A time-to-event model for acute rejections in paediatric renal transplant recipients treated with ciclosporin A.

AIMS: Ciclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUCs) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome. METHODS: Patient records at the Children's Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling, bootstrap-stepwise covariate modelling and cross-validated stepwise covariate modelling. The clinical relevance of the effects was assessed with the time at which 90% of the patients were AR free (t90). RESULTS: Data from 87 patients (0.7-19.8 years old, 54 experiencing an AR) were analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90% interval 1.13-8.40 h mg l⁻¹), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median t90 was 5.8 days (90% confidence interval 5.1-6.8) for long dialysis times (90th percentile) and 7.4 days (6.4-11.7) for short dialysis times (10th percentile). CONCLUSIONS: A survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help to avoid unnecessarily high CsA dosing in children.

Feasibility of diagnosing subclinical renal allograft rejection in children by whole blood gene expression analysis.

BACKGROUND: Protocol biopsies are used to monitor allograft histology after transplantation. However, biopsy is an invasive procedure with potential complications, requires special facilities, and is unpractical for repeated monitoring of the graft. A noninvasive, robust, and rapid diagnostic method would be welcomed. Monitoring gene expression from blood samples could provide such a means. METHODS: Whole blood samples taken at the time of 3- or 6-month protocol biopsy in 31 pediatric renal transplant recipients, 13 of whom had biopsy-proven subclinical rejection (SCR), were studied. The samples were collected into tubes containing an RNA stabilization reagent enabling feasible collection during a normal ward schedule. In all patients, the gene expression of candidate genes CD154 and inducible T-cell co-stimulator (ICOS) was measured. A low-density array containing 90 immunologic-related genes were measured with real-time quantitative PCR (RT-QPCR) in 10 patients. In addition, a whole genome microarray analysis was performed in eight patients. RESULTS: Neither CD154 nor ICOS gene expression was diagnostic for SCR (median expression level 1.25 vs. 1.16 and 1.95 vs. 1.61 for CD154 and ICOS, respectively). In addition, expression levels of none of the genes on the low-density array were associated with SCR. Finally, in the microarray analysis none of the found differences between SCR and normal patients' gene expression could be validated with RT-QPCR in 17 genes. CONCLUSIONS: In our relatively small series no robust whole blood gene expression biomarker for SCR was found. Further studies are needed to determine whether small changes in expression may provide a supporting diagnostic method.

Better renal function with enhanced immunosuppression and protocol biopsies after kidney transplantation in children.

Subclinical rejection may be associated with decreased graft function after renal transplantation (Tx). Detection by protocol biopsies and treatment could thus be important for the long-term prognosis. We have earlier discovered that glomerular filtration rate (GFR) declined in young children during the first 18 months. Consequently, we slightly enhanced and individualized each patient's immunosuppression. This was a retrospective study of 59 pediatric renal Tx patients between 1995 and 2001. The 35 historical controls received triple-therapy of azathioprine, methylprednisolone and cyclosporine. GFR was measured by protocol at discharge, 6 and 18 months, and a core biopsy was obtained at 18 months. The 24 study patients in addition received basiliximab, had GFR measured at 3 and 12 months, and a biopsy taken at 3 months. Based on histology and function, immunosuppression was individually adjusted. The groups were compared for GFR and histology at 18 months after Tx. There were less acute rejection episodes in the study group (0.38 vs. 1.23 per patient) and serum creatinine concentrations were lower. Subclinical rejection was detected and treated in 39% at 3 months. There were more chronic changes in the control (47%) than in the study group (29%) at 18 months. GFR was significantly higher in the study group at 18 months (87 vs. 68 mL/min/1.73 m(2)), most remarkably in patients < or =2 yr of age (99 vs. 68 mL/min/1.73 m(2)). Detection of subclinical rejection and slightly enhanced and individualized immunosuppression improved GFR 18 months after renal Tx, especially in the youngest patients.

Cyclosporine A monitoring--how to account for twice and three times daily dosing.

Cyclosporine A (CsA) dose-interval pharmacokinetic profiles, performed 1-4 years post-transplantation, were collected from 74 renal transplanted children. Forty patients were on three times daily dosing (t.i.d.) and 34 on twice daily dosing (b.i.d.). Regression models for prediction of area under the curve (AUC) using 1-3 concentration time points as independent variables were developed. With similar weight-adjusted single doses (mg kg(-1)) of CsA, t.i.d. dosing resulted in a trough-concentration (C0) similar to that from b.i.d. dosing, but a 30% lower 2 h post-dose concentration (C2). For b.i.d. dosing the relationship between C0 and AUC was poor (r2=0.23) and the prediction error was large (5.8+/-33.5%). For t.i.d. dosing the relationship was better (r2=0.79), but prediction error was still large (4.5+/-24.9%). For C2 relationships were similar to those for the b.i.d. (r2=0.59) and t.i.d. (r2=0.63) groups, but explained modestly the variations of AUC (prediction error=2.6+/-16.8% b.i.d., 4.8+/-23.2% t.i.d.). Both C0 and C2 are useful monitoring methods when CsA is administered t.i.d. If the aim is similar specified daily drug exposure, the target C2 should be roughly 30% smaller in t.i.d. dosing than in b.i.d. dosing and the target C0 could be similar. The prediction error of AUC can be large in individual patients when using single time-point determinations, however. The use of multiple time points reduces the variation, but is less feasible.

Predictive value of pretransplantation cyclosporine pharmacokinetic studies on initial post-transplantation dosing in pediatric kidney allograft recipients.

Despite the introduction of a variety of new immunosuppressive agents, cyclosporine A (CsA) has maintained a strong position in pediatric transplantation (Tx). Post-Tx dosing with CsA is a challenging task because of the narrow therapeutic window of the drug, the great individual variability of metabolism and the lack of consensus about the optimal dosage and targeted blood concentration. Sufficient administration of CsA may be protective against acute rejections and other early complications after Tx, which is crucial for the long-term survival of the graft. Individual doses based on pre-Tx pharmacokinetic studies might be helpful in achieving optimal early concentrations of CsA. To asses the usefulness of pharmacokinetic studies, we retrospectively compared the post-Tx doses administered with the individually predicted doses between 1988 and 1998. Multiple regression of data on 65 de novo renal transplant recipients, 1.1-15.5 yr old, was used to analyze the significance of the predicted dose, trough blood concentration of CsA (B-CsA), serum creatinine and age at the time of Tx in explaining the doses used during the first three post-Tx weeks. Patients were grouped according to age (<2, 2-8 and >8 yr), according to the predicted dose (within or outside +/-25% of age-group average), and according to the oral formulation of CsA. Standard dosing scheme was simulated by using age-specific average doses in the place of the individual predicted doses. Administered doses of CsA were high [averaging 22.6 (504), 20.7 (484), and 12.4 mg/kg/d (329 mg/m2/d) for patients <2, 2-8, and >8 yr old] but the average B-CsA remained in the target range of 250-450 microg/L. The predicted dose and age were significant parameters in explaining the administered doses during the first 3 wk after Tx. B-CsA and S-creatinine were non-significant. The predicted doses were used to initiate the dosing of CsA after Tx (R2 = 0.70) and adjustments to dosing were made during the next weeks (R2 = 0.59, 0.52). Multiple regression model showed better fit for 60% of our patients, who had atypical predicted doses (R2 = 0.74, 0.60, 0.64 for first, second and third post-Tx weeks, respectively), most remarkably in patients <2 yr of age, than for the study population as a whole. A simulated standard dose was not able to explain the administered doses of CsA. In conclusion, pre-Tx pharmacokinetic studies are valuable for determining individual post-Tx starting doses, especially for those patients who need high or low doses of CsA. Individual dosing led to relatively high initial CsA doses, which could be significant for the long-term survival of the graft.