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Pediatric Nephrology

, Volume 21, Issue 12, pp 1824–1829 | Cite as

The effect of aldosterone blockade in patients with Alport syndrome

  • Hiroshi Kaito
  • Kandai NozuEmail author
  • Kazumoto Iijima
  • Koichi Nakanishi
  • Kunihiko Yoshiya
  • Kyoko Kanda
  • Rafal Przybyslaw Krol
  • Norishige Yoshikawa
  • Masafumi Matsuo
Original Article

Abstract

Recent studies indicate that adding the mineralocorticoid receptor antagonist spironolactone (SP) to angiotensin converting enzyme inhibitors (ACEI) or ACEI and angiotensin receptor blocker (ARB), which is known as a triple blockade, enhances the more beneficial effects on urinary protein excretion of patients with chronic kidney diseases. In this study, we explored the effects of SP on urinary protein excretion in patients with Alport syndrome featuring persistent proteinuria in spite of the long-term use of ACEI (lisinopril) or both ACEI and ARB (candesartan). Five patients with Alport syndrome were enrolled and SP treatment (25 mg/day) was started. At the start of SP administration, all patients showed good renal function and none of them suffered from hypertension. We decided to assess the effect of SP by determining the morning urinary protein/creatinine ratio (U-P/C) and estimated glomerular filtration rate (EGFR). After SP treatment was started, U-P/C was significantly reduced at 3, 6, 12 and 18 months, while EGFR did not change. The drop in systolic and diastolic blood pressure was statistically significant and serum potassium level was slightly elevated. None of the patients showed signs of severe hyperkalemia (>5.0 mEq/l). These results suggest that aldosterone receptor blockade combined with ACEI and ARB therapy offers a valuable adjuvant treatment for the reduction of proteinuria in patients with Alport syndrome as in those with other chronic kidney diseases. SP can thus be expected to constitute a good renoprotective agent for Alport syndrome. These preliminary data indicate that large-scale trials of this therapy should be done.

Keywords

Alport syndrome Aldosterone blockade Spironolactone Angiotensin converting enzyme inhibitor (ACEI) Angiotensin receptor blocker (ARB) Proteinuria prevention 

Notes

Acknowledgement

This work was supported by grants from Fund of Kidney Disease Research from Hyogo Prefecture Health Promotion Association.

References

  1. 1.
    Kashtan CE (2000) Alport syndromes: phenotypic heterogeneity of progressive hereditary nephritis. Pediatr Nephrol 14:502–512CrossRefGoogle Scholar
  2. 2.
    Chen D, Jefferson B, Harvey SJ, Zheng K, Gartley CJ, Jacobs RM, Thorner PS (2003) Cyclosporine A slows the progressive renal disease of Alport syndrome (X-linked hereditary nephritis): results from a canine model. J Am Soc Nephrol 14:690–698CrossRefGoogle Scholar
  3. 3.
    Callis L, Vila A, Nieto J, Fortuny G (1992) Effect of cyclosporine A on proteinuria in patients with Alport’s syndrome. Pediatr Nephrol 6:140–144CrossRefGoogle Scholar
  4. 4.
    Callis L, Vila A, Carrera M, Nieto J (1999) Long-term effects of cyclosporine A in Alport’s syndrome. Kidney Int 55:1051–1056CrossRefGoogle Scholar
  5. 5.
    Grodecki KM, Gains MJ, Baumal R, Osmond DH, Cotter B, Valli VE, Jacobs RM (1997) Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin converting enzyme (ACE) inhibitor. J Comp Pathol 117:209–225CrossRefGoogle Scholar
  6. 6.
    Cohen EP, Lemann J Jr (1996) In hereditary nephritis angiotensin-converting enzyme inhibition decreases proteinuria and may slow the rate of progression. Am J Kidney Dis 27:199–203CrossRefGoogle Scholar
  7. 7.
    Gross O, Beirowski B, Koepke ML, Kuck J, Reiner M, Addicks K, Smyth N, Schulze-Lohoff E, Weber M (2003) Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int 63:438–446CrossRefGoogle Scholar
  8. 8.
    Proesmans W, Dyck MV (2004) Enarapril in children with Alport syndrome. Pediatr Nephrol 19:271–275CrossRefGoogle Scholar
  9. 9.
    Proesmans W, Knockaert H, Trouet D (2000) Enarapril in paediatric patients with Alport syndrome: 2 years’ experience. Eur J Pediatr 159:430–433CrossRefGoogle Scholar
  10. 10.
    Inoue M, Nomura S, Naito I, Ishikawa E, Katayama K, Oosugi K, Nakano T (2005) Renoprotection of angiotensin II receptor blocking agent for Alport’s mice. Abstract from American Society of Nephrology Renal Week 2005, 8–13 November 2005, PhiladelphiaGoogle Scholar
  11. 11.
    Epstein M (2001) Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am J Kidney Dis 37:677–688CrossRefGoogle Scholar
  12. 12.
    Epstein M (2003) Aldosterone receptor blockade and the role of eplerenone: evolving perspectives (2003) Nephrol Dial Transplant 18:1984–1992CrossRefGoogle Scholar
  13. 13.
    Chrysostomou A, Becker G (2001) Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med 345:925–926CrossRefGoogle Scholar
  14. 14.
    Sato A, Hayashi K, Naruse M, Saruta T (2003) Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 41:64–68CrossRefGoogle Scholar
  15. 15.
    Sato A, Hayashi K, Saruta T (2005) Antiproteinuric effects of mineralocorticoid receptor blockade in patients with chronic renal disease. Am J Hypertens 18:44–49CrossRefGoogle Scholar
  16. 16.
    Williams GH, Burgess E, Kolloch RE, Ruilope LM, Niegowska J, Kipnes MS, Roniker B, Patrick JL, Krause SL (2004) Efficacy of eplerenone versus enalapril as monotherapy in systemic hypertension. Am J Cardiol 93:990–996CrossRefGoogle Scholar
  17. 17.
    Kashtan CE, Michael AF (1996) Alport syndrome. Kidney Int 50:1445–1463CrossRefGoogle Scholar
  18. 18.
    Gregory MC, Terreros DA, Barker DF, Fain PN, Denison JC, Atkin CL (1996) Alport syndrome - clinical phenotypes, incidence, and pathology. Contrib Nephrol 117:1–28CrossRefGoogle Scholar
  19. 19.
    Pescucci C, Mari F, Longo I, Vogiatzi P, Caselli R, Scala E, Abaterusso C, Gusmano MS, Miglietti N, Bresin E, Renieri A (2004) Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney Int 65:1598–1603CrossRefGoogle Scholar
  20. 20.
    Yoshikawa N, Cameron AH, White RH (1981) The glomerular basal lamina in hereditary nephritis. J Pathol 135:199–209CrossRefGoogle Scholar
  21. 21.
    Ginsberg JM, Chang BS, Matarese RA, Garella S (1983) Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 309:1543–1546CrossRefGoogle Scholar
  22. 22.
    Abitbol C, Zilleruelo G, Freundlich M, Strauss J (1990) Quantitation of proteinuria with urinary protein/creatinine ratios and random testing with dipsticks in nephrotic children. J Pediatr 116:243–247CrossRefGoogle Scholar
  23. 23.
    Eknoyan G, Hostetter T, Bakris GL, Hebert L, Levey AS, Parving HH, Steffes MW, Toto R (2003) Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute if diabetes and digestive and kidney diseases (NIDDK). Am J Kidney Dis 42:617–622CrossRefGoogle Scholar
  24. 24.
    Schwartz GJ, Haycock MB, Edelmann CM Jr., Spizer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–263PubMedPubMedCentralGoogle Scholar
  25. 25.
    Schwartz GJ, Gauthier B (1985) A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr 106:522–526CrossRefGoogle Scholar
  26. 26.
    Charbit M, Dechaux M, Gagnadoux MF (2003) Cyclosporine A therapy in Alport syndrome. J Am Soc Nephrol 14:111AGoogle Scholar
  27. 27.
    Chrysostomou A, Pedagogos E, MacGregor L, Becker GJ (2006) Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. Clin J Am Soc Nephrol 1:256–262CrossRefGoogle Scholar
  28. 28.
    Sun Y, Zhang J, Zhang JQ, Ramires FJ (2000) Local angiotensin II and transforming growth factor beta 1 renal fibrosis of rats. Hypertension 35:1078–1084CrossRefGoogle Scholar
  29. 29.
    Blasi ER, Rocha R, Rudolph AE, Blomme EAG, Polly ML, McMahon EG (2003) Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int 63:1791–1800CrossRefGoogle Scholar
  30. 30.
    Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, Kondo S, Kiomoto H, Shokoji T, Kimura S, Kohno M, Abe Y (2004) Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt induced hypertensive rats. Hypertension 43:841–884CrossRefGoogle Scholar
  31. 31.
    Wakisaka M, Spiro MJ, Spiro RG (1994) Synthesis of type IV collagen by cultured glomerular cells and comparison of its regulation by glucose and other factors with that of type IV collagen. Diabetes 43:95–103CrossRefGoogle Scholar
  32. 32.
    Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA (2004) Rates of hyperkalemia after publication of the randomized Aldosterone Evaluation Study. N Engl J Med 351:543–551CrossRefGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Hiroshi Kaito
    • 1
  • Kandai Nozu
    • 1
    Email author
  • Kazumoto Iijima
    • 2
  • Koichi Nakanishi
    • 3
  • Kunihiko Yoshiya
    • 4
  • Kyoko Kanda
    • 1
  • Rafal Przybyslaw Krol
    • 1
  • Norishige Yoshikawa
    • 3
  • Masafumi Matsuo
    • 1
  1. 1.Department of PediatricsKobe University Graduate School of MedicineHyogoJapan
  2. 2.Department of NephrologyNational Center for Child Health and DevelopmentTokyoJapan
  3. 3.Department of PediatricsWakayama Medical UniversityWakayamaJapan
  4. 4.Department of NephrologyHara Urology HospitalHyogoJapan

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