Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Steroid-resistant idiopathic nephrotic syndrome in children

INTRODUCTION

The majority of children who present with idiopathic nephrotic syndrome (NS) have minimal change disease (MCD), which is generally responsive to steroid therapy. As a result, empirical steroid therapy is given to most children who present with idiopathic NS.

However, about 10 to 20 percent of patients will fail to respond to initial steroid treatment. In many cases, steroid-resistant cases are due to single gene mutations that affect glomerular podocyte differentiation and function. Patients with genetic forms of steroid-resistant nephrotic syndrome (SRNS) are usually unresponsive to immunosuppressive therapy. Thus, therapeutic decisions in children with SRNS are based on the underlying etiology.

The causes and management of steroid-resistant idiopathic nephrotic syndrome in children will be reviewed here. The etiology, clinical manifestations, diagnosis, and initial management of NS in children are discussed separately. In addition, the management of children with steroid-sensitive NS is presented elsewhere. (See "Etiology, clinical manifestations, and diagnosis of nephrotic syndrome in children" and "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial pharmacologic therapy' and "Treatment of idiopathic nephrotic syndrome in children", section on 'Steroid-sensitive nephrotic syndrome'.)

ETIOLOGY

In most children with steroid-resistant nephrotic syndrome (SRNS), the underlying cause is not known [1,2]. However, advances in molecular genetics of glomerular diseases have shown single gene defects that affect glomerular podocyte differentiation and function are responsible for a quarter to a third of all pediatric cases of SRNS in many parts of the world [3-5].

Genetic mutations — Mutations of the following genes are the most common cause of hereditary SRNS.

                            

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2014. | This topic last updated: Jul 7, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Haack D, Schärer K, Asam-Tauscher A, Vecsei P. Glucocorticoid receptors in idiopathic nephrotic syndrome. Pediatr Nephrol 1999; 13:653.
  2. Kim JS, Bellew CA, Silverstein DM, et al. High incidence of initial and late steroid resistance in childhood nephrotic syndrome. Kidney Int 2005; 68:1275.
  3. Büscher AK, Kranz B, Büscher R, et al. Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2010; 5:2075.
  4. Hildebrandt F. Genetic kidney diseases. Lancet 2010; 375:1287.
  5. Santín S, Bullich G, Tazón-Vega B, et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2011; 6:1139.
  6. Gigante M, Caridi G, Montemurno E, et al. TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype. Clin J Am Soc Nephrol 2011; 6:1626.
  7. Lipska BS, Iatropoulos P, Maranta R, et al. Genetic screening in adolescents with steroid-resistant nephrotic syndrome. Kidney Int 2013; 84:206.
  8. Philippe A, Nevo F, Esquivel EL, et al. Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2008; 19:1871.
  9. Boute N, Gribouval O, Roselli S, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000; 24:349.
  10. Weber S, Gribouval O, Esquivel EL, et al. NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 2004; 66:571.
  11. Ruf RG, Lichtenberger A, Karle SM, et al. Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 2004; 15:722.
  12. Caridi G, Bertelli R, Carrea A, et al. Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. J Am Soc Nephrol 2001; 12:2742.
  13. Karle SM, Uetz B, Ronner V, et al. Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2002; 13:388.
  14. Frishberg Y, Rinat C, Megged O, et al. Mutations in NPHS2 encoding podocin are a prevalent cause of steroid-resistant nephrotic syndrome among Israeli-Arab children. J Am Soc Nephrol 2002; 13:400.
  15. Caridi G, Bertelli R, Di Duca M, et al. Broadening the spectrum of diseases related to podocin mutations. J Am Soc Nephrol 2003; 14:1278.
  16. Berdeli A, Mir S, Yavascan O, et al. NPHS2 (podicin) mutations in Turkish children with idiopathic nephrotic syndrome. Pediatr Nephrol 2007; 22:2031.
  17. Fuchshuber A, Jean G, Gribouval O, et al. Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum Mol Genet 1995; 4:2155.
  18. Frishberg Y, Feinstein S, Rinat C, et al. The heart of children with steroid-resistant nephrotic syndrome: is it all podocin? J Am Soc Nephrol 2006; 17:227.
  19. Chernin G, Heeringa SF, Gbadegesin R, et al. Low prevalence of NPHS2 mutations in African American children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2008; 23:1455.
  20. Boyer O, Benoit G, Gribouval O, et al. Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome. J Med Genet 2010; 47:445.
  21. Ruf RG, Schultheiss M, Lichtenberger A, et al. Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome. Kidney Int 2004; 66:564.
  22. Lipska BS, Ranchin B, Iatropoulos P, et al. Genotype-phenotype associations in WT1 glomerulopathy. Kidney Int 2014; 85:1169.
  23. Niaudet P, Gubler MC. WT1 and glomerular diseases. Pediatr Nephrol 2006; 21:1653.
  24. Winn MP, Conlon PJ, Lynn KL, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 2005; 308:1801.
  25. Boyer O, Benoit G, Gribouval O, et al. Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol 2011; 22:239.
  26. Benoit G, Machuca E, Antignac C. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr Nephrol 2010; 25:1621.
  27. Clewing JM, Antalfy BC, Lücke T, et al. Schimke immuno-osseous dysplasia: a clinicopathological correlation. J Med Genet 2007; 44:122.
  28. Zivicnjak M, Franke D, Zenker M, et al. SMARCAL1 mutations: a cause of prepubertal idiopathic steroid-resistant nephrotic syndrome. Pediatr Res 2009; 65:564.
  29. Boyer O, Nevo F, Plaisier E, et al. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. N Engl J Med 2011; 365:2377.
  30. Niaudet P. Genetic forms of nephrotic syndrome. Pediatr Nephrol 2004; 19:1313.
  31. 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.
  32. Ehrich JH, Geerlings C, Zivicnjak M, et al. Steroid-resistant idiopathic childhood nephrosis: overdiagnosed and undertreated. Nephrol Dial Transplant 2007; 22:2183.
  33. Kitamura A, Tsukaguchi H, Maruyama K, et al. Steroid-resistant nephrotic syndrome. Kidney Int 2008; 74:1209.
  34. Meyrier A. An update on the treatment options for focal segmental glomerulosclerosis. Expert Opin Pharmacother 2009; 10:615.
  35. Caridi G, Gigante M, Ravani P, et al. Clinical features and long-term outcome of nephrotic syndrome associated with heterozygous NPHS1 and NPHS2 mutations. Clin J Am Soc Nephrol 2009; 4:1065.
  36. Schulman SL, Kaiser BA, Polinsky MS, et al. Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: superiority of response to corticosteroid therapy over histopathologic patterns. J Pediatr 1988; 113:996.
  37. Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr. Cyclophosphamide does not benefit patients with focal segmental glomerulosclerosis. A report of the International Study of Kidney Disease in Children. Pediatr Nephrol 1996; 10:590.
  38. Geary DF, Farine M, Thorner P, Baumal R. Response to cyclophosphamide in steroid-resistant focal segmental glomerulosclerosis: a reappraisal. Clin Nephrol 1984; 22:109.
  39. Hodson EM, Willis NS, Craig JC. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 2010; :CD003594.
  40. Mahmoud I, Basuni F, Sabry A, et al. Single-centre experience with cyclosporin in 106 children with idiopathic focal segmental glomerulosclerosis. Nephrol Dial Transplant 2005; 20:735.
  41. Niaudet P. Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology. J Pediatr 1994; 125:981.
  42. Gregory MJ, Smoyer WE, Sedman A, et al. Long-term cyclosporine therapy for pediatric nephrotic syndrome: a clinical and histologic analysis. J Am Soc Nephrol 1996; 7:543.
  43. Ponticelli C, Edefonti A, Ghio L, et al. Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial. Nephrol Dial Transplant 1993; 8:1326.
  44. Lieberman KV, Tejani A. A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. J Am Soc Nephrol 1996; 7:56.
  45. Ingulli E, Singh A, Baqi N, et al. Aggressive, long-term cyclosporine therapy for steroid-resistant focal segmental glomerulosclerosis. J Am Soc Nephrol 1995; 5:1820.
  46. Chishti AS, Sorof JM, Brewer ED, Kale AS. Long-term treatment of focal segmental glomerulosclerosis in children with cyclosporine given as a single daily dose. Am J Kidney Dis 2001; 38:754.
  47. Plank C, Kalb V, Hinkes B, et al. 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 2008; 23:1483.
  48. Gipson DS, Trachtman H, Kaskel FJ, et al. Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int 2011; 80:868.
  49. Hamasaki Y, Yoshikawa N, Nakazato H, et al. Prospective 5-year follow-up of cyclosporine treatment in children with steroid-resistant nephrosis. Pediatr Nephrol 2013; 28:765.
  50. Habib R, Niaudet P. Comparison between pre- and posttreatment renal biopsies in children receiving ciclosporine for idiopathic nephrosis. Clin Nephrol 1994; 42:141.
  51. Kengne-Wafo S, Massella L, Diomedi-Camassei F, et al. Risk factors for cyclosporin A nephrotoxicity in children with steroid-dependant nephrotic syndrome. Clin J Am Soc Nephrol 2009; 4:1409.
  52. Loeffler K, Gowrishankar M, Yiu V. Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome. Pediatr Nephrol 2004; 19:281.
  53. Bhimma R, Adhikari M, Asharam K, Connolly C. Management of steroid-resistant focal segmental glomerulosclerosis in children using tacrolimus. Am J Nephrol 2006; 26:544.
  54. Gulati S, Prasad N, Sharma RK, et al. Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant 2008; 23:910.
  55. Choudhry S, Bagga A, Hari P, et al. Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial. Am J Kidney Dis 2009; 53:760.
  56. Roberti I, Vyas S. Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol 2010; 25:1117.
  57. Butani L, Ramsamooj R. Experience with tacrolimus in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2009; 24:1517.
  58. Wang W, Xia Y, Mao J, et al. Treatment of tacrolimus or cyclosporine A in children with idiopathic nephrotic syndrome. Pediatr Nephrol 2012; 27:2073.
  59. Gulati A, Sinha A, Gupta A, et al. Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome. Kidney Int 2012; 82:1130.
  60. de Mello VR, Rodrigues MT, Mastrocinque TH, et al. Mycophenolate mofetil in children with steroid/cyclophosphamide-resistant nephrotic syndrome. Pediatr Nephrol 2010; 25:453.
  61. Li Z, Duan C, He J, et al. Mycophenolate mofetil therapy for children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2010; 25:883.
  62. Cattran DC, Wang MM, Appel G, et al. Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis. Clin Nephrol 2004; 62:405.
  63. Mendizábal S, Zamora I, Berbel O, et al. Mycophenolate mofetil in steroid/cyclosporine-dependent/resistant nephrotic syndrome. Pediatr Nephrol 2005; 20:914.
  64. Gargah TT, Lakhoua MR. Mycophenolate mofetil in treatment of childhood steroid-resistant nephrotic syndrome. J Nephrol 2011; 24:203.
  65. Nakayama M, Kamei K, Nozu K, et al. Rituximab for refractory focal segmental glomerulosclerosis. Pediatr Nephrol 2008; 23:481.
  66. Bagga A, Sinha A, Moudgil A. Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 2007; 356:2751.
  67. Gulati A, Sinha A, Jordan SC, et al. Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report. Clin J Am Soc Nephrol 2010; 5:2207.
  68. Magnasco A, Ravani P, Edefonti A, et al. Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 2012; 23:1117.
  69. Pradhan M, Furth S. Rituximab in steroid-resistant nephrotic syndrome in children: a (false) glimmer of hope? J Am Soc Nephrol 2012; 23:975.
  70. Chaumais MC, Garnier A, Chalard F, et al. Fatal pulmonary fibrosis after rituximab administration. Pediatr Nephrol 2009; 24:1753.
  71. Trompeter RS. Steroid resistant nephrotic syndrome: A review of the treatment of focal segmental glomerulosclerosis in children. In: Recent Advances in Pediatric Nephrology, Murakami K, Kitagawa T, Yabuta K, Sakai T (Eds), Excerpta Medica, Amsterdam 1987. p.363.
  72. Aizawa-Yashiro T, Tsuruga K, Watanabe S, et al. Novel multidrug therapy for children with cyclosporine-resistant or -intolerant nephrotic syndrome. Pediatr Nephrol 2011; 26:1255.
  73. Tune BM, Mendoza SA. Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults. J Am Soc Nephrol 1997; 8:824.
  74. Mendoza SA, Reznik VM, Griswold WR, et al. Treatment of steroid-resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents. Pediatr Nephrol 1990; 4:303.
  75. Tune BM, Kirpekar R, Sibley RK, et al. Intravenous methylprednisolone and oral alkylating agent therapy of prednisone-resistant pediatric focal segmental glomerulosclerosis: a long-term follow-up. Clin Nephrol 1995; 43:84.
  76. Kirpekar R, Yorgin PD, Tune BM, et al. Clinicopathologic correlates predict the outcome in children with steroid-resistant idiopathic nephrotic syndrome treated with pulse methylprednisolone therapy. Am J Kidney Dis 2002; 39:1143.
  77. Guillot AP, Kim MS. Pulse steroid therapy does not alter the course of focal segmental glomerulosclerosis (abstract). J Am Soc Nephrol 1993; 4:276.
  78. Montané B, Abitbol C, Chandar J, et al. Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. Pediatr Nephrol 2003; 18:772.
  79. Ellis D, Vats A, Moritz ML, et al. Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria. J Pediatr 2003; 143:89.
  80. Bagga A, Mudigoudar BD, Hari P, Vasudev V. Enalapril dosage in steroid-resistant nephrotic syndrome. Pediatr Nephrol 2004; 19:45.
  81. MacHardy N, Miles PV, Massengill SF, et al. Management patterns of childhood-onset nephrotic syndrome. Pediatr Nephrol 2009; 24:2193.
  82. Gellermann J, Stefanidis CJ, Mitsioni A, Querfeld U. Successful treatment of steroid-resistant nephrotic syndrome associated with WT1 mutations. Pediatr Nephrol 2010; 25:1285.
  83. Bensman A, Niaudet P. Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr Nephrol 2010; 25:1197.
  84. Malina M, Cinek O, Janda J, Seeman T. Partial remission with cyclosporine A in a patient with nephrotic syndrome due to NPHS2 mutation. Pediatr Nephrol 2009; 24:2051.
  85. Niaudet P. Podocin and nephrotic syndrome: implications for the clinician. J Am Soc Nephrol 2004; 15:832.
  86. Lovric S, Fang H, Vega-Warner V, et al. Rapid detection of monogenic causes of childhood-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 2014; 9:1109.
  87. Stefanidis CJ, Querfeld U. The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by WT1 mutations. Eur J Pediatr 2011; 170:1377.
  88. Wasilewska AM, Kuroczycka-Saniutycz E, Zoch-Zwierz W. Effect of cyclosporin A on proteinuria in the course of glomerulopathy associated with WT1 mutations. Eur J Pediatr 2011; 170:389.
  89. Lombel RM, Hodson EM, Gipson DS, Kidney Disease: Improving Global Outcomes. Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO. Pediatr Nephrol 2013; 28:409.