Skip to main content
SpringerLink
Log in

Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Children with multidrug-resistant nephrotic syndrome (MRNS) are exposed to drug toxicity (steroids/calcineurin inhibitors (CNI)/mycophenolate mofetil (MMF)) and have an increased risk of kidney disease progression. In small case series, the fully humanized anti-CD20 antibody ofatumumab (OFA) induced remission in children with MRNS when at high dose (10,300 mg/1.73 m2) and partial remission at standard dose (1000 mg/1.73 m2).

Methods

This double-blind randomized placebo-controlled trial tested the efficacy of single infusion OFA in children with proven MRNS and initial chronic renal failure (eGFR [median/range] 119/38–155 ml/min/1.73 m2 in Placebo arm vs. 65/19–103 ml/min/1.73 m2 Intervention). Children who had been resistant to a combination of CNI and steroids, with or without MMF or rituximab, were randomized to receive single infusion OFA (1500 mg/1.73 m2) (Intervention arm) or normal saline (Placebo arm). We assessed complete or partial remission of proteinuria after 3 months (primary outcome), and after 6 and 12 months (secondary outcomes), as well as progression to end-stage kidney disease.

Results

After 13 of the planned 50 children (25%) were randomized, the data safety and monitoring board recommended study termination for futility. All 13 children remained nephrotic. Renal function worsened in 5 children (2 in Intervention arm, 3 in Placebo arm) who required renal replacement therapy during the study period. Circulating CD20 was reduced following OFA infusion and remained low for > 3 months.

Conclusions

OFA given in one single infusion of 1500 mg/1.73 m2 doses does not induce remission in MRNS. Regimens based on higher OFA doses should be tested in clinical trials.

Trial registration

https://clinicaltrials.gov: NCT02394106

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  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 384:1273–1281

    Article  CAS  Google Scholar 

  2. 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 11:710–720

    Article  CAS  Google Scholar 

  3. Basu B, Sander A, Roy B, Preussler S, Barua S, Mahapatra TKS, Schaefer F (2018) Efficacy of rituximab vs tacrolimus in pediatric corticosteroid-dependent nephrotic syndrome: a randomized clinical trial. JAMA Pediatr 172:757–764

    Article  Google Scholar 

  4. 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 23:1117–1124

    Article  CAS  Google Scholar 

  5. Ravani P, Bonanni A, Ghiggeri GM (2017) Randomised controlled trial comparing ofatumumab to rituximab in children with steroid-dependent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome: study protocol. BMJ Open 7:e013319

    Article  Google Scholar 

  6. Vivarelli M, Colucci M, Bonanni A, Verzani M, Serafinelli J, Emma F, Ghiggeri G (2017) Ofatumumab in two pediatric nephrotic syndrome patients allergic to rituximab. Pediatr Nephrol 32:181–184

    Article  Google Scholar 

  7. Wang CS, Liverman RS, Garro R, George RP, Glumova A, Karp A, Jernigan S, Warshaw B (2017) Ofatumumab for the treatment of childhood nephrotic syndrome. Pediatr Nephrol 32:835–841

    Article  Google Scholar 

  8. Bernard J, Bruel A, Allain-Launay E, Dantal J, Roussey G (2018) Ofatumumab in post-transplantation recurrence of a pediatric steroid-resistant idiopathic nephrotic syndrome. Pediatr Transplant 22:e13175

    Article  CAS  Google Scholar 

  9. Basu B (2014) Ofatumumab for rituximab-resistant nephrotic syndrome. N Engl J Med 370:1268–1270

    Article  CAS  Google Scholar 

  10. Bonanni A, Rossi R, Murtas C, Ghiggeri GM (2015, 2015) Low-dose ofatumumab for rituximab-resistant nephrotic syndrome. BMJ Case Rep. https://doi.org/10.1136/bcr-2015-210208

  11. 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 84:1238–1249

    Article  CAS  Google Scholar 

  12. Vincenti F, Ghiggeri GM (2005) New insights into the pathogenesis and the therapy of recurrent focal glomerulosclerosis. Am J Transplant 5:1179–1185

    Article  CAS  Google Scholar 

  13. Dello Strologo L, Guzzo I, Laurenzi C, Vivarelli M, Parodi A, Barbano G, Camilla R, Scozzola F, Amore A, Ginevri F, Murer L (2009) Use of rituximab in focal glomerulosclerosis relapses after renal transplantation. Transplantation 88:417–420

    Article  CAS  Google Scholar 

  14. 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 6:1308–1315

    Article  CAS  Google Scholar 

  15. Ravani P, Ponticelli A, Siciliano C, Fornoni A, Magnasco A, Sica F, Bodria M, Caridi G, Wei C, Belingheri M, Ghio L, Merscher-Gomez S, Edefonti A, Pasini A, Montini G, Murtas C, Wang X, Muruve D, Vaglio A, Martorana D, Pani A, Scolari F, Reiser J, Ghiggeri GM (2013) Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome. Kidney Int 84:1025–1033

    Article  CAS  Google Scholar 

  16. 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 26:2259–2266

    Article  CAS  Google Scholar 

Download references

Funding

The study on ofatumumab was financially supported by the Istituto Giannina Gaslini deriving from “Cinque per mille of IRPEF-Finanziamento della ricerca sanitaria,” the Italian Ministry of Health, The Renal Child Foundation, and the “Fondazione La Nuova Speranza” (“Progetto integrato per la definizione dei meccanismi implicate nella glomerulosclerosifocale”). GC and GMG received a grant from Compagnia San Paolo (ROL-9849).

Author information

Authors and Affiliations

  1. Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Pietro Ravani

  2. Division of Nephrology, School of Nephrology, Department of Medicine and Surgery, University of Parma, Parma, Italy

    Isabella Pisani

  3. Laboratory of Molecular Nephrology and Division of Nephrology and Transplantation, IRCCS Istituto Giannina Gaslini, Largo G. Gaslini 5, Genoa, Italy

    Monica Bodria, Gianluca Caridi, Maria Ludovica Degl’Innocenti & Gian Marco Ghiggeri

Authors
  1. Pietro Ravani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isabella Pisani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monica Bodria
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gianluca Caridi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Ludovica Degl’Innocenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gian Marco Ghiggeri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gian Marco Ghiggeri.

Ethics declarations

Before initiation of the study, we obtained written approval of the protocol, the Informed Consent Form, and any information presented to potential subjects from the local Independent Ethics Committee (Comitato Etico Regione Liguria). We also obtained approval from the Italian Drug Agency (Agenzia Italiana del Farmaco, AIFA).

Conflict of interest

The authors declare that they have no conflict of interest

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ravani, P., Pisani, I., Bodria, M. et al. Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial. Pediatr Nephrol 35, 997–1003 (2020). https://doi.org/10.1007/s00467-020-04481-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-020-04481-y

Keywords

Search

Navigation