Skip to main content

Advertisement

SpringerLink
Log in

Combination therapy with mizoribine for severe childhood IgA nephropathy: a pilot study

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

In two previous randomized controlled trials we showed that treatment of severe childhood immunoglobulin A nephropathy (IgA-N) using prednisolone, azathioprine, heparin–warfarin, and dipyridamole prevented any increase of sclerosed glomeruli and that prednisolone alone did not prevent a further increase of sclerosed glomeruli. Accordingly, the immunosuppressant is considered to be important. Often, however, we were unable to complete azathioprine regimen due to toxicity. Therefore, a different but effective immunosuppressant may be worth trying. Mizoribine, like azathioprine, is an antimetabolite that exerts its immunosuppressant effect by inhibiting lymphocyte proliferation. In this pilot study, we administered mizoribine instead of azathioprine as part of the combination therapy for treating 23 children with severe IgA-N and evaluated the efficacy and safety. Eighteen patients reached the primary endpoint (urine protein/creatinine ratio <0.2) during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by Kaplan–Meier was 80.4%. Median protein excretion was reduced from 1.19 g/m2/day to 0.05 g/m2/day (p < 0.0001). After treatment, the median percentage of glomeruli showing sclerosis was unchanged in comparison with that before treatment. No patients required a change of treatment. In conclusion, the efficacy and safety of the mizoribine combination seems to be acceptable for treating children with severe IgA-N.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Donadio JV, Grande JP (2002) IgA nephropathy. N Engl J Med 347:738–748

    Article  CAS  Google Scholar 

  2. Alexopoulos E (2004) Treatment of primary IgA nephropathy. Kidney Int 65:341–355

    Article  Google Scholar 

  3. Yoshikawa N, Tanaka R, Iijima K (2001) Pathophysiology and treatment of childhood IgA nephropathy. Pediatr Nephrol 16:446–457

    Article  CAS  Google Scholar 

  4. Yoshikawa N, Ito H, Nakamura H (1992) Prognostic factors in childhood IgA nephropathy. Nephron 60:60–67

    Article  CAS  Google Scholar 

  5. Yoshikawa N, Ito H, Sakai T, Takekoshi Y, Honda M, Awazu M, Ito K, Iitaka K, Koitabashi Y, Yamaoka K, Nakagawa K, Nakamura N, Matsuyama S, Seino Y, Takeda N, Hattori S, Ninomiya M, Japanese Pediatric IgA Nephropathy Treatment Group (1999) A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. J Am Soc Nephrol 10:101–109

    CAS  Google Scholar 

  6. Yoshikawa N, Honda M, Iijima K, Awazu M, Hattori S, Nakanishi K, Ito H, Japanese Pediatric IgA Nephropathy Treatment Study Group (2006) Steroid treatment for severe childhood IgA nephropathy: a randomized controlled trial. Clin J Am Soc Nephrol 1:511–517

    Article  CAS  Google Scholar 

  7. Yokota S (2002) Mizoribine: mode of action and effects in clinical use. Pediatr Int 44:196–198

    Article  CAS  Google Scholar 

  8. Yoshikawa N, Ito H, Yoshiara S, Nakahara C, Yoshiya K, Hasegawa O, Matsuo T (1987) Clinical course of IgA nephropathy in children. J Pediatr 110:555–560

    Article  CAS  Google Scholar 

  9. Churg J, Bernstein J, Glassock RJ (1995) Renal disease: classification and atlas of glomerular diseases, 2nd edn. Igaku-shoin Medical Publishers, Tokyo, Japan, pp 86–88

    Google Scholar 

  10. Guignard JP, Santos F (2004) Laboratory investigations. In: Avner ED, Harmon WE, Niaudet P (eds) Pediatric nephrology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 399–424

    Google Scholar 

  11. Vogt BA, Avner ED (2004) Conditions particularly associated with proteinuria. In: Behrman RE, Kliegman RM, Jenson HB (eds) Nelson textbook of pediatrics, 17th edn. Elsevier Science, Philadelphia, pp 1751–1752

    Google Scholar 

  12. Kaiho S, Mizuno K (1985) Sensitive assay systems for the detection of hemoglobin with 2,7-diaminofluorene: histochemistry and colorimetry for erythrodifferentiation. Anal Biochem 149:117–120

    Article  CAS  Google Scholar 

  13. Amemiya H, Itoh H (1994) Mizoribine (Bredinin): mode of action, effects on graft rejection. In: Thomason AW, Starzl TE (eds) Immunosuppressive drugs. Edward Arnold, London, pp 161–176

    Google Scholar 

  14. Kamata K, Okubo M, Ishigamori E, Masaki Y, Uchida H, Watanabe K, Kashiwagi N (1983) Immunosuppressive effect of bredinin on cell-mediated and humoral immune reactions in experimental animals. Transplantation 35:144–149

    Article  CAS  Google Scholar 

  15. Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, Tanizawa T, Wada H, Maki S (2000) A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int 58:317–324

    Article  CAS  Google Scholar 

  16. Kusumi T, Tsuda M, Katsunuma T, Yamamura M (1989) Dual inhibitory effect of bredinin. Cell Biochem Funct 7:201–204

    Article  CAS  Google Scholar 

  17. LePage GA, Whitecar JP Jr (1971) Pharmacology of 6-thioguanine in man. Cancer Res 31:1627–1631

    CAS  PubMed  Google Scholar 

  18. Barratt J, Feehally J (2006) Treatment of IgA nephropathy. Kidney Int 69:1934–1938

    Article  CAS  Google Scholar 

  19. Wyatt RJ, Hogg RJ (2001) Evidence-based assessment of treatment options for children with IgA nephropathies. Pediatr Nephrol 16:156–167

    Article  CAS  Google Scholar 

  20. Samuels JA, Strippoli GF, Craig JC, Schena FP, Molony DA (2004) Immunosuppressive treatments for immunoglobulin A nephropathy: a meta-analysis of randomized controlled trials. Nephrology [Carlton] 9:177–185

    Article  CAS  Google Scholar 

  21. Pozzi C, Bolasco PG, Fogazzi GB, Andrulli S, Altieri P, Ponticelli C, Locatelli F (1999) Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet 353:883–887

    Article  CAS  Google Scholar 

  22. Pozzi C, Andrulli S, Del Vecchio L, Melis P, Fogazzi GB, Altieri P, Ponticelli C, Locatelli F (2004) Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J Am Soc Nephrol 15:157–163

    Article  CAS  Google Scholar 

  23. Ballardie FW, Roberts IS (2002) Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol 13:142–148

    CAS  PubMed  Google Scholar 

  24. Maes BD, Oyen R, Claes K, Evenepoel P, Kuypers D, Vanwalleghem J, Van Damme B, Vanrenterghem YF (2004) Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study. Kidney Int 65:1842–1849

    Article  CAS  Google Scholar 

  25. Frisch G, Lin J, Rosenstock J, Markowitz G, D’Agati V, Radhakrishnan J, Preddie D, Crew J, Valeri A, Appel G (2005) Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial. Nephrol Dial Transplant 20:2139–2145

    Article  CAS  Google Scholar 

  26. Tang S, Leung JC, Chan LY, Lui YH, Tang CS, Kan CH, Ho YW, Lai KN (2005) Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy. Kidney Int 68:802–812

    Article  CAS  Google Scholar 

  27. Nakanishi K, Honda M, Yoshikawa N (2004) Pediatric nephrology around the world: Japan. In Avner ED, Harmon WE, Niaudet P (eds) Pediatric nephrology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1491–1493

    Google Scholar 

  28. Stevens LA, Greene T, Levey AS (2006) Surrogate end points for clinical trials of kidney disease progression. Clin J Am Soc Nephrol 1:874–884

    Article  Google Scholar 

  29. Kawasaki Y, Suzuki J, Sakai N, Etoh S, Murai H, Nozawa R, Suzuki H (2004) Efficacy of prednisolone and mizoribine therapy for diffuse IgA nephropathy. Am J Nephrol 24:147–153

    Article  CAS  Google Scholar 

  30. Nagaoka R, Kaneko K, Ohtomo Y, Yamashiro Y (2002) Mizoribine treatment for childhood IgA nephropathy. Pediatr Int 44:217–223

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by Health and Labor Sciences Research Grants (Research on Children and Families) from the Japanese Ministry of Health Labor and Welfare and in part by a research grant from Asahi Kasei Pharma.

Part of this study was presented in the 14th Congress of IPNA, Budapest, Hungary, 2007, and the 40th Annual Meeting of the ASN, San Francisco, CA, USA, 2007, and was published in abstract form (J Am Soc Nephrol 18:559A, 2007).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan

    Norishige Yoshikawa & Koichi Nakanishi

  2. Department of Pediatric Nephrology, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo, Japan

    Kenji Ishikura, Hiroshi Hataya & Masataka Honda

  3. Department of Nephrology, National Center for Child Health and Development, Tokyo, Japan

    Kazumoto Iijima

Authors
  1. Norishige Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koichi Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenji Ishikura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroshi Hataya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazumoto Iijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masataka Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

For the Japanese Pediatric IgA Nephropathy Treatment Study Group

Corresponding author

Correspondence to Norishige Yoshikawa.

Additional information

*Participants listed at end of paper.

Appendix

Appendix

The Japanese Pediatric IgA Nephropathy Treatment Study Group

Coordinating committee: H. Ito (Tokyo), N. Yoshikawa (Wakayama).

Statistics committee: T. Kawamura (Nagoya).

Investigators: S. Hoshii (Sapporo); K. Kawamura (Sakura); M. Honda, M. Ikeda, H. Hataya, K. Ishikura, K. Iijima, (Tokyo); S. Ito (Yokohama); K. Nakanishi (Wakayama); K. Nozu (Kobe); A. Furuse (Kumamoto).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshikawa, N., Nakanishi, K., Ishikura, K. et al. Combination therapy with mizoribine for severe childhood IgA nephropathy: a pilot study. Pediatr Nephrol 23, 757–763 (2008). https://doi.org/10.1007/s00467-007-0731-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-007-0731-8

Keywords

Search

Navigation