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Clinical and Experimental Nephrology

, Volume 23, Issue 2, pp 244–250 | Cite as

Positive effects of single-daily high-dose mizoribine therapy after cyclophosphamide in young children with steroid-dependent nephrotic syndrome

  • Akira Mizutani
  • Shuichiro FujinagaEmail author
  • Koji Sakuraya
  • Daishi Hirano
  • Toshiaki Shimizu
Original article
  • 80 Downloads

Abstract

Background

Mizoribine (MZR) therapy after cyclophosphamide (CPM) therapy may be an attractive option in patients with steroid-dependent nephrotic syndrome (SDNS) for the purpose of maintaining remission. This is because CPM is administered only once due to its severe side effects such as gonadal toxicity. However, the long-term prognosis after the treatment regimen remains unknown.

Methods

We retrospectively analyzed the clinical course (median follow-up, 5.9 years) of 54 young children with SDNS (43 boys; age < 10 years) who had undergone 12-week CPM therapy. The patients were classified into two groups: group A, undergoing MZR therapy for > 12 months for maintaining remission after CPM therapy (N = 36), and group B, undergoing CPM monotherapy (N = 18).

Results

For 2 years after CPM therapy, 21 of the 36 group A patients were in sustained remission, whereas only 4 of the 18 group B patients had maintained remission (58% vs. 22%, p < 0.05). Furthermore, the rate of regression to SDNS after CPM was significantly lower in group A than in group B (6% vs. 39%, p < 0.05). At the last follow-up (mean age, 10.9 years), 27 of the 36 group A patients (75%) had not received any steroid-sparing agent after the treatment regimen.

Conclusions

Single daily high-dose MZR therapy after CPM therapy may have positive outcomes in young children with SDNS in the long term.

Keywords

Mizoribine Cyclophosphamide Steroid-dependent nephrotic syndrome Young children 

Notes

Funding

SF received clinical research funding B at Saitama Children’s Medical Center.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Research Committee and/or National Research Committee at which the study was conducted (approval number 2018-02-19) with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all participants included in this study.

References

  1. 1.
    Fujinaga S, Endo A, Ohtomo Y, Ohtsuka Y, Shimizu T. Uncertainty in management of childhood-onset idiopathic nephrotic syndrome: is the long-term prognosis really favorable? Pediatr Nephrol. 2013;28:2235–8.CrossRefGoogle Scholar
  2. 2.
    Ishikura K, Matsumoto S, Sako M, Tsuruga K, Nakanishi K, Kamei K, Saito H, Fujinaga S, Hamasaki Y, Chikamoto H, Ohtsuka Y, Komatsu Y, Ohta T, Nagai T, Kaito H, Kondo S, Ikezumi Y, Tanaka S, Kaku Y, Iijima K, Japanese Society for Pediatric Nephrology, Japanese Society for Pediatric Nephrology. Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: medical therapy. Clin Exp Nephrol. 2015;19:6–33.CrossRefGoogle Scholar
  3. 3.
    Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis: Steroid-sensitive nephrotic syndrome in children. Kidney Int Suppl. 2012;2:163–71.CrossRefGoogle Scholar
  4. 4.
    Fujinaga S, Hirano D, Nishizaki N, Someya T, Ohtomo Y, Ohtsuka Y, Shimizu T, Kaneko K. Single daily high-dose mizoribine therapy for children with steroid-dependent nephrotic syndrome prior to cyclosporine administration. Pediatr Nephrol. 2011;26:479–83.CrossRefGoogle Scholar
  5. 5.
    Fujinaga S, Endo A, Watanabe T, Hirano D, Ohtomo Y, Shimizu T, Kaneko K. Maintenance therapy with single-daily, high-dose mizoribine after cyclophosphamide therapy for prepubertal boys with severe steroid-dependent nephrotic syndrome. Clin Nephrol. 2012;78:251–2.CrossRefGoogle Scholar
  6. 6.
    International Study of Kidney Disease in Children. Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int. 1978;13:159–65.CrossRefGoogle Scholar
  7. 7.
    Ishikura K, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Yata N, Ando T, Honda M, for Japanese Study Group of Renal Disease in Children. Treatment with microemulsified cyclosporine in children with frequently relapsing nephrotic syndrome. Nephrol Dial Transpl. 2010;25:3956–62.CrossRefGoogle Scholar
  8. 8.
    Iijima K, Sako M, Oba MS, Ito S, Hataya H, Tanaka R, Ohwada Y, Kamei K, Ishikura K, Yata N, Nozu K, Honda M, Nakamura H, Nagata M, Ohashi Y, Nakanishi K, Yoshikawa N, Japanese Study Group of Kidney Disease in Children. Cyclosporine C2 monitoring for the treatment of frequently relapsing nephrotic syndrome in children: a multicenter randomized phase II trial. Clin J Am Soc Nephrol. 2014;9:271–8.CrossRefGoogle Scholar
  9. 9.
    Ishikura K, Yoshikawa N, Nakazato H, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ito S, Yata N, Ando T, Honda M, Japanese Study Group of Renal Disease in Children. Two-year follow-up of a prospective clinical trial of cyclosporine for frequently relapsing nephrotic syndrome in children. Clin J Am Soc Nephrol. 2012;7:1576–83.CrossRefGoogle Scholar
  10. 10.
    Ishikura K, Yoshikawa N, Nakazato H, Sasaki S, Nakanishi K, Matsuyama T, Ito S, Hamasaki Y, Yata N, Ando T, Iijima K, Honda M, Japanese Study Group of Renal Disease in Children. Morbidity in children with frequently relapsing nephrosis: 10-year follow-up of a randomized controlled trial. Pediatr Nephrol. 2015;30:459–68.CrossRefGoogle Scholar
  11. 11.
    Trompeter RS, Lloyd BW, Hicks J, White RH, Cameron JS. Long-term outcome for children with minimal-change nephrotic syndrome. Lancet. 1985;16:368–70.CrossRefGoogle Scholar
  12. 12.
    Lewis MA, Baildom EM, Davis N, Houston IB, Postlethwaite RJ. Nephrotic syndrome: from toddlers to twenties. Lancet. 1989;4:255–9.CrossRefGoogle Scholar
  13. 13.
    Fakhouri F, Bocquet N, Taupin P, Presne C, Gagnadoux MF, Landais P, Lesavre P, Chauveau D, Knebelmann B, Broyer M, Grünfeld JP, Niaudet P. Steroid-sensitive nephrotic syndrome: from childhood to adulthood. Am J Kidney Dis. 2003;41:550–7.CrossRefGoogle Scholar
  14. 14.
    Rüth EM, Kemper MJ, Leumann EP, Laube GF, Neuhaus TJ. Children with steroid-sensitive nephrotic syndrome come of age: long-term outcome. J Pediatr. 2005;147:202–7.CrossRefGoogle Scholar
  15. 15.
    Kyrieleis HA, Levtchenko EN, Wetzels JF. Long-term outcome after cyclophosphamide treatment in children with steroid-dependent and frequently relapsing minimal change nephrotic syndrome. Am J Kidney Dis. 2007;49:592–7.CrossRefGoogle Scholar
  16. 16.
    Cammas B, Harambat J, Bertholet-Thomas A, Bouissou F, Morin D, Guigonis V, Bendeddouche S, Afroukh-Hacini N, Cochat P, Llanas B, Decramer S, Ranchin B. Long-term effects of cyclophosphamide therapy in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. Nephrol Dial Transpl. 2011;26:178–84.CrossRefGoogle Scholar
  17. 17.
    Vester U, Kranz B, Zimmermann S, Hoyer PF. Cyclophosphamide in steroid-sensitive nephrotic syndrome: outcome and outlook. Pediatr Nephrol. 2003;18:661–4.Google Scholar
  18. 18.
    Azib S, Macher MA, Kwon T, Dechartres A, Alberti C, Loirat C, Deschênes G, Baudouin V. Cyclophosphamide in steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2011;26:927–32.CrossRefGoogle Scholar
  19. 19.
    Ueda N, Kuno K, Ito S. Eight and 12 week courses of cyclophosphamide in nephrotic syndrome. Arch Dis Child. 1990;65:1147–50.CrossRefGoogle Scholar
  20. 20.
    Kemper MJ, Altrogge H, Ludwig K, Timmermann K, Müller-Wiefel DE. Unfavorable response to cyclophosphamide in steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2000;14:772–5.CrossRefGoogle Scholar
  21. 21.
    Zagury A, de Oliveira AL, de Moraes CA, de Araujo Montalvão JA, Novaes RH, de Sá VM, de Carvalho DDBM, Matuck T. Long-term follow-up after cyclophosphamide therapy in steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2011;26:915–20.CrossRefGoogle Scholar
  22. 22.
    Takeuchi S, Hiromura K, Tomioka M, Takahashi S, Sakairi T, Maeshima A, Kaneko Y, Kuroiwa T, Nojima Y. The immunosuppressive drug mizoribine directly prevents podocyte injury in puromycin aminonucleoside nephrosis. Nephron Exp Nephrol. 2010;116:e3–10.CrossRefGoogle Scholar
  23. 23.
    Nakajo A, Khoshnoodi J, Takenaka H, Hagiwara E, Watanabe T, Kawakami H, Kurayama R, Sekine Y, Bessho F, Takahashi S, Swiatecka-Urban A, Tryggvason K, Yan K. Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance. J Am Soc Nephrol. 2007;18:2554–64.CrossRefGoogle Scholar
  24. 24.
    Ohtomo Y, Fujinaga S, Takada M, Murakami H, Akashi S, Shimizu T, Kaneko K, Yamashiro Y. High-dose mizoribine therapy for childhood-onset frequently relapsing steroid-dependent nephrotic syndrome with cyclosporin nephrotoxicity. Pediatr Nephrol. 2005;20:1744–9.CrossRefGoogle Scholar
  25. 25.
    Kawasaki Y, Suzuki J, Takahashi A, Isome M, Nozawa R, Suzuki H. Mizoribine oral pulse therapy for steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2005;20:96–8.CrossRefGoogle Scholar
  26. 26.
    Fujieda M, Ishihara M, Morita T, Hayashi A, Utsunomiya Y, Ohta T, Sakano T, Wakiguchi H. Effect of oral mizoribine pulse therapy for frequently relapsing steroid-dependent nephrotic syndrome. Clin Nephrol. 2008;69:179–84.CrossRefGoogle Scholar
  27. 27.
    Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, Tanizawa T, Wada H, Maki S. A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int. 2000;58:317–24.CrossRefGoogle Scholar
  28. 28.
    Takahashi S, Wakui H, Gustafsson JA, Zilliacus J, Itoh H. Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein. Biochem Biophys Res Commun. 2000;274(1):87–92.CrossRefGoogle Scholar
  29. 29.
    Ito S, Ikeda H, Harada T, Kamei K, Takahashi E. Cyclophosphamide followed by mizoribine as maintenance therapy against refractory steroid dependent nephrotic syndrome. Pediatr Nephrol. 2011;26:1921–2.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2018

Authors and Affiliations

  1. 1.Division of NephrologySaitama Children’s Medical CenterSaitama-cityJapan
  2. 2.Department of Pediatrics and Adolescent MedicineJuntendo University Graduate School of MedicineTokyoJapan
  3. 3.Department of PediatricsThe Jikei University School of MedicineTokyoJapan

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