Rationale and design of the Eplerenone combination Versus conventional Agents to Lower blood pressure on Urinary Antialbuminuric Treatment Effect (EVALUATE) trial: a double-blinded randomized placebo-controlled trial to evaluate the antialbuminuric effects of an aldosterone blocker in hypertensive patients with albuminuria

Ando, Katsuyuki; Ohtsu, Hiroshi; Arakawa, Yoshihiro; Kubota, Kiyoshi; Yamaguchi, Takuhiro; Nagase, Miki; Yamada, Akira; Fujita, Toshiro

doi:10.1038/hr.2010.46

Cited by 25 publications

(9 citation statements)

References 34 publications

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“…While it is increasingly noted that aldosterone mediates cardiac fibrosis (1,2,14), in the current study, there is no activation of aldosterone at 4 wk, which is, however, elevated at 16 wk. Other possible mechanisms that may contribute to the early fibrosis observed in this study can be related to the TGF-␤ and apoptosis pathways (17,27).…”

Section: Discussioncontrasting

confidence: 71%

Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection

Martín

McKie

Cataliotti

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Impaired renal function with loss of nephron number in chronic renal disease (CKD) is associated with increased cardiovascular morbidity and mortality. However, the structural and functional cardiac response to early and mild reduction in renal mass is poorly defined. We hypothesized that mild renal impairment produced by unilateral nephrectomy (UNX) would result in early cardiac fibrosis and impaired diastolic function, which would progress to a more global left ventricular (LV) dysfunction. Cardiorenal function and structure were assessed in rats at 4 and 16 wk following UNX or sham operation (Sham); (n = 10 per group). At 4 wk, blood pressure (BP), aldosterone, glomerular filtration rate (GFR), proteinuria, and plasma B-type natriuretic peptide (BNP) were not altered by UNX, representing a model of mild early CKD. However, UNX was associated with significantly greater LV myocardial fibrosis compared with Sham. Importantly, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis in the LV myocardium. Further, diastolic dysfunction, assessed by strain echocardiography, but with preserved LVEF, was observed. Changes in genes related to the TGF-β and apoptosis pathways in the LV myocardium were also observed. At 16 wk post-UNX, we observed persistent LV fibrosis and impairment in LV diastolic function. In addition, LV mass significantly increased, as did LVEDd, while there was a reduction in LVEF. Aldosterone, BNP, and proteinuria were increased, while GFR was decreased. The myocardial, structural, and functional alterations were associated with persistent changes in the TGF-β pathway and even more widespread changes in the LV apoptotic pathway. These studies demonstrate that mild renal insufficiency in the rat results in early cardiac fibrosis and impaired diastolic function, which progresses to more global LV remodeling and dysfunction. Thus, these studies importantly advance the concept of a kidney-heart connection in the control of myocardial structure and function.

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Section: Discussioncontrasting

confidence: 71%

Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection

Martín

McKie

Cataliotti

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Subsequent studies suggested that lower doses of eplerenone would be safe and sufficiently beneficial. We are conducting a double-blinded, randomized, placebo-controlled trial to evaluate the antialbuminuric effect of low dose of eplerenone (Eplerenone Combination Versus Conventional Agents to Lower Blood Pressure on Urinary Anti-albuminuric Treatment Effect Trial: EVALUATE) [89]. The study subjects will be 340 Japanese hypertensive patients with albuminuria receiving ACEIs or ARBs.…”

Section: Discussionmentioning

confidence: 99%

Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome

Nagase

2010

Clin Exp Nephrol

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Recent clinical and experimental studies have shown that aldosterone is a potent inducer of proteinuria and that mineralocorticoid receptor (MR) antagonists confer efficient antiproteinuric effects. We identified glomerular epithelial cells (podocytes) as novel targets of aldosterone; activation of MR injures podocytes possibly via oxidative stress, resulting in disruption of glomerular filtration barrier, proteinuria, and progression of chronic kidney disease. We also demonstrated that SHR/cp, a rat model of metabolic syndrome, was susceptible to podocyte injury and proteinuria. Aldosterone excess caused by adipocyte-derived aldosterone-releasing factors was suggested to underlie the nephropathy. High salt intake augmented MR activation in the kidney and exacerbated the nephropathy. Furthermore, we identified an alternative pathway of MR activation by small GTPase Rac1. RhoGDIalpha knockout mice, a model with Rac1 activation in the kidney, showed albuminuria, podocyte injury, and glomerulosclerosis. Renal injury in the knockout mice was accompanied by enhanced MR signaling in the kidney despite normoaldosteronemia, and was ameliorated by an MR antagonist, eplerenone. Moreover, Rac-specific inhibitor significantly reduced the nephropathy, concomitantly with repression of MR activation. In vitro transfection studies provided direct evidence of Rac1-mediated MR activation. In conclusion, our findings suggest that MR activation plays a pivotal role in the pathogenesis of chronic kidney disease in metabolic syndrome, and that MR may be activated both aldosterone dependently (via aldosterone-releasing factors) and independently (via Rac1). MR antagonists are promising antiproteinuric drugs in metabolic syndrome, although long-term effects on renal outcomes, mortality, and safety need to be established.

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“…Currently, EVALUATE (Eplerenone Combination Versus Conventional Agents to Lower Blood Pressure on Urinary Antialbuminuric Treatment Effect Trial) is ongoing as a placebo-controlled, double-blind trial to validate the additional effects of eplerenone on conventional therapies, primarily with RA inhibitors, in Japanese essentially hypertensive patients with albuminuria. 38 DM nephropathy patients and patients with an eGFR of o50 ml per minute per 1.73 m 2 for whom eplerenone is contraindicated were excluded from this trial. The result of this trial is expected to have a significant influence on the future treatment of CKD in Japan.…”

Section: Differentiation Of the Two Drugsmentioning

confidence: 99%

Mineralocorticoid receptor antagonists: their use and differentiation in Japan

Sato

2012

Hypertens Res

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In the presence of salt, aldosterone causes hypertension and organ damage via the mineralocorticoid receptor (MR) through various mechanisms. MR antagonists are considered to be potassium-sparing diuretics that exert their effect by blocking MR in the kidney, and they are not the first choice for treating hypertension. However, the importance and usefulness of inhibiting aldosterone in the management of hypertension have recently been revealed in both the basic and clinical fields. In Japan, both the selective MR antagonist eplerenone and the non-selective MR antagonist spironolactone are indicated for the treatment of hypertension. Although these drugs are generally used in the same manner, in some cases they require differentiation. This differentiation is divided into two types due to the differences in their features and differences in their contraindications in Japan. Based on a number of studies on MR antagonists that have been recently published, the diseases and clinical conditions targeted by MR antagonists appear to be likely to increase in the future. In Japan, we consider it necessary to carefully differentiate spironolactone from eplerenone in regard to their intended uses.

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Cited by 25 publications

References 34 publications

Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection

Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection

Activation of the aldosterone/mineralocorticoid receptor system in chronic kidney disease and metabolic syndrome

Mineralocorticoid receptor antagonists: their use and differentiation in Japan

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