A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: the TWIST study.

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard-dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 +/- 0.32 with TAC/MMF/DAC and 0.03 +/- 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04-0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05-0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy-proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.

Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: a systematic review.

As most prior reviews on NA focus on adult transplant patients, there is a need for a comprehensive overview on adherence to the immunosuppressive regimen in pediatric kidney transplant patients. This systematic review searched for English-language papers (1990-2008) addressing the prevalence of NA to the immunosuppressive regimen, its consequences, determinants, and interventions in pediatric kidney transplant patients (< age 21 yr). We found 36 papers, showing a prevalence of NA (weighted mean) of 31.8% with adolescents being more at risk compared to younger patients. About 44% of all graft losses and 23% of late acute rejection episodes are associated with NA. Most studies investigated socio-economic, condition-related or treatment-related determinants. Only one educational intervention has been tested but yielded inconclusive results. NA to the immunosuppressive regimen is prevalent with serious clinical consequences in pediatric kidney transplant patients, but the economic consequences have not yet been explored. More studies on determinants of NA are needed. The literature currently lacks fully powered RCTs testing adherence-enhancing interventions. The results of this systematic review identify the gaps in the present evidence-based information regarding NA and can be used as a tool to pursue future adherence research in pediatric populations.

Testicular torsion after pediatric kidney transplantation.

Kidney transplantation has become the treatment of choice for children with end-stage renal disease and offers recipients an excellent quality of life. Following kidney transplantation several types of medical and surgical complications can arise. In this report, a testicular torsion occurring on the sixth day after pediatric kidney transplantation is described. It remains unclear whether this unusual complication should be regarded as coincidental or as a direct consequence of the transplantation.

Outbreak of verocytotoxin-producing E. coli O145 and O26 infections associated with the consumption of ice cream produced at a farm, Belgium, 2007.

In October 2007, an outbreak of verocytotoxin-producing Escherichia coli (VTEC) O145 and E. coli O26 occurred among consumers of ice cream produced and sold in September 2007 at a farm in the province of Antwerp (Belgium). The ice cream was consumed at two birthday parties and also eaten at the farm. Five children, aged between two and 11 years, developed haemolytic uraemic syndrome (HUS), and seven other co-exposed persons contracted severe diarrhoea. In three of the five HUS cases VTEC O145 infections were laboratory confirmed, one in association with VTEC O26. Identical isolates of E. coli O145 and O26 were detected with PCR and PFGE in faecal samples of patients and in ice cream leftovers from one of the birthday parties, in faecal samples taken from calves, and in samples of soiled straw from the farm at which the ice cream was produced. Ice cream was made from pasteurised milk and most likely contaminated by one of food handlers.

Paediatric kidney transplantation in Belgium.

In Belgium, kidney transplantation is currently the treatment of choice for a child with end-stage renal disease (ESRD). Dialysis remains the life-saving bridge to transplantation. Within the Eurotransplant (ET) community, Belgium represents 14% of the cadaveric transplantations and 22% of the living-related transplantation (LD) in children less than 16 years of age. Single-centre analysis (KUL) shows a patient survival of 94% at 3 year and 91% at 5 year. The overall graft survival is 82% at 3 year and 74% at 5 year. In the LD group, the graft survival rate is 10% better than the overall actuarial graft survival rate. Multivariate Cox regression analysis performed on all transplantations of one centre (KUL) demonstrate the following factors to be significant and independent predictors of poor graft outcome: absence of calcineurin inhibitors, two HLA- mismatches, duration of pre-transplant dialysis and creatinine clearance at one year after transplantation. The outcome improves by a short dialysis waiting time, the use of living-related donors, the prevention of delayed graft function (DGF), and of acute rejection. Within the ET community, the waiting child has priority compared to the adult, but if we want to avoid morbidity, waiting times must be shortened and the incidence of pre-emptive transplantation, which is currently 24% in Belgium, must increase. The good results with LD is certainly an attractive alternative to be actively encouraged for paediatric kidney recipients and the use of young deceased donors especially for children with ESRD must be supported since the results in terms of graft survival with these donors are very good, especially in children. In paediatric kidney transplantation the long-term graft survival is still the major challenge and has still to be documented by randomized trials. The success of the past, however, allows us to face the future with hope and confidence.

A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation.

In a 6-month, multicenter, randomized, controlled, open-label, parallel-group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus-based regimen in pediatric renal transplant recipients. Patients < 18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10-20 ng/mL between days 0-21 and 5-15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients < 40 kg) or 20 mg (patients > or = 40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy-proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid-resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 micromol/L in the TAS and 91 micromol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus-based regimen is safe in pediatric patients, but does not improve clinical efficacy.

Single-dose pharmacokinetics and tolerability of everolimus in stable pediatric renal transplant patients.

Everolimus (Certican; RAD), a novel macrolide with potent immunosuppressive and anti-proliferative activities, prevents acute rejection in adult recipients of renal transplantation. This phase I trial conducted in stable pediatric renal transplant patients examined the single-dose pharmacokinetics, safety, and tolerability of everolimus in combination with cyclosporin A (CsA; Neoral) and corticosteroids, with or without azathioprine. Nineteen pediatric patients were enrolled and received a single 1.2 mg/m2 dose of everolimus. Everolimus was safe and well tolerated, with a low incidence of adverse events reported and none judged to be related to the study medication. Everolimus administration did not increase infection rates or produce clinically significant changes in vital signs or changes in electrocardiograms. Apparent clearance and volume of distribution of everolimus increased with age, weight, and body surface area in a generally linear manner across the pediatric demographic ranges. Compared with adults from a previous study, apparent clearance (L/h) and distribution volume (L) were lower in pediatric patients, whereas the elimination half-life was similar. Single-dose everolimus co-administration did not affect the steady-state pharmacokinetics of CsA. Based on this information, pediatric patients will need a dose scaled down for body size, but can probably maintain the same twice-daily dosing schedule used in adults.

Recent advances and future prospects in intestinal and multi-visceral transplantation.

From an experimental procedure, intestinal transplantation (ITx) has evolved over the last 10 yr into a treatment option for patients suffering from short bowel syndrome and who develop life-threatening complications from total parenteral nutrition (TPN) (e.g. liver dysfunction, line sepsis, shortage of venous access, etc.). One-year survival rates are approximately 70% and thus similar to lung Tx. However, the intestine remains the most challenging abdominal organ to transplant. This is because of the severe immune response (mostly rejection) that is produced, and therefore the need for profound immunosuppression with its attendant complications (sepsis, lymphoma, direct drug toxicity). Unlike other organs, graft loss as a result of acute rejection can occur late after transplantation (more than 1 yr post-transplant). With regard to the actual immunosuppressive regimens, considerable experience in patient management is required to optimize outcome of those complex transplants, which are permanently at risk of rejection and infection. ITx remains an unfinished product, and the application of ITx to patients doing well on TPN warrants further research in the understanding of the rejection process, in the development of less toxic and more efficient immunosuppressive protocols, and in the development of immunomodulatory strategies, to better control rejection and thereby reduce the need for immunosuppression.

Dysplasia of tubular cells in a kidney- transplanted patient treated with recombinant human growth hormone.

After renal transplantation (Tx), children with growth retardation can be successfully treated with recombinant human growth hormone (rhGH). However, the impact of this treatment on kidney allograft function remains a source of concern. We report on one boy who received a cadaveric kidney transplant at 12 yr of age, after developing end-stage focal and segmental glomerulosclerosis and hyalinosis. The early post-transplant period was complicated by thrombosis of an arterial branch of the graft and two acute rejection episodes. Because of poor growth, the boy was treated with rhGH starting 22 months after the Tx. The renal function remained relatively stable for 22 months after initiation of rhGH therapy and then progressively deteriorated over a period of 10 months, with the patient ending up on dialysis. Several biopsies, performed for rejection episodes or before the start of rhGH, or to elucidate the deterioration of the renal function, were analyzed. Histologically, a progressive increase in the amount of hypertrophy of the tubules and of the glomeruli was seen after initiation of rhGH. Hyperplasia of the tubular epithelium with crowding of cells of the proximal tubules, hyperchromasia and irregularities in the shape of the nuclei, and abrupt changes of chromatism along the tubuli, were also observed. These lesions of tubular dysplasia are extremely unusual in transplanted kidneys and are unlikely to be caused by compensatory hypertrophy secondary to destruction of renal tissue. They may be an effect of rhGH treatment. The prognostic significance of these lesions is unknown but merits attention.

Pediatric renal transplantation: a single Belgian center experience over 20 years.

Between 1980 and 2000, 100 renal transplantations were performed in 91 children at the pediatric unit of the University Hospital Leuven. The proportion of living-related donors (LRD) was 20%. Patient survival rates were 94% at 3 yr, 91% at 5 yr, and 87% at 10 yr. The commonest causes of death were bacterial infections and cardiovascular complications, which underscores the need for aggressive preventative procedures in this area after transplantation. The overall actuarial graft survival was 82% at 3 yr (n = 73), 74% at 5 yr (n = 53), and 56% at 10 yr (n = 29). In the LRD group, the graft survival was 10% better than the overall actuarial graft survival rate. The overall incidence of acute rejection was 55% but has shown a decrease to 34% in more recent years (1993-99). The major causes of graft failure were chronic rejection and recurrence of the initial disease, and these remain a major concern. Improvement of these results could be achieved by tight immunosuppression management, early aggressive treatment of infection and rejection, and careful educational and psychological support.

Distal limb deficiencies, oral involvement, and renal defect: report of a third patient and confirmation of a distinct entity.

In 1987 Buttiens and Fryns [1987: Am J Med Genet 27:651-660] reported on two sibs, brother and sister, with severe distal limb defects, micrognathia, and mild to moderate mental retardation. The male also showed severe myopia and oligomeganephronia. To the best of our knowledge, no other similar patients have been described since. We report on a boy with a similar phenotype. .

Evaluation of anti-human leukocyte antigen allo-immunization in pediatric cadaveric kidney transplantation.

Forty-eight pediatric cadaveric renal transplantations, performed between May 1986 and February 1997, were retrospectively screened, pre- and post-transplant, for antibodies to human leukocyte antigen (anti-HLA) using complement-dependent cytotoxicity (CDC) assay and enzyme immunoassay (EIA). The correlation between anti-HLA immunization and graft outcome was investigated. The combined analysis of CDC and EIA enabled the differentiation between complement-fixing and non-complement-fixing, anti-HLA class I and anti-HLA class II antibodies. The median post-transplant follow-up for all patients with a functioning graft was 86 months (range 10-138 months). In the whole population, 16 grafts were lost: six following a non-immunologic complication; and 10 as a result of rejection. Of these 10 grafts lost, eight were in patients with pre- and/or post-transplant donor antigen specific (DAS) anti-HLA class I or class I + II antibodies; and two were in patients with DAS anti-HLA class II antibodies only. Three of these grafts were lost in patients with weak pre-existing DAS anti-HLA class I antibodies. Immunological graft loss appeared at a median post-transplant time of 38 months (range 2-68 months). All patients without DAS anti-HLA antibodies had a good graft outcome. The presence of pre- and post-transplant DAS anti-HLA antibodies, especially if directed against HLA class I, were associated with a poor graft outcome. A systematic search for, and identification of, anti-HLA antibodies should therefore be part of a pretransplant evaluation to allow the identification of 'unacceptable' donor HLA antigens, following which the impact of the HLA-cross-match on graft outcome will improve. Screening for DAS anti-HLA antibodies post-transplant could be helpful for detecting patients with an increased risk for graft loss following rejection episodes.

Sandimmune to Neoral conversion and value of abbreviated AUC monitoring in stable pediatric kidney transplant recipients.

Neoral is a new microemulsion formulation of cyclosporin A (CsA) that has been reported to have better absorption characteristics than sandimmune. We converted 25 long-term pediatric renal transplant recipients with a mean age of 14.1 yr and a mean follow-up period of 6.4 yr from sandimmune (SIM) to neoral (NEO) on a 1:1 basis. The mean dosage of SIM or NEO required to maintain 'therapeutic range' steady-state trough levels between 100 and 200 ng/mL was similar. We compared 6-h CsA pharmacokinetic profiles taken approximately 6 months after the conversion to NEO with the previous SIM profiles of the same patients. Generally, in the NEO profiles the time to reach the maximum concentration was shorter and the maximum concentration was higher, showing a rapid decline towards the trough-level when compared to the previous SIM profiles. During intake of NEO the AUC0-12 h in the 12-h profiles correlates strongly with the AUC0-6 h in the 6-h profiles (r = 0.98), a similar finding to that which we reported previously for SIM. The median AUC0-6 h for NEO demonstrates a 70% increase compared to the median AUC0-6 h for SIM. Despite the increased drug exposure NEO was well tolerated and did not cause any apparent toxicity within the first 6 months after conversion. The CsA blood level 2 h after intake of NEO showed a higher correlation with the AUC0-12 h (r = 0.91) than the trough level (r = 0.64). The abbreviated profile based on three early sampling points and calculated by AUCPRED = 335.9 + 1.1*(C1) + 1.1*(C2) + 5.4*(C4) correlated well with the full AUC (r2 = 0.98, p < 0.0001). Mean prediction error (+/- SD) was 0.16% (+/- 4.32), and in no patients did the calculated values fall outside the 10% prediction error limit. We therefore conclude that NEO exhibits a higher bioavailability in children compared to SIM without causing apparent toxicity. Monitoring of the C2 might be a better alternative for trough level monitoring in daily clinical practice. A strategy of three early sampling points (C1, C2 and C4) allows a reliable AUC0-12 h prediction and can reduce the length of observation, making it a useful and cost-effective tool in clinical practice.

Erythropoietin treatment in children with renal failure.

Erythropoietin (EPO) treatment dramatically changes the life of a child with end-stage renal disease. The administration of recombinant human (rHu)EPO is beneficial and safe in the predialysis period, during hemodialysis or peritoneal dialysis, and after renal transplantation. The goal of hemoglobin correction should be the level at which normal quality of life is possible without adverse events: in children this is usually 10-11 g/dl. rHuEPO is administered once to twice a week subcutaneously to children before dialysis, during peritoneal dialysis, and after transplantation. There is no real benefit of intraperitoneal administration. In children on hemodialysis two to three times a week IV administration is preferred. Among the many reasons for non-response to rHuEPO, iron deficiency (absolute or functional), infections, and hyperparathyroidism are the most common in the pediatric renal patient. Hypertension is the most-frequent side effect of rHuEPO treatment and needs careful monitoring. Iron should be supplemented orally or IV. No significant beneficial effect of rHuEPO on growth has been demonstrated. However, the association with recombinant human growth hormone therapy is not detrimental in children.

Impact of growth hormone treatment on a Belgian population of short children with renal allografts.

We retrospectively analyzed the effects of recombinant human growth hormone (rhGH) in a Belgian population of 36 short children with renal allografts. Seven children were dropped from the growth study: 1 had skeletal dysplasia and in 6 cases rhGH was given for less than 1 yr (1 died, 1 developed genu valgum, 2 were non-compliant and 2 grafts deteriorated). Final height was reached in 17 patients, and 12 children were still growing at the end of the study. Median height standard deviation score (SDS) in the 29 patients was -2.3 at the time of transplantation, and -2.7 when rhGH therapy was initiated. During rhGH therapy (median duration 3.2 yr, range 0.6-7.7 yr), height SDS increased by a mean of 0.4 per year, and bone maturation was not accelerated. Final height reached was 162.7 (149.0-169.5) cm (median SDS -1.8) in males and 151.0 (130.5-169.5) cm (median SDS -1.9) in females. Final height is significantly greater in males than females compared with a historical control group of untreated patients. Final height is within the parental target height range in 6 out of the 17 patients. The increase in height SDS in patients who were at an advanced stage of puberty (Tanner stages 4-5) when rhGH therapy was initiated exceeded our expectations (mean height gain 14.2 cm in boys and 10 cm in girls). In the cohort of 36 children, 4 patients developed an acute allograft rejection, all of whom had an underlying chronic rejection. This resulted in 3 graft losses within 5 yr. Our results indicate that rhGH treatment has a positive effect in short children with renal allografts, even if it is started in late puberty. In the presence of underlying chronic rejection, rhGH treatment needs careful monitoring to minimize the risk of graft loss.

Risk factors for chronic rejection in pediatric renal allograft recipients.

To determine the risk factors predictive of graft loss from chronic rejection in pediatric renal allograft recipients, we reviewed the collaborative study database of the Société de Néphrologie Pédiatrique which registered 314 grafts from January 1987 to December 1991. Of the 289 grafts analyzed, 71 failed during follow-up, chronic rejection being the most common cause of graft loss (35%). The clinical features of the chronic rejection group (n = 25) were compared with those of the group without failure (n = 218). The variables tested by monovariate analysis were cyclosporine dose at 1 year, donor type, donor and recipient age, and acute rejection episodes. The incidence of graft loss due to chronic rejection was 4% (4/109) in patients who had no acute rejection and 16% (21/134) in those with at least one acute rejection episode (P = 0.002). Donor age (< or = 5 years) was a risk factor for chronic rejection (P = 0.024). Recipient age and donor type were not significantly different between the chronic rejection group and the control group. Using time-dependent covariates, the risk factors were an acute rejection episode (P = 0.003) and low cyclosporine doses at 1 year (P = 0.02). We conclude that acute rejection and low cyclosporine doses in these pediatric patients were risk factors for graft loss due to chronic rejection.