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Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial

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Abstract

Background

Several studies have demonstrated that spironolactone has an anti-albuminuric property in diabetic nephropathy. As an adverse event, spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia. Therefore, we aimed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

Methods

Fifty-two Japanese patients with diabetic nephropathy and albuminuria (100 mg/gCr–2000 mg/gCr) treated with renin–angiotensin system (RAS) blockade were enrolled in a prospective, randomized, open-label study. The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks. The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value. This study was registered with UMIN Clinical Trials Registry (000008016).

Results

Albuminuria was reduced by 33 % (95 % confidence interval: 22–54; P = 0.0002) at 8 weeks with spironolactone. In the spironolactone group, blood pressure tended to lower and the estimated glomerular filtration rate (eGFR) was significantly decreased compared to those in the control group. When adjusted by systolic blood pressure and eGFR, spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model (coefficient ± standard error; 514.4 ± 137.6 mg/gCr, P < 0.0005). No patient was excluded from the study because of hyperkalemia.

Conclusions

Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy. Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations.

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Acknowledgments

This study included the following researchers. Principal investigator: Shoichi Maruyama. Steering Committee: Seiichi Matsuo, Hirofumi Makino, Enyu Imai, Takashi Uzu, Daisuke Koya and Yutaka Oiso. Data and Safety Monitoring Committee: Yukio Yuzawa and Mutsuharu Hayashi. Clinical Research Coordinator and Data Management Group: Masami Hamada, Kana Uchida, Miho Oba and Yumiko Omura.

Conflict of interest

This study was funded by Nagoya University Graduate School of Medicine. This study was supported in part by a Grant-in-Aid for Progressive Renal Diseases Research, Research on Rare and Intractable Disease, from the Ministry of Health, Labour and Welfare of Japan. The Department of Nephrology, Nagoya University Graduate School of Medicine, reported receiving research promotion grants from Astellas, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, Mochida, MSD, Nihon Medi-Physics, Novartis, Otsuka, Pfizer, Takeda, Teijin, Mitsubishi Tanabe and Torii. S.K. receives speaker honoraria from Novartis. Sh.M. receives speaker honoraria from Bayer, Chugai, Dainippon Sumitomo, Genzyme, Kowa, Kyowa Hakko Kirin, Mochida, MSD, Novartis, Otsuka, Public Health Research Center, Teijin and Mitsubishi Tanabe. Se.M. receives speaker honoraria from Alexon, Astellas, Baxter, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Kaneka Medix, Kyowa Hakko Kirin, Mochida, MSD, Nihon Medi-Physics, Novartis, Otsuka, Public Health Research Center, Sanwa, Takeda, Teijin, Mitsubishi Tanabe and Torii. However, the research topics of these donation grants are not restricted. The Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences receives grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Pfizer, Takeda and Tanabe Mitsubishi. D.O. belongs to the Department of Diabetic Nephropathy, endowed by Boehringer Ingelheim, and receives grant support from Eli Lilly. J.W. is a consultant for Boehringer Ingelheim and receives speaker honoraria from Boehringer Ingelheim, Novartis and Novo Nordisk. H.M. is a consultant for AbbVie, Astellas and Teijin, and receives speaker honoraria from Astellas, MSD, Takeda and Tanabe Mitsubishi. However, the research topics of these donation grants are not restricted. Kanazawa Medical University receives donation from Pfizer and the donation is not directly associated with this study. Also, Kanazawa Medical University receives donation for research promotion from the following: MSD, Astellas, Kyowa Hakko Kirin, Daiichi Sankyo, Takeda, Mitsubishi Tanabe, Boehringer Ingelheim, Novartis and Japan Tobacco Inc. D.K. receives speaker honoraria from MSD, Astellas, Kyowa Hakko Kirin, Daiichi Sankyo, Takeda, Mitsubishi Tanabe, Boehringer Ingelheim, Novartis, Dainippon Sumitomo, Novo Nodisk, Sanofi, Kowa, Eli Lilly and Pfizer. K.K. receives speaker honoraria from, MSD, Astellas, Kyowa Hakko Kirin, Daiichi Sankyo, Mitsubishi Tanabe, Boehringer Ingelheim, Novartis, Dainippon Sumitomo, Sanofi and Eli Lilly. The Department of Medicine, Shiga University of Medical Science, reported receiving research promotion grants from Astellas, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Takeda, Teijin, Mitsubishi Tanabe and Chugai. T.U. receives speaker honoraria from MSD. The Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, reported receiving research promotion grants from Astellas, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Kowa, Sanwa, Teijin, Mitsubishi Tanabe, Lilly and Novo Nordisk. Y.O. receives speaker honoraria from MSD and Ono. M.G. receives speaker honoraria from Astellas, Kowa, Mitsubishi Tanabe, Novo Nordisk, Takeda and Mochida. However, the research topics of these donation grants are not restricted. Department of Pharmacology, Faculty of Medicine, Kagawa University receives donation from Pfizer and the donation is not directly associated with this study. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, receives donation from Pfizer and the donation is not directly associated with this study. Pfizer organized the advisory meeting about aldosterone antagonist use in patients with diabetic nephropathy and S.K., Sh.M., H.M., T.U., K.K., E.I. and Se.M. were reimbursed for travel costs and received honoraria.

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Authors and Affiliations

  1. Department of Nephrology, Nagoya University Graduate School of Medicine, Aichi, Japan

    Sawako Kato, Shoichi Maruyama & Seiichi Matsuo

  2. Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Hirofumi Makino, Jun Wada & Daisuke Ogawa

  3. Department of Medicine, Shiga University of Medical Science, Shiga, Japan

    Takashi Uzu & Hisazumi Araki

  4. Department of Diabetology and Endocrinology, Kanazawa Medical University, Ishikawa, Japan

    Daisuke Koya & Keizo Kanasaki

  5. Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Aichi, Japan

    Yutaka Oiso & Motomitsu Goto

  6. Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Akira Nishiyama & Hiroyuki Kobori

  7. Nakayama-temple Imai Clinic, Hyogo, Japan

    Enyu Imai

  8. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Aichi, Japan

    Masahiko Ando

Authors
  1. Sawako Kato
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  2. Shoichi Maruyama
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  3. Hirofumi Makino
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  4. Jun Wada
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  5. Daisuke Ogawa
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  6. Takashi Uzu
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  7. Hisazumi Araki
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  8. Daisuke Koya
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  9. Keizo Kanasaki
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  11. Motomitsu Goto
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  12. Akira Nishiyama
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  13. Hiroyuki Kobori
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  14. Enyu Imai
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  15. Masahiko Ando
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  16. Seiichi Matsuo
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Corresponding author

Correspondence to Sawako Kato.

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Kato, S., Maruyama, S., Makino, H. et al. Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial. Clin Exp Nephrol 19, 1098–1106 (2015). https://doi.org/10.1007/s10157-015-1106-2

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