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Belimumab for the treatment of children with frequently relapsing nephrotic syndrome: the BELNEPH study

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Abstract

Background

Effectiveness of rituximab in pediatric idiopathic nephrotic syndrome suggests that B cells play a pathogenic role. We tested safety and efficacy of the B-cell-modulating agent belimumab in frequently relapsing nephrotic syndrome (FRNS).

Methods

An open-label, prospective, single-arm pilot study (EUDRACT 2017-003839-11) was designed to treat 10 children with FRNS with i.v. belimumab for 12 months. Prednisone was tapered/stopped. Safety, number of relapses, cumulative prednisone dose and B-cell subset "levels" are referred to both B cell subset and immunoglobulin.

Results

Five patients were enrolled, and four reached the primary 6-month endpoint. Of these, two completed the 12-month endpoint. Three patients experienced ≥2 relapses while on belimumab, requiring additional immunosuppression. Compared to the 6 months before belimumab treatment, the mean number of relapses (1.4 vs. 2, p=0.21) and the mean cumulative prednisone dose (1.86 vs. 2.62 g/m2, p=0.17) were not significantly reduced during the 6 months on belimumab. This study was terminated by the steering committee after the interim evaluation because belimumab failed to show clear benefits to counterbalance the inconvenience of monthly i.v. infusion. During follow-up, total and mature-naïve B cells decreased, while no change in memory B-cells was observed. Serum immunoglobulins remained stable. No infusion reaction was observed.

Conclusions

Short-term treatment with belimumab in pediatric FRNS was well tolerated. The number of patients was too small to draw conclusions on efficacy. Nonetheless, we did not observe clear improvements. The burden of monthly in-hospital i.v. infusions outweighed potential benefits. Persistence of circulating memory B cells supports their pathogenic role in the disease.

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References

  1. Noone DG, Iijima K, Parekh R (2018) Idiopathic nephrotic syndrome in children. Lancet 392:61–74

    Article  PubMed  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  PubMed  Google Scholar 

  3. Heybeli C, Erickson SB, Fervenza FC, Hogan MC, Zand L, Leung N (2020) Comparison of treatment options in adults with frequently relapsing or steroid-dependent minimal change disease. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfaa133

  4. Delbe-Bertin L, Aoun B, Tudorache E, Lapillone H, Ulinski T (2013) Does rituximab induce hypogammaglobulinemia in patients with pediatric idiopathic nephrotic syndrome? Pediatr Nephrol 28:447–451

    Article  PubMed  Google Scholar 

  5. Kronbichler A, Windpessl M, Pieringer H, Jayne DRW (2017) Rituximab for immunologic renal disease: what the nephrologist needs to know. Autoimmun Rev 16:633–643

    Article  CAS  PubMed  Google Scholar 

  6. Colucci M, Carsetti R, Serafinelli J, Rocca S et al (2019) Prolonged impairment of immunological memory after anti-CD20 treatment in pediatric idiopathic nephrotic syndrome. Front Immunol 10:1653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Navarra SV, Guzman RM, Gallacher AE, Hall S et al (2011) Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377:721–731

    Article  CAS  PubMed  Google Scholar 

  8. Sciascia S, Radin M, Yazdany J, Levy RA et al (2017) Efficacy of belimumab on renal outcomes in patients with systemic lupus erythematosus: a systematic review. Autoimmun Rev 16:287–293

    Article  CAS  PubMed  Google Scholar 

  9. Brunner HI, Abud-Mendoza C, Viola DO, Calvo Penades I et al (2020) Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial. Ann Rheum Dis 79:1340–1348

    Article  CAS  PubMed  Google Scholar 

  10. Banham GD, Flint SM, Torpey N, Lyons PA et al (2018) Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial. Lancet 391:2619–2630

    Article  CAS  PubMed  Google Scholar 

  11. Barrett C, Willcocks LC, Jones RB, Tarzi RM et al (2020) Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy. Nephrol Dial Transplant 35:599–606

    Article  CAS  PubMed  Google Scholar 

  12. Ginzler EM, Wallace DJ, Merrill JT, Furie RA et al (2014) Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol 41:300–309

    Article  CAS  PubMed  Google Scholar 

  13. Chatham WW, Wallace DJ, Stohl W, Latinis KM et al (2012) Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial. J Rheumatol 39:1632–1640

    Article  CAS  PubMed  Google Scholar 

  14. Huang W, Quach TD, Dascalu C, Liu Z et al (2018) Belimumab promotes negative selection of activated autoreactive B cells in systemic lupus erythematosus patients. JCI Insight 3:e122525

    Article  PubMed Central  Google Scholar 

  15. Vivarelli M, Massella L, Ruggiero B, Emma F (2017) Minimal change disease. Clin J Am Soc Nephrol 12:332–345

    Article  CAS  PubMed  Google Scholar 

  16. Schwartz GJ, Munoz A, Schneider MF, Mak RH et al (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  17. Colucci M, Carsetti R, Cascioli S, Casiraghi F et al (2016) B cell reconstitution after rituximab treatment in idiopathic nephrotic syndrome. J Am Soc Nephrol 27:1811–1822

    Article  CAS  PubMed  Google Scholar 

  18. Bhatia D, Sinha A, Hari P, Sopory S et al (2018) Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome. Pediatr Res 84:520–526

    Article  CAS  PubMed  Google Scholar 

  19. Chan EY, Webb H, Yu E, Ghiggeri GM, Kemper MJ, Ma AL et al (2020) Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes. Kidney Int 97:393–401

    Article  CAS  PubMed  Google Scholar 

  20. Hoffman W, Lakkis FG, Chalasani G (2016) B cells, antibodies, and more. Clin J Am Soc Nephrol 11:137–154

    Article  CAS  PubMed  Google Scholar 

  21. Wallace DJ, Stohl W, Furie RA, Lisse JR et al (2009) A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 61:1168–1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jacobi AM, Huang W, Wang T, Freimuth W et al (2010) Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum 62:201–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Colucci M, Carsetti R, Cascioli S, Serafinelli J, Emma F, Vivarelli M (2019) B cell phenotype in pediatric idiopathic nephrotic syndrome. Pediatr Nephrol 34:177–181

    Article  PubMed  Google Scholar 

  24. Fleischer SJ, Daridon C, Fleischer V, Lipsky PE, Dorner T (2016) Enhanced tyrosine phosphatase activity underlies dysregulated b cell receptor signaling and promotes survival of human lupus B cells. Arthritis Rheum 68:1210–1221

    CAS  Google Scholar 

  25. Rosenzwajg M, Languille E, Debiec H, Hygino J et al (2017) B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney Int 92:227–237

    Article  CAS  PubMed  Google Scholar 

  26. Delville M, Sigdel TK, Wei C, Li J et al (2014) A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 6:256ra136

    Article  PubMed  PubMed Central  Google Scholar 

  27. Jamin A, Berthelot L, Couderc A, Chemouny JM et al (2018) Autoantibodies against podocytic UCHL1 are associated with idiopathic nephrotic syndrome relapses and induce proteinuria in mice. J Autoimmun 89:149–161

    Article  CAS  PubMed  Google Scholar 

  28. Baker D, Pryce G, James LK, Schmierer K, Giovannoni G (2020) Failed B cell survival factor trials support the importance of memory B cells in multiple sclerosis. Eur J Neurol 27:221–228

    Article  CAS  PubMed  Google Scholar 

  29. Guzman M, Hui-Yuen JS (2020) Management of pediatric systemic lupus erythematosus: focus on belimumab. Drug Des Devel Ther 14:2503–2513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kraaij T, Arends EJ, van Dam LS, Kamerling SWA et al (2020) Long-term effects of combined B-cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfaa117

  31. Lavie F, Miceli-Richard C, Ittah M, Sellam J, Gottenberg JE, Mariette X (2007) Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production. Ann Rheum Dis 66:700–703

    Article  CAS  PubMed  Google Scholar 

  32. Piatosa B, Wolska-Kusnierz B, Pac M, Siewiera K, Galkowska E, Bernatowska E (2010) B cell subsets in healthy children: reference values for evaluation of B cell maturation process in peripheral blood. Cytometry B Clin Cytom 78:372–381

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank Dr. Ines L’Erario, Dr. Marco Busutti, and Dr. Federica Zotta for their help in patient care and Marco Scarsella and Ezio Giorda for technical assistance.

Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Funding

This study was funded by Fondazione Bambino Gesù Onlus.

Author information

Author notes

  1. Marina Vivarelli and Manuela Colucci contributed equally to this work.

Authors and Affiliations

  1. Division of Nephrology, Department of Pediatric Subspecialties, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Marina Vivarelli, Antonio Gargiulo, Chiara Bettini & Francesco Emma

  2. Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Viale S. Paolo 15, 00146, Rome, Italy

    Marina Vivarelli, Manuela Colucci & Francesco Emma

  3. Core Facilities, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Anna Lo Russo

Authors
  1. Marina Vivarelli
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  2. Manuela Colucci
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Contributions

Research idea and study design: MV, MC, AG, FE; data acquisition: MC, CB, AG, ALR; data analysis/interpretation: MV, MC, AG, CB, ALR, FE; supervision or mentorship: MV, FE.

Corresponding author

Correspondence to Manuela Colucci.

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Ethics approval

The study was approved by Bambino Gesù Children’s Hospital Ethics Committee and was conducted in compliance with the Declaration of Helsinki.

Consent to participate

Written informed consent on behalf of the minors/children enrolled was obtained from parents.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Vivarelli, M., Colucci, M., Gargiulo, A. et al. Belimumab for the treatment of children with frequently relapsing nephrotic syndrome: the BELNEPH study. Pediatr Nephrol 37, 377–383 (2022). https://doi.org/10.1007/s00467-021-05175-9

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  • DOI: https://doi.org/10.1007/s00467-021-05175-9

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