Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.

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.

Acute focal bacterial nephritis in 25 children.

Acute focal bacterial nephritis (AFBN), formerly known as lobar nephronia, is a rare form of interstitial bacterial nephritis. Most often described in adults with diabetes, there is only limited knowledge of AFBN in children. Ultrasound shows circular hypoechogenic, hypoperfused parenchyma lesions, which may be misdiagnosed as a renal abscess or tumor. From 1984 to 2005, AFBN was diagnosed in 30 children at the University Hospital Münster and the General Hospital Celle, Germany. Data of 25 cases (14 girls, 11 boys) were available for retrospective evaluation. Twenty-five children with AFBN, mean age 4.5 years (range: 0.25-17.5 years), were followed up on average 4.2 years (range: 0.5-11 years). All children were admitted to hospital due to fever and rapid deterioration of clinical condition, initially suspected of having meningitis (four patients), urinary tract infections (five patients), renal tumor (three patients), pneumonia (two patients), appendicitis (one patient), or with only unspecific symptoms (ten patients). AFBN was diagnosed by ultrasound on average 3 days (range: 1-10 days) after onset of symptoms. Pyuria was found in 18/25 children, bacteriuria in 20/25 children, and hematuria in one patient. Blood cultures were negative in all but one patient. Urinary tract abnormalities were found in 12 children, including vesicoureteral reflux (8), megaureter (1), urethral valves (1), unilateral renal hypoplasia (1), and one patient with megacystis, megaureter, caudal dystopic left kidney combined with hypoplasia and dysplasia of the right kidney. High-resolution ultrasound showed AFBN lesions to have resolved completely within 12 weeks after onset of intravenous antibiotic therapy in 20/25 children. Renal parenchymal cysts remained in three cases and focal scarring in two. Blood pressure and renal function was normal in 24/25 cases. AFBN should be suspected in children with fever and rapid deterioration of clinical condition. Residual lesions such as cysts or scarring of renal parenchyma could remain.

Five-year outcome in pediatric patients with mycophenolate mofetil-based renal transplantation.

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.

Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome.

Individuals with Denys-Drash syndrome (DDS) develop diffuse mesangial sclerosis, ultimately leading to renal failure. The disease is caused by mutations that affect the zinc finger structure of the Wilms' tumor protein (WT1), but the mechanisms whereby these mutations result in glomerulosclerosis remain largely obscure. How WT1 regulates genes is likely to be complex, because it has multiple splice forms, binds both DNA and RNA, and associates with spliceosomes. Herein is described that in DDS podocytes, the ratio of both WT1 +KTS isoforms C to D differs considerably from that of normal child and adult control podocytes and more closely resembles fetal profiles. Aside from the delay in podocyte maturation, DDS glomeruli show swollen endothelial cells, reminiscent of endotheliosis, together with incompletely fused capillary basement membranes; a dramatic decrease in collagen alpha4(IV) and laminin beta2 chains; and the presence of immature or activated mesangial cells that express alpha-smooth muscle actin. Because appropriate vascular endothelial growth factor A (VEGF-A) expression is known to be essential for the development and maintenance of glomerular architecture and function, this article addresses the question of whether VEGF-A expression is deregulated in DDS. The data presented here show that DDS podocytes express high levels of the proangiogenic isoform VEGF165, but completely lack the inhibitory isoform VEGF165b. The VEGF165/VEGF165b ratio in DDS resembles that of fetal S-shaped bodies, rather than that of normal child or adult control subjects. The alteration in VEGF-A expression presented here may provide a mechanistic insight into the pathogenesis of DDS.

High prevalence of febrile urinary tract infections after paediatric renal transplantation.

BACKGROUND: Adult data suggest that urinary tract infections occur frequently after renal transplantation (RTx) and contribute to mortality and graft loss; data in children are limited. Therefore, we evaluated prevalence, short and long-term morbidity and confounding factors of febrile UTI (fUTI) after paediatric RTx. METHODS: In a retrospective cross-sectional study of three centres, we analysed data on 110 children followed for 4.9+/-3.4 years after successful transplantation. RESULTS: 40/110 (36%) patients had at least one fUTI at a median time of 0.98 years (range 0.02-8.96) after RTx; 11 patients (28%) had recurrent fUTI. Serum creatinine (SCr) rose significantly from 1.15+/-1.13 to 1.83+/-1.69 mg/dl, (P<0.001) during the fUTI, declining to baseline values after treatment. At the last followed-up calculated mean, GFR was comparable between fUTI and non-fUTI groups (75+/-26 vs 71+/-22 ml/min/1.73 m2). During fUTI mean, C-reactive protein (CRP) increased to 123+/-75 mg/l. Febrile UTI were significantly more frequent in girls compared to boys (22/44 vs 18/66, P<0.05) but occurred significantly earlier in boys than in girls [median 0.63 (range 0.02-4.15) vs 1.07 (0.04-8.96) years after RTx; P<0.02]. Also, patients with urinary tract malformations (UTMs) and neurogenic bladder as underlying diagnosis and those with urological surgery prior to transplantation had an increased risk for fUTI. CONCLUSION: fUTI is a frequent complication with significant short-term morbidity especially in girls and children with UTMs, neurogenic bladder and those with urological surgery. Long-term follow-up and prospective studies confirming specific risk factors, preventive measures and impact on graft survival are necessary.

Primary focal segmental glomerulosclerosis--long-term outcome after pediatric renal transplantation.

Recurrence of the primary disease is a significant issue in pediatric renal transplantation (RTx). According to data reported by the North American Pediatric Renal Transplantation Cooperative Study, patients with focal segmental glomerulosclerosis (FSGS) as primary renal disease have a recurrence rate of 30% after the first RTx. The relative risk of an early graft loss because of recurrent disease is increased to 1.6-3.1 in pediatric patients with FSGS. In a German open multicenter study, which was initiated to investigate mycophenolate mofetil (MMF) after pediatric RTx [Transplantation 2001:71:638, Transplantation 2003:75:454], patients with FSGS were evaluated for recurrence rate, risk factors for recurrence, long-term graft function, glomerular filtration rate and transplant survival. All patients received immunosuppression with MMF, cyclosporine A and prednisone without induction therapy. Renal function and survival data for FSGS patients were compared with the results of patients with other primary renal diseases within the same study population. Among 86 patients transplanted between 1996 and 1999 eight patients suffered from FSGS as primary disease. Recurrence was diagnosed in two of the eight patients. One out of these two patients lost his graft as a result of recurrence. Risk factors such as time between diagnosis and end stage renal disease (ESRD) and age at onset did not predict recurrence. A three-year patient survival in the FSGS group was 100%, graft survival 87% vs. 97% in the non-FSGS group. Acute rejections occurred in three out of eight FSGS patients and in 37 out of 78 among the non-FSGS group. Long-term renal function, calculated using mathematical modeling based on glomerular filtration rate (GFR) data during 3 yr after RTx, was similar in FSGS patients - including a patient who had recurrence with a functioning graft - and those without FSGS. In patients with FSGS, recurring disease after RTx remains an important cause of graft loss (one of two patients in this population) even under modern immunosuppressants. Nevertheless, the immunosuppressive regimen used was associated with a similar graft survival rate and long-term renal function of FSGS patients compared with patients with other primary diseases.

Hepatitis after sevoflurane exposure in an infant suffering from primary hyperoxaluria type 1.

An 11-mo-old child with primary hyperoxaluria was scheduled for a nephroureteromia procedure. Anesthesia was induced and maintained with sevoflurane. Two days after the operation, a hepatomegaly was diagnosed, and a considerable increase in liver enzymes was observed. These pathologic findings disappeared without treatment within 7 days. In a subsequent operation 2 wk later, general anesthesia was performed (sevoflurane was avoided). After the second operation, no pathologic findings could be detected. Nothing in this patient's disease or the conduct of the anesthesia suggested a cause for the injury other than an idiosyncratic response to sevoflurane.

Recurrence of severe steroid dependency in cyclosporin A-treated childhood idiopathic nephrotic syndrome.

BACKGROUND: In patients with steroid-dependent nephrotic syndrome (SDNS), long-term remission (LTR) can usually be achieved with cyclosporin A (CSA), after alternative treatment with cytotoxic drugs or levamisole has failed. Nevertheless, severe SDNS recurs in some patients despite CSA maintenance therapy. Few data are available on the clinical course and treatment strategies in these patients. METHODS: We carried out a retrospective chart analysis of 46 patients with SDNS treated with CSA, after failure of cytotoxic treatment with cyclophosphamide (CPO). Median age at primary manifestation was 3.0 years (range 0.8-6.9) and median current age is 20.4 years (range 8.6-29.1). Patients were recruited from three centres caring for a total of 186 patients with steroid-sensitive nephrotic syndrome. RESULTS: In 14 of the 46 patients (30%; 10 male), severe SDNS recurred again despite CSA maintenance therapy. Seven patients relapsed beyond the age of 18 years. Nine of 14 patients received a further course of cytotoxic treatment as first intervention: six were treated with chlorambucil (CLA) and three with CPO. Four of the CLA-treated patients remained in LTR in contrast to none after CPO. Five patients received levamisole after CSA: only one went into LTR, while in one other CSA could be discontinued although further relapses occurred. One further patient was switched to CLA after levamisole, finally inducing LTR. Overall, six patients required two or more drugs, and in four of these CSA maintenance ultimately had to be restarted. CONCLUSION: We conclude that SDNS can recur in patients despite CSA maintenance therapy. Treatment strategies for this subgroup of patients are complex and should be standardized to optimize long-term outcome. A subgroup of patients with childhood SDNS continues to relapse into adulthood.

Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years.

BACKGROUND: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantation results have been reported for adults but not for children thus far. In the present open-labeled study, patients 18 years old and younger were evaluated prospectively for up to 3 years after renal transplantation (RTX). METHODS: Eighty-six patients receiving MMF in combination with cyclosporine and prednisone without induction were evaluated for patient survival, transplant survival, renal function, arterial blood pressure, adverse events, and opportunistic infections. These patients were compared with a historic control group (n=54) receiving azathioprine (AZA) instead of MMF. RESULTS: Patient survival after 3 years was 98.8% in the MMF group and 94.4% in the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes occurred in 47% of patients in the MMF group versus 61% in the AZA group (P<0.05). Renal function was not significantly different, neither after 3 years nor in the long-term calculation. Antihypertensive medication was administered to 73% to 84% of patients, similar in both groups. Opportunistic infections were recorded only for MMF. Infection rates were comparable to those reported in adults. CONCLUSIONS: These results suggest that MMF is safe and beneficial as a longer term maintenance immunosuppressive drug in children and adolescents.