Cited by 466Chronic Kidney Disease and DiabetesHormonal Regulation and HypertensionRenin-Angiotensin System Studies

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Effectiveness of Aldosterone Blockade in Patients With Diabetic Nephropathy

Sato, Atsuhisa, Hayashi, Koichi, Naruse, Mitsuhide, Saruta, Takao·2003·Hypertension

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Abstract

It has been reported that continuous ACE inhibitor therapy does not necessarily produce a maintained decrease in plasma aldosterone levels, which may remain high or increase eventually during long-term use (aldosterone escape). We have examined the role of aldosterone escape in 45 patients with type 2 diabetes and early nephropathy treated with an ACE inhibitor for 40 weeks. With treatment, there was a 40% reduction in average urinary albumin excretion, although urinary albumin excretion in patients with aldosterone escape (18 patients) was significantly higher than that in patients without escape (27 patients). In the 18 patients with escape, spironolactone (25 mg/d) was added to ACE inhibitor treatment in 13. After a 24-week study period, urinary albumin excretion and left ventricular mass index were significantly reduced without blood pressure change. In conclusion, the present study demonstrates that aldosterone escape is observed in 40% of patients with type 2 diabetes with early nephropathy despite the use of ACE inhibitors. Our study suggests the possibility that aldosterone blockade may represent optimal therapy for patients with early diabetic nephropathy who show aldosterone escape during ACE inhibitor treatment and who no longer show maximal antiproteinuric effects of ACE inhibition. Additional, larger, prospectively randomized, double-blind studies will be needed before adaptation of this strategy.

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Background
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BackgroundInfluential
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Self-citation
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Method
Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx
Crompton, M., Ferguson, J., Ramnath, R. D., Onions, K. L., Ogier, A. S., Gamez, M., Down, C. J., Skinner, L., Wong, K., Dixon, L. K., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.154164 · Cited by 52
Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy
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“Aldosterone inhibitors have shown potential for alteration of the fibrotic mechanisms in animal models of kidney fibrosis, in the reduction of proteinuria in diabetic nephropathy, and in proteinuric chronic kidney diseases [12, 46, 47].”
Background
The treatment of coronary artery disease in patients with chronic kidney disease
Edwards, N. C., Steeds, R. P., Ferro, C. J., & Townend, J. (2006) · QJM · doi:10.1093/qjmed/hcl101 · Cited by 37
Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study
Ito, S., Kashihara, N., Shikata, K., Nangaku, M., Wada, T., Okuda, Y., & Sawanobori, T. (2021) · Clinical and Experimental Nephrology · doi:10.1007/s10157-021-02075-y · Cited by 37
The effect of aldosterone and aldosterone blockade on the progression of chronic kidney disease: a randomized placebo-controlled clinical trial
Minakuchi, H., Wakino, S., Urai, H., Kurokochi, A., Hasegawa, K., Kanda, T., Tokuyama, H., & Itoh, H. (2020) · Scientific Reports · doi:10.1038/s41598-020-73638-4 · Cited by 36
Therapies on the Horizon for Diabetic Kidney Disease
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Chronic inhibition of nuclear factor kappa B attenuates aldosterone/salt-induced renal injury
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“It has recently been shown [46] that in such patients, additional blockade of the mineralocorticoid receptor by spironolactone or by eplerenone further confers proteinuria.”
Background
Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease: Efficacy and Safety
Bomback, A. S. (2016) · Blood Purification · doi:10.1159/000441262 · Cited by 35
Ginsenoside Rg1 protects mouse podocytes from aldosterone-induced injury in vitro
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“A number of studies [99-102] showed that Spironolactone or Eplerenone, i.e. mineralocorticoid receptor blockers, reduce the risk of escape and can achieve reversal of escape.”
Background
Aldosterone breakthrough from a pharmacological perspective
Mogi, M. (2022) · Hypertension Research · doi:10.1038/s41440-022-00913-4 · Cited by 32
“In addition, several papers have shown a correlation between renal function impairment and Aldo breakthrough [27, 32, 33].”
Background
Pathophysiology of diabetic nephropathy
Vinod, P. (2012) · doi:10.1016/s2211-9477(12)70005-5 · Cited by 33
Effect of Combination Therapy with Angiotensin Receptor Blocker and 1,25-Dihydroxyvitamin D3 in Type 2 Diabetic Nephropathy in KK-Ay/Ta Mice
Ohara, I., Tanimoto, M., Gohda, T., Yamazaki, T., Hagiwara, S., Murakoshi, M., Aoki, T., Toyoda, H., Ishikawa, Y., Funabiki, K., et al. (2010) · Nephron Experimental Nephrology · doi:10.1159/000320284 · Cited by 33
“In our study, 1,25(OH) 2 D 3 inhibited the tissue renin expression such that 1,25(OH) 2 D 3 may limit the compensatory increase in renin that results from ARB treatment. In addition, ‘aldosterone breakthrough’ is reported with ARB administration [”
Background
Aldosterone Breakthrough Caused by Chronic Blockage of Angiotensin II Type 1 Receptors in Human Adrenocortical Cells: Possible Involvement of Bone Morphogenetic Protein-6 Actions
Otani, H., Otsuka, F., Inagaki, K., Suzuki, J., Miyoshi, T., Kano, Y., Goto, J., Ogura, T., & Makino, H. (2008) · Endocrinology · doi:10.1210/en.2007-1476 · Cited by 34
Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats
Yoneda, M., Sanada, H., Yatabe, J., Midorikawa, S., Hashimoto, S., Sasaki, M., Katoh, T., Watanabe, T., Andrews, P. M., José, P. A., et al. (2005) · Hypertension · doi:10.1161/01.hyp.0000171587.44736.ba · Cited by 31
Drug Insight: eplerenone, a mineralocorticoid-receptor antagonist
McManus, F., Mcinnes, G., & Connell, J. (2008) · Nature Clinical Practice Endocrinology &Metabolism · doi:10.1038/ncpendmet0676 · Cited by 32
“Observational data show that there is a correlation between aldosterone levels and the extent of proteinurea in patients with diabetic nephropathy, and limited, uncontrolled studies by Sato et al”
Background
Cardiovascular and Renal Outcomes with Finerenone, a Selective Mineralocorticoid Receptor Antagonist
Palanisamy, S., Hernandez, M. F., Chang, T. I., & Mahaffey, K. W. (2022) · Cardiology and Therapy · doi:10.1007/s40119-022-00269-3 · Cited by 32
“Further studies demonstrated a continued risk of kidney disease progression, partly explained by the incomplete blockade of the RAAS system [48, 49].”
Background
Effects of Treating Primary Aldosteronism on Renal Function
Kramers, B., Kramers, C., Lenders, J., & Deinum, J. (2017) · The Journal of Clinical Hypertension · doi:10.1111/jch.12914 · Cited by 31
Comparison of Agents That Affect Aldosterone Action
Tamargo, J. L., Solini, A., & Ruilope, L. M. (2014) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2014.04.005 · Cited by 31
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Ritz, E. (2011) · Diabetes Care · doi:10.2337/dc11-s242 · Cited by 25
“In diabetic patients with escape, spironolactone or eplerenone has been shown to cause secondary reduction of proteinuria (53,54).”
Background
Intensified inhibition of renin-angiotensin system: A way to improve renal protection?
Cravedi, P., Ruggenenti, P., & Remuzzi, G. (2007) · Current Hypertension Reports · doi:10.1007/s11906-007-0078-3 · Cited by 31
“Recently, evidence has been provided of an additive antiproteinuric effect of antialdosterone combined with ACE inhibitor and ARB therapy [ 39 ].”
Background
Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease
Nielsen, S. E., Schjoedt, K. J., Rossing, K., Persson, F., Schalkwijk, C. G., Stehouwer, C. D. A., Parving, H., & Rossing, P. R. (2012) · Journal of the Renin-Angiotensin-Aldosterone System · doi:10.1177/1470320312460290 · Cited by 28
Aldosterone in the Pathogenesis of Chronic Kidney Disease and Proteinuria
Lu, Y., Ku, E., & Campese, V. (2010) · Current Hypertension Reports · doi:10.1007/s11906-010-0116-4 · Cited by 30
“Sato et al. [ 32 ] conducted an open-label study in which diabetic patients with nephropathy and proven aldosterone escape were treated with spironolactone for 24 weeks.”
Background
Optimizing Therapy in the Diabetic Patient with Renal Disease
Deferrari, G., Ravera, M., Berruti, V., Leoncini, G., & Deferrari, L. (2004) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000105881.71167.44 · Cited by 26
“A recent study reported that aldosterone escape is observed in 40% of the type 2 diabetes patients with early nephropathy, despite the use of ACEI (40).”
Background
Long-term mineralocorticoid receptor blockade ameliorates progression of experimental diabetic renal disease.
Lian, M., Hewitson, T., Wigg, B., Samuel, C., Chow, F. Y. F., & Becker, G. (2012) · Nephrology, Dialysis and Transplantation · doi:10.1093/ndt/gfr495 · Cited by 29
“Again, recent clinical [4–8] and experimental studies [9] suggest that aldosterone antagonism, through mineralocorticoid receptor blockade, ameliorates progression of diabetic renal complications.”
Background
The Role of Mineralocorticoid Receptor Expression in Brain Remodeling after Cerebral Ischemia
Oyamada, N., Sone, M., Miyashita, K., Park, K., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N., et al. (2008) · Endocrinology · doi:10.1210/en.2007-1770 · Cited by 58
SPIRONOLACTONE FURTHER REDUCES URINARY ALBUMIN EXCRETION AND PLASMA B‐TYPE NATRIURETIC PEPTIDE LEVLES IN HYPERTENSIVE TYPE II DIABETES TREATED WITH ANGIOTENSIN‐CONVERTING ENZYME INHIBITOR
Ogawa, S., Takeuchi, K., Mori, T., Nako, K., & Ito, S. (2006) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2006.04390.x · Cited by 29
“Previously, Sato et al.(2) have reported that, in 13 diabetic patients with aldosterone escape following ACEI treatment, the addition”
BackgroundInfluential
Modifying chronic kidney disease progression with the mineralocorticoid receptor antagonist finerenone in patients with type 2 diabetes
DeFronzo, R. A., & Bakris, G. L. (2022) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14696 · Cited by 32
Efficacy and safety of mineralocorticoid receptor antagonists with ACEI/ARB treatment for diabetic nephropathy: A meta‐analysis
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Aldosterone, organ damage and dietary salt
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Spironolactone ameliorates podocytic adhesive capacity via restoring integrin α3 expression in streptozotocin-induced diabetic rats
Lin, S., Li, D., Jia, J.-Y., Zheng, Z.-F., Jia, Z.-H., & Shang, W.-Y. (2010) · Journal of the Renin-Angiotensin-Aldosterone System · doi:10.1177/1470320310369603 · Cited by 28
Clinical effects of eplerenone, a selective aldosterone blocker, in Japanese patients with essential hypertension
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Self-citation
Is it time for spironolactone therapy in dialysis patients?
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Background
Japanese Society of Hypertension
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Background
Evaluation of spironolactone plus hydrochlorothiazide in reducing proteinuria in type 2 diabetic nephropathy
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Authors: Sato, A., Hayashi, K., Naruse, M., & Saruta, T.
Affiliations: Keio University (JP)
From the Department of Internal Medicine, Mito Red Cross Hospital (A.S.), Ibaraki; the Department of Internal Medicine, Keio University (K.H., T.S.), Tokyo; and the Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women’s Medical University (M.N.), Tokyo, Japan.
ORCID: Naruse, Mitsuhide
Venue: Hypertension
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2003-01
Volume: 41
Issue: 1
Pages: 64-68
ISSN: 0194-911X (ISSN-L)
1524-4563
DOI: 10.1161/01.hyp.0000044937.95080.e9
OpenAlex: W2163709605
Cited by: 466
References: 0
Citations by year: 2026: 7 · 2025: 8 · 2024: 5 · 2023: 15 · 2022: 20 · 2021: 9 · 2020: 10 · 2019: 13 · 2018: 11 · 2017: 4 · 2016: 13 · 2015: 16 · 2014: 20 · 2013: 19 · 2012: 28
FWCI: 28.03
Type: journal article
Language: en
Open access: closed
Locations: Hypertension (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
Keywords: aldosterone escape, aldosterone blockade, spironolactone, ACE inhibitors, diabetic nephropathy, type 2 diabetes, urinary albumin excretion, proteinuria, left ventricular mass, renin-angiotensin system
MeSH terms: Albuminuria, Aldosterone, Mineralocorticoid Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Drug Therapy, Combination, Female, Heart Ventricles, Humans, Male, Middle Aged, Spironolactone, Ultrasonography

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Effectiveness of Aldosterone Blockade in Patients With Diabetic Nephropathy

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