Population pharmacokinetics of mizoribine in pediatric recipients of renal transplantation.

BACKGROUND: An immunosuppressive agent, mizoribine, is excreted predominantly in the urine. The aim of this study was to investigate the pharmacokinetic variability of mizoribine in pediatric recipients of renal transplantation. METHODS: Pharmacokinetic data for population analysis were collected from 51 recipients (32 males and 19 females) treated with oral administration of mizoribine (0.83-5.56 mg/day/kg). The population pharmacokinetic parameters of mizoribine were estimated using a nonlinear mixed effects model program. RESULTS: The pharmacokinetics of mizoribine in pediatric recipients of renal transplantation was well described by a one-compartment model with first-order absorption. The mean value of the absorption lag time (ALAG) and absorption rate constant (K (A)) was estimated to be 0.363 h and 0.554 h(-1), respectively. Apparent volume of distribution (V/F) was modeled as a function of body weight (WT), and the mean value was estimated to be 1.03 · WT L. Oral clearance (CL/F) was modeled as a function of creatinine clearance (CL(cr)), and the mean value was estimated to be 2.81 · CL(cr) · 60/1000 L/h. In addition, there was a positive correlation between CL(cr)-corrected CL/F and WT-corrected V/F in the pediatric recipients, indicating large interindividual variability in the bioavailability (F) of mizoribine. CONCLUSION: The present findings indicated that the rate of renal excretion and also the extent of intestinal absorption of mizoribine are responsible for the large interindividual pharmacokinetic variability of the drug.

Final height in a prospective trial of late steroid withdrawal after pediatric renal transplantation treated with cyclosporine and mizoribine.

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 MP was reduced to an alternate-day dose in 49 patients and was withdrawn in 23.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 In 18 patients who had been withdrawn from MP for more than two yr before reaching final height, mean age at transplantation was 8.9 yr.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.

Beneficial effect of chlorambucil in steroid-dependent and cyclophosphamide-resistant minimal change nephrotic syndrome.

BACKGROUND: Little information is available on the effect of second cytotoxic therapy in steroid-dependent children with minimal change nephrotic syndrome (MCNS). METHODS: Response to second cytotoxic therapy and side effects were reviewed in 33 steroid-dependent and cyclophosphamide-resistant children with MCNS who received chlorambucil (n=11, group 1) or cyclophosphamide (n=22, group 2). RESULTS: Age at onset of nephrosis, beginning of first and second therapy, sex ratio, duration of nephrosis before first cytotoxic therapy, interval between first and second cytotoxic therapy, number of relapses, cumulative doses of steroids and length of remission off steroids before second therapy were similar between groups. Four patients (36.4%, p<0.05) in group 1 remained in remission for a median 34.0 months, whereas only 1 patient (4.5%) in group 2 did for 53.0 months. Two patients in group 1 and 1 patient in group 2 became infrequent relapsers. Total number of nonrelapsers and infrequent relapsers was higher in group 1 (54.5%, p<0.05) than in group 2 (9.1%). Number of relapses and cumulative doses of steroids were reduced and length of remission off steroids was longer in group 1 than in group 2 (p<0.05). There was no difference between groups in frequency of side effects, and none had serious toxicity. However, the short period of follow-up in our study does not exclude the risk of azoospermia. CONCLUSIONS: Our data suggest a superior effect of chlorambucil over cyclophosphamide in steroid-dependent and cyclophosphamide-resistant children with MCNS. A future randomized controlled clinical trial is required to confirm our findings.

EYA1 and SIX1 gene mutations in Japanese patients with branchio-oto-renal (BOR) syndrome and related conditions.

We isolated genomic DNA from 15 patients with branchio-oto-renal (BOR) syndrome or BOR-related conditions. Seven patients had BOR syndrome (two familial and five sporadic), and eight had deafness and renal malformations without branchial fistula (BOR-related conditions). We analyzed all exons and exon-intron boundaries of EYA1 and SIX1 using the polymerase chain reaction (PCR) direct sequencing, and characterized their mutations. In some patients, analysis of mRNA by reverse transcription (RT)-PCR was performed to examine whether the mutation affects the mRNA splicing. We identified five novel disease-causing heterozygous EYA1 mutations in five patients with BOR syndrome (two familial and three sporadic, 5/7=71%), but EYA1 and SIX1 mutations were not detected in the other two patients with BOR syndrome or any of the patients with BOR-related conditions. The detected EYA1 mutations were two nonsense mutations, two splicing acceptor-site mutations, and a point mutation (G>T) of the first base of exon 10. Analysis of mRNA by RT-PCR direct sequencing revealed that the latter point mutation led to the skipping of exon 10. In conclusion, (1) EYA1 mutations are a major cause of BOR syndrome in Japanese, (2) EYA1 and SIX1 mutations were not a major cause of BOR-related conditions, (3) we demonstrated for the first time that the point mutation (G>T) of the first base of the exon in EYA1 gene induced exon skipping.

A prospective trial of steroid withdrawal after renal transplantation treated with cyclosporine and mizoribine in children: results obtained between 1990 and 2003.

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.

Methylenetetrahydrofolate reductase polymorphism in childhood primary focal segmental glomerulosclerosis.

AIM: The purpose of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C/T polymorphism and the prevalence and course of focal segmental glomerulosclerosis (FSGS) in our pediatric population. METHODS: Genotypes for MTHFR were determined in 15 primary FSGS patients (male/female, 6/9) and 238 control subjects (male/female, 110/128) by the polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: For the whole group, the genotype frequencies (CC/CT/TT) of MTHFR in FSGS and control subjects were almost comparable. The TT genotype was associated with early onset of the disease as compared with the CC genotype. Furthermore, all the patients with the TT genotype had steroid-resistant FSGS and developed into end-stage renal failure, while those carrying either CC or CT genotype did not. CONCLUSION: We speculate that the TT genotype may be associated with early development and progression of childhood FSGS. Confirmatory studies using larger and ethnically distinct populations are needed to reveal the role of homocysteine in FSGS with consideration of medical interventions.

Role of mizoribine in renal transplantation.

Renal transplantation is the optimal form of therapy for children and adolescents with end-stage renal disease. Usually histocompatibility differences exist between donor and recipient, so it is necessary to modify or suppress the immune response to enable the recipient to accept a graft. Calcineurin inhibitors (CNI), which include cyclosporin (CsA) and tacrolimus (FK506), give many benefits on the outcome after renal transplantation, but have some toxic effects, especially nephrotoxicity. Therefore, inhibitors of purine synthesis revived as newer generation of more specific inhibitors, mizoribine (MZ) and mycophenolate mofetil (MMF). The Japanese pediatric renal transplantation clinical study group attempted to reduce and then discontinue steroid administration in combination with another three immunosuppressive drugs, CsA, MZ and anti-lymphocyte globulin (ALG). This study showed good clinical results. Mizoribine is an effective immunosuppressive drug in human renal transplantation. However, it is not as popular as other inhibitors of purine synthesis, such as azathioprine (AZA) and MMF, because MZ has been used mainly in Japan and infrequently in other countries. However, MZ is a more useful immunosuppressive drug than AZA, when it is used in combination with CNI.