Pediatric Nephrology

, Volume 28, Issue 7, pp 1001–1009 | Cite as

Indications for use and safety of rituximab in childhood renal diseases



Rituximab was initially developed for the treatment of patients with B cell lymphoma but has during the last decade proven to be quite effective in treating a range of kidney diseases including lupus nephritis, nephrotic syndrome, and also in different situations before and after a renal transplant. We will here review the scientific basis for the use of rituximab in children with renal diseases and give recommendations both regarding its clinical use and need for further research.


Rituximab SLE Nephrotic syndrome Renal transplant 


  1. 1.
    Cambier JC, Gauld SB, Merrell KT, Vilen BJ (2007) B-cell anergy: from transgenic models to naturally occurring anergic B cells? Nat Rev Immunol 7(8):633–643PubMedCrossRefGoogle Scholar
  2. 2.
    Ganne V, Siddiqi N, Kamaplath B, Chang CC, Cohen EP, Bresnahan BA, Hariharan S (2003) Humanized anti-CD20 monoclonal antibody (rituximab) treatment for post-transplant lymphoproliferative disorder. Clin Transplant 17(5):417–422PubMedCrossRefGoogle Scholar
  3. 3.
    Hainsworth JD, Burris HA III, Morrissey LH, Litchy S, Scullin DC Jr, Bearden JD III, Richards P, Greco FA (2000) Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood 95(10):3052–3056PubMedGoogle Scholar
  4. 4.
    Dar O, Salaman MR, Seifert MH, Isenberg DA (1988) B lymphocyte activation in systemic lupus erythematosus: spontaneous production of IgG antibodies to DNA and environmental antigens in cultures of blood mononuclear cells. Clin Exp Immunol 73(3):430–435PubMedGoogle Scholar
  5. 5.
    Odendahl M, Keitzer R, Wahn U, Hiepe F, Radbruch A, Dorner T, Bunikowski R (2003) Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus. Ann Rheum Dis 62(9):851–858PubMedCrossRefGoogle Scholar
  6. 6.
    Chan O, Shlomchik MJ (1998) A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 160(1):51–59PubMedGoogle Scholar
  7. 7.
    Chan OT, Madaio MP, Shlomchik MJ (1999) The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 169:107–121PubMedCrossRefGoogle Scholar
  8. 8.
    Reininger L, Winkler TH, Kalberer CP, Jourdan M, Melchers F, Rolink AG (1996) Intrinsic B cell defects in NZB and NZW mice contribute to systemic lupus erythematosus in (NZB x NZW)F1 mice. J Exp Med 184(3):853–861PubMedCrossRefGoogle Scholar
  9. 9.
    Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, Lipsky PE, Radbruch A, Dorner T (2000) Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 165(10):5970–5979PubMedGoogle Scholar
  10. 10.
    ten Cate R, Smiers FJ, Bredius RG, Lankester AC, van Suijlekom-Smit LW, Huizinga TW, Egeler RM (2004) Anti-CD20 monoclonal antibody (rituximab) for refractory autoimmune thrombocytopenia in a girl with systemic lupus erythematosus. Rheumatology (Oxford) 43(2):244CrossRefGoogle Scholar
  11. 11.
    Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA (2002) An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 46(10):2673–2677PubMedCrossRefGoogle Scholar
  12. 12.
    Lu TY, Ng KP, Cambridge G, Leandro MJ, Edwards JC, Ehrenstein M, Isenberg DA (2009) A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients. Arthritis Rheum 61(4):482–487PubMedCrossRefGoogle Scholar
  13. 13.
    Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, Sanz I (2004) Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 50(11):3580–3590PubMedCrossRefGoogle Scholar
  14. 14.
    Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, Sloand JA, Rosenblatt J, Sanz I (2004) B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 50(8):2580–2589PubMedCrossRefGoogle Scholar
  15. 15.
    Vigna-Perez M, Hernandez-Castro B, Paredes-Saharopulos O, Portales-Perez D, Baranda L, Abud-Mendoza C, Conzalez-Amaro R (2006) Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 8(3):R83PubMedCrossRefGoogle Scholar
  16. 16.
    Diaz-Lagares C, Croca S, Sangle S, Vital EM, Catapano F, Martinez-Berriotxoa A, Garcia-Hernandez F, Callejas-Rubio JL, Rascon J, D’Cruz D, Jayne D, Ruiz-Irastorza G, Emery P, Isenberg D, Ramos-Casalas M, Khamashta MA, UK-BIOGEAS (2012) Registry efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 11(5):357–364PubMedCrossRefGoogle Scholar
  17. 17.
    Marks SD, Patey S, Brogan PA, Hasson N, Pilkington C, Woo P, Tullus K (2005) B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 52(10):3168–3174PubMedCrossRefGoogle Scholar
  18. 18.
    Podolskaya A, Stadermann M, Pilkington C, Marks SD, Tullus K (2008) B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch Dis Child 93(5):401–406PubMedCrossRefGoogle Scholar
  19. 19.
    Willems M, Haddad E, Niaudet P, Kone-Paut I, Bensman A, Cochat P, Deschenes G, Fakhouri F, Leblanc T, Llanas B, Loirat C, Pillet P, Ranchin B, Salomon R, Ulinski T, Badaer-Meunier B, French Pediatric-Onset SLE Study Group (2006) Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 148(5):623–627PubMedCrossRefGoogle Scholar
  20. 20.
    Marks SD, Tullus K (2010) Modern therapeutic strategies for paediatric systemic lupus erythematosus and lupus nephritis. Acta Paediatr 99(7):967–974PubMedCrossRefGoogle Scholar
  21. 21.
    Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG (2010) Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62(1):222–233PubMedCrossRefGoogle Scholar
  22. 22.
    Merrill J, Buyon J, Furie R, Latinis K, Gordon C, Hsieh HJ, Brunetta P (2011) Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER). Lupus 20(7):709–716PubMedCrossRefGoogle Scholar
  23. 23.
    Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G, LUNAR Investigator Group (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab (LUNAR) study. Arthritis Rheum 64(4):1215–1226PubMedCrossRefGoogle Scholar
  24. 24.
    Mysler E, Spindler A, Guzman R, Bijl M, Jayne D, Furie R, Maciura RD, Drappa J, Shahdad S, Close D (2010) Study design and baseline patient characteristics of BELONG, the randomised double-blind, placebo-controlled phase III trial of ocrelizumab, a humanised anti-CD20 antibody, in lupus nephritis. 9th International Congress on Systemic Lupus Erythematosus, Vancouver, Canada, June 24–27, Poster PO2 E 20 2010, doi:10.1177/09612033100190010101
  25. 25.
    Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, Sanchez-Guerrero J, Schwarting A, Merrill JT, Chatham WW, Stohl W, Ginzler EM, Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF, Bliss-76 Study Group (2011) A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 63(12):3918–3930PubMedCrossRefGoogle Scholar
  26. 26.
    Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, Leon MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA, BLISS-52 Study Group (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377:721–731PubMedCrossRefGoogle Scholar
  27. 27.
    Guerry MJ, Brogan P, Bruce IN, D’Cruz DP, Harper L, Luqmani R, Pusey CD, Salama AD, Scott DG, Savage CO, Watts RA, Jayne DR (2011) Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 51(4):634–643CrossRefGoogle Scholar
  28. 28.
    Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St. Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monarch PA, Piekert T, Stegeman C, Ytterberg SR, Specks U, RAVE-ITN Research Group (2010) Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 363(3):221–232PubMedCrossRefGoogle Scholar
  29. 29.
    Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR, European Vasculitis Study Group (2010) Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 363(3):211–220PubMedCrossRefGoogle Scholar
  30. 30.
    Mansfield N, Hamour S, Habib AM, Tarzi R, Levy J, Griffith M, Cairns T, Cook HT, Pusey CD, Salama AD (2011) Prolonged disease-free remission following rituximab and low-dose cyclophosphamide therapy for renal ANCA-associated vasculitis. Nephrol Dial Transplant 26(10):3280–3286PubMedCrossRefGoogle Scholar
  31. 31.
    Eleftheriou D, Melo M, Marks SD, Tullus K, Sills J, Cleary G, Dolezalova P, Ozen S, Pilkington C, Woo P, Klein N, Dillon MJ, Brogan PA (2009) Biologic therapy in primary systemic vasculitis of the young. Rheumatology (Oxford) 48(8):978–986CrossRefGoogle Scholar
  32. 32.
    Benz K, Dotsch J, Rascher W, Stachel D (2004) Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol 19(7):794–797PubMedCrossRefGoogle Scholar
  33. 33.
    Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le CC, 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(8):1269–1279PubMedCrossRefGoogle Scholar
  34. 34.
    Prytula 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(3):461–468PubMedCrossRefGoogle Scholar
  35. 35.
    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(12):2207–2212PubMedCrossRefGoogle Scholar
  36. 36.
    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, Dotsch J (2012) Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant 27(5):1910–1915PubMedCrossRefGoogle Scholar
  37. 37.
    Sinha A, Bagga A, Gulati A, Hari P (2012) Short-term efficacy of rituximab versus tacrolimus in steroid-dependent nephrotic syndrome. Pediatr Nephrol 27(2):235–241PubMedCrossRefGoogle Scholar
  38. 38.
    Bagga A, Sinha A, Moudgil A (2007) Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356(26):2751–2752PubMedCrossRefGoogle Scholar
  39. 39.
    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(3):539–544PubMedCrossRefGoogle Scholar
  40. 40.
    Ito S, Kamei K, Ogura M, Sato M, Fujimaru T, Ishikawa T, Udagawa T, Iijima K (2011) Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome. Pediatr Nephrol 26(10):1823–1828PubMedCrossRefGoogle Scholar
  41. 41.
    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(7):1321–1328PubMedCrossRefGoogle Scholar
  42. 42.
    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(6):1117–1124PubMedCrossRefGoogle Scholar
  43. 43.
    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(11):1660–1663PubMedCrossRefGoogle Scholar
  44. 44.
    Pescovitz MD, Book BK, Sidner RA (2006) Resolution of recurrent focal segmental glomerulosclerosis proteinuria after rituximab treatment. N Engl J Med 354(18):1961–1963PubMedCrossRefGoogle Scholar
  45. 45.
    Marks SD, McGraw M (2007) Does rituximab treat recurrent focal segmental glomerulosclerosis post-renal transplantation? Pediatr Nephrol 22(1):158–160PubMedCrossRefGoogle Scholar
  46. 46.
    Tyden G, Genberg H, Tollemar J, Ekberg H, Persson NH, Tufveson G, Wadstrom J, Gabel M, Mjornstedt L (2009) A randomized, double-blind, placebo-controlled, study of single-dose rituximab as induction in renal transplantation. Transplantation 87(9):1325–1329PubMedCrossRefGoogle Scholar
  47. 47.
    Tyden G, Donauer J, Wadstrom J, Kumlien G, Wilpert J, Nilsson T, Genberg H, Pisarski P, Tufveson G (2007) Implementation of a Protocol for ABO-incompatible kidney transplantation–a three-center experience with 60 consecutive transplantations. Transplantation 83(9):1153–1155PubMedCrossRefGoogle Scholar
  48. 48.
    Munoz AS, Rioveros AA, Cabanayan-Casasola CB, Danguilan RA, Ona ET (2008) Rituximab in highly sensitized kidney transplant recipients. Transplant Proc 40(7):2218–2221PubMedCrossRefGoogle Scholar
  49. 49.
    Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, WeyK Royston I, Davis T, Levy R (1997) IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90(6):2188–2195PubMedGoogle Scholar
  50. 50.
    EBPG Expert Group on Renal Transplantation (2002) European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment. Nephrol Dial Transplant 17(Suppl 4):31–36Google Scholar
  51. 51.
    Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, Neuhaus R, Lehmkuhl H, Horst HA, Salles G, Morschhauser F, Jaccard A, Lamy T, Leithauser M, Zimmermann H, Anagnostopoulos I, Raphael M, Riess H, Choquet S, German PTLD Study Group; European PTLD Network (2012) Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol 13(2):196–206PubMedCrossRefGoogle Scholar
  52. 52.
    Lehnhardt A, Mengel M, Pape L, Ehrich JH, Offner G, Strehlau J (2006) Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab. Am J Transplant 6(4):847–851PubMedCrossRefGoogle Scholar
  53. 53.
    Muorah MR, Brogan PA, Sebire NJ, Trompeter RS, Marks SD (2009) Dense B cell infiltrates in paediatric renal transplant biopsies are predictive of allograft loss. Pediatr Transplant 13(2):217–222PubMedCrossRefGoogle Scholar
  54. 54.
    Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Salvatierra Masek M, Jr O (2003) Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 349(2):125–138PubMedCrossRefGoogle Scholar
  55. 55.
    Steinmetz OM, Lange-Husken F, Turner JE, Vernauer A, Helmchen U, Stahl RA, Thaiss F, Panzer U (2007) Rituximab removes intrarenal B cell clusters in patients with renal vascular allograft rejection. Transplantation 84(7):842–850PubMedCrossRefGoogle Scholar
  56. 56.
    Faguer S, Kamar N, Guilbeaud-Frugier C, Fort M, Modesto A, Mari A, Ribes D, Cointault O, Lavayssiere L, Guitard J, Durand D, Rostaing L (2007) Rituximab therapy for acute humoral rejection after kidney transplantation. Transplantation 83(9):1277–1280PubMedCrossRefGoogle Scholar
  57. 57.
    Willems M, Haddad E, Niaudet P, Kone-Paut I, Bensman A, Cochat P, Deschenes G, Fakhouri F, Leblanc T, Llanas B, Loirat C, Pillet P, Ranchin B, Salomon R, Ulinski T, Bader-Neunier B, French Pediatric-Onset SLE Study Group (2006) Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 148(5):623–627PubMedCrossRefGoogle Scholar
  58. 58.
    Chaumais MC, Garnier A, Chalard F, Peuchmaur M, Dauger S, Jacqz-Agrain E (2009) Deschenes G (2009) Fatal pulmonary fibrosis after rituximab administration. Pediatr Nephrol 24(9):1753–1755PubMedCrossRefGoogle Scholar
  59. 59.
    Bitzan M, Anselmo M, Carpineta L (2009) Rituximab (B-cell depleting antibody) associated lung injury (RALI): a pediatric case and systematic review of the literature. Pediatr Pulmonol 44(9):922–934PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2012

Authors and Affiliations

  1. 1.Department of Paediatric NephrologyGreat Ormond Street Hospital for Children NHS TrustLondonUK

Personalised recommendations