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Mizoribine in the treatment of pediatric-onset glomerular disease

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Abstract

Background

Mizoribine (MZR) is a selective inhibitor of inosine monophosphate dehydrogenase, a key enzyme in the pathway responsible for de novo synthesis of guanine nucleotides. As an immunosuppressant, MZR has been used successfully without any serious adverse effects in the treatment of renal diseases in children as well as adults. Besides its immunosuppressive effect, MZR has been reported to ameliorate tubulointerstitial fibrosis in rats via suppression of macrophage infiltration.

Data Sources

In this review, we summarize reported possible benefits of MZR in the treatment of pediatriconset glomerular disease.

Results

We recently observed that MZR itself selectively attenuates the expression of monocyte chemoattractant protein-1 at both the mRNA and protein levels in human mesangial cells. Since MZR binds specifically to 14-3-3 proteins and heat shock protein 60, both of which are reportedly expressed in inflamed glomeruli, MZR may bind directly to inflamed glomerular cells, thereby possibly preventing progressive damage from glomerulonephritis through a suppressive effect on activated macrophages and intrinsic renal cells. Moreover, it has recently been reported that MZR directly prevents podocyte injury through correction of the intracellular energy balance and nephrin biogenesis in cultured podocyte and rat models, suggesting a direct anti-proteinuric effect of MZR.

Conclusions

These beneficial mechanisms of action of MZR as well as its immunosuppressive effect would warrant its use in the treatment of pediatric-onset glomerular disease. Although further studies remain to be done, we believe that MZR may be an attractive treatment of choice for children with glomerular diseases from a histologic as well as clinical standpoint.

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References

  1. Yokota S. Mizoribine: mode of action and effects in clinical use. Pediatr Int 2002;44:196–198.

    Article  CAS  PubMed  Google Scholar 

  2. Kawasaki Y. Mizoribine: a new approach in the treatment of renal disease. Clin Dev Immunol 2009;2009:681482.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Sonda K, Takahashi K, Tanabe K, Funchinoue S, Hayasaka Y, Kawaguchi H, et al. Clinical pharmacokinetic study of mizoribine in renal transplantation patients. Transplant Proc 1996;28:3643–3648.

    CAS  PubMed  Google Scholar 

  4. Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, et al. A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int 2000;58:317–324.

    Article  CAS  PubMed  Google Scholar 

  5. Honda M. Nephrotic syndrome and mizoribine in children. Pediatr Int 2002;44:210–216.

    Article  PubMed  Google Scholar 

  6. Kawasaki Y, Hosoya M, Suzuki J, Onishi N, Takahashi A, Isome M, et al. Efficacy of multidrug therapy combined with mizoribine in children with diffuse IgA nephropathy in comparison with multidrug therapy without mizoribine and with methylprednisolone pulse therapy. Am J Nephrol 2004;24:576–581.

    Article  CAS  PubMed  Google Scholar 

  7. Yoshikawa N, Nakanishi K, Ishikura K, Hataya H, Iijima K, Honda M. Combination therapy with mizoribine for severe childhood IgA nephropathy: a pilot study. Pediatr Nephrol 2008;23:757–763.

    Article  PubMed  Google Scholar 

  8. Tanaka H, Tsugawa K, Tsuruga K, Suzuki K, Nakahata T, Ito E, et al. Mizoribine for the treatment of lupus nephritis in children and adolescents. Clin Nephrol 2004;62:412–417.

    Article  CAS  PubMed  Google Scholar 

  9. Yumura W, Suganuma S, Uchida K, Moriyama T, Otsubo S, Takei T, et al. Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis. Clin Nephrol 2005;64:28–34.

    Article  CAS  PubMed  Google Scholar 

  10. Shibasaki T, Matsuda H, Gomi H, Usui M, Ishimoto F, Sakai O. Mizoribine reduces urinary protein excretion in rats given puromycin aminonucleoside. Am J Nephrol 1996;16:167–172.

    Article  CAS  PubMed  Google Scholar 

  11. Takahashi S, Wakui H, Gustafsson JA, Zilliacus J, Itoh H. Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein. Biochem Biophys Res Commun 2000;274:87–92.

    Article  CAS  PubMed  Google Scholar 

  12. Tanaka H, Suzuki K, Nakahata T, Tsugawa K, Ito E, Waga S. Mizoribine oral pulse therapy for patients with disease flare of lupus nephritis. Clin Nephrol 2003;60:390–394.

    Article  CAS  PubMed  Google Scholar 

  13. Tanaka H, Tsugawa K, Suzuki K, Nakahata T, Ito E. Long-term mizoribine intermittent pulse therapy for young patients with flare of lupus nephritis. Pediatr Nephrol 2006;21:962–966.

    Article  PubMed  Google Scholar 

  14. Kuroda T, Hirose S, Tanabe N, Sato H, Nakatsue T, Ajiro J, et al. Mizoribine therapy for patients with lupus nephritis: the association between peak mizoribine concentration and clinical efficacy. Mod Rheumatol 2007;17:206–212.

    Article  CAS  PubMed  Google Scholar 

  15. Tanaka H, Oki E, Tsuruga K, Sato N, Matsukura H, Matsunaga A, et al. Mizoribine treatment of young patients with severe lupus nephritis: a clinicopathologic study by the tohoku pediatric study group. Nephron Clin Pract 2008;110:c73–c79.

    Article  CAS  PubMed  Google Scholar 

  16. Ohtomo Y, Fujinaga S, Takada M, Murakami H, Akashi S, Shimizu T, et al. High-dose mizoribine therapy for childhoodonset frequently relapsing steroid-dependent nephrotic syndrome with cyclosporin nephrotoxicity. Pediatr Nephrol 2005;20:1744–1749.

    Article  PubMed  Google Scholar 

  17. Kawasaki Y, Takano K, Isome M, Suzuki J, Suyama K, Kanno H, et al. Efficacy of single dose of oral mizoribine pulse therapy two times per week for frequently relapsing nephrotic syndrome. J Nephrol 2007;20:52–56.

    CAS  PubMed  Google Scholar 

  18. Doi T, Masaki T, Shiraki N, Kawai T, Yorioka N. Oral mizoribine pulse therapy for steroid-dependent focal segmental glomerulosclerosis. Clin Nephrol 2008;69:433–435.

    Article  CAS  PubMed  Google Scholar 

  19. Fuke T, Abe Y, Hibino S, Takeshi M, Saito T, Sakurai S, et al. Mizoribine requires individual dosing due to variation of bioavailability. Pediatr Int 2012;54:885–891.

    Article  CAS  PubMed  Google Scholar 

  20. Ikezumi Y, Suzuki T, Karasawa T, Kawachi H, Nikolic-Paterson DJ, Uchiyama M. Use of mizoribine as a rescue drug for steroid-resistant pediatric IgA nephropathy. Pediatr Nephrol 2008;23:645–650.

    Article  PubMed  Google Scholar 

  21. Tanaka H, Oki ES, Tsugawa K, Suzuki K, Tsuruga K, Ito E. Long-term intermittent pulse therapy with mizoribine attenuates histologic progression in young patients with severe lupus nephritis: report of two patients. Nephrology (Carlton) 2007;12:376–379.

    Article  CAS  Google Scholar 

  22. Tanaka H, Oki E, Tsuruga K, Aizawa-Yashiro T, Ito Y, Sato N, et al. Mizoribine attenuates renal injury and macrophage infiltration in patients with severe lupus nephritis. Clin Rheumatol 2010;29:1049–1054.

    Article  PubMed  Google Scholar 

  23. Sato N, Shiraiwa K, Kai K, Watanabe A, Ogawa S, Kobayashi Y, et al. Mizoribine ameliorates the tubulointerstitial fibrosis of obstructive nephropathy. Nephron 2001;89:177–185.

    Article  CAS  PubMed  Google Scholar 

  24. Kikuchi Y, Imakiire T, Yamada M, Saigusa T, Hyodo T, Hyodo N, et al. Mizoribine reduces renal injury and macrophage infiltration in non-insulin-dependent diabetic rats. Nephrol Dial Transplant 2005;20:1573–1581.

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi S, Taniguchi Y, Nakashima A, Arakawa T, Kawai T, Doi S, et al. Mizoribine suppresses the progression of experimental peritoneal fibrosis in a rat model. Nephron Exp Nephrol 2009;112:e59–e69.

    Article  CAS  PubMed  Google Scholar 

  26. Itoh H, Komatsuda A, Wakui H, Miura AB, Tashima Y. Mammalian HSP60 is a major target for an immunosuppressant mizoribine. J Biol Chem 1999;274:35147–35151.

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka H, Tsugawa K, Oki E, Suzuki K, Waga S, Ito E. Longterm mizoribine intermittent pulse therapy, but not azathioprine therapy, attenuated histologic progression in a patient with severe lupus nephritis. Clin Nephrol 2007;68:198–200.

    Article  CAS  PubMed  Google Scholar 

  28. Stypinski D, Obaidi M, Combs M, Weber M, Stewart AJ, Ishikawa H. Safety, tolerability and pharmacokinetics of higherdose mizoribine in healthy male volunteers. Br J Clin Pharmacol 2006;63:459–468.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Kawachi H, Nikolic-Paterson DJ, et al. Contrasting effects of steroids and mizoribine on macrophage activation and glomerular lesions in rat thy-1 mesangial proliferative glomerulonephritis. Am J Nephrol 2010;31:273–282.

    Article  CAS  PubMed  Google Scholar 

  30. Anders HJ. Pseudoviral immunity-a novel concept for lupus. Trends Mol Med 2009;15:553–561.

    Article  CAS  PubMed  Google Scholar 

  31. Imaizumi T, Tanaka H, Matsumiya T, Yoshida H, Tanji K, Tsuruga K, et al. Retinoic acid-inducible gene-I is induced by double-stranded RNA and regulates the expression of CC chemokine ligand (CCL) 5 in human mesangial cells. Nephrol Dial Transplant 2010;25:3534–3539.

    Article  CAS  PubMed  Google Scholar 

  32. Imaizumi T, Aizawa-Yashiro T, Tsuruga K, Tanaka H, Matsumiya T, Yoshida H, et al. Melanoma differentiation-associated gene 5 regulates the expression of a chemokine CXCL10 in human mesangial cells: implications for chronic inflammatory renal diseases. Tohoku J Exp Med 2012;228:17–26.

    Article  CAS  PubMed  Google Scholar 

  33. Aizawa-Yashiro T, Imaizumi T, Tsuruga K, Watanabe S, Matsumiya T, Hayakari R, et al. Glomerular expression of fractalkine is induced by polyinosinic-polycytidylic acid in human mesangial cells: possible involvement of fractalkine after viral infection. Pediatr Res 2013;73:180–186.

    Article  CAS  PubMed  Google Scholar 

  34. Tanaka H, Imaizumi T. Inflammatory chemokine expression via Toll-like receptor 3 signaling in normal human mesangial cells. Clin Dev Immunol 2013;2013:984708.

    PubMed Central  PubMed  Google Scholar 

  35. Aizawa T, Imaizumi T, Tsuruga K, Watanabe S, Chiba Y, Matsumiya T, et al. Mizoribine selectively attenuates monocyte chemoattractant protein-1 production in cultured human glomerular mesangial cell: a possible benefit of its use in the treatment of lupus nephritis. Nephrology (Carlton) 2014;19:47–52.

    Article  CAS  Google Scholar 

  36. Yamabe H, Shimada M, Murakami R, Fujita T, Shimaya Y, Nakamura N. Mizoribine suppresses proliferation of rat glomerular epithelial cells in culture and inhibits increase of monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 stimulated by thrombin. Biol Pharm Bull 2012;35:705–708.

    Article  CAS  PubMed  Google Scholar 

  37. Uemura O, Ushijima K, Yamada T, Kimpara Y. Blood concentration and urinary excretion of mizoribine for internal use in pediatric kidney disease patients. Jpn J Pediatr Nephrol 2007;20:9–13. [In Japanese]

    Google Scholar 

  38. Takeuchi S, Hiromura K, Tomioka M, Takahashi S, Sakairi T, Maeshima A, et al. The immunosuppressive drug mizoribine directly prevents podocyte injury in puromycin aminonucleoside nephrosis. Nephron Exp Nephrol 2010;116:e3–e10.

    Article  CAS  PubMed  Google Scholar 

  39. Nakajo A, Khoshnoodi J, Takenaka H, Hagiwara E, Watanabe T, Kawakami H, et al. Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance. J Am Soc Nephrol 2007;18:2554–2564.

    Article  CAS  PubMed  Google Scholar 

  40. Fujita T, Shimizu C, Ito K, Fuke Y, Satomura A, Matsumoto K. Anti-proteinuric effect of mizoribine monotherapy in three patients with membranous nephropathy. Clin Nephrol 2010;74:81–82.

    Article  CAS  PubMed  Google Scholar 

  41. Shimizu H, Takahashi M, Takeda S, Tahara K, Inoue S, Hakamata Y, et al. Effect of conversion from cyclosporine A to mizoribine on transplant arteriosclerosis in rat aortic allograft models. Microsurgery 2003;23:454–457.

    Article  PubMed  Google Scholar 

  42. Hara S, Umino D, Someya T, Fujinaga S, Ohtomo Y, Murakami H, et al. Protective effects of Mizoribine on Cyclosporine A nephropathy in rats. Pediatr Res 2009;66:524–527.

    Article  CAS  PubMed  Google Scholar 

  43. Aizawa-Yashiro T, Tsuruga K, Watanabe S, Oki E, Ito E, Tanaka H. Novel multidrug therapy for children with cyclosporineresistant or -intolerant nephrotic syndrome. Pediatr Nephrol 2011;26:1255–1261.

    Article  PubMed  Google Scholar 

  44. Hirose C, Aizawa T, Watanabe S, Tsuruga K, Ito E, Tanaka H. Efficacy of long-term multidrug therapy in a patient with focal segmental glomerulosclerosis. Pediatr Int 2014;56:129–130.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of School Health Science, Faculty of Education, Hirosaki University, Hirosaki, 036-8560, Japan

    Hiroshi Tanaka

  2. Department of Pediatrics, Hirosaki University Hospital, Hirosaki, 036-8563, Japan

    Hiroshi Tanaka & Kazushi Tsuruga

  3. Department of Vacular Biology, Graduate School of Medicine, Hirosaki University, Hirosaki, 036-8562, Japan

    Taddatsu Imaizumi

Authors
  1. Hiroshi Tanaka
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  2. Kazushi Tsuruga
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  3. Taddatsu Imaizumi
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Correspondence to Hiroshi Tanaka.

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Tanaka, H., Tsuruga, K. & Imaizumi, T. Mizoribine in the treatment of pediatric-onset glomerular disease. World J Pediatr 11, 108–112 (2015). https://doi.org/10.1007/s12519-015-0013-7

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  • DOI: https://doi.org/10.1007/s12519-015-0013-7

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