Long-term results in mizoribine-treated renal transplant recipients: a prospective, randomized trial of mizoribine and azathioprine under cyclosporine-based immunosuppression

Tanabe, Kazunari; Tokumoto, Tadahiko; Ishikawa, Noriyuki; Kanematsu, Akihiro; Oshima, Tadashi; Harano, Masahiko; Inui, Masashi; Yagisawa, T; Nakajima, Ichiro; Fuchinoue, S; Takahashi, K; Toma, Hiromu

doi:10.1016/s0041-1345(99)00599-0

Cited by 38 publications

(18 citation statements)

References 3 publications

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“…Previous report indicated that MZR administration had fewer severe adverse events than other immunosuppressants [25]. Indeed, in this study, there were no serious adverse events among patients in the MZR group.…”

Section: Discussionsupporting

confidence: 46%

Efficacy and safety of adding mizoribine to standard treatment in patients with immunoglobulin A nephropathy: A randomized controlled trial

Hirai

Ookawara

Kitano

et al. 2017

Kidney Res Clin Pract.

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BackgroundMizoribine (MZR) is an immunosuppressive drug used in Japan for treating patients with lupus nephritis and nephrotic syndrome and has been also reportedly effective in patients with immunoglobulin A (IgA) nephropathy. However, to date, few randomized control studies of MZR are performed in patients with IgA nephropathy. Therefore, this prospective, open-label, randomized, controlled trial aimed to investigate the efficacy and safety of adding MZR to standard treatment in these patients, and was conducted between April 1, 2009, and March 31, 2016, as a multicenter study.MethodsPatients were randomly assigned (1:1) to receiving standard treatment plus MZR (MZR group) or standard treatment (control group). MZR was administered orally at a dose of 150 mg once daily for 12 months.ResultsPrimary outcomes were the percentage reduction in urinary protein excretion from baseline and the rate of patients with hematuria disappearance 36 months after study initiation. Secondary outcomes were the rate of patients with proteinuria disappearance, clinical remission rate, absolute changes in estimated glomerular filtration rate from baseline, and the change in daily dose of prednisolone. Forty-two patients were randomly assigned to MZR (n = 21) and control groups (n = 21). Nine patients in MZR group and 15 patients in the control group completed the study. No significant differences were observed between the two groups with respect to primary and secondary outcomes.ConclusionThe addition of MZR to standard treatment has no beneficial effect on reducing urinary protein excretion and hematuria when treating patients with IgA nephropathy.

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Section: Discussionsupporting

confidence: 46%

Efficacy and safety of adding mizoribine to standard treatment in patients with immunoglobulin A nephropathy: A randomized controlled trial

Hirai

Ookawara

Kitano

et al. 2017

Kidney Res Clin Pract.

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“…First, it was used to add on the steroids and AZP (4). In 1989, a randomized trial to compare CyA + AZP and CyA + MIZ revealed that MIZ had an equal immunosuppressive effect to AZP and fewer side effects such as myelosuppression and liver dysfunction (8). The application was extended for lupus nephritis, chronic rheumatoid arthritis and nephrotic syndrome afterward (9).…”

Section: Discussionmentioning

confidence: 99%

Revival of effective and safe high‐dose mizoribine for the kidney transplantation*

Sugitani

Kitada

Ota

et al. 2006

Clinical Transplantation

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We investigated whether high-dose Mizoribine (MIZ: a water-soluble anti-metabolite), 4-6 mg/kg/d was as effective and safe as mycophenolate mofetil (MMF) for patients after kidney transplantation. Between January 2001 and December 2005, 36 recipients at a stable phase more than one month passed after transplantation underwent conversion from MMF to MIZ, two from Azathioprine to MIZ, and two cases on MIZ from the beginning. There were 24-male and 16-female patients whose average age was 43.3 yr old and average weight was 54.0 kg. The types of transplantations were living donor renal transplantation 25, cadaveric renal transplantation 11, and simultaneous pancreas-kidney transplantation four examples. Of these, 33 patients were on Tacrolimus-based triple regimen and seven patients on Cyclosporine A base. The drugs used together with MIZ were basically the same as those before conversion. The reasons for conversion to MIZ were infection in 18 cases (45.0%), bone marrow suppression in nine cases (22.5%) and diarrhea in eight cases (20.0%), and post-transplant lymphoproliferative disorder in one case (2.5%). We initiated 4-6 mg/kg/d of MIZ divided twice a day depending on the serum creatinine (sCr) value of each patient. There was no big difference in the sCr value before and after MIZ administration in each individual patient, 1.79 +/- 1.37 and 1.65 +/- 1.30 mg/dL, respectively. A 12 h pharmaco-kinetic study of MIZ revealed that a peak value reached 2.87 microg/mL on average at three h (C3) followed by a slow decrease afterward. Acute rejection occurred in two cases and adverse effects were seen in five cases. The results of analysis of 349 points divided into three groups by renal function were as follows; poor renal function Group A revealed a trough level of 2.21 +/- 0.99 microg/mL and dosage 2.20 +/- 1.06 mg/kg, good renal function Group B had a trough level of 1.06 +/- 0.82 microg/mL and dosage 4.40 +/- 1.72 mg/kg, and excellent function Group C had a trough level of 0.92 +/- 0.55 microg/mL and dosage of 4.36 +/- 1.08 mg/kg. High-dose MIZ 4-6 mg/kg/d is an anti-metabolite having an equivalent immunosuppressive effect, fewer serious adverse events and good cost-effectiveness as MMF even for patients with prolonged hemodialysis period and declined digestive function in Japan.

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“…Clinical studies showed that no gastrointestinal disturbance was observed in MZ‐treated recipients at the dose of 2–5 mg/kg [20–23]. The therapeutic range for serum concentration has been reported to be 0.1–3 μ g/ml [24].…”

Section: Discussionmentioning

confidence: 99%

Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection

et al. 2005

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Summary Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2–5 mg/kg) is much lower than that of MMF (20–60 mg/kg). The purpose of this study was to examine whether high‐dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti‐donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high‐dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 μg/ml. Treatment with high‐dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.

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Long-term results in mizoribine-treated renal transplant recipients: a prospective, randomized trial of mizoribine and azathioprine under cyclosporine-based immunosuppression

Cited by 38 publications

References 3 publications

Efficacy and safety of adding mizoribine to standard treatment in patients with immunoglobulin A nephropathy: A randomized controlled trial

Efficacy and safety of adding mizoribine to standard treatment in patients with immunoglobulin A nephropathy: A randomized controlled trial

Revival of effective and safe high‐dose mizoribine for the kidney transplantation*

Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection

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