Clinical and Experimental Nephrology

, Volume 19, Issue 6, pp 1098–1106 | Cite as

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

  • Sawako Kato
  • Shoichi Maruyama
  • Hirofumi Makino
  • Jun Wada
  • Daisuke Ogawa
  • Takashi Uzu
  • Hisazumi Araki
  • Daisuke Koya
  • Keizo Kanasaki
  • Yutaka Oiso
  • Motomitsu Goto
  • Akira Nishiyama
  • Hiroyuki Kobori
  • Enyu Imai
  • Masahiko Ando
  • Seiichi Matsuo
Original Article

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.

Keywords

Albuminuria Diabetic nephropathy Randomized study Spironolactone 

References

  1. 1.
    International Diabetes Federation (2013) IDF Diabetes Altas, 6 ed. Brussels. pp 29–49.Google Scholar
  2. 2.
    Nathan DM, Bayless M, Cleary P, Genuth S, Gubitosi-Klug R, Lachin JM, et al. Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes. 2013;62(12):3976–86. doi:10.2337/db13-1093.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414(6865):782–7. doi:10.1038/414782a.CrossRefPubMedGoogle Scholar
  4. 4.
    Iseki K. Predictors of diabetic end-stage renal disease in Japan. Nephrol Carlton. 2005;10(Suppl):S2–6. doi:10.1111/j.1440-1797.2005.00447.x.CrossRefGoogle Scholar
  5. 5.
    Nakai S, Iseki K, Itami N, Ogata S, Kazama JJ, Kimata N, et al. Overview of regular dialysis treatment in Japan (as of 31 December 2009). Ther Apher Dial. 2012;16(1):11–53. doi:10.1111/j.1744-9987.2011.01050.x.CrossRefPubMedGoogle Scholar
  6. 6.
    Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y, et al. Microalbuminuria reduction with telmisartan in normotensive and hypertensive Japanese patients with type 2 diabetes: a post hoc analysis of The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study. Hypertens Res. 2008;31(4):657–64. doi:10.1291/hypres.31.657.CrossRefPubMedGoogle Scholar
  7. 7.
    Araki S, Haneda M, Koya D, Hidaka H, Sugimoto T, Isono M, et al. Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients with type 2 diabetes. Diabetes. 2007;56(6):1727–30. doi:10.2337/db06-1646.CrossRefPubMedGoogle Scholar
  8. 8.
    Bilous R. Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabet Med. 2008;25(Suppl 2):25–9. doi:10.1111/j.1464-5491.2008.02496.x.CrossRefPubMedGoogle Scholar
  9. 9.
    Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89. doi:10.1056/NEJMoa0806470.CrossRefPubMedGoogle Scholar
  10. 10.
    Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870–8. doi:10.1056/NEJMoa011489.CrossRefPubMedGoogle Scholar
  11. 11.
    Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y, et al. Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes. Diabetes Care. 2007;30(6):1577–8. doi:10.2337/dc06-1998.CrossRefPubMedGoogle Scholar
  12. 12.
    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(12):925–6. doi:10.1056/NEJM200109203451215.CrossRefPubMedGoogle Scholar
  13. 13.
    Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20(12):2641–50. doi:10.1681/ASN.2009070737.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 2005;68(6):2829–36. doi:10.1111/j.1523-1755.2005.00756.x.CrossRefPubMedGoogle Scholar
  15. 15.
    Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care. 2005;28(9):2106–12.CrossRefPubMedGoogle Scholar
  16. 16.
    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(12):2116–23. doi:10.1038/sj.ki.5001854.PubMedGoogle Scholar
  17. 17.
    Furumatsu Y, Nagasawa Y, Tomida K, Mikami S, Kaneko T, Okada N, 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. 2008;31(1):59–67. doi:10.1291/hypres.31.59.CrossRefPubMedGoogle Scholar
  18. 18.
    Konishi Y, Nishiyama A, Morikawa T, Kitabayashi C, Shibata M, Hamada M, et al. Relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. Hypertension. 2011;58(2):205–11. doi:10.1161/HYPERTENSIONAHA.110.166843.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982–92. doi:10.1053/j.ajkd.2008.12.034.CrossRefPubMedGoogle Scholar
  20. 20.
    Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S. GFR estimation using standardized serum cystatin C in Japan. Am J Kidney Dis. 2013;61(2):197–203. doi:10.1053/j.ajkd.2012.07.007.CrossRefPubMedGoogle Scholar
  21. 21.
    Woo KS, Choi JL, Kim BR, Kim JE, An WS, Han JY. Urinary neutrophil gelatinase-associated lipocalin levels in comparison with glomerular filtration rate for evaluation of renal function in patients with diabetic chronic kidney disease. Diabetes Metab J. 2012;36(4):307–13. doi:10.4093/dmj.2012.36.4.307.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Kobori H, Ozawa Y, Suzaki Y, Nishiyama A. Enhanced intrarenal angiotensinogen contributes to early renal injury in spontaneously hypertensive rats. J Am Soc Nephrol. 2005;16(7):2073–80. doi:10.1681/ASN.2004080676.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis. 2008;51(2):199–211. doi:10.1053/j.ajkd.2007.10.040.CrossRefPubMedGoogle Scholar
  24. 24.
    Morales E, Millet VG, Rojas-Rivera J, Huerta A, Gutierrez E, Gutierrez-Solis E, et al. Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases. Nephrol Dial Transplant. 2013;28(2):405–12. doi:10.1093/ndt/gfs429.CrossRefPubMedGoogle Scholar
  25. 25.
    Esteghamati A, Noshad S, Jarrah S, Mousavizadeh M, Khoee SH, Nakhjavani M. Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial. Nephrol Dial Transplant. 2013;28(11):2823–33. doi:10.1093/ndt/gft281.CrossRefPubMedGoogle Scholar
  26. 26.
    van den Meiracker AH, Baggen RG, Pauli S, Lindemans A, Vulto AG, Poldermans D, et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J Hypertens. 2006;24(11):2285–92. doi:10.1097/01.hjh.0000249708.44016.5c.CrossRefPubMedGoogle Scholar
  27. 27.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709–17. doi:10.1056/NEJM199909023411001.CrossRefPubMedGoogle Scholar
  28. 28.
    Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003;41(1):64–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Yoneda T, Takeda Y, Usukura M, Oda N, Takata H, Yamamoto Y, et al. Aldosterone breakthrough during angiotensin II receptor blockade in hypertensive patients with diabetes mellitus. Am J Hypertens. 2007;20(12):1329–33. doi:10.1016/j.amjhyper.2007.09.001.CrossRefPubMedGoogle Scholar
  30. 30.
    Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nature medicine. 2008;14(12):1370–6. doi:10.1038/nm.1879.CrossRefPubMedGoogle Scholar
  31. 31.
    Nishiyama A, Kobori H, Konishi Y, Morikawa T, Maeda I, Okumura M, et al. Mineralocorticoid receptor blockade enhances the antiproteinuric effect of an angiotensin II blocker through inhibiting podocyte injury in type 2 diabetic rats. The Journal of pharmacology and experimental therapeutics. 2010;332(3):1072–80. doi:10.1124/jpet.109.158113.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Chen H, Sun F, Zhong X, Shao Y, Yoshimura A, Liu Y. Eplerenone-mediated aldosterone blockade prevents renal fibrosis by reducing renal inflammation, interstitial cell proliferation and oxidative stress. Kidney Blood Press Res. 2013;37(6):557–66. doi:10.1159/000355736.CrossRefPubMedGoogle Scholar
  33. 33.
    Ojeda-Cervantes M, Barrera-Chimal J, Alberu J, Perez-Villalva R, Morales-Buenrostro LE, Bobadilla NA. Mineralocorticoid receptor blockade reduced oxidative stress in renal transplant recipients: a double-blind, randomized pilot study. Am J Nephrol. 2013;37(5):481–90. doi:10.1159/000350539.CrossRefPubMedGoogle Scholar
  34. 34.
    Ziyadeh FN, Goldfarb S. The renal tubulointerstitium in diabetes mellitus. Kidney Int. 1991;39(3):464–75.CrossRefPubMedGoogle Scholar
  35. 35.
    Fujisawa G, Okada K, Muto S, Fujita N, Itabashi N, Kusano E, et al. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int. 2004;66(4):1493–502. doi:10.1111/j.1523-1755.2004.00913.x.CrossRefPubMedGoogle Scholar
  36. 36.
    Kramer AB, van der Meulen EF, Hamming I, van Goor H, Navis G. Effect of combining ACE inhibition with aldosterone blockade on proteinuria and renal damage in experimental nephrosis. Kidney Int. 2007;71(5):417–24. doi:10.1038/sj.ki.5002075.CrossRefPubMedGoogle Scholar
  37. 37.
    Mavrakanas TA, Gariani K, Martin PY. Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review. Eur J Int Med. 2014;25(2):173–6. doi:10.1016/j.ejim.2013.11.007.CrossRefGoogle Scholar
  38. 38.
    Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int. 2005;67(3):799–812. doi:10.1111/j.1523-1755.2005.00145.x.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2015

Authors and Affiliations

  • Sawako Kato
    • 1
  • Shoichi Maruyama
    • 1
  • Hirofumi Makino
    • 2
  • Jun Wada
    • 2
  • Daisuke Ogawa
    • 2
  • Takashi Uzu
    • 3
  • Hisazumi Araki
    • 3
  • Daisuke Koya
    • 4
  • Keizo Kanasaki
    • 4
  • Yutaka Oiso
    • 5
  • Motomitsu Goto
    • 5
  • Akira Nishiyama
    • 6
  • Hiroyuki Kobori
    • 6
  • Enyu Imai
    • 7
  • Masahiko Ando
    • 8
  • Seiichi Matsuo
    • 1
  1. 1.Department of NephrologyNagoya University Graduate School of MedicineAichiJapan
  2. 2.Department of Medicine and Clinical ScienceOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  3. 3.Department of MedicineShiga University of Medical ScienceShigaJapan
  4. 4.Department of Diabetology and EndocrinologyKanazawa Medical UniversityIshikawaJapan
  5. 5.Department of Endocrinology and DiabetesNagoya University Graduate School of MedicineAichiJapan
  6. 6.Department of Pharmacology, Faculty of MedicineKagawa UniversityKagawaJapan
  7. 7.Nakayama-temple Imai ClinicHyogoJapan
  8. 8.Center for Advanced Medicine and Clinical ResearchNagoya University HospitalAichiJapan

Personalised recommendations