Usefulness of mizoribine administration in children with frequently relapsing nephrotic syndrome, and the relationship between pharmacokinetic parameters and efficacy: a multicenter prospective cohort study in China

  • Zheng-Kun XiaEmail author
  • Yuan-Fu Gao
  • Li-Ping Rong
  • Xi-Qiang Dang
  • Qian Shen
  • Xiao-Yun Jiang
  • Zhu-Wen Yi
  • Hong Xu
Original Article



Mizoribine (MZR) is an immunosuppressant used to treat adult nephropathy. There is little experience with the drug in treating Chinese children with frequently relapsing nephrotic syndrome (FRNS). We investigated the efficacy and safety for treating MZR with FRNS. Furthermore, the relationship between efficacy and serum concentration was investigated.


A prospective multicenter observational 12-month study was performed for evaluating the usefulness of MZR with FRNS. Serum MZR concentration was measured, and the relationships between pharmacokinetic parameters (Cmax, AUC), number of relapses, and urinary protein were evaluated.


Eighty-two pediatric patients from four hospitals were treated with MZR and prednisone. MZR treatment significantly reduced the number of relapses and steroid doses. A correlation between pharmacokinetic parameters and relapses was observed, which fits well with the sigmoidal Emax model. Even in the relationship between pharmacokinetic parameters and urinary proteins, it was recognized that there was a threshold in the pharmacokinetic parameters for the therapeutic effect similar to the results obtained with the sigmoidal Emax model. Eleven patients (13.4%) experienced mild adverse events.


MZR therapy was effective in reducing the number of relapses and steroid doses. No severe adverse reactions were observed. Therapeutically effective serum concentrations were estimated to be Cmax ≥ about 2 μg/mL or AUC ≥ about 10 μg h/mL. MZR and steroid treatment were effective and safe for pediatric FRNS.


Frequently relapsing nephrotic syndrome Mizoribine Pharmacokinetic parameters 


Author contributions

YFG, LPR, XQD, and QS contributed to the study design, collection, evaluation, and interpretation of the data. XYJ, ZWY, HX, and ZKX contributed to the study design. All authors contributed to the critical revision and final approval of the manuscript.


This study was supported by a grant from the medical innovation team project of Jiangsu Province, China (grant number CXTDA2017022). The authors thank the participants and their parents, and other persons who assisted in undertaking this study. The funders had no role in drafting or submitting this manuscript.

Compliance with ethical standards

Ethical approval

This study was approved by the Institutional Ethics Committee of Nanjing University School of Medicine.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    KDIGO Clinical Practice Guideline for Glomerulonephritis. Chapter 3: Steroid-sensitive nephrotic syndrome in children. Kidney Int. 2012;2:163–71.Google Scholar
  2. 2.
    Koskimies O, Vilska J, Rapola J, Hallman N. Long-term outcome of primary nephrotic syndrome. Arch Dis Child. 1982;57:544–8.CrossRefGoogle Scholar
  3. 3.
    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;8:769–76.Google Scholar
  4. 4.
    Kyrieleis HA, Löwik MM, Pronk I, Cruysberg HR, Kremer JA, Oyen WJ, et al. Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol. 2009;4:1593–600.CrossRefGoogle Scholar
  5. 5.
    Niaudet P, Broyer M, Habib R. Treatment of idiopathic nephrotic syndrome with cyclosporin A in children. Clin Nephrol. 1991;35(Suppl 1):S31–6.Google Scholar
  6. 6.
    El-Husseini A, El-Basuony F, Mahmoud I, Sheashaa H, Sabry A, Hassan R, et al. Long-term effects of cyclosporine in children with idiopathic nephrotic syndrome: a single-centre experience. Nephrol Dial Transplant. 2005;20:2433–8.CrossRefGoogle Scholar
  7. 7.
    Dötsch J, Dittrich K, Plank C, Rascher W. Is tacrolimus for childhood steroid dependent nephrotic syndrome better than ciclosporin A? Nephrol Dial Transplant. 2006;21:1761–3.CrossRefGoogle Scholar
  8. 8.
    Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf. 2001;24:645–63.CrossRefGoogle Scholar
  9. 9.
    Koyama H, Tsuji M. Genetic and biochemical studies on the activation and cytotoxic mechanism of Bredinin, a potent inhibitor of purine biosynthesis in mammalian cells. Biochem Pharmacol. 1983;32:3547–53.CrossRefGoogle Scholar
  10. 10.
    Kusumi T, Tsuda M, Katsunuma T, Yamamura M. Dual Inhibitory effect of bredinin. Cell Biochem Funct. 1989;7:201–4.CrossRefGoogle Scholar
  11. 11.
    Turka LA, Dayton J, Sinclair G, Thompson CB, Mitchell BS. Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of action of the immunosuppressive drug mizoribine. J Clin Invest. 1991;87:940–8.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    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;20:52–6.Google Scholar
  14. 14.
    Ohtomo Y, Fujinaga S, Takada M, Murakami H, Akashi S, Shimizu T, et al. High-dose mizoribine therapy for childhood-onset frequently relapsing steroid-dependent nephrotic syndrome with cyclosporin nephrotoxicity. Pediatr Nephrol. 2005;20:1744–9.CrossRefGoogle Scholar
  15. 15.
    Fujinaga S, Hirano D, Nishizaki N, Someya T, Ohtomo Y, Ohtsuka Y, et al. Single daily high-dose mizoribine therapy for children with steroid-dependent nephrotic syndrome prior to cyclosporine administration. Pediatr Nephrol. 2011;26:479–83.CrossRefGoogle Scholar
  16. 16.
    Kawasaki Y. Mizoribine: a new approach in the treatment of renal disease. Clin Dev Immunol. 2009;2009:681482.CrossRefGoogle Scholar
  17. 17.
    Xing S, Yang J, Zhang X, Zhou P. Comparative efficacy and safety of mizoribine with mycophenolate mofetil for Asian renal transplantation—a meta-analysis. Clin Biochem. 2014;47:663–9.CrossRefGoogle Scholar
  18. 18.
    Hosotsubo H, Takahara S, Taenaka N. Simplified high-performance liquid chromatographic method for determination of mizoribine in human serum. J Chromatogr. 1988;432:340–5.CrossRefGoogle Scholar
  19. 19.
    Ishida K, Kaneda H, Uemura O, Ushijima K, Ohta K, Goto Y, et al. Evaluation of limited sampling designs to estimate maximal concentration and area under the curve of mizoribine in pediatric patients with renal disease. Drug Metab Pharmacokinet. 2011;26:71–8.CrossRefGoogle Scholar
  20. 20.
    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;17:206–12.CrossRefGoogle Scholar
  21. 21.
    Tanaka H, Tsugawa K, Nakahata T, Kudo M, Suzuki K, Ito E. Implication of the peak serum level of mizoribine for control of the serum anti-dsDNA antibody titer in patients with lupus nephritis. Clin Nephrol. 2005;63:417–22.CrossRefGoogle Scholar
  22. 22.
    Choe S, Lee D. Parameter estimation for sigmoid Emax models in exposure–response relationship. Transl Clin Pharmacol. 2017;25:74–84.CrossRefGoogle Scholar
  23. 23.
    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;58:317–24.CrossRefGoogle Scholar
  24. 24.
    Yoshikawa N, Nakanishi K, Ishikura K, Hataya H, Iijima K, Honda M. Japanese Pediatric IgA Nephropathy Treatment Study Group. Pediatr Nephrol. 2008;23:757–63.CrossRefGoogle Scholar
  25. 25.
    Saito T, Iwano M, Matsumoto K, Mitarai T, Yokoyama H, Yorioka N, et al. Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome. Clin Exp Nephrol. 2017;21:961–70.CrossRefGoogle Scholar
  26. 26.
    Sonda K, Takahashi K, Tanabe K, Funchinoue S, Hayasaka Y, Kawaguchi H, et al. Clinical pharmacokinetic study of mizoribine in renal transplantation patients. Transpl Proc. 1996;28:3643–8.Google Scholar

Copyright information

© Children's Hospital, Zhejiang University School of Medicine 2019

Authors and Affiliations

  • Zheng-Kun Xia
    • 1
    Email author
  • Yuan-Fu Gao
    • 1
  • Li-Ping Rong
    • 2
  • Xi-Qiang Dang
    • 3
  • Qian Shen
    • 4
  • Xiao-Yun Jiang
    • 2
  • Zhu-Wen Yi
    • 3
  • Hong Xu
    • 4
  1. 1.Department of PediatricsJinling Hospital, Nanjing University School of MedicineNanjing 210002China
  2. 2.Department of PediatricsThe First Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510080China
  3. 3.Department of Pediatric Nephrology, Children’s Medical CenterSecond Xiangya Hospital, Central South UniversityChangsha 410011China
  4. 4.Department of Nephrology and RheumatologyChildren’s Hospital of Fudan UniversityShanghai 201102China

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