Abstract
Background
Calcineurin inhibitors (CIs) with/without intravenous methylprednisolone pulse therapy (MPT) constitute the standard treatment for childhood-onset, steroid-resistant nephrotic syndrome (SRNS). However, some patients fail to achieve remission. We treated SRNS patients resistant to CIs and MPT with additional rituximab combined with MPT and immunosuppressive agents.
Methods
Ten patients (aged 2–14 years) with CI- and MPT-resistant SRNS were enrolled. Patients were administered rituximab (1–4 doses; 375 mg/m2) followed by MPT (30 mg/kg/day of methylprednisolone for 3 consecutive days) once every 2–4 weeks until complete remission (CR). We analyzed clinical outcome and safety.
Results
Six patients received a single dose of rituximab, 2 received two doses, and 2 received four doses. Seven patients achieved CR, 1 achieved partial remission, and 2 showed no response. Although 2 patients with no response progressed to end-stage renal failure, 7 patients with CR preserved normal renal function without proteinuria at the last observation. There were two serious adverse events.
Conclusions
Additional rituximab combined with conventional MPT and immunosuppressive agents is a promising option for overcoming refractory SRNS. Aggressive B cell suppression by rituximab may ameliorate resistance to conventional treatments and a cocktail of other immunosuppressive agents, such as CIs, MMF, mizoribine, may be beneficial. However, as intense immunosuppression may cause serious adverse events, further evaluation is necessary.
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References
Hamasaki Y, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ishikura K, Yata N, Kaneko T, Honda M, Japanese Study Group of Renal Disease (2009) Cyclosporine and steroid therapy in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 24:2177–2185
Kidney Disease: Improving Global Outcomes (KDIGO) (2012) Steroid-resistant nephrotic syndrome in children. Kidney Int Suppl 2:172–176
Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H, Raynaud N, Taque S, Ronco P, Bouissou F (2008) Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr Nephrol 23:1269–1279
Kamei K, Ito S, Nozu K, Fujinaga S, Nakayama M, Sako M, Saito M, Yoneko M, Iijima K (2009) Single dose of rituximab for refractory steroid-dependent nephritic syndrome in children. Pediatr Nephrol 24:1321–1328
Prytuła A, Iijima K, Kamei K, Geary D, Gottlich E, Majeed A, Taylor M, Marks SD, Tuchman S, Camilla R, Ognjanovic M, Filler G, Smith G, Tullus K (2010) Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 25:461–468
Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK, Sharma S, Srivastava RN, Moudgil A, Bagga A (2010) Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report. Clin J Am Soc Nephrol 5:2207–2212
Fujinaga S, Hirano D, Nishizaki N, Kamei K, Ito S, Ohtomo Y, Shimizu T, Kaneko K (2010) Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr Nephrol 25:539–544
Ito S, Kamei K, Ogura M, Sato M, Fujimaru T, Ishikawa T, Udagawa T, Iijima K (2011) Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome. Pediatr Nephrol 26:1823–1828
Sellier-Leclerc AL, Baudouin V, Kwon T, Macher MA, Guérin V, Lapillonne H, Deschênes G, Ulinski T (2012) Rituximab in steroid-dependent idiopathic nephrotic syndrome in childhood–follow-up after CD19 recovery. Nephrol Dial Transplant 27:1083–1089
Kemper MJ, Gellermann J, Habbig S, Krmar RT, Dittrich K, Jungraithmayr T, Pape L, Patzer L, Billing H, Weber L, Pohl M, Rosenthal K, Rosahl A, Mueller-Wiefel DE, Dötsch J (2012) Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant 27:1910–1915
Ito S, Kamei K, Ogura M, Udagawa T, Fujinaga S, Saito M, Sako M, Iijima K (2013) Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome. Pediatr Nephrol 28:257–264
Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, Benetti E, Murtas C, Messina G, Massella L, Porcellini MG, Montagna M, Regazzi M, Scolari F, Ghiggeri GM (2012) Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23:1117–1124
Bagga A, Sinha A, Moudgil A (2007) Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356:2751–2752
Suri M, Tran K, Sharma AP, Filler G, Grimmer J (2008) Remission of steroid-resistant nephrotic syndrome due to focal and segmental glomerulosclerosis using rituximab. Int Urol Nephrol 40:807–810
Peters HP, van de Kar NC, Wetzels JF (2008) Rituximab in minimal change nephropathy and focal segmental glomerulosclerosis: report of four cases and review of the literature. Neth J Med 66:408–415
Fernandez-Fresnedo G, Segarra A, González E, Alexandru S, Delgado R, Ramos N, Egido J, Praga M, for the Grupo de Trabajo de Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN) (2009) Rituximab treatment of adult patients with steroid-resistant focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 4:1317–1323
Chaumais MC, Garnier A, Chalard F, Peuchmaur M, Dauger S, Jacqz-Agrain E, Deschênes G (2009) Fatal pulmonary fibrosis after rituximab administration. Pediatr Nephrol 24:1753–1755
Kari JA, El-Morshedy SM, El-Desoky S, Alshaya HO, Rahim KA, Edrees BM (2011) Rituximab for refractory cases of childhood nephrotic syndrome. Pediatr Nephrol 26:733–737
Hirano D, Fujinaga S, Nishizaki N (2012) The uncertainty of rituximab and steroid dosing in refractory steroid-resistant nephrotic syndrome. Clin Nephrol 77:510–512
Nakayama M, Kamei K, Nozu K, Matsuoka K, Nakagawa A, Sako M, Iijima K (2008) Rituximab for refractory focal segmental glomerulosclerosis. Pediatr Nephrol 23:481–485
Kaito H, Kamei K, Kikuchi E, Ogura M, Matsuoka K, Nagata M, Iijima K, Ito S (2010) Successful treatment of collapsing focal segmental glomerulosclerosis with a combination of rituximab, steroids and ciclosporin. Pediatr Nephrol 25:957–959
Nagai T, Uemura O, Ishikura K, Ito S, Hataya H, Gotoh Y, Fujita N, Akioka Y, Kaneko T, Honda M (2013) Creatinine-based equations to estimate glomerular filtration rate in Japanese children aged between 2 and 11 years old with chronic kidney disease. Clin Exp Nephrol 17:877–881
Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, Li J, Mattiazzi A, Ciancio G, Chen L, Zilleruelo G, Abitbol C, Chandar J, Seeherunvong W, Ricordi C, Ikehata M, Rastaldi MP, Reiser J, Burke GW 3rd (2011) Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 3:85–95
Acknowledgements
The authors thank Drs Y. Akioka (Tokyo), Y. Kaku (Fukuoka), W. Simabukuro (Fukuoka), N. Tanaka (Okayama), H. Nagasako (Kagoshima), and M. Hattori (Tokyo) for their contributions to this study.
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Kamei, K., Okada, M., Sato, M. et al. Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome. Pediatr Nephrol 29, 1181–1187 (2014). https://doi.org/10.1007/s00467-014-2765-z
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DOI: https://doi.org/10.1007/s00467-014-2765-z