Steroid-sparing therapy of frequently recurrent nephrotic syndrome with levamizole

Therapy of patients with relapsing steroid-sensitive nephrotic syndrome is an important and unresolved problem. Long-term and frequent use of high doses of corticosteroids is associated with the development of side effects of therapy. The long-term goal of steroid-sensitive nephrotic syndrome treatment is stable remission of the disease, minimization of side effects and improvement of the patient’s quality of life. In 2023, the International Association of Pediatric Nephrologists (IPNA) published updated recommendations for the diagnosis and treatment of steroid-sensitive nephrotic syndrome in children, according to which, in order to choose the best initial option for steroid-sparing therapy and the optimal sequence of agents, it is recommended to take into account the type and severity of the disease, age, onset of puberty, potential adherence, side effect profile, comorbidities, cost and availability of drugs. In our review, we aimed to consider one of the options for steroid-sparing therapy for steroid-sensitive nephrotic syndrome using the drug levamisole. Levamisole is a drug with an immunomodulatory effect, normalizes cellular immunity. The conducted clinical trials have increased the quality of evidence of the efficacy and safety of levamisole in the treatment of children with steroid-sensitive nephrotic syndrome. For the purpose of demonstration, a clinical case of a patient with a steroid-sensitive frequently relapsing variant of nephrotic syndrome treated with levamisole is presented. Against the background of taking levamisole for 1.5 years, the child did not have relapses of nephrotic syndrome, proteinuria according to urine tests. In our case, there were no side effects of levamisole therapy. Low toxicity profile, ease of monitoring, low cost of the drug are the advantages of this drug in a number of steroid-sparing agents used for the treatment of steroid-sensitive nephrotic syndrome.

1. Noone DG., Iijima K., Parekh R. Idiopathic nephrotic syndrome in children. Lancet 2018; 392: 61–74. DOI: 10.1016/S0140-6736(18)30536-1

2. Tullus K., Webb H., Bagga A. Management of steroidresistant nephrotic syndrome in children and adolescents. Lancet Child Adolesc Health 2018; 2: 880–890. DOI: 10.1016/S2352-4642(18)30283-9

3. Tarshish P., Tobin JN., Bernstein J., Edelmann CM. Jr. Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephrol 1997; 8: 769–776. DOI: 10.1681/ASN.V85769

4. Carter SA., Mistry S., Fitzpatrick J., Banh T., Hebert D., Langlois V. et al. Prediction of short- and long-term outcomes in childhood nephrotic syndrome. Kidney Int Rep 2020; 5: 426–434. DOI: 10.1016/j.ekir.2019.12.015

5. Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN). Effect of cytotoxic drugs in frequently relapsing nephrotic syndrome with and without steroid dependence. N Engl J Med 1982; 306: 451–454. DOI: 10.1056/NEJM198202253060803

6. Rüth E.M., Kemper M.J., Leumann E.P., Laube G.F., Neuhaus T.J. Children with steroid-sensitive nephrotic syndrome come of age: long-term outcome. J Pediatr 2005; 147: 202–207. DOI: 10.1016/j.jpeds.2005.03.050

7. Korsgaard T., Andersen RF., Joshi S., Hagstrom S., Rittig S. Childhood onset steroid-sensitive nephrotic syndrome continues into adulthood. Pediatr Nephrol 2019; 34: 641–648. DOI: 10.1007/s00467-018-4119-8

8. Marchel D.M., Gipson D.S. Adult survivors of idiopathic childhood onset nephrotic syndrome. Pediatr Nephrol 2021; 36: 1731–1737. DOI: 10.1007/s00467-020-04773-3

9. Vivarelli M., Massella L., Ruggiero B., Emma F. Minimal Change Disease. Clin J Am Soc Nephrol 2017; 12: 332–345. DOI: 10.2215/CJN.05000516

10. Rovin B.H., Adler S.G., Barratt J., Bridoux F., Burdge K.A., Chan T.M. et al. Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases. Kidney Int 2021; 100: 753–779. DOI: 10.1016/j.kint.2021.05.015

11. Trautmann A., Boyer O., Hodson E., Bagga A., Gipson Debbie S., Samue S., еt al. on behalf of the International Pediatric Nephrology Association. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome. Pediatric Nephrology 2023; 38: 877–919. DOI.org/10.1007/s00467–022–05739–3

12. Hahn D., Samuel S.M., Willis N.S., Craig J.C., Hobson E.M. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2020; 2020; 8: CD001533. DOI: 10.1002/14651858.CD001533.pub6

13. Gellermann J., Querfeld U. Frequently relapsing nephrotic syndrome: treatment with mycophenolate mofetil. Pediatr Nephrol 2004; 19: 101–104. DOI: 10.1007/s00467-003-1300-4

14. Larkins N.G., Liu I.D., Willis N.S., Craig J.C., Hodson E.M. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev. 2020; 4:CD002290. DOI: 10.1002/14651858.CD002290.pub5

15. Latta K., von Schnakenburg C., Ehrich J.H. A meta-analysis of cytotoxic treatment for frequently relapsing nephritic syndrome in children. Pediatr Nephrol 2001; 16: 271–282. DOI: 10.1007/s004670000523

16. Webb N.J.A., Woolley R.L., Lambe T., Frew E., Brettell E.A., Barsoum E.N. et al. Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation. BMJ 2019; 365:l1800. DOI: 10.1136/bmj.l1800

17. Basu B., Babu B.G., Mahapatra T.K. Long-term efficacy and safety of common steroid-sparing agents in idiopathic nephrotic children. Clin Exp Nephrol 2017; 21: 143–151. DOI: 10.1007/s10157-016-1266-8.

18. Gruppen M.P., Bouts A.H., Jansen-van der Weide M.C., Merkus M.P., Zurowska A., Maternik M. et al. A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome. Kidney Int 2018; 93: 510–518. DOI: 10.1016/j.kint.2017.08.011

19. Donia A.F., Ammar H.M., El-Agroudy Ael B., Moustafa Fel H., Sobh M.A. Long-term results of two unconventional agents in steroid-dependent nephrotic children. Pediatr Nephrol 2005; 20: 1420–1425. DOI: 10.1007/s00467-005-1943-4

20. Alsaran K., Grisaru S., Stephens D., Arbus G. Levamisole vs. cyclophosphamide for frequently-relapsing steroid-dependent nephrotic syndrome. Clin Nephrol 2001; 56(4): 289–294

21. Sinha A., Puraswani M., Kalaivani M., Goyal P., Hari P., Bagga A. Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: an openlabel randomized controlled trial. Kidney Int 2019; 95: 210–218 DOI: 10.1016/j.kint.2018.08.039

22. Ekambaram S., Mahalingam V., Nageswaran P., Udani A., Geminiganesan S., Priyadarshini S. Efficacy of levamisole in children with frequently relapsing and steroid-dependent nephritic syndrome. Ind Pediatr 2014; 51: 371–373. DOI: 10.1007/s13312-014-0419-7

23. Moorani K.N., Zubair A.M., Veerwani N.R., Hotchandani H.J. Efficacy of Levamisole in children with frequent relapsing and steroid dependent nephrotic syndrome at tertiary care Center-Karachi. Pak J Med Sci 2020; 36: 1193–1198. DOI: 10.12669/pjms.36.6.2337

24. Sümegi V., Haszon I., Iványi B., Bereczki C., Papp F., Túri S. Long-term effects of levamisole treatment in childhood nephritic syndrome. Pediatr Nephrol 2004; 19: 1354–1360. DOI: 10.1007/s00467-004-1608-8

25. Kiruba Samuel E.M., Krishnamurthy S., Bhanudeep S., Muske S. Levamisole in Frequently-relapsing and Steroid-dependent Nephrotic Syndrome. Ind Pediatr 2017; 54: 831–834. DOI: 10.1007/s13312-017-1144-9.

26. Fu L.S., Shien C.Y., Chi C.S. Levamisole in steroid-sensitive nephrotic syndrome children with frequent relapses and/or steroid dependency: comparison of daily and every-other-day usage. Nephron Clin Pract 2004; 97: 137–141. DOI: 10.1159/000079172

27. Abeyagunawardena A.S., Karunadasa U., Jayaweera H., Thalgahagoda S., Tennakoon S., Abeyagunawardena S. Efficacy of higher-dose levamisole in maintaining remission in steroiddependant nephrotic syndrome. Pediatr Nephrol 2017; 32: 1363–1367. DOI: 10.1007/s00467-017-3616-5

28. Papizh S.V., Moskaleva E.S., Fokeeva E.V., Ruzhiczkaya E.A., Turpitko O.Yu., Katy`sheva O.V. Levamisole in the treatment of hormone-dependent and frequently relapsing nephrotic syndrome in children. Pediatricheskaya farmakologiya 2003; 1(2): 14–18. (in Russ.)