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.
Similar content being viewed by others
References
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 760:1299–1302
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 8:1326–1332
Inoue Y, Iijima K, Nakamura H, Yoshikawa N (1999) Two-year cyclosporine treatment in children with steroid dependent nephrotic syndrome. Pediatr Nephrol 13:33–38
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 56:2220–2226
Habib R, Klein knechtle (1971) The primary nephrotic syndrome of childhood-classification and clinicopathologic study of 406 cases. Path Annu 6:417–474
Durkan AM, Hodson EM, Willis NS, Craig JC (2001) Immunosuppressive agents in childhood nephrotic syndrome: A meta-analysis of randomized controlled trials. Kidney Int 59:1919–1927
Filler G (2003) Treatment of nephrotic syndrome in children and controlled trials. Nephrol Dial Transplant [Suppl 6]:75–7810
Choi MJ, Eustacew JA, Gimenez LF, Atta MG, Scheel PJ, Sothinathan R, Briggs WA (2002). Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int 61:1098–1114
Chandra M, Susin M, Abitbol C (2000) Remission of relapsing childhood nephrotic syndrome with mycophenolate mofetil. Pediatr Nephrol 14:224–226
Bagga A, Hari P, Moudgil A, Jordan SC (2003) Mycophenolate mofetil and prednisolone therapy in steroid dependent nephrotic syndrome. Am J Kidney Dis 42:1114–1120
Gellermann J, Querfeld U. Frequently relapsing nephrotic syndrome: treatment with mycophenolate mofetil (2004) Pediatr Nephrol 19:101–104
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 152:357–61
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 41:1155–1162
Vester U, kranz B, Zimmerman S, Hoyer PF (2003) Cyclophosphamide in steroid-sensitive nephrotic syndrome: outcome and outlook. Pediatr Nephrol 7:661–664
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 10:2054–2058
Blumenfeld Z, Dann E, Avivi I, Epelbaum R, Rowe JM (2002) Fertility after treatment for Hodgkin’s disease. Ann Oncol 13 [Suppl 1]:138–147
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 6:1–3
Habashi D, Hodson E, Craig J (2004) Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane database system review 2: CD 003594
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 61:1801–1805
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 11:1286–1290
Schweda FLiebl R, Riegger GA, Kramer BK (1997) Tacrolimus treatment for steroid- and cyclosporine- resistant minimal change nephrotic syndrome. Nephrol Dial Transplant 12:2433–243
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 65:617–619
Niaudet P, Drachman R, Gagnadoux MF, Broyer M (1984) Treatment of idiopathic nephrotic syndrome with levamisole. Acta Pediatr Scand 73:637–641
British Association for Paediatric Nephrology (1991) Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. Lancet 337:1555–1557
Bagga A, Sharma A, Srivastava RN (1997) Levamisole therapy in corticosteroid dependent nephrotic syndrome. Pediatr Nephrol 11:415–417
Barbano G, Ginevri F, Ghiggeri GM, Gusmano R (1999) Disseminated autoimmune disease during levamisole treatment of nephrotic syndrome. Pediatr Nephrol 13:602–603
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 52:462–463
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 14:776–778
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 24:59–67
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 291:1100–1112
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 10:1542–1549
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 17:2011–2013
Mogyorosi A, Lippman HR, Feldman GM (2002) Successful treatment of steroid resistant minimal change disease with mycophenolate mofetil. Am J Nephrol 22:569–572
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 18:833–837
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 20:482–485
Montane B, Abitbol C, Chandar J, Strauss J, Jillerulo G (2003) Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. Pediatr Nephrol 18:772–777
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) 8:105–109
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.
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 164:1817–1826
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 350:971–980
Ingulli E, Tejani A (1991) Racial differences in the incidence and renal outcome of idiopathic focal segmental glomerulosclerosis in children. Pediatr Nephrol 5: 393–397
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 12:764–768
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 46:73–77
Adhikari M, Bhimma R, Coovadia HM (1997) Intensive pulse therapies for focal glomerulosclerosis in South African children. Pediatr Nephrol 11:423–428
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 4:303–307
Hari P, Bagga A, Jindal N, Srivastava RN (2001) Treatment of focal glomeulosclerosis with pulse steroids and cyclophosphamide. Pediatr Nephrol 16:901–905
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 43:84–88
Waldo FB, Benefield MR, Kohaut EC (1992) Methylprednisolone treatment of patients with steroid-resistant nephrotic syndrome. Pediatr Nephrol 6:503–505
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
Rennert WP, Kala UK, Jacobs D, Goetsch S, Verhaart S (1999) Pulse cyclophosphamide for steroid-resistant focal segmental glomerulosclerosis. Pediatr Nephrol 13:113–11651
Bajpai A, Bagga A, Hari P, Dinda A, Srivastava RN (2003) Intravenous cyclophosphamide in steroid-resistant nephrotic syndrome. Pediatr Nephrol 18:351–356
Delucchi A, Cano F, Rodriguez E, Wolff E, Gonzalez X, Cumsille MA (2000) Enalapril and prednisone in children with nephrotic-range proteinuria. Pediatr Nephrol 14:1088–1091
Korbet SM (2003) Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis. Semin Nephrol 23:219–228
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 36:315–324
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 3:534–542
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 13:759–768
Nowak I, Shaw LM (1995) Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem 41:1011–1017
Gataneo D, Perico N, Gaspari F, Gotti E, Remuzzi G (2002) Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int 62:1060–1067
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moudgil, A., Bagga, A. & Jordan, S.C. Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions. Pediatr Nephrol 20, 1376–1381 (2005). https://doi.org/10.1007/s00467-005-1964-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-005-1964-z