Pediatric Nephrology

, Volume 28, Issue 2, pp 257–264 | Cite as

Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome

  • Shuichi Ito
  • Koichi Kamei
  • Masao Ogura
  • Tomohiro Udagawa
  • Shuichiro Fujinaga
  • Mari Saito
  • Mayumi Sako
  • Kazumoto Iijima
Original Article



Rituximab (RTX) is a promising option for treating childhood-onset steroid-dependent (SDNS), frequently relapsing (FRNS), and steroid-resistant (SRNS) nephrotic syndrome.


We retrospectively surveyed RTX treatment for these conditions to evaluate its indications, efficacy and adverse events. Questionnaires were sent to 141 hospitals in Japan.


Seventy-four patients (52 SDNS; 3 FRNS; 19 SRNS) were treated with RTX because of resistance to various immunosuppressive agents. Most patients received a single administration of RTX (85%). Forty-one of 53 SDNS/FRNS (77%) and 5 of 17 SRNS (29%) patients successfully discontinued prednisolone (16 SDNS/FRNS and 6 SRNS achieved their first discontinuation since onset), and 17 out of 53 SDNS/FRNS patients (31%) discontinued cyclosporine. However, 28 of the 53 patients (51%) relapsed. Although immunosuppressive agents did not extend B cell depletion, relapses were significantly less if immunosuppressive agents were continued after RTX (P = 0.006; hazard ratio = 0.2). Among the SRNS patients, complete (n = 6) and partial remission (n = 6) were achieved. No life-threatening adverse events were experienced.


Although this was a multi-center survey where treatment of nephrotic syndrome varied between centers, the steroid-sparing effect of RTX in SDNS/FRNS was excellent. If single administration of RTX is chosen, continuation of immunosuppressive agents is recommended for prevention of relapse.


Rituximab Nephrotic syndrome Children Steroid Steroid-dependent nephrotic syndrome Steroid-resistant nephrotic syndrome Immunosuppressive agents 



This work had no financial support. The authors appreciate the doctors who collaborated on our questionnaire: Daishi Hirano, Saitama Children’s Medical Center, Saitama, Japan; Hiroshi Kaito, Kobe University, Kobe, Japan; Tomonori Harada, Yokohama City University Medical Center, Yokohama, Japan; Hiroshi Tanaka, Hirosaki University, Hirosaki, Japan; Toshio Watanabe, Gunma University, Maebashi, Japan; Masaki Shimizu, Kanazawa University, Kanazawa, Japan; Naohiro Wada, Shizouka Children’s Hospital, Shizuoka, Japan; Osamu Uemura, Aichi Children’s Health and Medical Center, Ohbu, Japan; Masashi Nishida, Kyoto Prefectural University of Medicine, Kyoto, Japan; Kenichi Satomura, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan; Rika Fujimaru, Osaka City General Hospital, Osaka Japan; Ryojiro Tanaka, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan; and Kohei Maekawa, Hyogo College of Medicine, Nishinomiya, Japan.


  1. 1.
    Bagga A, Sinha A, Moudgil A (2007) Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356:2751–2752PubMedCrossRefGoogle Scholar
  2. 2.
    Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H, Raynaud N, Taque S, Ronco P, Bouissou F (2008) Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr Nephrol 23:1269–1279PubMedCrossRefGoogle Scholar
  3. 3.
    Kamei K, Ito S, Nozu K, Fujinaga S, Nakayama M, Sako M, Saito M, Yoneko M, Iijima K (2009) Single dose of rituximab for refractory steroid-dependent nephrotic syndrome in children. Pediatr Nephrol 24:1321–1328PubMedCrossRefGoogle Scholar
  4. 4.
    Prytuła A, Iijima K, Kamei K, Geary D, Gottlich E, Majeed A, Taylor M, Marks SD, Tuchman S, Camilla R, Ognjanovic M, Filler G, Smith G, Tullus K (2010) Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 25:461–468PubMedCrossRefGoogle Scholar
  5. 5.
    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 5:2207–2212PubMedCrossRefGoogle Scholar
  6. 6.
    Kemper MJ, Gellermann J, Habbig S, Krmar RT, Dittrich K, Jungraithmayr T, Pape L, Patzer L, Billing H, Weber L, Pohl M, Rosenthal K, Rosahl A, Mueller-Wiefel DE, Dötsch J (2012) Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant 27:1910–1915PubMedCrossRefGoogle Scholar
  7. 7.
    Ravani P, Magnasco A, Edefonti A, Murer L, Rossi R, Ghio L, Benetti E, Scozzola F, Pasini A, Dallera N, Sica F, Belingheri M, Scolari F, Ghiggeri GM (2011) Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial. Clin J Am Soc Nephrol 6:1308–1315PubMedCrossRefGoogle Scholar
  8. 8.
    Sellier-Leclerc AL, Baudouin V, Kwon T, Macher MA, Guérin V, Lapillonne H, Deschênes G, Ulinski T (2012) Rituximab in steroid-dependent idiopathic nephrotic syndrome in childhood–follow-up after CD19 recovery. Nephrol Dial Transplant 27:1083–1089PubMedCrossRefGoogle Scholar
  9. 9.
    Benz K, Dötsch J, Rascher W, Stachel D (2001) Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol 19:794–797CrossRefGoogle Scholar
  10. 10.
    Nozu K, Iijima K, Fujisawa M, Nakagawa A, Yoshikawa N, Matsuo M (2005) Rituximab treatment for posttransplant lymphoproliferative disorder (PTLD) induces complete remission of recurrent nephrotic syndrome. Pediatr Nephrol 20:1660–1663PubMedCrossRefGoogle Scholar
  11. 11.
    Ito S, Kamei K, Ogura M, Sato M, Fujimaru T, Ishikawa T, Udagawa T, Iijima K (2011) Maintenance therapy with MMF after rituximab in pediatric patients with steroid-dependent nephrotic syndrome. Pediatr Nephrol 26:1823–1828PubMedCrossRefGoogle 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-charge nephritic syndrome after long-term cyclosporine. Pediatr Nephrol 25:539–544PubMedCrossRefGoogle Scholar
  13. 13.
    Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Furmann RR, Winter JN, Vose JM, Zelenets AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Litell NR, Talley RL, Sartot O, Green D, Major EO, lBennett CL (2009) Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113:4834–4840PubMedCrossRefGoogle Scholar
  14. 14.
    Chaumais MC, Garnier A, Chalard F, Peuchmaur M, Dauger S, Jacqz-Agrain E, Deschênes G (2009) Fatal pulmonary fibrosis after rituximab administration. Pediatr Nephrol 24:1753–1755PubMedCrossRefGoogle Scholar
  15. 15.
    Ardelean DS, Gonska T, Wires S, Cutz E, Griffiths A, Harvey E, Tse SM, Benseler SM (2010) Severe ulcerative colitis after rituximab therapy. Pediatrics 126:e243–e246PubMedCrossRefGoogle Scholar
  16. 16.
    Gipson DS, Massengill SF, Yao L, Nagaraj S, Smoyer WE, Mahan JD, Wigfall D, Miles P, Powell L, Lin JJ, Trachtman H, Greenbaum LA (2009) Management of childhood onset nephrotic syndrome. Pediatrics 124:747–757PubMedCrossRefGoogle Scholar
  17. 17.
    Sairam VK, Kalia A, Rajaraman S, Travis LB (2002) Secondary resistance to cyclosporin A in children with nephrotic syndrome. Pediatr Nephrol 17:842–846PubMedCrossRefGoogle Scholar
  18. 18.
    Kemper MJ, Kuwertz-Broeking E, Bulla M, Mueller-Wiefel DE, Neuhaus TJ (2004) Recurrence of severe steroid dependency in cyclosporin A-treated childhood idiopathic nephrotic syndrome. Nephrol Dial Transplant 19:1136–1141PubMedCrossRefGoogle Scholar
  19. 19.
    Fujinaga S, Kaneko K, Muto T, Ohtomo Y, Murakami H, Yamashiro Y (2006) Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome. Arch Dis Child 91:666–670PubMedCrossRefGoogle Scholar
  20. 20.
    Iijima K, Hamahira K, Tanaka R, Kobayashi A, Nozu K, Nakamura H, Yoshikawa N (2002) Risk factors for cyclosporine-induced tubulointerstitial lesions in children with minimal change nephrotic syndrome. Kidney Int 618:1801–1805CrossRefGoogle Scholar
  21. 21.
    Hamasaki Y, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ishikura K, Yata N, Kaneko T, Honda M (2009) Cyclosporine and steroid therapy in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 24:2177–2185PubMedCrossRefGoogle Scholar
  22. 22.
    Plank C, Kalb V, Hinkes B, Hildebrandt F, Gefeller O, Rascher W, for Arbeitsgemeinschaft für Pädiatrische Nephrologie (2008) Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie. Pediatr Nephrol 23:1483–1493PubMedCrossRefGoogle Scholar
  23. 23.
    Sinha A, Bagga A, Gulati A, Hari P (2012) Short-term efficacy of rituximab versus tacrolimus in steroid-dependent nephritic syndrome. Pediatr Nephrol 27:235–241PubMedCrossRefGoogle Scholar
  24. 24.
    Nakayama M, Kamei K, Nozu K, Matsuoka K, Nakagawa A, Sako M, Iijima K (2008) Rituximab for refractory focal segmental glomerulosclerosis. Pediatr Nephrol 23:481–485PubMedCrossRefGoogle Scholar
  25. 25.
    Kari JA, El-Morshedy SM, El-Desoky S, Alshaya HO, Rahim KA, Edrees BM (2011) Rituximab for refractory cases of childhood nephrotic syndrome. Pediatr Nephrol 26:733–737PubMedCrossRefGoogle Scholar
  26. 26.
    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 23:1117–1124PubMedCrossRefGoogle Scholar
  27. 27.
    Teichmann LL, Woenckhaus M, Vogel C, Salzberger B, Scholmerich J, Fleck M (2008) Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology 47:1256–1257PubMedCrossRefGoogle Scholar
  28. 28.
    Kumar D, Gourishankar S, Mueller T, Cockfield S, Weinkauf J, Vethanayagam D, Humar A (2009) Pneumocystis jirovecii pneumonia after rituximab therapy for antibody-mediated rejection in a renal transplant recipient. Transpl Infect Dis 11:167–170PubMedCrossRefGoogle Scholar
  29. 29.
    Shelton E, Yong M, Cohney S (2009) Late onset Pneumocystis pneumonia in patients receiving rituximab for humoral renal transplant rejection. Nephrology 14:96–99CrossRefGoogle Scholar
  30. 30.
    Kamei K, Ito S, Iijima K (2010) Severe respiratory adverse events associated with rituximab infusion. Pediatr Nephrol 25:1193PubMedCrossRefGoogle Scholar
  31. 31.
    Yri OE, Torfoss D, Hungnes O, Tierens A, Waalen K, Nordøy T, Dudman S, Kilander A, Wader KF, Ostenstad B, Ekanger R, Meyer P, Kolstad A (2011) Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood 118:6769–6771PubMedCrossRefGoogle Scholar
  32. 32.
    Sharma AP, Filler G (2009) Role of mycophenolate mofetil in remission maintenance after a successful response to rituximab. Pediatr Nephrol 24:423–424PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2012

Authors and Affiliations

  • Shuichi Ito
    • 1
    • 5
  • Koichi Kamei
    • 1
  • Masao Ogura
    • 1
  • Tomohiro Udagawa
    • 1
  • Shuichiro Fujinaga
    • 2
  • Mari Saito
    • 3
  • Mayumi Sako
    • 3
  • Kazumoto Iijima
    • 4
  1. 1.Division of Pediatric Nephrology and RheumatologyNational Center for Child Health and DevelopmentTokyoJapan
  2. 2.Division of NephrologySaitama Children’s Medical CenterSaitamaJapan
  3. 3.Clinical Research CenterNational Center for Child Health and DevelopmentTokyoJapan
  4. 4.Division of Child Health & Development, Department of PediatricsKobe University Graduate School of MedicineKobeJapan
  5. 5.Division of Nephrology and RheumatologyNational Center for Child Health and DevelopmentTokyoJapan

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