Growing experience with mTOR inhibitors in pediatric solid organ transplantation.

Controlled trials of mTOR inhibitors in children following solid organ transplantation are scarce, although evidence from prospective single-arm studies is growing. Everolimus with reduced CNI therapy has been shown to be efficacious and safe in de novo pediatric kidney transplant patients in prospective trials. Prospective and retrospective data in children converted from CNI therapy to mTOR inhibition following kidney, liver, or heart transplantation suggest preservation of immunosuppressive efficacy. Good renal function has been maintained when mTOR inhibitors are used de novo in children following kidney transplantation or after conversion to mTOR inhibition with CNI minimization. mTOR inhibition with reduced CNI exposure is associated with a low risk for developing infection in children. Growth and development do not appear to be impaired during low-dose mTOR inhibition, but more studies are required. No firm conclusions can be drawn as to whether mTOR inhibitors should be discontinued in children requiring surgical intervention or whether mTOR inhibition delays progression of hepatic fibrosis after pediatric liver transplantation. In conclusion, current evidence suggests that use of mTOR inhibitors in children undergoing solid organ transplantation is efficacious and safe, but a number of issues remain unresolved and further studies are required.

Different models of transition to adult care after pediatric kidney transplantation: a comparative study.

Transition from pediatric to adult care is a critical and difficult step for young people with transplants and for the multidisciplinary team involved. In our retrospective study, we investigated the clinical course in a two-yr period of transition. Data from 66 teenagers were collected one yr before and after their transfer to three different adult care settings: (i) a specialized transition clinic, (ii) a general transplantation clinic, and (iii) a nephrologist. Patient survival rate was 100%. Three patients developed graft loss. GFR development was comparable in the three settings (ΔGFR 1.4 ± 8.7 vs. 3.1 ± 10.6 vs. 0.8 ± 4.4 mL/min/1.73 m2 , p = ns). Immunosuppressive therapy was stable in setting 1, whereas the number of changes increased in setting 2 and even more in setting 3. The percentage of patients with steroids increased from 36% to 38% and 52% in settings 1-3. Patient satisfaction was highest in setting 1 (100% vs. 64% and 78%, p < 0.05). Setting 1 was associated with fewer changes in therapy (13% vs. 91% and 45%, p < 0.05). The use of a specialized transition clinic is associated with fewer changes in medication and care and a higher level of patient satisfaction. This was not associated with a lower increase in GFR one yr after transition. Long-term results are awaited.

De novo therapy with everolimus, low-dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation.

The number of acute rejections and infections after pediatric kidney transplantation (KTX) could not be reduced in the last years. To reduce these events, we investigated a new immunosuppressive protocol in a prospective trial. After KTX, 20 children (median age 12 years, range 1-17) were initially treated with Basiliximab, ciclosporine A (CsA) (trough-level = C0 200-250 ng/mL) and prednisolone. After 2 weeks, CsA dose was reduced to 50% (C0 75-100 ng/mL, after 6 months: 50-75 ng/mL) and everolimus (1.6 mg/m²) /day) was started (C0 3-6 ng/mL). Six months after KTX prednisolone was set to alternate dose and stopped 3 months later. All 20 protocol biopsies 6 months after KTX showed no acute rejection or borderline findings. Indication biopsies resulted in no acute rejections and two borderline findings. Mean glomerular filtration rate (GFR) 1 year after KTX was 71 ± 25 mL/min/1.73 m². Without cytomegalovirus (CMV)-prophylaxis, only two primary CMV infections were seen despite a donor/recipient-CMV-constellation pos./neg. in 10/20 children. In pediatric KTX, de novo immunosuppression with low-dose CsA, everolimus and steroid withdrawal after 9 months led to promising results according to numbers of acute rejections and infections. Further follow up is needed. Future larger trials will have to confirm our findings.

Protocol biopsy-driven interventions after pediatric renal transplantation.

The therapeutic value of protocol biopsies (PBs) in renal transplant recipients remains unclear. We performed protocol biopsies in 57 children six months after transplantation. We increased the CNI dose in patients with borderline findings. In cases of Banff grade Ia, six prednisolone IV-pulses were given and the CNI dose was increased. CNI toxicity and polyomavirus nephropathy led to a reduction in the CNI dose. GFR was compared with a control group of 51 children with no PBs transplanted in the same period. Forty-two percent of PBs had no pathological changes, 24% IF/TA. Borderline findings were detected in 11%, Banff grade Ia in 15% (CNI), toxicity in 8%, and one case showed polyomavirus nephropathy. GFR after 1.5 and 2.5 yr was similar in both groups. GFR 3.5 yr after transplantation was significantly higher in the intervention group (57 ± 17 vs. 46 ± 20). Patients treated with low-dose CNI and everolimus had a significantly lower number of pathological findings in PBs. The performance of protocol biopsies followed by a standardized treatment algorithm led to better graft function 3.5 yr after transplantation. Prospective randomized studies to confirm our findings are needed.

Superior long-term graft function and better growth of grafts in children receiving kidneys from paediatric compared with adult donors.

BACKGROUND: Organs from paediatric donors are often not accepted for paediatric recipients because previous reports suggested inferior graft function for small kidneys transplanted in children. On the other hand, studies have shown that kidneys of adult donors transplanted into children down-regulate filtration after transplantation and may not increase their function to the need of the growing child. METHODS: We assessed 64 male and 35 female (total n = 99) white children aged <10 years (male: mean 5.1 years, SD 2.8; female: mean 5.8 years, SD 3.4) who had received cadaveric kidney transplants at our centre between 1990 and 2005. Mean observation time was 5.9 years, SD 4.0. The children were divided into two groups depending on the kidney donor age: 63 children (mean age 5.0 years, SD 2.9) received an organ of an adult, and 39 (mean age 6.4 years, SD 3.4) of a paediatric donor. Immunosuppression was performed with prednisolone, cyclosporin A microemulsion+/-mycophenolate mofetil. RESULTS: Three to five years after transplantation the calculated glomerular filtration rate corrected to body surface was significantly higher in recipients of paediatric organs. The size of paediatric grafts doubled in the first years after transplantation while adult grafts had a stable size. Graft survival was comparable in both groups during observation time. CONCLUSIONS: We conclude that paediatric donor kidneys should be given preferentially to paediatric recipients due to better long-term function.