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.

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.

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.

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.

Recombinant human erythropoietin increases blood pressure, platelet aggregability and platelet free calcium mobilisation in uraemic children: a possible link?

Recombinant human erythropoietin was administered to 10 uraemic children on chronic haemodialysis, all of whom responded by correcting their haemoglobin. In addition, they showed an increase in blood pressure; platelet aggregations, subnormal before therapy, improved during treatment. The intracellular free calcium concentration in platelets after thrombin stimulation also increased significantly during erythropoietin administration. We hypothesize that the effect of erythropoietin on platelet aggregability and on blood pressure may be due to an increase in the intracellular free calcium mobilisation in platelets and possibly in smooth muscle cells respectively.

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. .

Reversible arterial spasm in an adolescent with primary oxalosis.

A 16-year-old girl with primary oxalosis type I presented with progressive claudication soon after being treated with chronic intermittent hemodialysis. Arterial insufficiency of the lower limbs was confirmed clinically (purple discoloration of the skin and absence of arterial pulses) and with Doppler sonography. The arteriogram showed diffuse and symmetric narrowing with smooth vessel walls. Treatment with sodium nitroprusside had a spectacular effect; nifedipine was less effective. Renal transplantation with the father's kidney resulted in a rapid, complete and sustained reversal of the ischemic features. Magnesium withdrawal is assumed to be a pathogenic factor of the vascular spasm in this patient.

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.

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.

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.

Autosomal recessive chronic granulomatous disease associated with 18q-syndrome and end-stage renal failure due to Henoch-Schönlein nephritis.

Chronic granulomatous disease (CGD) is an inherited disorder in which phagocytes, including polymorphonuclear neutrophils, are unable to generate oxygen-derived microbicidal compounds, among them superoxide. Two main types of CGD are known, an X-linked form which is normally associated with the absence of cytochrome b558, a component of the membrane-associated reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which generates superoxide and an autosomal recessive form, in which cytochrome b558 is present, caused by the deficiency of a cytosolic factor required to activate NADPH oxidase. Patients with the X-linked type are highly susceptible to infections; those with the autosomal recessive form may be less severely affected. We report the unusual association of autosomal CGD with 18q--syndrome in a girl who developed terminal renal insufficiency caused by Henoch-Schönlein nephritis, and speculate on the possibility that the gene defect of autosomal recessive CGD may be located on chromosome 18.

Specific eye fundus lesions in type II membranoproliferative glomerulonephritis.

In three adolescents, suffering from membrano-proliferative glomerulonephritis type II, ophthalmoscopy and fluorescein angiography revealed retinal pigment epithelium lesions, referred to as basal laminar drusen. The patient with the longest renal history had the most pronounced fundus changes. These lesions, earlier described in adult patients, are believed to be specific for this particular form of chronic glomerulonephritis.

Long-term cyclosporin A pharmacokinetic profiles in pediatric renal transplant recipients.

To study the long-term effect of cyclosporin A (CyA), 94 6-h and 29 12-h pharmacokinetic profiles were evaluated in 32 children at least 1 year after renal transplantation. Children weighing less than 25 kg needed significantly higher doses of CyA than those weighing more than 25 kg (9.8 vs 5.3 mg/kg per day; P < 0.001) to achieve similar trough levels (TL). The average dose of CyA required to achieve the target TL declined gradually with time after transplantation. The average area under the curve over 6 h (AUC/6) correlated strongly with the AUC/12 (r = 0.967; P < 0.001). The AUC/6 of patients with biopsy-proven CyA toxicity was significantly higher than for those without toxicity (Mann-Whitney U-test P < 0.05) despite similar TL. We conclude that AUC monitoring for 6 h provides valuable information not only on TL but also on the absorption and elimination characteristics of CyA as well as on the potential for CyA toxicity.

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.