Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation.

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low-dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard-dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high-risk (donor+/recipient-) patients (n = 88), the EVR-based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val-)ganciclovir (n = 63), the CMV-free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR-based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard-dose calcineurin inhibitor-based regimen.

Distributed expertise: qualitative study of a British network of multidisciplinary teams supporting parents of children with chronic kidney disease.

BACKGROUND: Long-term childhood conditions are often managed by hospital-based multidisciplinary teams (MDTs) of professionals with discipline specific expertise of a condition, in partnership with parents. However, little evidence exists on professional-parent interactions in this context. An exploration of professionals' accounts of the way they individually and collectively teach parents to manage their child's clinical care at home is, therefore, important for meeting parents' needs, informing policy and educating novice professionals. Using chronic kidney disease as an exemplar this paper reports on one aspect of a study of interactions between professionals and parents in a network of 12 children's kidney units in Britain. METHODS: We conducted semi-structured, qualitative interviews with a convenience sample of 112 professionals (clinical-psychologists, dietitians, doctors, nurses, pharmacists, play-workers, therapists and social workers), exploring accounts of their parent-educative activity. We analysed data using framework and the concept of distributed expertise. RESULTS: Four themes emerged that related to the way expertise was distributed within and across teams: (i) recognizing each other's' expertise, (ii) sharing expertise within the MDT, (iii) language interpretation, and (iv) acting as brokers. Two different professional identifications were also seen to co-exist within MDTs, with participants using the term 'we' both as the intra-professional 'we' (relating to the professional identity) when describing expertise within a disciplinary group (for example: 'As dietitians we aim to give tailored advice to optimize children's growth'), and the inter-professional 'we' (a 'team-identification'), when discussing expertise within the team (for example: 'We work as a team and make sure we're all happy with every aspect of their training before they go home'). CONCLUSIONS: This study highlights the dual identifications implicit in 'being professional' in this context (to the team and to one's profession) as well as the unique role that each member of a team contributes to children's care. Our methodology and results have the potential to be transferred to teams managing other conditions.

Unmet needs in the measurement of blood pressure in primary care.

BACKGROUND: Blood pressure (BP) monitoring in UK children at risk of hypertension takes place predominantly in secondary and tertiary care. OBJECTIVES: To investigate (i) the availability of paediatric BP equipment in primary care (PC) and (ii) the confidence of PC professionals in measuring and interpreting children's BP. METHODS: 103 PC practices were approached to complete a questionnaire. BP equipment availability and confidence with BP measurement and interpretation were recorded (interval scale 1-10). Cuff size and equipment type were documented. RESULTS: 95 (92%) practices responded; 40/95 possessed paediatric BP cuffs. 35/51 devices were validated for paediatric use. Median (IQR) confidence in BP measurement was 7 (2-8). Confidence in BP interpretation was 3 (2-6), though this improved if normal ranges were provided (8 (6-9), p<0.01). CONCLUSIONS: Investment in appropriate equipment and education is required to allow PC to successfully monitor BP in children.

The CERTAIN Registry: a novel, web-based registry and research platform for pediatric renal transplantation in Europe.

BACKGROUND: The results of pediatric renal transplantation have improved markedly in the last decade. However, a number of relevant clinical problems remain, such as organ damage caused by chronic rejection, long-term toxicity of immunosuppressive therapy, difficulty in developing tolerance-inducing protocols, secondary cardiovascular comorbidity, post-transplantation lymphoproliferative disease, suboptimal longitudinal growth, quality of life, adherence to immunosuppressive medication, and structured transition programs to adult care. These unmet clinical needs require intense collaborative and interdisciplinary clinical research. We recently founded the Cooperative European Paediatric Renal TransplAnt INitiative (CERTAIN; www.certain-registry.eu) as a research network and platform built on a novel, web-based registry. RESULTS: The registry's dataset provides essential information on generic kidney transplantation-related topics and also captures pediatric-specific topics, such as growth, physical and psychosocial development, and adherence. Due to its flexibility the system can be used as follows: (1) as a registry capturing a minimal or an extended dataset; (2) as a center and/or country-specific transplantation database; or (3) as a patient-specific electronic transplantation chart. The data can be exported directly from the CERTAIN web application into statistical software packages for scientific analyses. The rights regarding data ownership, evaluation, and publications are regulated in the registry's rules of procedure. Data quality is ensured by automatic software validation and a manual data review process. To avoid redundant data entry, CERTAIN has established interfaces for data change with Eurotransplant, the Collaborative Transplant Study (CTS), and the registry of the European Society of Pediatric Nephrology (ESPN) and European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) (ESPN/ERA-EDTA registry). CERTAIN fulfils all regulatory and ethical requirements of the European Union and Germany, in particular, regarding patients' data privacy and security. CONCLUSION: Using modern information technology, the recently established multinational CERTAIN Registry fills a gap in Europe for collaborative 5 research and quality assurance in the field of pediatric renal transplantation.

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.

Vitamin D deficiency in children with renal disease.

AIMS: The purpose of this study was to assess the vitamin D status of children with renal disease attending the outpatient clinics of our tertiary nephrology centre, allowing us to determine the prevalence of vitamin D deficiency and study its relationship with glomerular filtration rate (GFR) and serum parathyroid hormone (PTH) concentration. METHODS: 90 boys and 53 girls (99 white Caucasians, 38 of South Asian origin and six from other ethnic groups) were enrolled into the study. 18 were on dialysis (15 peritoneal dialysis and three haemodialysis), 61 had a functioning renal transplant (19 with reduced GFR), 18 had chronic renal failure and 46 had a variety of renal disorders with normal renal function. Serum/plasma concentrations of 25(OH)D, 1,25(OH)2D, PTH, creatinine, calcium, phosphate and alkaline phosphatase were measured. Patients with serum 25(OH)D concentrations of less than 25 nmol/l were considered to be deficient and those with levels of 25-50 nmol/l considered insufficient. RESULTS: 26% of all patients were 25(OH)D deficient and a further 32% were insufficient. The prevalence in South Asians was higher (87% deficient/insufficient) than in white Caucasians (46% deficient/insufficient, p<0.001). In children with reduced GFR who were not on dialysis, 25(OH)D levels of less than 50 nmol/l were associated with a high PTH in 90% of cases compared to only 50% of those with normal vitamin D concentrations (p = 0.013). CONCLUSION: A high proportion of renal patients were vitamin D deficient/insufficient, particularly children of South Asian origin. High PTH values in the setting of reduced GFR might be due to vitamin D deficiency and should lead to estimation of serum 25(OH)D concentration.

Diabetes mellitus following paediatric renal transplantation: a single centre experience.

BACKGROUND/AIMS: Post-transplant diabetes mellitus (PTDM) has a variably reported incidence of 4-41% among adults and children. We describe our recent experience of four children with PTDM in a paediatric renal transplantation centre. METHODS: We undertook a retrospective analysis of the glycaemic status of all paediatric patients undergoing renal transplantation at our centre in the 2-year study period. The clinical features and investigations of those who developed PTDM were further reviewed. RESULTS: Five episodes of PTDM occurred in 4/32 children. There was a variable onset and a wide range of symptoms. Investigations revealed a combination of insulinopenia with peripheral insulin resistance. Insulin therapy was required for variable durations with resolution of PTDM in four episodes. PTDM did not adversely affect the renal graft function. CONCLUSION: PTDM requires increased awareness among paediatric nephrologists and endocrinologists for early recognition and prompt effective intervention.

What delay should there be between primary infectious mononucleosis and renal transplantation?

A 17-yr-old girl in end-stage renal failure was due to undergo living-related pre-emptive renal transplantation when she developed acute infectious mononucleosis (AIM) from Epstein-Barr virus (EBV). In view of the risk of post-transplant lymphoproliferative disorder (PTLD) we were unsure as to the optimal delay between AIM and renal transplantation. This report describes the process used to determine maturation of the immune response to EBV using a combination of serology, immunophenotyping and molecular viral load estimation. These tests showed that EBV had not been cleared and dialysis was instituted rather than proceed directly to transplantation. After EBV viral load became undetectable in the blood, living-related donor was successfully performed 13 months after AIM. With 42-month post-transplant follow up there has been no evidence of PTLD.

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.

Association between ICAM-1 Gly-Arg polymorphism and renal parenchymal scarring following childhood urinary tract infection.

Renal parenchymal scarring (RPS) following urinary tract infection (UTI) is an important cause of renal morbidity in children. Studies have shown that the intensity of the inflammatory response following infection is related to the risk of RPS. However, genetic variability in this response has not been studied. Adhesion molecules play a crucial role in leucocyte recruitment following infection, and polymorphisms have been reported in the genes for key cell adhesion molecules. We have investigated the possibility that children who develop RPS following UTI may exhibit altered genotype or allele frequencies for polymorphisms of the intercellular adhesion molecule-1 (ICAM-1) (exons 4 and 6), E-selectin (exons 2 and 4), platelet endothelial cell adhesion molecule-1 (PECAM-1) (exon 3) and CD11b (3'UTR) genes, which may predict outcome of UTI. DNA was isolated from 99 children shown to have developed RPS, 43 children with no evidence of scarring (NS) following UTI and 170 healthy controls. Genotyping was performed by restriction fragment length polymorphism (RFLP) analysis. When the RPS group was compared with the NS group, there was a significant reduction in the frequency of the ICAM-1 exon 4 A allele (10.6 vs. 21.3%, respectively, chi2 = 6.01, P = 0.014). There was no significant difference in either allele or genotype frequency for any of the other polymorphisms studied. These data suggest that the A allele of the ICAM-1 exon 4 polymorphism may protect against the risk of RPS following UTI and may participate in the regulation of the inflammatory response following UTI.

Steroid-sensitive nephrotic syndrome and vascular endothelial growth factor gene polymorphisms.

Genetic polymorphisms have been recognized as important determinants of gene expression. Three common single nucleotide polymorphisms have been identified in the promoter and 5' untranslated region of the vascular endothelial growth factor (VEGF) gene: -460 C --> T, -141 A --> C and +405 G --> C. As VEGF has been postulated to play a role in the pathogenesis of childhood steroid-sensitive nephrotic syndrome (SSNS), this study tested the hypothesis that VEGF genotype may be associated with susceptibility to SSNS. We examined the genotype frequencies of these polymorphisms in a total of 116 children with SSNS and 150 control subjects, using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). There were no statistically significant differences in any of the genotype frequencies between SSNS patients and controls. We conclude that VEGF -460, -141 and +405 genotypes are not associated with susceptibility to childhood SSNS.

A PCR-RFLP typing method for adhesion molecule gene polymorphisms and allele frequencies in a normal UK population.

We report simple and reproducible PCR-RFLP typing methods for the polymorphisms in the ICAM-1, E-selectin and PECAM-1 genes. The genotype and allele frequencies detected in a normal UK population did not deviate significantly from the Hardy-Weinberg equilibrium; neither did they differ from frequencies previously reported using SSP or SSCP methods.

Plasma and urinary soluble adhesion molecule expression is increased during first documented acute pyelonephritis.

BACKGROUND: The degree of inflammatory reaction and leucocyte trafficking during acute pyelonephritis has been related to the risk of developing renal parenchymal scarring. Adhesion molecules play a central role in leucocyte recruitment during inflammation. AIMS: (1) To determine whether circulating and urinary concentrations of E-selectin and intercellular adhesion molecule 1 (ICAM-1) were abnormal during first documented acute pyelonephritis; (2) to investigate whether circulating or urinary concentrations were predictive for the development of abnormalities on DMSA imaging. METHODS: Plasma and urine samples were collected from 40 children with a first episode of acute pyelonephritis within one week of infection (acute sample) and at six weeks (late sample). Control samples were collected from 21 healthy age matched controls and 18 age matched controls with febrile illness not secondary to urinary tract infection. RESULTS: Plasma and urinary sE-selectin were higher in acute samples (median 176.3 ng/ml and 0.12 ng/mmol respectively) compared with late (97.8 ng/ml and 0.029 ng/mmol) and both control (65.6 ng/ml and 0 ng/mmol) and febrile control (urine 0 ng/mmol) samples. Plasma sICAM-1 was higher in acute samples (428 ng/ml) than controls (365.2 ng/ml), and acute sICAM-1 urine concentrations were higher than febrile control concentrations (3.2 v 0.7 ng/mmol). No correlations were detected between sE-selectin or sICAM-1 and acute or late DMSA scan changes. CONCLUSION: Plasma and urinary sE-selectin and sICAM-1 are significantly increased during acute pyelonephritis, though no correlation exists between the presence of high plasma or urine concentrations and DMSA scan changes, both during acute infection and six weeks post-infection.