Comparative assessment of the efficacy and safety of mycophenolate mofetil versus cyclosporine A in children with steroid dependent nephrotic syndrome

Long-term therapy with corticosteroids of patients with steroid-dependent nephrotic syndrome (SDNS) causes significant side effects. For this reason, patients with signs of steroid toxicity need to alternative immunosuppressive therapy. Currently, there is no consensus about the most appropriate first-line steroid-sparing agent in children with steroid-dependent nephrotic syndrome. This study aimed to investigate the efficacy and safety of mycophenolate mofetil (MMF) compared with cyclosporine A (CsA) in children with SDNS. Methods. We conducted a retrospective analysis of treatment outcomes of patients with steroid-dependent nephrotic syndrome who were treated with CsA and MMF at the nephrology department between 2003 and 2018. The efficacy of reducing the cumulative steroid dosages and time without steroids have been accessed. Results. During the CsA therapy, the maximal duration of remission without steroids was 14 [6; 24] months, the cumulative steroid dosage was reduced from 183.4 [122.9; 216.2] to 63.6 [35.5; 85] mg/kg/year, persistent remission during the year was in 60% of children, mean relapse rates decreased from 2.2 [1.3; 3.6] to 0.7 [0.4; 1.6]. 88.8% of children treated with MMF had no relapses during the time of observation, the maximal duration of remission after corticosteroids withdrawal was 19.69±10 month, steroid dosage decreased from 191.3 [122.4; 241.5] to 46.7 [25.8; 63.6] mg/kg/year. MMF demonstrated similar efficacy, with no adverse effects, while 12% of children receiving CSA were revealed tubulointerstitial changes on repeated nephrobiopsy, in another 12% therapy was discontinued due to hyperazotemia. Conclusion. The effectiveness of MMF as a steroid-sparing agent is comparable to CSA, but a potential nephrotoxicity of CsA allows to recommend mycophenolate mofetil as an alternative to cyclosporine A for the first-line therapy of patients with steroid-dependent nephrotic syndrome.

дети, стероид-зависимый нефротический синдром, циклоспорин А, микофенолата мофетил, преднизолон, children, steroid-dependent nephrotic syndrome, cyclosporin A, mycophenolate mofetil, prednisone

1. International Study of Kidney Disease in Children. Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children, Kidney Int, 1978, vol. 13 (p. 159-165)

2. McGrogan A., Franssen C., Vries C. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011 Feb;26(2):414-30. doi: 10.1093/ndt/gfq665.

3. Chanchlani R., Parekh R. Ethnic Differences in Childhood Nephrotic Syndrome. Front Pediatr. 2016. DOI: 10.3389/fped.2016.00039

4. Pravitsitthikul N., Willis N., Hodson E. et al. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev. 2013 Oct 29;(10):CD002290. DOI: 10.1002/14651858.CD002290.pub4.

5. Vijay A., Kusum D., Laxmikant M. et al. Study on Steroid Induced Ocular Findings in Children with Nephrotic Syndrome. J Clin Diagn Res. 2017 Mar; 11(3): SC05-SC06. Published online 2017 Mar 1. doi: 10.7860/JCDR/2017/24694.9334

6. Park S., Shin J. Complications of nephrotic syndrome. Korean J Pediatr. 2011 Aug; 54(8): 322-328. doi: 10.3345/kjp.2011.54.8.322

7. KDIGO Clinical Practice Guideline for Glomerulonephritis, 2012

8. Latta K, von Schnakenburg C, Ehrich J. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr Nephrol (2001) 16: 271. doi.org/10.1007/s004670000523

9. Iijima K, Hamahira K, Tanaka R et al. Risk factors for cyclosporine-induced tubulointerstitial lesions in children with minimal change nephrotic syndrome. Kidney Int. 2002 May; 61(5):1801-5. DOI: 10.1046/j.1523-1755.2002.00303.x

10. Yoshiyuki K, Yoshimitsu G, Katsuaki K et al. Effectiveness and nephrotoxicity of a 2-year medium dose of cyclosporine in pediatric patients with steroid-dependent nephrotic syndrome: determination of the need for follow-up kidney biopsy. Clinical and Experimental Nephrology. April 2018, Volume 22, Issue 2, pp 413-419. DOI: 10.1007/s10157-017-1444-3

11. Banerjee S., Pahari A., Sengupta J., Patnaik S. Outcome of severe steroid-dependent nephrotic syndrome treated with mycophenolate mofetil. Pediatr Nephrol 2013;28:93-7. DOI: 10.1007/s00467-012-2278-6.

12. Nandi M., Mandal S., Samanta M., Majhi A. et al. Efficacy of Mycophenolate Mofetil as a Remission Maintaining Agent in Idiopathic Childhood Nephrotic Syndrome. Indian J Nephrol. 2019 Jan-Feb;29(1):34-41. doi:10.4103/ijn.IJN_330_17.

13. Lim T., Kim S.H, Kim S.Y. Efficacy and Safety of Mycophenolate Mofetil in Children with Steroid Dependent Nephrotic Syndrome. M.D. 2015 DOI: DOI: 10.3339/chikd.2015.19.2.105

14. Hettiarachchi, Raja M., Karunadasa U. et al. Efficacy and side effects of mycophenolate mofetil therapy in children with steroid dependent nephrotic syndrome in a tertiary paediatric nephrology centre in Sri Lanka. Sri Lanka Journal of Child Health, 2018; 48(1): 53-58. DOI:10.4038/sljch.v48i1.8652

15. Dehoux L, Hogan J, Dossier C et al. Mycophenolate mofetil in steroid-dependent idiopathic nephrotic syndrome. Pediatr Nephrol. 2016 Nov;31(11):2095-101. DOI: 10.1007/s00467-016-3400-y.

16. Kapoor, K., Saha, A., Kaur, M., Dubey, N. K., & Upadhyay, A. D. (2017). Mycophenolate sodium for children with frequently relapsing or steroid dependent nephrotic syndrome. Indian Pediatrics, 54(10), 885-886. doi:10.1007/s13312-017-1156-5

17. Ronald J., Fitzgibbons L., Bruick J. Et al. Mycophenolate Mofetil in Children with Frequently Relapsing Nephrotic Syndrome: A Report from the Southwest Pediatric Nephrology Study Group. CJASN November 2006, 1 (6) 1173-1178; DOI:https://doi.org/10.2215/CJN.00550206

18. Sinha, A., Puraswani, M., Kalaivani, M et al. Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: an open-label randomized controlled trial. Kidney International. doi:10.1016/j.kint.2018.08.039

19. Myers B, Ross J, Newton L et al. Cyclosporine-associated chronic nephropathy. N Engl J Med311:699-705,1984

20. Fujinaga S., Kaneko K., Muto T. et al. Independent risk factors for chronic cyclosporine-induced nephropathy in children with nephrotic syndrome. Arch Dis Child. 2006 Aug;91(8):666-70. Epub 2006 May 2. DOI: 10.1136/adc.2005.080960

21. Iyengar A, Karthik S, Kumar A et al. Cyclosporine in steroid dependent and resistant childhood nephrotic syndrome. Indian Pediatr. 2006 Jan;43(1):14-9. PMID:16465001