Pediatric Nephrology

, Volume 34, Issue 2, pp 353–357 | Cite as

Long-term outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome

  • Shuichiro FujinagaEmail author
  • Tomohiko Nishino
  • Chisato Umeda
  • Yuji Tomii
  • Yoshitaka Watanabe
  • Koji Sakuraya
Brief Report



Although rituximab (RTX) may be effective treatment in children with nephrotic syndrome who are resistant to cyclosporine A and steroid (CsA-SRNS), long-term outcomes after B cell depleting therapy remain unclear.


We retrospectively reviewed the clinical courses (median follow-up, 5.1 years) of six CsA-SRNS children (three boys; median age at RTX, 4.2 years) unresponsive to oral cyclosporine combined with ≥ 2 courses of intravenous methylprednisolone pulses, who received RTX within 6 months after disease onset (median 11 weeks). After initial RTX treatment (median two doses of 375 mg/m2) followed by retreatment with intravenous methylprednisolone pulses and/or high-dose prednisolone, all patients achieved complete remission at a median of 158 days. Although 17 relapses occurred in five patients during follow-up, all but one patient became steroid sensitive. Severe neutropenia and hypogammaglobulinemia developed in two and four patients, respectively. However, no life-threatening infections were identified in the cohort. At last visit (median age, 11.3 years), all patients maintained complete remission without renal insufficiency.


Although late-onset adverse events should be considered, particularly for young patients, early RTX treatment may have positive outcomes in children with CsA-SRNS in the long term.


Steroid-resistant nephrotic syndrome Rituximab Cyclosporine Intravenous methylprednisolone pulse Neutropenia Hypogammaglobulinemia 



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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

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 with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

All patients and their parents provided written informed consent. The use of RTX in patients with refractory SR/SDNS in this study was approved by the ethics committee of the aforementioned center (approved number at Saitama Children’s Medical Center, 2007-03-001).


  1. 1.
    Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, Miura K, Aya K, Nakanishi K, Ohtomo Y, Takahashi S, Tanaka R, Kaito H, Nakamura H, Ishikura K, Ito S, Ohashi Y, Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group (2014) Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 384:1273–1281CrossRefGoogle Scholar
  2. 2.
    Ravani P, Rossi R, Bonanni A, Quinn RR, Sica F, Bodria M, Pasini A, Montini G, Edefonti A, Belingheri M, De Giovanni D, Barbano G, Degl'Innocenti L, Scolari F, Murer L, Reiser J, Fornoni A, Ghiggeri GM (2015) Rituximab in children with steroid-dependent nephrotic syndrome: a multicenter, open-label, noninferiority, randomized controlled trial. J Am Soc Nephrol 26:2259–2266CrossRefGoogle Scholar
  3. 3.
    Nakayama M, Kamei K, Nozu K, Matsuoka K, Nakagawa A, Sako M, Iijima K (2008) Rituximab for refractory focal segmental glomerulosclerosis. Pediatr Nephrol 23:481–485CrossRefGoogle Scholar
  4. 4.
    Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK, Sharma S, Srivastava RN, Moudgil A, Bagga A (2010) Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report. Clin J Am Soc Nephrol 5:2207–2212CrossRefGoogle Scholar
  5. 5.
    Ito S, Kamei K, Ogura M, Udagawa T, Fujinaga S, Saito M, Sako M, Iijima K (2013) Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome. Pediatr Nephrol 28:257–264CrossRefGoogle Scholar
  6. 6.
    Kamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M, Kaito H, Iijima K, Ito S (2014) Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome. Pediatr Nephrol 29:1181–1187CrossRefGoogle Scholar
  7. 7.
    Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, Benetti E, Murtas C, Messina G, Massella L, Porcellini MG, Montagna M, Regazzi M, Scolari F, Ghiggeri GM (2012) Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23:1117–1124CrossRefGoogle Scholar
  8. 8.
    Jellouli M, Charfi R, Maalej B, Mahfoud A, Trabelsi S, Gargah T (2018) Rituximab in the management of pediatric steroid-resistant nephrotic syndrome: a systematic review. J Pediatr 197:191–197CrossRefGoogle Scholar
  9. 9.
    Hirano D, Fujinaga S, Nishizaki N (2012) The uncertainty of rituximab and steroid dosing in refractory steroid-resistant nephrotic syndrome. Clin Nephrol 77:510–512CrossRefGoogle Scholar
  10. 10.
    Fujinaga S, Sakuraya K (2017) Repeated administrations of rituximab along with steroids and immunosuppressive agents in refractory steroid-resistant nephrotic syndrome. Indian Pediatr 54:49–50CrossRefGoogle Scholar
  11. 11.
    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 (2015) Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: medical therapy. Clin Exp Nephrol 19:6–33CrossRefGoogle Scholar
  12. 12.
    Fujinaga S, Hirano D, Nishizaki N, Kamei K, Ito S, Ohtomo Y, Shimizu T, Kaneko K (2010) Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr Nephrol 25:539–544CrossRefGoogle Scholar
  13. 13.
    Fujinaga S, Hirano D, Mizutani A, Sakuraya K, Yamada A, Sakurai S, Shimizu T (2017) Predictors of relapse and long-term outcome in children with steroid-dependent nephrotic syndrome after rituximab treatment. Clin Exp Nephrol 21:671–676CrossRefGoogle Scholar
  14. 14.
    Fujinaga S, Ozawa K, Sakuraya K, Yamada A, Shimizu T (2016) Late-onset adverse events after a single dose of rituximab in children with complicated steroid-dependent nephrotic syndrome. Clin Nephrol 85:340–345CrossRefGoogle Scholar
  15. 15.
    Kamei K, Takahashi M, Fuyama M, Saida K, Machida H, Sato M, Ogura M, Ito S (2015) Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature. Nephrol Dial Transplant 30:91–96CrossRefGoogle Scholar
  16. 16.
    Bonanni A, Calatroni M, D'Alessandro M, Signa S, Bertelli E, Cioni M, Di Marco E, Biassoni R, Caridi G, Ingrasciotta G, Bertelli R, Di Donato A, Bruschi M, Canepa A, Piaggio G, Ravani P, Ghiggeri GM (2018) Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome. Br J Clin Pharmacol 84:1238–1249CrossRefGoogle Scholar
  17. 17.
    Prasad N, Manjunath R, Rangaswamy D, Jaiswal A, Agarwal V, Bhadauria D, Kaul A, Sharma R, Gupta A (2018) Efficacy and safety of cyclosporine versus tacrolimus in steroid and cyclophosphamide resistant nephrotic syndrome: a prospective study. Indian J Nephrol 28:46–52CrossRefGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  1. 1.Division of NephrologySaitama Children’s Medical CenterSaitama cityJapan

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