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Pediatric Nephrology

, Volume 34, Issue 2, pp 253–259 | Cite as

Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome

  • Julien HoganEmail author
  • Claire Dossier
  • Thérésa Kwon
  • Marie-Alice Macher
  • Anne Maisin
  • Anne Couderc
  • Olivier Niel
  • Véronique Baudouin
  • Georges Deschênes
Original Article

Abstract

Background

Several studies have demonstrated that rituximab (RTX) improves relapse-free survival in patients with steroid-dependent nephrotic syndrome (SDNS). However, these studies used various RTX regimens and there are few data comparing these regimens in children with SDNS. In this retrospective study, we assessed the effect of three different initial RTX regimens on both time to B cell reconstitution and to first relapse.

Methods

Sixty-one SDNS patients receiving a first course of RTX were included. Group 1 received one injection of 100 mg/m2, group 2 received one injection of 375 mg/m2, and group 3 received two injections of 375 mg/m2 at day 0 and day 7. Time to B cell reconstitution and time to first relapse and respective risk factors were studied.

Results

Median time to B cell reconstitution was 2.5 [1.8–3.5], 5.0 [3.9–6.0], and 6.6 [4.6–7.8] months in groups 1, 2, and 3, respectively. RTX regimen was associated with time to B cell reconstitution (HRs group 2 vs. 3, 4.07 [1.96–8.48]; group 1 vs. 3, 11.13 [4.04–30.67]). One-year relapse-free survival was 50% [58–77], 59% [42–76], and 72% [46–87] in groups 1, 2, and 3, respectively. RTX regimen was associated with risk of relapse (HRs group 2 vs. 3, 1.55 [0.51–4.65]; group 1 vs. 3, 4.98 [1.15–21.60]).

Conclusions

The initial dose of rituximab impacts time to B cell reconstitution and the probability of relapse. Risk of relapse is also associated with patient characteristics, suggesting that RTX regimen could be modified for each patient to balance efficacy, cost, and side effects.

Keywords

Idiopathic nephrotic syndrome Children B cell Rituximab 

Notes

Authors’ contributions

JHo and GD participated to the conception of the paper, to the analysis of the data, and the writing of the manuscript. CD, TK, MAM, AM, AC, ON, and VB participated to the data collection and to the writing of the manuscript. All the authors have revised the article and approved the final version.

Compliance with ethical standards

Ethics approval was granted through our institutional ethics committee.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

467_2018_4052_MOESM1_ESM.png (26 kb)
Supplementary Figure 1 Predicted time to B cell reconstitution adjusted for age and prior or concomitant Mycophenolate mofetil (MMF) treatment. Group 1: 1 injection 100 mg/m2; Group 2: 1 injection 375 mg/m2; Group 3: 2 injections 375 mg/m2 (PNG 25 kb)
467_2018_4052_MOESM2_ESM.png (16 kb)
Supplementary Figure 2 Predicted time to B cell reconstitution by age adjusted for Rituximab (RTX) regimen and prior or concomitant Mycophenolate mofetil (MMF) treatment (PNG 16 kb)

References

  1. 1.
    Schlesinger ER, Sultz HA, Mosher WE, Feldman JG (1968) The nephrotic syndrome. Its incidence and implications for the community. Am J Dis Child 116:623–632CrossRefGoogle Scholar
  2. 2.
    McKinney PA, Feltbower RG, Brocklebank JT, Fitzpatrick MM (2001) Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK. Pediatr Nephrol 16:1040–1044CrossRefGoogle Scholar
  3. 3.
    Pasini A, Aceto G, Ammenti A, Ardissino G, Azzolina V, Bettinelli A, Cama E, Cantatore S, Crisafi A, Conti G, D’Awgostino M, Dozza A, Edefonti A, Fede C, Groppali E, Gualeni C, Lavacchini A, Lepore M, Maringhini S, Mariotti P, Materassi M, Mencarelli F, Messina G, Negri A, Piepoli M, Ravaglia F, Simoni A, Spagnoletta L, Montini G, NefroKid Study Group (2015) Best practice guidelines for idiopathic nephrotic syndrome: recommendations versus reality. Pediatr Nephrol 30:91–101CrossRefGoogle Scholar
  4. 4.
    Dossier C, Lapidus N, Bayer F, Sellier-Leclerc A-L, Boyer O, de Pontual L, May A, Nathanson S, Orzechowski C, Simon T, Carrat F, Deschênes G (2016) Epidemiology of idiopathic nephrotic syndrome in children: endemic or epidemic? Pediatr Nephrol 31:2299–2308CrossRefGoogle Scholar
  5. 5.
    Benz K, Dötsch J, Rascher W, Stachel D (2004) Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol 19:794–797CrossRefGoogle Scholar
  6. 6.
    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
  7. 7.
    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 23:1269–1279CrossRefGoogle Scholar
  8. 8.
    Sellier-Leclerc A-L, Macher M-A, Loirat C, Guérin V, Watier H, Peuchmaur M, Baudouin V, Deschênes G (2010) Rituximab efficiency in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol 25:1109–1115CrossRefGoogle Scholar
  9. 9.
    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
  10. 10.
    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
  11. 11.
    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
  12. 12.
    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 27:1910–1915CrossRefGoogle Scholar
  13. 13.
    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
  14. 14.
    Sellier-Leclerc A-L, Belli E, Guérin V, Dorfmüller P, Deschênes G (2013) Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome. Pediatr Nephrol 28:1875–1879CrossRefGoogle Scholar
  15. 15.
    Trivin C, Tran A, Moulin B, Choukroun G, Gatault P, Courivaud C, Augusto J-F, Ficheux M, Vigneau C, Thervet E, Karras A (2017) Infectious complications of a rituximab-based immunosuppressive regimen in patients with glomerular disease. Clin Kidney J 10:461–469PubMedGoogle Scholar
  16. 16.
    Colucci M, Carsetti R, Cascioli S, Casiraghi F, Perna A, Ravà L, Ruggiero B, Emma F, Vivarelli M (2016) B cell reconstitution after rituximab treatment in idiopathic nephrotic syndrome. J Am Soc Nephrol 27:1811–1822CrossRefGoogle Scholar
  17. 17.
    Sellier-Leclerc A-L, Baudouin V, Kwon T, Macher M-A, 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 27:1083–1089CrossRefGoogle Scholar
  18. 18.
    Kim JH, Park E, Hyun HS, Cho MH, Ahn YH, Choi HJ, Kang HG, Ha I-S, Cheong HI (2017) Long-term repeated rituximab treatment for childhood steroid-dependent nephrotic syndrome. Kidney Res Clin Pract 36:257–263CrossRefGoogle Scholar
  19. 19.
    Ahn YH, Kang HG, Lee JM, Choi HJ, Ha I-S, Cheong HI (2014) Development of antirituximab antibodies in children with nephrotic syndrome. Pediatr Nephrol 29:1461–1464CrossRefGoogle Scholar
  20. 20.
    Schmidt E, Hennig K, Mengede C, Zillikens D, Kromminga A (2009) Immunogenicity of rituximab in patients with severe pemphigus. Clin Immunol 132:334–341CrossRefGoogle Scholar
  21. 21.
    Einarsson JT, Evert M, Geborek P, Saxne T, Lundgren M, Kapetanovic MC (2017) Rituximab in clinical practice: dosage, drug adherence, Ig levels, infections, and drug antibodies. Clin Rheumatol 36:2743–2750CrossRefGoogle Scholar
  22. 22.
    Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Marasà M, Chianca A, Rubis N, Ene-Iordache B, Rudnicki M, Pollastro RM, Capasso G, Pisani A, Pennesi M, Emma F, Remuzzi G, Rituximab in Nephrotic Syndrome of Steroid-Dependent or Frequently Relapsing Minimal Change Disease Or Focal Segmental Glomerulosclerosis (NEMO) Study Group (2014) Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol 25:850–863CrossRefGoogle Scholar
  23. 23.
    Ravani P, Bonanni A, Rossi R, Caridi G, Ghiggeri GM (2016) Anti-CD20 antibodies for idiopathic nephrotic syndrome in children. Clin J Am Soc Nephrol 11:710–720CrossRefGoogle Scholar
  24. 24.
    Hackl A, Ehren R, Weber LT (2017) Effect of mycophenolic acid in experimental, nontransplant glomerular diseases: new mechanisms beyond immune cells. Pediatr Nephrol 32:1315–1322CrossRefGoogle Scholar
  25. 25.
    Bagga A, Hari P, Moudgil A, Jordan SC (2003) Mycophenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome. Am J Kidney Dis 42:1114–1120CrossRefGoogle Scholar
  26. 26.
    Mendizábal S, Zamora I, Berbel O, Sanahuja MJ, Fuentes J, Simon J (2005) Mycophenolate mofetil in steroid/cyclosporine-dependent/resistant nephrotic syndrome. Pediatr Nephrol 20:914–919CrossRefGoogle Scholar
  27. 27.
    Hogg RJ, Fitzgibbons L, Bruick J, Bunke M, Ault B, Baqi N, Trachtman H, Swinford R (2006) Mycophenolate mofetil in children with frequently relapsing nephrotic syndrome: a report from the southwest pediatric nephrology study group. Clin J Am Soc Nephrol 1:1173–1178CrossRefGoogle Scholar
  28. 28.
    Fujinaga S, Ohtomo Y, Umino D, Takemoto M, Shimizu T, Yamashiro Y, Kaneko K (2007) A prospective study on the use of mycophenolate mofetil in children with cyclosporine-dependent nephrotic syndrome. Pediatr Nephrol 22:71–76CrossRefGoogle Scholar
  29. 29.
    Dorresteijn EM, Kist-van Holthe JE, Levtchenko EN, Nauta J, Hop WCJ, van der Heijden AJ (2008) Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome. Pediatr Nephrol 23:2013–2020CrossRefGoogle Scholar
  30. 30.
    Baudouin V, Alberti C, Lapeyraque A-L, Bensman A, André J-L, Broux F, Cailliez M, Decramer S, Niaudet P, Deschênes G, Jacqz-Aigrain E, Loirat C (2012) Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial. Pediatr Nephrol 27:389–396CrossRefGoogle Scholar
  31. 31.
    Dehoux L, Hogan J, Dossier C, Fila M, Niel O, Maisin A, Macher MA, Kwon T, Baudouin V, Deschênes G (2016) Mycophenolate mofetil in steroid-dependent idiopathic nephrotic syndrome. Pediatr Nephrol 31:2095–2101CrossRefGoogle Scholar
  32. 32.
    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 26:1823–1828CrossRefGoogle Scholar
  33. 33.
    Basu B, Mahapatra TKS, Mondal N (2015) Mycophenolate mofetil following rituximab in children with steroid-resistant nephrotic syndrome. Pediatrics 136:e132–e139CrossRefGoogle Scholar
  34. 34.
    Filler G, Huang S-HS, Sharma AP (2011) Should we consider MMF therapy after rituximab for nephrotic syndrome? Pediatr Nephrol 26:1759–1762CrossRefGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  • Julien Hogan
    • 1
    Email author return OK on get
  • Claire Dossier
    • 1
  • Thérésa Kwon
    • 1
  • Marie-Alice Macher
    • 1
  • Anne Maisin
    • 1
  • Anne Couderc
    • 1
  • Olivier Niel
    • 1
  • Véronique Baudouin
    • 1
  • Georges Deschênes
    • 1
  1. 1.Pediatric Nephrology DepartmentRobert-Debré Hospital, APHPParisFrance

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