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Background: Cytomegalovirus (CMV) replication and disease, with its associated morbidity and poor transplant outcome, represents a serious threat to transplant recipients. The pediatric kidney transplant population is at a particularly increased risk of CMV infection., Methods: We therefore analyzed CMV epidemiology in a large cohort of pediatric renal transplant recipients (n = 242) and assessed the impact of antiviral chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) on CMV replication and morbidity., Results: While antiviral chemoprophylaxis with VGCV or GCV in patients with a high (D+/R-) or intermediate (D+/R+) CMV risk (n = 82) compared to preemptive therapy (n = 47) had no significant effect on the incidence of CMV syndrome or tissue-invasive disease, chemoprophylaxis was associated with a better preservation of transplant function at 3 years posttransplant (loss of estimated glomerular filtration rate in the chemoprophylaxis cohort, 16.0 ± 3.4 vs. 30.1 ± 4.7 mL/min per 1.73 m(2) in the preemptive therapy cohort, P < 0.05).CMV replication was associated with a more pronounced decline of graft function (difference in estimated glomerular filtration rate of 9.6 mL/min per 1.73 m(2) at 3 years) compared to patients without CMV replication. However, patients undergoing VGCV or GCV chemoprophylaxis had more leukocytopenia., Conclusion: Antiviral chemoprophylaxis with VGCV or GCV in recipients with a high or moderate CMV risk is associated with a better preservation of transplant function. Hence, the prevention of CMV replication in this patient population has the potential to improve transplant outcome.

Background: : Many transplant centers practice late steroid withdrawal after pediatric renal transplantation, but evidence-based data on the overall risk-to-benefit ratio in this patient population are lacking., Methods: : We therefore conducted the first prospective, randomized, open-label multicenter study to validate this strategy: 42 low-immunologic risk pediatric kidney allograft recipients, aged 10.3+/-4.3 years, on cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids were randomly assigned, more than or equal to 1-year posttransplant, to continue steroids or to withdraw over 3 months. This report contains the 1-year results., Results: : In response to steroid withdrawal, patients experienced a significant catch-up growth with a mean standardized height gain of 0.3+/-0.1 standard deviation score (SDS) per year (P<0.05 vs. control), whereas mean height SDS in the control group did not change (0.0+/-0.1 SDS). Standardized body mass index declined significantly by 0.68+/-0.23 SDS after steroid withdrawal, but rose significantly by 0.26+/-0.34 SDS in the control group. Patients off steroids had less frequent arterial hypertension (50% vs. 87.5% (P<0.05) and significantly lower serum cholesterol (by 21%) and triglyceride values (by 36%) than control patients. Patient and graft survival were 100%. The incidence of acute rejection episodes in the steroid-withdrawal group was 1 of 23 (4%) compared with 1 of 19 (5%) in controls. Transplant function remained stable in both groups., Conclusion: : Late steroid withdrawal in low-immunologic risk European pediatric kidney transplant recipients on cyclosporine microemulsion and mycophenolate mofetil is not associated with an increased rate of acute rejection episodes, enables catch-up growth and ameliorates cardiovascular risk factors.

Background: Basiliximab, a monoclonal CD25 antibody has proofed effective in reducing acute rejection episodes in adults in various immunosuppressive regimens. The effect of basiliximab in the pediatric population is controversial., Methods: In a 12-month, double-blind, placebo-controlled trial, renal transplant patients aged 1 to 18 years were randomized to basiliximab or placebo with cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids. The intent-to-treat population comprised 192 patients (100 basiliximab and 92 placebo)., Results: The primary efficacy endpoint, time to first biopsy-proven acute rejection episode, or treatment failure by month 6, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo-treated patients (Kaplan-Meier estimates; hazard ratio 0.72, two-sided 90% confidence interval 0.416-1.26, n.s.). The rate and severity of subclinical rejections in protocol biopsies performed at 6 months posttransplant was higher in the basiliximab group (25.0%) than in the placebo group (11.7%). Patient and death-censored graft survival at 12 months was 97% and 99%, respectively, in the basiliximab cohort, and 100% and 99% among placebo-treated patients (n.s.). Renal function was similar in both treatment groups, and there were no significant between-treatment differences in the incidence of adverse events or infections., Conclusions: Addition of basiliximab induction to a regimen of cyclosporine microemulsion, mycophenolate mofetil, and steroids resulted in a numerically lower but not significant incidence of biopsy-proven acute rejection versus placebo and excellent graft and patient survival at 1 year in pediatric renal transplant recipients. Whether this numerical difference is a true therapeutic benefit in view of the higher rate and severity of subclinical rejections in the basiliximab group in the protocol biopsy will be investigated in a long-term follow-up study.

Background: The aim of this substudy within a prospective, multicenter, placebo-controlled trial was to assess the pharmacokinetics and immunodynamics of basiliximab in pediatric renal transplant recipients on comedication with mycophenolate mofetil (MMF)., Methods: Eighty-two patients aged 3 to 18 years, receiving cyclosporine microemulsion, MMF, corticosteroids, and basiliximab or placebo were investigated. Basiliximab serum concentrations were determined by ELISA, CD25+, and CD122+ T lymphocytes by flow cytometry., Results: Basiliximab clearance adjusted to body surface area was significantly (P<0.05) greater in children versus adults, but the relatively higher basiliximab dose given to children yielded similar exposure compared with adolescents. A cross-study comparison revealed that MMF reduced basiliximab clearance and prolonged CD25 saturation duration from approximately 5 weeks in the absence of MMF to 10 weeks in the presence of MMF. Basiliximab led to a marked reduction of CD25+ T-cell fraction during the first 8 to 10 weeks posttransplant, but did not specifically affect CD122+ T cells. The majority of biopsy-proven acute rejection episodes (BPAR) were observed after interleukin (IL) 2-R desaturation, whereas about a quarter of BPARs occurred despite adequate IL2-R blockade., Conclusions: The currently recommended basiliximab dose for pediatric patients, when used with cyclosporine microemulsion and corticosteroids, yielded adequate drug exposure in children and adolescents also under MMF comedication. The observation that about a quarter of BPARs occurred despite adequate IL2-R blockade suggests that another T-cell activation pathway independent of the IL-2/IL-2R pathway is operative, for example, the IL-15 signaling pathway.

Background: Mycophenolate mofetil (MMF) based immunosuppression after renal transplantation has proven to be safe and beneficial for children and adolescents. However, long-term analysis, in particular of pediatric patients, is scarce., Patients: Data of 140 patients receiving MMF versus azathioprine (AZA) in combination with cyclosporine A (CsA) and prednisone without induction were analyzed with a main focus on survival and renal function in long-term follow-up., Results: After 5 years of follow-up, 44 MMF and 20 AZA patients were still on study. Graft survival of intent to treat (ITT) groups was 90.7% for MMF and 68.5% for AZA patients (P<0.001). Cumulative rejection free survival was 51.2% in MMF versus 37.0% in AZA patients (P<0.05). In association with early acute rejections (ARE), projected half-life was 14.4/4.5 years in patients with and 18.7/14.5 years without rejection in the MMF/AZA group, respectively., Conclusions: MMF based protocols improved long-term graft survival without an increase in side effects. Early ARE were associated with worse half-life of the graft, although more stressed in the AZA group. Thus, to improve quality of life in children for very long-term outcome, ARE should be further decreased and renal function should be better preserved.