Pediatric Nephrology

, Volume 20, Issue 10, pp 1376–1381

Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions

Editorial Commentary

Abstract

Clinicians are often faced with therapeutic dilemmas and challenges while treating children with frequently relapsing steroid-dependent nephrotic syndrome (SDNS) and steroid-resistant nephrotic syndrome (SRNS). In the past, children with SDNS have been treated with long-term alternate day steroids cyclophosphamide, cyclosporine (CSA), chlorambucil, levamisole, and azathioprine. The essential aim of these therapies is to maintain remission while limiting exposure to steroids. These medications have variable efficacy and undesirable toxicity profiles. Recently, mycophenolate mofetil (MMF) has emerged as a new therapeutic option for the management of SDNS in a few uncontrolled clinical trials. Preliminary data are encouraging. MMF was found to be useful in maintaining remission and has a steroid-sparing effect. Clearly, more data are needed to further characterize the safety and efficacy of MMF, define adequate length of treatment, and optimize drug exposure and monitoring. The management of SRNS is primarily aimed at decreasing proteinuria and inducing remission, if possible. By doing so, one would aim to preserve renal function. CSA therapy is known to be useful in this regard but has undesirable side effects, the most concerning being nephrotoxicity. MMF in combination with steroids and angiotensin-converting enzyme-inhibitor drugs is known to have some efficacy in the management of SRNS. These preliminary data have prompted the National Institutes of Health to sponsor a multicentric controlled trial to compare the safety and efficacy of MMF with that of CSA in the treatment of steroid-resistant focal segmental glomerulosclerosis (FSGS). If MMF therapy is found to be efficacious, it would help obviate the need for CSA and its associated nephrotoxicity. Clearly, MMF has emerged as an important new therapeutic option for the treatment of childhood nephrotic syndrome and FSGS. Further data are required to assess those conditions most likely to respond.

Keywords

Nephrotic syndrome Focal segmental glomerulosclerosis Mycophenolate mofetil Steroid dependence Steroid resistance Chronic renal failure 

References

  1. 1.
    Churg J, Habib R, White RHR (1970) Pathology of nephrotic syndrome in children: a report for the International Study of Kidney Disease in Children. Lancet 760:1299–1302CrossRefPubMedGoogle Scholar
  2. 2.
    Ponticelli C, Edefonti A, Ghio L, Rizzoni G, Rinaldi S, Gusmano R, Lama G, Zacchello G, Confalonieri R, Altieri P (1993) Cyclosporine versus cyclophosphamide for patients with steroid dependent and frequently relapsing idiopathic nephrotic syndrome: a multicenter randomized controlled trial. Nephrol Dial Transplant 8:1326–1332Google Scholar
  3. 3.
    Inoue Y, Iijima K, Nakamura H, Yoshikawa N (1999) Two-year cyclosporine treatment in children with steroid dependent nephrotic syndrome. Pediatr Nephrol 13:33–38CrossRefPubMedGoogle Scholar
  4. 4.
    Cattran DC. Appel GB. Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, Maxwell DR, Kunis CL for the North America Nephrotic Syndrome Study Group (1999) A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis Kidney Int 56:2220–2226Google Scholar
  5. 5.
    Habib R, Klein knechtle (1971) The primary nephrotic syndrome of childhood-classification and clinicopathologic study of 406 cases. Path Annu 6:417–474Google Scholar
  6. 6.
    Durkan AM, Hodson EM, Willis NS, Craig JC (2001) Immunosuppressive agents in childhood nephrotic syndrome: A meta-analysis of randomized controlled trials. Kidney Int 59:1919–1927CrossRefPubMedGoogle Scholar
  7. 7.
    Filler G (2003) Treatment of nephrotic syndrome in children and controlled trials. Nephrol Dial Transplant [Suppl 6]:75–7810Google Scholar
  8. 8.
    Choi MJ, Eustacew JA, Gimenez LF, Atta MG, Scheel PJ, Sothinathan R, Briggs WA (2002). Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int 61:1098–1114CrossRefPubMedGoogle Scholar
  9. 9.
    Chandra M, Susin M, Abitbol C (2000) Remission of relapsing childhood nephrotic syndrome with mycophenolate mofetil. Pediatr Nephrol 14:224–226CrossRefPubMedGoogle Scholar
  10. 10.
    Bagga A, Hari P, Moudgil A, Jordan SC (2003) Mycophenolate mofetil and prednisolone therapy in steroid dependent nephrotic syndrome. Am J Kidney Dis 42:1114–1120CrossRefPubMedGoogle Scholar
  11. 11.
    Gellermann J, Querfeld U. Frequently relapsing nephrotic syndrome: treatment with mycophenolate mofetil (2004) Pediatr Nephrol 19:101–104CrossRefPubMedGoogle Scholar
  12. 12.
    Ehrlich JH, Brodehl J (1993) Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Eur J pediatr 152:357–61PubMedGoogle Scholar
  13. 13.
    Hiraoka M, Tsukahara H, Matsubara K, Tsurusawa M, Takeda N, Haruki S, Hayashi S, Ohta K, Momoi T, Ohshima Y, Sugunuma N, Mayumi M, for the West Japan Cooperative Study of Kidney Disease in Children (2003) A randomized study of two long- course prednisolone regimens for nephrotic syndrome in children. Am J Kidney Dis 41:1155–1162CrossRefPubMedGoogle Scholar
  14. 14.
    Vester U, kranz B, Zimmerman S, Hoyer PF (2003) Cyclophosphamide in steroid-sensitive nephrotic syndrome: outcome and outlook. Pediatr Nephrol 7:661–664Google Scholar
  15. 15.
    Donia AF, Gazareen SH, Ahmed HA, Shoeib AA, Ismail AM, Khamis S, Sobh MA (2003) Pulse cyclophosphamide inadequately suppresses reoccurrence of minimal change nephrotic syndrome in corticoid dependent children. Nephrol Dial Transplant 10:2054–2058Google Scholar
  16. 16.
    Blumenfeld Z, Dann E, Avivi I, Epelbaum R, Rowe JM (2002) Fertility after treatment for Hodgkin’s disease. Ann Oncol 13 [Suppl 1]:138–147Google Scholar
  17. 17.
    Niaudet P (1992). Comparison of cyclosporine and chlorambucil in the treatment of steroid-dependent nephrotic syndrome: a multicentric randomized controlled trial. The French Society of Paediatric Nephrology. Pediatr Nephrol 6:1–3CrossRefPubMedGoogle Scholar
  18. 18.
    Habashi D, Hodson E, Craig J (2004) Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane database system review 2: CD 003594Google Scholar
  19. 19.
    Iijima K, Hamashira K, Tanaka R, Kobayashi A, Nozu K, Nakamura H, Yoshikawa N (2002) Risk factors for cyclosporine-induced tubulointerstitial lesions in children with minimal change nephrotic syndrome. Kidney Int 61:1801–1805CrossRefPubMedGoogle Scholar
  20. 20.
    McCauley J, Shapiro R, Ellis D, Igdal H, Tzakis A, Starzl TE (1993) Pilot trial of FK 506 in the management of steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 11:1286–1290Google Scholar
  21. 21.
    Schweda FLiebl R, Riegger GA, Kramer BK (1997) Tacrolimus treatment for steroid- and cyclosporine- resistant minimal change nephrotic syndrome. Nephrol Dial Transplant 12:2433–243Google Scholar
  22. 22.
    Moxey-Mims MM, Kay C, Light JA, Kher KK (1998) Increased incidence of insulin dependent diabetes mellitus in pediatric renal transplant patients receiving tacrolimus (FK 506). Transplantation 65:617–619CrossRefPubMedGoogle Scholar
  23. 23.
    Niaudet P, Drachman R, Gagnadoux MF, Broyer M (1984) Treatment of idiopathic nephrotic syndrome with levamisole. Acta Pediatr Scand 73:637–641Google Scholar
  24. 24.
    British Association for Paediatric Nephrology (1991) Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. Lancet 337:1555–1557PubMedGoogle Scholar
  25. 25.
    Bagga A, Sharma A, Srivastava RN (1997) Levamisole therapy in corticosteroid dependent nephrotic syndrome. Pediatr Nephrol 11:415–417CrossRefPubMedGoogle Scholar
  26. 26.
    Barbano G, Ginevri F, Ghiggeri GM, Gusmano R (1999) Disseminated autoimmune disease during levamisole treatment of nephrotic syndrome. Pediatr Nephrol 13:602–603CrossRefPubMedGoogle Scholar
  27. 27.
    Barratt TM, Cameron JS, Chantler C, Counahan R, Ogg CS, Soothill JF (1977) Controlled trial of azathioprine in treatment of steroid responsive nephrotic syndrome of childhood. Arch Dis Child 52:462–463PubMedGoogle Scholar
  28. 28.
    Hiraoka M, Tsukahara H, Hori C, Oshima Y, Momoi T, Seo A, Mayumi M (2000) Efficacy of long-term azathioprine for relapsing nephrotic syndrome. Pediatr Nephrol 14:776–778PubMedGoogle Scholar
  29. 29.
    Laurent AF, Dumont S, Poindron P, Muller CD (1996) Mycophenolic acid suppresses protein N-linked glycosylation in human monocytes and their adhesion to endothelial cells and some substrates. Exp Hematol 24:59–67PubMedGoogle Scholar
  30. 30.
    Gummert JF, Barten MJ, Sherwood SW, Vangelder R, Billingham ME, Morris RE (1999) Pharmacodynamics of immunosuppression by mycophenolic acid: inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics. Pharmacol Exp Ther 291:1100–1112Google Scholar
  31. 31.
    Remuzzi G, Zoja C, Gagliardini E, Coma D, Abbate M, Benigni A (1999) Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals. JASN 10:1542–1549PubMedGoogle Scholar
  32. 32.
    Day CJ, Cockwell P, Liokin GW, Savage CO, Howie AJ, Adu D (2002) Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome. Nephrol Dial Transplant 17:2011–2013CrossRefPubMedGoogle Scholar
  33. 33.
    Mogyorosi A, Lippman HR, Feldman GM (2002) Successful treatment of steroid resistant minimal change disease with mycophenolate mofetil. Am J Nephrol 22:569–572CrossRefPubMedGoogle Scholar
  34. 34.
    Barletta GM, Smoyer WE, Bunchman TE, Flynn JT, Kershaw DB (2003) Use of mycophenolate mofetil in steroid-dependent and steroid-resistant nephrotic syndrome Pediatr Nephrol 18:833–837Google Scholar
  35. 35.
    Ulinski T, Duborg L, Said MH, Parchoux B, Ranchin B, Cochat P (2005) Switch from cyclosporine A to mycophenolate mofetil in nephrotic children. Pediatr Nephrol 20:482–485CrossRefPubMedGoogle Scholar
  36. 36.
    Montane B, Abitbol C, Chandar J, Strauss J, Jillerulo G (2003) Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. Pediatr Nephrol 18:772–777CrossRefPubMedGoogle Scholar
  37. 37.
    Zhao M, Chen X, Chen Y, Lieu Y, Lu F, Zhang Y, Wang H. Clinical observations of mycophenolate mofetil therapy in refractory primary nephrotic syndrome (2003) Nephrology (Carlton) 8:105–109Google Scholar
  38. 38.
    Neylan JF (1997). Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 64:1277–82.CrossRefPubMedGoogle Scholar
  39. 39.
    Tejara N, Gomez-Garre D, Lazaro A, Gallego-Delgdo J, Alamo C, Blanco J, Oritz A Egido J (2004) Persistent proteinuria up-regulates angiotensin II type 2 receptor and induces apoptosis in proximal tubular cells. Am J Pathol 164:1817–1826PubMedGoogle Scholar
  40. 40.
    Contreras G, Parado V, Leclereg B, Lenz O, Tozman E, O’Nan P, Roth D (2004) Sequential therapies for proliferative lupus nephritis. N Engl J Med 350:971–980CrossRefPubMedGoogle Scholar
  41. 41.
    Ingulli E, Tejani A (1991) Racial differences in the incidence and renal outcome of idiopathic focal segmental glomerulosclerosis in children. Pediatr Nephrol 5: 393–397CrossRefPubMedGoogle Scholar
  42. 42.
    Sorof J, Hawkins EP, Brewer ED, Boydstun II, Kale AS, Powell DR (1998) Age ethnicity affect the risk and outcome of focal segmental glomerulosclerosis. Pediatr Nephrol 12:764–768CrossRefPubMedGoogle Scholar
  43. 43.
    Grisweld WR, Tune BM, Reznik VM, Varquez M, Prime DJ, Brock P, Mendoza SA (1987) Treatment of childhood prednisone resistant nephrotic syndrome and focal segmental glomerulosclerosis with intravenous pulse methylprednisolone and oral alkylating agents. Nephron 46:73–77PubMedGoogle Scholar
  44. 44.
    Adhikari M, Bhimma R, Coovadia HM (1997) Intensive pulse therapies for focal glomerulosclerosis in South African children. Pediatr Nephrol 11:423–428CrossRefPubMedGoogle Scholar
  45. 45.
    Mendoza SA, Reznik VM, Grisweld WR, Krensky AM, Yorgin PD, Tune BM (1990) Treatment of steroid-resistant focal segmental glomerulosclerosis with intravenous pulse methylprednisolone and alkylating agents. Pediatr Nephrol 4:303–307CrossRefPubMedGoogle Scholar
  46. 46.
    Hari P, Bagga A, Jindal N, Srivastava RN (2001) Treatment of focal glomeulosclerosis with pulse steroids and cyclophosphamide. Pediatr Nephrol 16:901–905CrossRefPubMedGoogle Scholar
  47. 47.
    Tune BM, Kirpekar R, Sibley RK, Reznik VM, Grisweld WR, Mendoza SA (1995) Intravenous pulse methylprednisolone and oral alkylating agent therapy of prednisone-resistant pediatric focal segmental glomerulosclerosis: A long-term follow-up. Clin Nephrol 43:84–88PubMedGoogle Scholar
  48. 48.
    Waldo FB, Benefield MR, Kohaut EC (1992) Methylprednisolone treatment of patients with steroid-resistant nephrotic syndrome. Pediatr Nephrol 6:503–505CrossRefPubMedGoogle Scholar
  49. 49.
    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 8:1–3CrossRefPubMedGoogle Scholar
  50. 50.
    Rennert WP, Kala UK, Jacobs D, Goetsch S, Verhaart S (1999) Pulse cyclophosphamide for steroid-resistant focal segmental glomerulosclerosis. Pediatr Nephrol 13:113–11651CrossRefPubMedGoogle Scholar
  51. 51.
    Bajpai A, Bagga A, Hari P, Dinda A, Srivastava RN (2003) Intravenous cyclophosphamide in steroid-resistant nephrotic syndrome. Pediatr Nephrol 18:351–356PubMedGoogle Scholar
  52. 52.
    Delucchi A, Cano F, Rodriguez E, Wolff E, Gonzalez X, Cumsille MA (2000) Enalapril and prednisone in children with nephrotic-range proteinuria. Pediatr Nephrol 14:1088–1091CrossRefPubMedGoogle Scholar
  53. 53.
    Korbet SM (2003) Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis. Semin Nephrol 23:219–228CrossRefPubMedGoogle Scholar
  54. 54.
    Bullingham R, Monroe S, Nichols A. Hale M (1996) Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single dose oral and intravenous administration. J Clin Pharmacol 36:315–324Google Scholar
  55. 55.
    Shaw LM, Korecka M, Venkatatamanan R, Goldberg L, Bloom R, Brayman KL (2003) Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 3:534–542Google Scholar
  56. 56.
    Weber LT, Shipakova M, Armstrong VW (2002) The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients: a report of German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 13:759–768CrossRefPubMedGoogle Scholar
  57. 57.
    Nowak I, Shaw LM (1995) Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem 41:1011–1017PubMedGoogle Scholar
  58. 58.
    Gataneo D, Perico N, Gaspari F, Gotti E, Remuzzi G (2002) Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int 62:1060–1067CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2005

Authors and Affiliations

  • Asha Moudgil
    • 1
  • Arvind Bagga
    • 2
  • Stanley C. Jordan
    • 3
  1. 1.Divisions of Pediatric NephrologyChildren’s National Medical CenterWashingtonUSA
  2. 2.All India Institute of Medical SciencesNew DelhiIndia
  3. 3.David Geffen School of Medicine at UCLACedars-Sinai Medical CenterLos AngelesUSA

Personalised recommendations