Renal transplantation
Immunosuppression
A Japanese Multicenter Study of High-Dose Mizoribine Combined With Cyclosporine, Basiliximab, and Corticosteroid in Renal Transplantation (The Fourth Report)

https://doi.org/10.1016/j.transproceed.2013.03.016Get rights and content

Abstract

We examined the efficacy and safety of 4-drug combination therapy using high-dose mizoribine (MZR) (8 mg/kg/d), cyclosporine (CsA), basiliximab (BXM), and steroid (STR) in 39 renal transplant recipients. Acute rejection episodes (ARE), which occurred in 9 (23.1%) patients, correlated with lower blood levels of MZR (trough levels ≥2 μg/mL). In addition, lower MZR concentrations tended to be associated with a higher incidence of rejection episodes in children aged ≤10 years than in those aged ≥11 years. The area under the received operating characteristics (ROC) curve of MZR trough level to pred ARE was 0.825 (95% confidence interval, 0.690–0.962; P = .002). Based on the ROC analysis, are MZR cut-off of 1.6 μg/mL showed a sensitivity of 81.8% and a specificity of 75.0%. Adverse events were observed in 23 patients, including infections in 11 (7 patients positive for cytomegalovirus [CMV] antigen and 4 treated with anti-CMV drugs). The MZR trough levels seemed to be higher among patients with adverse events than in those free of them, but it was no significant. All patients experienced successful engraftment except 1 who died of unknown cause with a functioning graft. In conclusion, our study showed that low MZR trough levels correlated with the incidence of ARE. No serious adverse effects were encountered with this therapy.

Section snippets

Study Subjects and Immunosuppression Protocol

The 39 patients aged ≤70 years underwent ABO-compatible or identical kidney transplantation after June 2006 at one of the following 6 institutes: Keio University Hospital, Fujita Health University Hospital, Toho University Omori Medical Center, Kitasato University Hospital, National Defense Medical College Hospital, and University of the Ryukyus Hospital. All patients provided informed consent. The study was approved by the ethics committees of the participating institutes. The

Results

The 39 patients treated with the high-dose MZR immunosuppressive protocol (Table 1) showed an average age of 30.7 years, including 9 aged ≤10 years (25.6%) and 30 aged ≥11 years (74.6%). The patients consisted of 26 males and 13 females, with donor type being living donor in 37 and deceased in 2.

Twelve ARE occurred in 9/39 patients (23.1%). ARE-free survival in children aged ≤10 years tended to be lower than that in those aged ≥11 years (Fig 2). The incidence of ARE correlated with MZR blood

Discussion

Although MMF has decreased early post-transplantation rejection rate, it has increased the incidence of CMV infection. Both the increased incidence of infections with CMV, BK virus, and adenovirus as well as the adverse side effects of diarrhea, abdominal discomfort, and leukopenia have led to a conversion of treatment of some transplant recipients to MZR.3 Although MZR has been used as an immunosuppressive agent in Japan for over 25 years, at standard doses (1–3 mg/kg/d) it is less effective

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    Because of the predominant renal metabolism, the dosage of MZR should be adapted to the glomerular filtration rate and MZR plasma trough level to avoid overimmunosuppression and adverse effects. As MZR passes a cell membrane according to the gradient of its concentration, currently, most of the RCTs from Japan are conducted to prove the efficacy and safety of high-dose MZR, distinguishing from the low-dose MZR use previously [10,11]. In this study, we examined whether high-dose MZR (≧ 3 mg/kg/d) was as effective and safe as MMF for patients at a stable phase after renal transplantation.

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