Skip to main content
SpringerLink
Log in

Intravenous cyclophosphamide therapy in children with calcineurin inhibitor-resistant steroid-resistant nephrotic syndrome in a resource-limited setting

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

Abstract

Background

In pediatric steroid-resistant nephrotic syndrome (SRNS), calcineurin inhibitors (CNIs) are recommended as first-line therapy, with efficacy ranging between 60 and 80%, implying a substantial proportion will exhibit CNI resistance. Which alternate immunosuppressive therapy should be used in non-genetic pediatric SRNS exhibiting CNI resistance is especially relevant in low- to middle-income countries (LMIC), where the prohibitive costs of certain drugs such as monoclonal antibodies often determine therapy choice.

Methods

The primary objective was to assess the efficacy of intravenous cyclophosphamide in a proportion of children aged 1–18 years with CNI-resistant SRNS with a complete response (CR) or partial response (PR) at 6 months from commencement of pulse therapy. The secondary objectives were to assess the proportion and profile of infections and adverse effects.

Results

Of 90 children with idiopathic SRNS presenting between January 2013 and December 2022, 29 (32.2%) had CNI resistance and were enrolled. They were administered monthly intravenous cyclophosphamide pulses (6 pulses). Median (IQR) duration of follow-up was 48 (29.5, 63.5) months. At the end of 6 months of cyclophosphamide therapy, 13 (44.8%) attained CR and 4 (13.8%) attained PR, with an overall cyclophosphamide success rate of 58.6%. The efficacy of intravenous cyclophosphamide was higher in secondary (9/10; 90%) versus primary CNI resistance (8/19; 42.1%) (p = 0.029). Three children (3/29; 10.3%) developed systemic infections within 12 months of initiation of cyclophosphamide therapy, similar to the rate of systemic infections among children receiving CNI for SRNS management (6/41; 14.6%) (p = 0.85).

Conclusions

It is prudent to try intravenous cyclophosphamide in CNI-resistant SRNS in LMIC, given the reasonable cost and good efficacy rates (58.6%).

Graphical Abstract

A higher resolution version of the Graphical abstract is available as Supplementary information

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
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

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

Code availability

Not applicable. Data subsets are available with the corresponding author.

References

  1. Vasudevan A, Thergaonkar R, Mantan M, Sharma J, Khandelwal P, Hari P, Expert Group of the Indian Society of Pediatric Nephrology et al (2021) Consensus guidelines on management of steroid-resistant nephrotic syndrome. Indian Pediatr 58:650–666

    Article  PubMed  Google Scholar 

  2. Sinha A, Sharma A, Mehta A, Gupta R, Gulati A, Hari P et al (2013) Calcineurin inhibitor induced nephrotoxicity in steroid resistant nephrotic syndrome. Indian J Nephrol 23:41–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mantan M, Sriram CS, Hari P, Dinda A, Bagga A (2008) Efficacy of intravenous pulse cyclophosphamide treatment versus combination of intravenous dexamethasone and oral cyclophosphamide treatment in steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:1495–1502

    Article  PubMed  Google Scholar 

  4. Plank C, Kalb V, Hinkes B, Hildebrandt F, Gefeller O, Rascher W, 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 23:1483–1493

    Article  PubMed  PubMed Central  Google Scholar 

  5. Elhence R, Gulati S, Kher V, Gupta A, Sharma RK (1994) Intravenous pulse cyclophosphamide-a new regime for steroid-resistant minimal change nephrotic syndrome. Pediatr Nephrol 8:1–3

    Article  CAS  PubMed  Google Scholar 

  6. Liu ID, Willis NS, Craig JC, Hodson EM (2019) Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 2019:CD 003594

    Google Scholar 

  7. Gulati A, Sinha A, Gupta A, Kanitkar M, Sreenivas V, Sharma J et al (2012) Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome. Kidney Int 82:1130–1135

    Article  CAS  PubMed  Google Scholar 

  8. Sinha A, Bhatia D, Gulati A, Rawat M, Dinda AK, Hari P, Bagga A (2015) Efficacy and safety of rituximab in children with difficult-to-treat nephrotic syndrome. Nephrol Dial Transplant 30:96–106

    Article  CAS  PubMed  Google Scholar 

  9. Jellouli M, Charfi R, Maalej B, Mahfoud A, Trabelsi S, Gargah T (2018) Rituximab in the management of pediatric steroid-resistant nephrotic syndrome: a systematic review. J Pediatr 197:191–197

    Article  CAS  PubMed  Google Scholar 

  10. Kamei K, Ishikura K, Sako M, Ito S, Nozu K, Iijima K (2020) Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children. Pediatr Nephrol 35:17–24

    Article  PubMed  Google Scholar 

  11. Trautmann A, Schnaidt S, Lipska-Ziętkiewicz BS, Bodria M, Ozaltin F, Emma F, PodoNet Consortium et al (2017) Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol 28:3055–3065

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gargah TT, Lakhoua MR (2011) Mycophenolate mofetil in treatment of childhood steroid-resistant nephrotic syndrome. J Nephrol 24:203–207

    Article  CAS  PubMed  Google Scholar 

  13. Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, International Pediatric Nephrology Association et al (2020) IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 35:1529–1561

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bagga A, Ali U, Banerjee S, Kanitkar M, Phadke KD, Senguttuvan P, Sethi S, Shah M, Indian Pediatric Nephrology Group, Indian Academy of Pediatrics (2008) Management of steroid sensitive nephrotic syndrome: revised guidelines. Indian Pediatr 45:203–214

    PubMed  Google Scholar 

  15. Sairam VK, Kalia A, Rajaraman S, Travis LB (2002) Secondary resistance to cyclosporin A in children with nephrotic syndrome. Pediatr Nephrol 17:842–846

    Article  PubMed  Google Scholar 

  16. Topaloglu R, Gulhan B, Celegen K, Inozu M, Hayran M, Duzova A et al (2019) Rituximab for children with difficult-to-treat nephrotic syndrome: its effects on disease progression and growth. Front Pediatr 7:313

    Article  PubMed  PubMed Central  Google Scholar 

  17. Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M et al (2012) Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23:1117–1124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pradhan M, Furth S (2012) Rituximab in steroid-resistant nephrotic syndrome in children: a (false) glimmer of hope? J Am Soc Nephrol 23:975–978

    Article  CAS  PubMed  Google Scholar 

  19. Chaumais MC, Garnier A, Chalard F, Peuchmaur M, Dauger S, Jacqz-Agrain E et al (2009) Fatal pulmonary fibrosis after rituximab administration. Pediatr Nephrol 24:1753–1755

    Article  PubMed  Google Scholar 

  20. El-Reshaid K, El-Reshaid W, Madda J (2005) Combination of immunosuppressive agents in treatment of steroid-resistant minimal change disease and primary focal segmental glomerulosclerosis. Ren Fail 27:523–530

    Article  CAS  PubMed  Google Scholar 

  21. Wu B, Mao J, Shen H, Fu H, Wang J, Liu A et al (2015) Triple immunosuppressive therapy in steroid-resistant nephrotic syndrome children with tacrolimus resistance or tacrolimus sensitivity but frequently relapsing. Nephrology 20:18–24

    Article  CAS  PubMed  Google Scholar 

  22. Ravani P, Pisani I, Bodria M, Caridi G, Degl’Innocenti ML, Ghiggeri GM (2020) Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial. Pediatr Nephrol 35:997–1003

    Article  PubMed  Google Scholar 

  23. Bonanni A, Bertelli E, Panicucci C, D’Alessandro M, Moscatelli A, Lampugnani E et al (2017) Ofatumumab-associated acute pneumonitis: not new but still the first case. Pharmacol Res Perspect 5:e00267

    Article  PubMed  Google Scholar 

  24. Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM et al (2021) Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int 100:753–779

    Article  PubMed  Google Scholar 

  25. Bhimma R, Adhikari M, Asharam K (2006) Steroid-resistant nephrotic syndrome: the influence of race on cyclophosphamide sensitivity. Pediatr Nephrol 21:1847–1853

    Article  PubMed  Google Scholar 

  26. Bajpai A, Bagga A, Hari P, Dinda A, Srivastava RN (2003) Intravenous cyclophosphamide in steroid-resistant nephrotic syndrome. Pediatr Nephrol 18:351–356

    Article  PubMed  Google Scholar 

  27. Haddad M, Kale A, Butani L (2021) Intravenous cyclophosphamide induces remission in children with difficult to treat steroid resistant nephrotic syndrome from minimal change disease. BMC Nephrol 22:395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li H, Shi X, Shen H, Li X, Wang H, Li H et al (2012) Tacrolimus versus intravenous pulse cyclophosphamide therapy in Chinese adults with steroid-resistant idiopathic minimal change nephropathy: a multicenter, open-label, nonrandomized cohort trial. Clin Ther 34:1112–1120

    Article  CAS  PubMed  Google Scholar 

  29. Hymes LC (1995) Steroid-resistant, cyclosporin-responsive, relapsing nephrotic syndrome. Pediatr Nephrol 9:137–139

    Article  CAS  PubMed  Google Scholar 

  30. Ponticelli C, Rizzoni G, Edefonti A, Altieri P, Rivolta E, Rinaldi S, Ghio L, Lusvarghi E, Gusmano R, Locatelli F, Pasquali S, Castellani A, Della Casa-Alberighi OD (1993) A randomized trial of cyclosporine in steroid resistant idiopathic nephrotic syndrome. Kidney Int 43:1377–1384

    Article  CAS  PubMed  Google Scholar 

  31. Niaudet P, Habib R, Tete MJ, Hinglais N, Broyer M (1987) Cyclosporin in the treatment of idiopathic nephrotic syndrome in children. Pediatr Nephrol 1:566–573

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported, in part, by the Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.

Author information

Authors and Affiliations

  1. Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India

    Paraselli Saiteja, Bobbity Deepthi, Sudarsan Krishnasamy, Madhileti Sravani & Sriram Krishnamurthy

Authors
  1. Paraselli Saiteja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bobbity Deepthi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sudarsan Krishnasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Madhileti Sravani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sriram Krishnamurthy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PS, BD, SuK, MS, and SK managed the patients. PS participated in study protocol preparations, recruited patients, participated in data analysis, and drafted the first version of the manuscript. SK conceptualized the study design, collected the data, interpreted the data, and critically revised the manuscript. BD, SuK, and MS assisted in the recruitment of the patients, data analysis, and drafting of the manuscript. All authors contributed to the protocol preparation and drafting of the manuscript and approved the final version of the manuscript. Sriram Krishnamurthy shall act as the corresponding author and guarantor of the paper.

Corresponding author

Correspondence to Sriram Krishnamurthy.

Ethics declarations

Ethics approval

Approved by the Ethics Committee of the institute (IEC/2021/111 dated 19 July 2021).

Consent to participate

The authors affirm that human research participants provided informed consent.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images if applicable.

Conflict of interest

The authors have no competing interests to declare that are relevant to the content of this article. The authors have no financial or proprietary interests in any material discussed in this article.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Graphical abstract (PPTX 76.3 KB)

Supplementary file1 (DOCX 15.7 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saiteja, P., Deepthi, B., Krishnasamy, S. et al. Intravenous cyclophosphamide therapy in children with calcineurin inhibitor-resistant steroid-resistant nephrotic syndrome in a resource-limited setting. Pediatr Nephrol 39, 1149–1160 (2024). https://doi.org/10.1007/s00467-023-06187-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-023-06187-3

Keywords

Search

Navigation