Abstract
An effective treatment for children with refractory nephrotic syndrome (NS), especially in those with cyclosporine (CsA)-resistant or CsA-intolerant NS, has yet to be established. Recently, the efficacy of multidrug therapy consisting of tacrolimus (Tac), mycophenolate mofetil (MMF) in combination with prednisolone (PDN) in adult patients with refractory NS has been reported. We successfully treated 14 consecutive children with refractory CsA-resistant or CsA-intolerant NS using combination therapy consisting of relatively low-dose Tac, mizoribine (MZR), which has a mechanism of action very similar to that of MMF, and PDN. There were no serious clinical toxicities. Of the 14 children, 9 with a mean age of 13.0 years had steroid-dependent NS (SDNS) and 5 with a mean age of 9.6 years had steroid-resistant NS (SRNS). All SDNS patients had minimal change disease (MCD), 4 with SRNS had focal segmental glomerulosclerosis (FSGS), and the remaining child had MCD on renal biopsy. All patients were in a prospective cohort, but were evaluated retrospectively. The mean follow-up from the initiation of multidrug therapy was 18.4 months in SDNS and 18.6 months in SRNS patients. At the last observation point, the calculated relapse rate and minimum dose of PDN required for maintenance of clinical remission after the start of multidrug therapy were significantly decreased compared with those prior to this therapy, while on CsA, in SDNS patients (0.4 ± 0.5 times/year vs 2.9 ± 1.5 times/year, P = 0.0077, and 0.3 ± 0.2 mg/kg on alternate days vs 0.5 ± 0.2 mg/kg on alternate days, P = 0.0184 respectively). All SDNS and two SRNS patients (40%) achieved complete remission, allowing further decreases in the minimal doses of PDN required for maintenance of clinical remission in most our patients. However, one patient with FSGS remained refractory to multidrug therapy and subsequently developed end-stage renal disease. These clinical observations, although preliminary and involving a small number of patients, suggest that multidrug therapy consisting of relatively low-dose Tac, MZR, and PDN might be effective and safe for treating children with refractory CsA-resistant or CsA-intolerant NS. However, further studies involving larger numbers of patients are needed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Hino S, Takemura T, Okada M, Murakami K, Yagi K, Fukushim K, Yoshioka K (1998) Follow-up study of children with nephrotic syndrome treated with a long-term moderate dose of cyclosporine. Am J Kidney Dis 31:932–939
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
El-Husseini A, El-Basuony F, Mahmoud I, Sheashaa H, Sabry A, Hassan R, Taha N, Hassan N, Sayed-Ahamad N, Sobh M (2005) Long-term effects of cyclosporine in children with idiopathic nephrotic syndrome: a single-centre experience. Nephrol Dial Transplant 20:2433–2438
Hamasaki Y, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ishikura K, Yata N, Kaneko T, Honda M (2009) Cyclosporine and steroid therapy in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 24:2177–2185
Suzuki K, Oki E, Tsuruga K, Aizawa-Yashiro T, Ito E, Tanaka H (2010) Benefits of once-daily administration of cyclosporine A for children with steroid-dependent, relapsing nephrotic syndrome. Tohoku J Exp Med 220:183–186
Bhimma R, Adhikari M, Asharam K, Connolly C (2006) Management of steroid-resistant focal segmental glomerulosclerosis in children using tacrolimus. Am J Nephrol 26:544–551
Suzuki K, Tsugawa K, Tanaka H (2006) Tacrolimus for the treatment of focal segmental glomerulosclerosis resistant to cyclosporine A. Pediatr Nephrol 21:1913–1914
Gulati S, Prasad N, Sharma RK, Kumar A, Gupta A, Baburaj VP (2008) Tacrolimus: a new therapy steroid-resistant nephrotic syndrome in children. Nephrol Dial Transplant 23:910–913
Butani L, Ramsamooj R (2009) Experience with tacrolimus in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 24:1517–1523
Roberti I, Vyas S (2010) Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus. Pediatr Nephrol 25:1117–1124
Cattran DC, Wang MM, Appel G, Matalon A, Briggs W (2004) Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis. Clin Nephrol 62:405–411
Okada M, Sigimoto K, Yagi K, Yanagida H, Tabata N, Takemura T (2007) Mycophenolate mofetil therapy for children with intractable nephrotic syndrome. Pediatr Int 49:933–937
Oki E, Tsuruga K, Kudo M, Tsugawa K, Suzuki K, Tanaka H (2009) A novel multidrug therapy for difficult cyclosporine-resistant focal segmental glomerulosclerosis. Pediatr Nephrol 24:773–775
Ballarin J, Poveda R, Ara J, Perez L, Calero C, Grinyo JM, Romero R (2007) Treatment of idiopathic membranous nephropathy with the combination of steroids, tacrolimus and mycophenolate mofetil: results of a pilot study. Nephrol Dial Transplant 22:3196–3201
International Study of Kidney Disease in Children (1981) The primary nephrotic syndrome in children: identification of patients with minimal change nephrotic syndrome from initial response to prednisone: a report of the International Study of Kidney Disease in Children. J Pediatr 98:561–564
Takeda A, Horike K, Onoda H, Ohtsuka Y, Yoshida A, Uchida K, Morozumi K (2007) Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile. Nephrology (Carlton) 12:197–204
Schwartz GJ (1992) Does kL/Pcr estimate GFR, or does GFR determine k? Pediatr Nephrol 6:512–515
Tanaka H, Oki E, Tsuruga K, Yashiro T, Hanada I, Ito E (2009) Management of young patients with lupus nephritis using tacrolimus administered as a single daily dose. Clin Nephrol 72:430–436
Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, Tanizawa T, Wada H, Maki S (2000) A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int 58:317–324
Honda M (2002) Nephrotic syndrome and mizoribine in children. Pediatr Int 44:210–216
Shimizu H, Takahashi M, Takeda S, Tahara K, Inoue S, Nakamata Y, Kaneko T, Takeyoshi I, Morishita Y, Kobayashi E (2003) Effect of conversion from cyclosporine A to mizoribine on transplant arteriosclerosis in rat aortic allograft models. Microsurgery 23:454–457
Hara S, Umino D, Someya T, Fujinaga S, Ohtomo Y, Murakami H, Shimizu T (2009) Protective effects of mizoribine on cyclosporine A nephropathy in rats. Pediatr Res 66:524–527
Takeuchi S, Hiromura K, Tomioka M, Takahashi S, Sakairi T, Maeshima A, Kaneko Y, Kuroiwa T, Nojima Y (2010) The immunosuppressive drug mizoribine directory prevents podocyte injury in puromycin aminosucleoside nephrosis. Nephron Exp Nephrol 116:e3–e10
Tanaka H, Oki E, Tsuruga K, Aizawa-Yashiro T, Ito Y, Sato N, Kawasaki Y, Suzuki J (2010) Mizoribine attenuates renal injury and macrophage infiltration in patients with severe lupus nephritis. Clin Rheumatol 29:1049–1054
Lanata CM, Mahmood T, Fine DM, Petri M (2010) Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis. Lupus 19:935–940
Conflict of interest
None declared.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Aizawa-Yashiro, T., Tsuruga, K., Watanabe, S. et al. Novel multidrug therapy for children with cyclosporine-resistant or -intolerant nephrotic syndrome. Pediatr Nephrol 26, 1255–1261 (2011). https://doi.org/10.1007/s00467-011-1876-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-011-1876-z