment, proteinuria was reduced by 58% in the SPL group but did not change significantly in the control group.…”

Section: Nondiabetic Chronic Proteinuric Nephropathymentioning

confidence: 99%

Mineralocorticoid Receptor Antagonist for Renal Protection

King-Wing

Szeto

2012

Renal Failure

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The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular and renal diseases. In chronic kidney disease (CKD), blockade of RAS by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been shown to reduce proteinuria and retard the progression of renal function deterioration. However, aldosterone, another key hormone of the RAS, is not directly targeted by ACEI or ARB. Hyperaldosteronism, apart from promoting sodium and fluid retention, causes inflammation and fibrosis in the heart and kidney. Studies have shown that although plasma aldosterone level shows an initial decrease following ACEI or ARB treatment, it returns to pretreatment level or even increases paradoxically after prolonged treatment. This "aldosterone breakthrough" forms the basis of adding mineralocorticoid receptor (MR) antagonist on top of ACEI or ARB for renal protection. New insights into the pathophysiological role of aldosterone in CKD further expands its potential indications, and there was a growing body of evidence in the past 10 years, which showed a substantial antiproteinuric effect and possibly a considerable renoprotective effect of MR antagonist. Since aldosterone does not act on the efferent glomerular arteriole and has no effect on intraglomerular hemodynamics, the very fact that MR antagonist ameliorates proteinuria sheds light on the physiology of glomerular permeability barrier. This review summarizes the data regarding the theoretical benefit as well as clinical use of MR antagonist in renal diseases.

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“…Eight studies included diabetic patients; the large study of Bianchi et al included patients with various forms of glomerulonephritis (23); the remaining two studies included patients with nondiabetic renal disease encompassing IgA nephropathy, benign nephrosclerosis, and membranous nephropathy (35,36). All studies excluded patients with GFR Ͻ30 ml/mim/1.73m 2 .…”

Section: Trial Characteristicsmentioning

confidence: 99%

“…Bianchi et al reported that six out of 83 patients developed gynecomastia (only one patient warranting discontinuation of medication and five patients with mild gynecomastia) in the spirinolactone group but none (out of 82 patients) in the placebo arm (23). Furamatsu et al reported one of 15 patients who developed gynecomastia in the spironolactone group that did not require discontinuation of therapy (35).…”

Section: Gynecomastiamentioning

confidence: 99%

Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease

Navaneethan

Nigwekar

Sehgal³

et al. 2009

Clinical Journal of the American Society of Nephrology

229

133

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Background and objectives: Addition of aldosterone antagonists (AA) might provide renal benefits to proteinuric chronic kidney disease (CKD) patients over and above the inhibition of renin-angiotensin system blockers (RAS). We evaluated the benefits and harms of adding selective and nonselective AA in CKD patients already on RAS.Design, setting, participants, & measurements: MEDLINE, EMBASE, and Renal Health Library were searched for relevant randomized clinical trials in adult CKD patients. Results were summarized using the random-effects model.Results: Eleven trials (991 patients) were included. In comparison to angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB) plus placebo, nonselective AA along with ACEi and/or ARB significantly reduced 24 h proteinuria (seven trials, 372 patients, weighted mean difference [WMD] ؊0.80 g, 95% CI ؊1.27, ؊0.33) and BP. This did not translate into an improvement in GFR (WMD ؊0.70 ml/min/1.73m 2 , 95% CI ؊4.73, 3.34). There was a significant increase in the risk of hyperkalemia with the addition of nonselective AA to ACEi and/or ARB (relative risk 3.06, 95% CI 1.26, 7.41). In two trials, addition of selective AA to ACEi resulted in an additional reduction in 24 h proteinuria, without any impact on BP and renal function. Data on cardiovascular outcomes, long-term renal outcomes and mortality were not available in any of the trials.Conclusions: Aldosterone antagonists reduce proteinuria in CKD patients already on ACEis and ARBs but increase the risk of hyperkalemia. Long-term effects of these agents on renal outcomes, mortality, and safety need to be established. Clin J Am Soc Nephrol 4: 542-551, 2009. doi: 10.2215 C hronic kidney disease (CKD) affects 25 to 30 million Americans and several million people across the globe in both developed and developing nations (1,2). A number of treatment options have been shown to delay the progression of kidney damage (3,4). To date, the major impact on delaying the progression of CKD and the risk of end-stage kidney disease (ESKD) has been provided by the use of renin-angiotensin system (RAS) blockers such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor-blocking agents (ARB). These agents have become standard of care in proteinuric CKD patients (5-8). Both ACEi and ARB significantly reduce proteinuria and the risk of ESKD by about 20 to 30% (9). But this is suboptimal given the higher costs and burden of ESKD (10). Thus, studies exploring interventions for traditional and nontraditional risk factors for CKD are advocated (11).Animal studies have shown that aldosterone has an independent role in the development of hypertensive nephropathy and vascular injury resulting in myocardial and renal fibrosis, and its blockade reduces proteinuria (12-16). In humans, RAS blockade with ACEi or ARB results in an incomplete suppression of serum aldosterone levels, a phenomenon known as "aldosterone escape" (17). When patients are treated with ACEi or ARB, aldosterone levels decrease during...

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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

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

Cited by 89 publications

References 59 publications

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism

Mineralocorticoid Receptor Antagonist for Renal Protection

Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease

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