A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome.

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.

Identification of subgroups by risk of graft failure after paediatric renal transplantation: application of survival tree models on the ESPN/ERA-EDTA Registry.

BACKGROUND: Identification of patient groups by risk of renal graft loss might be helpful for accurate patient counselling and clinical decision-making. Survival tree models are an alternative statistical approach to identify subgroups, offering cut-off points for covariates and an easy-to-interpret representation. METHODS: Within the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry data we identified paediatric patient groups with specific profiles for 5-year renal graft survival. Two analyses were performed, including (i) parameters known at time of transplantation and (ii) additional clinical measurements obtained early after transplantation. The identified subgroups were added as covariates in two survival models. The prognostic performance of the models was tested and compared with conventional Cox regression analyses. RESULTS: The first analysis included 5275 paediatric renal transplants. The best 5-year graft survival (90.4%) was found among patients who received a renal graft as a pre-emptive transplantation or after short-term dialysis (<45 days), whereas graft survival was poorest (51.7%) in adolescents transplanted after long-term dialysis (>2.2 years). The Cox model including both pre-transplant factors and tree subgroups had a significantly better predictive performance than conventional Cox regression (P < 0.001). In the analysis including clinical factors, graft survival ranged from 97.3% [younger patients with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) and dialysis <20 months] to 34.7% (adolescents with eGFR <60 mL/min/1.73 m(2) and dialysis >20 months). Also in this case combining tree findings and clinical factors improved the predictive performance as compared with conventional Cox model models (P < 0.0001). CONCLUSIONS: In conclusion, we demonstrated the tree model to be an accurate and attractive tool to predict graft failure for patients with specific characteristics. This may aid the evaluation of individual graft prognosis and thereby the design of measures to improve graft survival in the poor prognosis groups.

Long-term pharmacokinetics of mycophenolic acid in pediatric renal transplant recipients over 3 years posttransplant.

Data on exposure to mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), in pediatric renal transplant recipients beyond the first year posttransplant are scarce. The authors therefore analyzed the long-term pharmacokinetics of MPA in 25 pediatric patients treated with 600 mg MMF/m body surface area twice a day in conjunction with cyclosporine A and prednisone. Plasma samples for 12-hour pharmacokinetic profiles were collected on day 7, and after 3, 9, 24, and 36 months posttransplant. Both the actual and the dose-normalized MPA-area under the concentration-time curve (AUC0-12) increased approximately 2-fold between day 7 and month 9 but stabilized thereafter. Both the actual and the dose-normalized MPA-AUC0-12 at months 24 and 36 were comparable to that at month 9. Presuming a therapeutic window of 30-60 mg h/L, 15 (60%) of 25 patients at day 7 had an MPA-AUC0-12 <30 mg h/L, indicating potential underexposure, whereas the proportion of patients with an MPA-AUC0-12 <30 mg h/L between months 3 and 36 was low (5%-17%). These data suggest that the recommended MMF dose of 600 mg/m body surface area twice a day in conjunction with cyclosporine A leads to MPA underexposure early posttransplant in a significant subset of patients, indicating a need for a higher initial MMF dose. Dose-normalized MPA exposure increases in the first 9 months posttransplant, consistent with a reduced MPA metabolism and increased enterohepatic recycling of MPA.

Validation of an abbreviated pharmacokinetic profile for the estimation of mycophenolic acid exposure in pediatric renal transplant recipients.

The pharmacokinetics of mycophenolic acid (MPA), the active moiety of the immunosuppressant mycophenolate mofetil (MMF), exhibits large inter-individual variability. Concentration-controlled dosing of MMF based on therapeutic drug monitoring may therefore be advantageous compared to a fixed-dose regimen. Because full AUC(0-12) monitoring is not practical and predose MPA concentrations correlate only moderately with the corresponding AUC(0-12), the estimation of MPA exposure by a limited sampling strategy has been suggested. However, before such an algorithm is transferred to clinical practice, it is compulsory to prospectively validate it in a different data set, in order to avoid biased results. The aim of this investigation was therefore to prospectively validate an algorithm based on an abbreviated pharmacokinetic (PK) profile for the estimation of MPA exposure in 54 pediatric renal transplant recipients (169 PK profiles) on MMF in conjunction with CsA and prednisone on a second data set in a different group of patients with a similar immunosuppressive regimen (25 patients, 119 PK profiles). An algorithm based on three PK sampling timepoints during the first 2 hours after MMF dosing (estimated AUC(0-12) = 18.6 + 4.3 x C(0) + 0.54 x C(0.5) + 2.15 x C(2)) was able to predict the corresponding MPA-AUC(0-12) with a low percentage prediction error (10.7%) and an acceptable coefficient of determination (r = 0.76). The performance of this algorithm was comparable among different pediatric age groups. By ROC curve analysis, the calculated MPA-AUC(0-12) based on this algorithm was able to differentiate between rejecters and non-rejecters with a comparable prognostic sensitivity (66.7%) and specificity (61.9%) as the full-time MPA-AUC(0-12). In conclusion, the use of this validated algorithm for the estimation of MPA exposure based on a limited sampling strategy during the first 2 hours after MMF dosing has the potential to optimize MMF therapy in pediatric renal transplant recipients.