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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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Recurrence of focal segmental glomerulosclerosis (FSGS) in pediatric kidney allografts is associated with poor graft survival. Several therapeutic regimens have been proposed, with conflicting results., Methods: Ten pediatric patients with recurrent FSGS after kidney transplantation were treated with a protocol of methylprednisolone (MP) infusions in combination with cyclosporine (CsA)-based immunosuppression. The patients received a drug regimen with infusions of 20 mg/kg MP on three consecutive days at week 1, week 3, and week 5, and then monthly until six months after transplantation. If a complete or partial remission (PR) was obtained, MP pulse continued every three months until 24 months after transplantation. The CsA dose was adjusted according to AUC0-4., Results: Seven of 10 patients (70%) achieved complete remission (CR) with stable renal function within 18 months of beginning of treatment. One of two patients with PR entered CR 3.5 yr after transplantation. One patient lost her graft due to recurrence four months after transplantation. After observation for 26-119 months, seven patients maintained remission with normal glomerular filtration rate. Few major side effects were observed in association with the high-dose MP infusion therapy., Conclusions: MP infusion therapy in combination with CsA-based immunosuppression could be safe and effective in treating recurrent FSGS after kidney transplantation., (© 2013 John Wiley & Sons A/S.)

A prospective trial of corticosteroid (steroid) withdrawal after pediatric renal transplantation was started in 1990. Fifty-eight recipients with functioning grafts reached their final height. They were transplanted at a mean age of 10.7 yr. Immunosuppressive therapy with CyA, MP, and MZ was started after transplantation. MP was reduced to an alternate-day dose in 49 patients and was withdrawn in 23. Their mean height SDS was -2.4 at the time of transplantation and -2.1 at their final height. Mean final height was 157.9 cm in men and 147.6 cm in women. In 18 patients who had been withdrawn from MP for more than two yr before reaching final height, mean age at transplantation was 8.9 yr. Their mean height SDS of -2.2 at the time of transplantation increased to -1.6 at their final height (p = 0.02), and mean final height was 163.8 cm in men and 147.8 cm in women. The height SDS in all 58 patients was maintained during the immunosuppressive therapy with steroid minimization, and final height SDS increased in recipients older than five yr at transplantation with steroid withdrawal., (© 2011 John Wiley & Sons A/S.)

A prospective trial of adrenocorticostertoid (steroid) withdrawal after pediatric renal transplantation was begun in 1990. Ninety-four pediatric renal transplant recipients were enrolled in our multicenter study. Immunosuppressive therapy with cyclosporine (CyA), methylprednisolone (MPL), and mizoribine (MZ) was started after transplantation. MPL was reduced to administration on alternate days in 69 patients (73.4%) and was withdrawn in 27 patients (28.7%). Rejection episodes occurred in nine patients (33.3%) after withdrawal of MPL. It occurred within 3 months after withdrawal of MPL in two patients and more than 6 months in the others. Among them, two patients lost the grafts. Thirteen-year patient survival rate and graft survival rate were 94.6 and 83.1%, respectively. Forty-four of the 94 patients reached their final height. Mean final height was 155.0 cm in males and 146.3 cm in females and their height standard deviation score was -2.6 s.d., the same as that at the time of transplantation. Management of growth retardation before transplantation and further reduction in the steroid dose after transplantation will increase the final height of children with chronic renal failure.

Ten-year graft survival rate was 89% after immunosuppressive therapy with cyclosporine, methylprednisolone, and mizoribine in pediatric renal transplant recipients enrolled in our multicenter study. Adrenocorticosteroids, which cause growth retardation, were reduced by administration on alternate days in 67% and withdrawn in 23% of recipients. Acute rejection episodes occurred in 30% of patients after withdrawal of steroids. Graft function returned to prerejection levels after treatment with high-dose methylprednisolone. Catch-up growth occurred after alternate day administration and steroid withdrawal. Twenty-eight of 94 patients reached the final height of 156 cm in boys and 145 cm in girls, because of the gradually reduced growth rate. Management of growth retardation before transplantation, especially in patients with congenital renal diseases, and early reduction of the steroid dose after transplantation will increase the final height of children with chronic renal failure.

We conducted a multi-center prospective study to evaluate the safety and efficacy of steroid withdrawal after renal transplantation in children. In 52 children (51 living-related donor transplants and 1 cadaver donor transplant), immunosuppressive therapy was started with cyclosporine (CyA), mizoribine (MZ), methylprednisolone (MPL) and anti-lymphocyte globulin. Administration of MPL was reduced to alternate days more than 6 months after transplantation, and attempts were made to withdraw it. Acute rejection was noted in 19 patients (36.5%) by 1 month after transplantation. The whole-blood CyA trough level using monoclonal antibody was 175.0+/-17.0 ng/ml in patients who developed acute rejection and 282.0+/-25.3 ng/ml in those who did not show acute rejection (p<0.01). During the 37 attempts at alternate-day MPL administration, clinical acute rejection was observed in only 1 patient and chronic rejection in 3. During 10 attempts to withdraw MPL, acute rejection was noted in 3 patients, but graft function recovered to the pre-rejection level after treatment of the acute rejection. At the last observation, graft function was lost in 3 patients, 22 were receiving MPL on alternate days, and MPL had been withdrawn from 7 for a mean period of 16.7 months. The survival rate of the patients and the grafts was 100% and 94% after an average follow-up period of 4 years. Evaluation of growth showed catch-up growth in all patients during the withdrawal period.