Role of glucocorticoid metabolism in childhood obesity-associated hypertension.

Objective: Childhood obesity is associated with alterations in hypothalamus-pituitary-adrenal axis activity. We tested the hypothesis that multiple alterations in the metabolism of glucocorticoids are required for the development of hypertension in children who become overweight. Methods: Spot urine for targeted gas chromatography-mass spectrometry steroid metabolome analysis was collected from (1) overweight/hypertensive children (n = 38), (2) overweight/non-hypertensive children (n = 83), and (3) non-overweight/non-hypertensive children (n = 56). Results: The mean (± s.d.) age of participants was 10.4 ± 3.4 years, and 53% of them were male. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3 (869 (interquartile range: 631-1352) vs 839 (609-1123) vs 608 (439-834) µg/mmol creatinine × m2 body surface area, P < 0.01, for the sum of cortisol metabolites), and group 1 had a higher excretion rate of naive cortisol than group 3. Furthermore, groups differed in cortisol metabolism, in particular in the activities of 11ß-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), 5α-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3). Discussion: The sequence of events leading to obesity-associated hypertension in children may involve an increase in the production of glucocorticoids, downregulation of 11ß-hydroxysteroid dehydrogenase type 1 activity, and upregulation of 5α-reductase activity, along with a decrease in CYP3A4 activity and an increase in bioavailable cortisol.

Is mid-upper arm circumference in Dutch children useful in identifying obesity?

BACKGROUND: Mid-upper arm circumference (MUAC) is suggested as being a valid measure in detecting overweight/obesity in children and adolescents, due to the strong relation with weight. We examined this relation and compared MUAC to body mass index (BMI) according to the International Obesity Task Force (IOTF) in children. METHODS: Anthropometric data including MUAC were collected in 2009 by trained healthcare professionals in the context of the fifth Dutch Nationwide Growth Study, in a sample of 6167 children (2891 boys and 3276 girls) aged 2-18 years of Dutch origin. We propose MUAC SDS cut-off values for overweight and obesity, and compared MUAC with BMI IOTF in sex-specific and age-specific categories (2-5, 6-11, 12-18 years). RESULTS: The area under the curve is used as a measure of diagnostic accuracy; the explained variance (R²) is good to excellent (0.88-0.94). Sensitivity ranges from 51.8% to 95.3% and specificity from 71.4% to 93.8%. Across age and gender groups, 65.1% to 89.0% participants are classified by both MUAC and BMI as normal weight, overweight or obese. We constructed three equations to predict weight using MUAC, with small differences between observed and predicted weight with an explained variance ranging from 0.88 to 0.94. CONCLUSIONS: Compared with BMI, MUAC is a valid measure for detecting overweight and obesity and thus a good alternative for BMI. When weight has to be estimated, it can be accurately predicted using MUAC. Based on our observations, we recommend developing diagrams with international (IOTF) cut-offs for MUAC SDS similar to BMI.

Is There an Association Between Cortisol and Hypertension in Overweight or Obese Children?

OBJECTIVE: The precise mechanisms behind the development of hypertension in overweight or obese children are not yet completely understood. Alterations in hypothalamic-pituitary-adrenal axis activity may play a role. We aimed to investigate the association between cortisol parameters and hypertension in overweight or obese children. METHODS: Random urine (n=180) and early-morning saliva samples (n=126) for assessment of cortisol and cortisone were collected from 1) hypertensive overweight children (n=50), 2) normotensive overweight children (n=145), and 3) normotensive non-overweight children (n=75). RESULTS: The age of participants was 10.4±3.3 years and 53% were boys. The urinary cortisol-to-cortisone ratio [ß 1.11, 95% confidence interval (CI) 1.05-1.19] as well as urinary cortisol/creatinine (ß 1.38, 95% CI 1.09-1.54), and cortisone/creatinine ratios (ß 1.26, 95% CI 1.17-1.36) were significantly higher in overweight or obese than in non-overweight children. After adjusting for body mass index-standard deviation score and urinary cortisone/creatinine ratio, but not cortisol/creatinine ratio, was significantly associated with presence of hypertension (ß 1.12, 95% CI 1.02-1.23). Salivary cortisol and cortisone levels were significantly lower in overweight or obese than in non-overweight children (ß -4.67, 95% CI -8.19- -1.15, and ß 0.89, 95% CI 0.80-0.97 respectively). There were no significant differences in cortisol parameters between hypertensive and normotensive overweight or obese children. CONCLUSION: This study provided further evidence for an increased cortisol production rate with decreased renal 11ß-hydroxysteroid dehydrogenase 2 activity and flattening of early-morning peak cortisol and cortisone in overweight or obese children. However, there were no significant differences in cortisol parameters between hypertensive and normotensive overweight and obese children.

Screening, diagnosis and treatment of hypertension in obese children: an international policy comparison.

Hypertension in obese children may require a different diagnostic and treatment approach from that for children with secondary hypertension, yet there is neither consensus nor a clear guideline. The aim of this study was to assess how obese children with hypertension are currently diagnosed and treated by paediatric nephrologists, what obstacles exist and what can be improved. In the period May-November 2014, an online questionnaire was sent to all members of the European Society for Paediatric Nephrology (n = 2148). Questions focused on current practices and obstacles regarding screening, diagnosis and treatment of hypertension in obese children. A total of 214 paediatric nephrologists responded. Although nearly 100 % agreed that screening of obese children for hypertension is indicated, it was current practice in only 56 % of participating countries; 88 % of respondents diagnosed hypertension with 24-h ambulatory blood pressure measurement. Diagnostics used to rule out causes or consequences of hypertension varied among the respondents; they included, in particular, the use of serum renin/aldosterone, urine sodium/potassium, and dimercaptosuccinic acid scan. Concerning treatment, 45 % of respondents preferred to start treatment with a lifestyle program, 2 % with antihypertensive medication, and 40 % with both. For 73 % of respondents, angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers were the drugs of first choice. The findings of this study emphasize the urgent need for an international guideline for screening, diagnosis and treatment of hypertension in obese children.

Is the prevalence of hypertension in overweight children overestimated?

OBJECTIVES: The aim of this study is to explore different methods for screening and diagnosing hypertension-which definitions and criteria to use-in children and in addition to determine the prevalence of hypertension in Dutch overweight children. DESIGN: A cross-sectional study performed in the Dutch Child Health Care setting. SETTING: Four Child Health Care centres in different cities in the Netherlands. PARTICIPANTS: 969 overweight (including obese) and 438 non-overweight children, median age 11.7 years (range 4.1-17.10), 49% boys. MAIN OUTCOME MEASURES: The main outcome was blood pressure, and the difference in prevalence of hypertension using different criteria for blood pressure interpretation: using the first blood pressure measurement, the mean of two measurements and the lowest of three measurements on two different occasions. RESULTS: Looking at the first measurement alone, 33% of overweight and 21% of non-overweight children had hypertension. By comparing the mean of the first two measurements with reference values, 28% of overweight children and 16% of non-overweight children had hypertension. Based on the lowest of three consecutive measurements, the prevalence decreased to 12% among overweight children and 5% among non-overweight children at visit one and at visit two 4% of overweight children still had hypertension. CONCLUSIONS: The prevalence of hypertension is highly dependent on the definitions and criteria used. We found a prevalence of 4% in overweight children, which is considerably lower than suggested by recent literature (4%-33%). This discrepancy can be explained by our more strict definition of hypertension. However, to draw any conclusions on the prevalence, normal values using the same definition of hypertension should be established. Despite the low prevalence, we recommend measuring blood pressure in all overweight children in view of later cardiovascular morbidity and mortality.

Population Pharmacokinetics of Prednisolone in Relation to Clinical Outcome in Children With Nephrotic Syndrome.

BACKGROUND: The relapse frequency in children with nephrotic syndrome (NS) is highly variable despite standardized prednisolone treatment regimens. Existing evidence on the relationship between prednisolone pharmacokinetics (PK) and clinical response in children with NS is scarce and limited. The aim of this study was to develop a pediatric popPK model for prednisolone based on our previous model based on healthy adults using salivary measurements in children with NS and to correlate clinical outcome with between-subject variability in prednisolone exposure. METHODS: The pharmacokinetics of prednisolone in a well-defined, prospective cohort consisting of 104 children with NS while in remission was determined. Pharmacokinetic parameters were analyzed in relation to relapse patterns and side effects. Noninvasive salivary prednisolone measurements were performed using a sparse sampling strategy. A population pharmacokinetic approach was used to derive individual estimates of apparent clearance (CL/F) and apparent volume of distribution (V/F) from the salivary concentration-time curve, followed by calculation of the area under the curve (AUC) of free prednisolone. The individual free serum prednisolone exposure from prednisolone in saliva was derived from the salivary concentration-time curves. Genetic polymorphisms of CYP3A4, CYP3A5, ABCB1, NR1L2, and POR were explored in relation to between-subject variability of CL/F. RESULTS: Moderate interindividual variability was found for CL/F (CV, 44.7%). Unexplained random between-subject variability (eta) of CL/F was lower in patients carrying 1 or 2 ABCB1 3435C>T alleles compared to wild type: median -0.04 (interquartile range, -0.17 to 0.21) and 0.00 (-0.11 to 0.16) versus 0.17 (-0.08 to 0.47), P = 0.046. Exposure to free prednisolone was not associated with frequent relapses or adverse effects. CONCLUSIONS: This study provides evidence for the possibility of prednisolone drug monitoring through salivary measurements and this may be of particular usefulness in pediatric patients. However, the observed variability in prednisolone exposure, in the therapeutic dose range studied, is not considered to be a major determinant of clinical outcome in children with NS.

Genetic and in vivo determinants of glucocorticoid sensitivity in relation to clinical outcome of childhood nephrotic syndrome.

Following initial glucocorticoid treatment, the clinical course in children with nephrotic syndrome is highly variable. Intrinsic sensitivity to glucocorticoids might be a determinant of this variability. Functional polymorphisms of the glucocorticoid receptor gene NR3C1 have been associated with either relatively impaired (GR-9ß) or increased (BclI) glucocorticoid sensitivity. Here, in a prospective, well-defined cohort of children with nephrotic syndrome, we evaluated both carriage of GR-9ß+TthIII-1 and BclI haplotypes in 113 children and a dexamethasone suppression test in 90 children in relation to their clinical outcome over a median follow-up of 4.4 years. Carriers of GR-9ß+TthIII-1 had a significantly higher incidence of steroid dependence 13/25 (52%) compared with noncarriers 19/75 (25%) with a hazard ratio adjusted for gender, age, and descent of 3.04 with 95% confidence interval 1.37-6.74. Both first and frequent relapses happened significantly more often in GR-9ß+TthIII-1 carriers than in noncarriers. There were no significant differences in therapeutic outcomes between carriers and noncarriers of the BclI haplotype. Results of the dexamethasone test showed no associations with clinical outcome. Thus, the GR-9ß+TthIII-1 haplotype of the glucocorticoid receptor gene offers new insights into the clinical course of children with nephrotic syndrome.

Monitoring prednisolone and prednisone in saliva: a population pharmacokinetic approach in healthy volunteers.

BACKGROUND: Prednisolone (PLN) is a widely used corticosteroid in a variety of immune-mediated diseases. Treatment regimes generally consist of empirically derived treatment doses, whereas therapeutic response among patients is highly variable. Drug monitoring of serum PLN levels might support a more rational approach to dose selection, yet is invasive and laborious. In analogy to cortisol, salivary PLN may offer a good alternative for serum PLN, being a representative approximation of free serum PLN. The aims of this study were to evaluate the correlation between free serum and salivary PLN levels and to quantify this relationship within a population pharmacokinetic model. METHODS: PLN and prednisone (PN) concentrations were measured in 396 samples from 19 healthy volunteers after oral ingestion of 80 mg PLN. Measurements in serum, ultrafiltrate, and saliva were performed with a recently validated liquid chromatography tandem mass spectrometry method. Population pharmacokinetic analysis was performed with nonlinear mixed effect modeling using NONMEM. RESULTS: Salivary PLN levels correlated well with free serum PLN levels (r = 0.931, P < 0.01). A weaker correlation was found for PN (r = 0.318, P < 0.01), which may be explained by the finding that salivary PN levels mainly seemed to consist of PLN enzymatically converted to PN. Total and free serum PLN concentrations decreased over time after drug administration and showed a nonlinear mutual relationship, consistent with concentration-dependent protein binding. Modeled PLN pharmacokinetics corresponded with previous reports. Low to moderate interindividual variability was found for V/F and CL/F (coefficients of variation were 13.8% and 14.6%, respectively). Free and salivary PLN showed a nonlinear relationship with total PLN. An equation predicting free serum levels from salivary levels was successfully derived from the data. CONCLUSIONS: This study is the first to describe the relationship between salivary and (free) serum PLN using a population pharmacokinetic model. Salivary PLN was found to be a reliable predictor of free and total serum PLN in healthy volunteers. The results of this study encourage further exploration of the use of saliva as a noninvasive and feasible method for drug monitoring of PLN.

Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome.

Prolonged prednisolone treatment for the initial episode of childhood nephrotic syndrome may reduce relapse rate, but whether this results from the increased duration of treatment or a higher cumulative dose remains unclear. We conducted a randomized, double-blind, placebo-controlled trial in 69 hospitals in The Netherlands. We randomly assigned 150 children (9 months to 17 years) presenting with nephrotic syndrome to either 3 months of prednisolone followed by 3 months of placebo (n=74) or 6 months of prednisolone (n=76), and median follow-up was 47 months. Both groups received equal cumulative doses of prednisolone (approximately 3360 mg/m(2)). Among the 126 children who started trial medication, relapses occurred in 48 (77%) of 62 patients who received 3 months of prednisolone and 51 (80%) of 64 patients who received 6 months of prednisolone. Frequent relapses, according to international criteria, occurred with similar frequency between groups as well (45% versus 50%). In addition, there were no statistically significant differences between groups with respect to the eventual initiation of prednisolone maintenance and/or other immunosuppressive therapy (50% versus 59%), steroid dependence, or adverse effects. In conclusion, in this trial, extending initial prednisolone treatment from 3 to 6 months without increasing cumulative dose did not benefit clinical outcome in children with nephrotic syndrome. Previous findings indicating that prolonged treatment regimens reduce relapses most likely resulted from increased cumulative dose rather than the treatment duration.

[Guideline 'Overweight' for child health care]. / Richtlijn 'Overgewicht' voor de jeugdgezondheidszorg.

The '5th National Growth Study' indicates that the percentage of overweight children in the Netherlands has risen from 9-12% in 1997 to 13-15% in 2009. Child Health Care is a unique setting for promotion of development, growth and behaviour of children, in which tailored prevention can be offered. Detection of overweight in children and intervention by Child Health Care takes place in a multidisciplinary setting linking general practitioners, paediatricians, dieticians, teachers, physiotherapists, pedagogues and psychologists. For overweight children, a change plan is created based on exercise, playing outside, having breakfast every day, as little as possible sweetened beverages and fast-food, and less time spent in front of the television or computer, with fewer energy-rich snacks. As recommended in the Dutch CBO guideline 'Obesity', obese children are referred to a general practitioner or paediatrician.

High prevalence of hypertension in obese children in the Caribbean.

BACKGROUND: The prevalence of obesity is increasing worldwide. Obesity in children and adults leads to diabetes mellitus type 2 and cardiovascular disease. AIM: To determine the prevalence of high blood pressure in overweight and obese children in the Caribbean. METHODS: In a cross-sectional study, weight and height were measured in all 5-16-year-old children attending public school in 2008 on Bonaire, an island in the Caribbean. Cut-off values for body mass index (BMI) are defined by the International Obesity Task Force. Blood pressure was measured in all overweight and obese children as well as in a control group with normal weight and compared with reference values from the National High Blood Pressure Working Group on Children. RESULTS: 94% (2023/2152) of all children participated in the study. 17% (335/2023) of the children were overweight (excluding obesity) and a further 12% (246/2023) were obese. Hypertension was found in 13% (67/526) of children of normal weight, in 23% (71/307) of overweight children and in 53% (127/242) of obese children. Compared with normal-weight children, the odds for hypertension were 2.1 (95% CI 1.4-3.0) for overweight children and 7.2 (95% CI 5.0-10.3) for obese children. CONCLUSION: There is a high prevalence of hypertension in overweight and obese children on Bonaire. As hypertension is a harbinger of cardiovascular disease, early detection and treatment of overweight and obese children is of paramount importance and their blood pressure needs to be measured regularly.

High cardiovascular risk in severely obese young children and adolescents.

OBJECTIVE: To assess the prevalence of cardiovascular risk factors in severely obese children and adolescents. METHODS: A nationwide prospective surveillance study was carried out from July 2005 to July 2007 where paediatricians were asked to report all new cases of severe obesity in 2-18-year-old children to the Dutch Paediatric Surveillance Unit. Severe obesity is defined by gender and age-dependent cut-off points for body mass index based on Dutch National Growth Studies corresponding to the adult cut-off point of 35 kg/m(2). Paediatricians were asked to complete a questionnaire for every severely obese child regarding socio-demographic characteristics and cardiovascular risk factors (blood pressure, fasting blood glucose and lipids). RESULTS: In 2005, 2006 and 2007, 94%, 87% and 87%, respectively, of paediatricians in the Netherlands responded to the monthly request from the Dutch Paediatric Surveillance Unit and 500 children with newly diagnosed severe obesity were reported. 72.6% (n=363) of paediatricians responded to a subsequent questionnaire. Cardiovascular risk factor data were available in 255/307 (83%) children who were correctly classified as severely obese. 67% had at least one cardiovascular risk factor (56% hypertension, 14% high blood glucose, 0.7% type 2 diabetes and up to 54% low HDL-cholesterol). Remarkably, 62% of severely obese children aged ≤12 years already had one or more cardiovascular risk factors. CONCLUSION: A high number (2/3) of severely obese children have cardiovascular risk factors. Internationally accepted criteria for defining severe obesity and guidelines for early detection and treatment of severe obesity and comorbidity are urgently needed.

Nephrocalcinosis in preterm neonates.

The prevalence of nephrocalcinosis (NC) in preterm neonates in recent reports is 7-41%. The wide range in prevalence is a consequence of different study populations and ultrasound equipment and criteria, in addition to a moderate interobserver variation. NC in preterm neonates has a multifactorial aetiology, consisting of low gestational age and birth weight, often in combination with severe respiratory disease, and occurs as a result of an imbalance between stone-promoting and stone-inhibiting factors. A limited number of histological studies suggest that calcium oxalate crystals play an important role in NC in premature neonates. In 85% of children resolution of NC occurs in the first years of life. Prematurity, per se, is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. In addition, NC in preterm neonates can have long-term sequelae for glomerular and tubular function. Long-term follow-up of blood pressure and renal function of prematurely born children, especially with neonatal NC, is recommended. Prevention of NC with (low) oral doses of citrate has not resulted in a significant decrease in the prevalence of NC; a higher citrate dosage deserves further study. Future research pertaining to prevention of NC in preterm neonates is crucial.

Regulatory allospecific T cell clones abrogate chronic allograft rejection.

True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig-treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4+CD25+Foxp3+ cells and strong mononuclear cell staining for IL-10 but negligible IFN-gamma, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.

Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome.

We performed a multi-centre randomized controlled trial to compare the efficacy of mycophenolate mofetil (MMF) to that of cyclosporine A (CsA) in treating children with frequently relapsing nephrotic syndrome and biopsy-proven minimal change disease. Of the 31 randomized initially selected patients, seven were excluded. The remaining 24 children received either MMF 1200 mg/m(2) per day (n = 12) or CsA 4-5 mg/kg per day (n = 12) during a 12-month period. Of the 12 patients in the MMF group, two discontinued the study medication. Evaluation of the changes from the baseline glomerular filtration rate showed an overall significant difference in favour of MMF over the treatment period (p = 0.03). Seven of the 12 patients in the MMF group and 11 of the 12 patients in the CsA group remained in complete remission during the entire study period. Relapse rate in the MMF group was 0.83/year compared to 0.08/year in the CsA group (p = 0.08). None of the patients reported diarrhea. Pharmacokinetic profiles of mycophenolic acid were performed in seven patients. The patient with the lowest area under the curve had three relapses within 6 months. In children with frequently relapsing minimal change nephrotic syndrome, MMF has a favourable side effect profile compared to CsA; however, there is a tendency towards a higher relapse risk in patients treated with MMF.

Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction.

BACKGROUND AND OBJECTIVES: Lowe syndrome is defined by congenital cataracts, mental retardation, and proximal tubulopathy and is due to mutations in OCRL. Recently, mutations in OCRL were found to underlie some patients with Dent disease, characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. This phenotypic heterogeneity is poorly understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The renal phenotype of 16 patients with Lowe syndrome (10.9 +/- 7.0 yr) under care of the authors was characterized to define overlap of symptoms with Dent disease and infer clues about OCRL function. Medical charts of patients were reviewed for data regarding glomerular filtration rate and markers of proximal tubular function. RESULTS: All patients had low molecular weight proteinuria and albuminuria. Lysosomal enzymuria was elevated in all 11 patients assessed. Fifteen patients had hypercalciuria, and 14 aminoaciduria. Seven patients required bicarbonate and three required phosphate replacement; all others maintained normal serum values without supplementation. None of the patients had detectable glycosuria, and none had clinically overt rickets. GFR was mildly to moderately impaired and highly variable, with a trend of deterioration with age. CONCLUSIONS: Patients with Lowe syndrome do not have renal Fanconi syndrome but a selective proximal tubulopathy, variable in extent and dominated by low molecular weight proteinuria and hypercalciuria, the classical features of Dent disease. These findings suggest that OCRL and ClC-5, the chloride channel mutated in Dent disease, are involved in similar reabsorption pathways in the proximal tubule.

Absence of tolerance and toxicity to high-dose continuous intravenous furosemide in haemodynamically unstable infants after cardiac surgery.

AIM: To evaluate a high-dose continuous furosemide regimen in infants after cardiac surgery. METHODS: Fifteen haemodynamically unstable infants with volume overload admitted to a paediatric intensive care unit were treated with an aggressive furosemide regimen consisting of a loading bolus (1-2 mg kg(-1)) followed by a continuous infusion at 0.2 mg kg(-1) h(-1) which was adjusted according to a target urine output of 4 ml kg(-1) h(-1). Frequent sampling for furosemide concentrations in blood and urine was done for 3 days with simultaneous assessment of sodium excretion and urine output. RESULTS: The mean furosemide dose was 0.22 (+/- 0.06), 0.25 (+/- 0.10) and 0.22 (+/- 0.11) mg kg(-1) h(-1) on the first, second and third day, respectively. Median urine production was 3.0 (0.6-5.3), 4.2 (1.7-6.6) and 3.9 (2.0-8.5) ml kg(-1) h(-1), respectively, on the first, second and third day of the study. The target urine production was reached at a median time of 24 (6-60) h and this was maintained during the study period. The regimen did not result in toxic serum concentrations and was haemodynamically well tolerated. CONCLUSION: High-dose continuous furosemide infusion for 72 h in haemodynamically unstable infants after cardiac surgery appears to be a safe and effective treatment for volume overload. Development of tolerance against the effects of furosemide and ototoxic furosemide concentrations were not observed.

Is nephrocalcinosis in preterm neonates harmful for long-term blood pressure and renal function?

OBJECTIVE: The aim of our study was to examine long-term effects of nephrocalcinosis in prematurely born children. PATIENTS AND METHODS: Preterm neonates (gestational age <32 weeks) with (n = 42) and without (n = 32) nephrocalcinosis were prospectively studied at a mean age of 7.5 (+/-1.0) years. RESULTS: Blood pressure did not differ in ex-preterm infants with and without nephrocalcinosis but was significantly higher than expected for healthy children. In comparison to healthy children, more ex-preterm infants with neonatal nephrocalcinosis had (mild) chronic renal insufficiency (glomerular filtration rate: <85 mL/min per 1.73 m2; 6 of 40); this is in contrast to ex-preterm infants without neonatal nephrocalcinosis (2 of 32). Tubular phosphate reabsorption and plasma bicarbonate were significantly lower in children with nephrocalcinosis compared with children without nephrocalcinosis. In addition, more ex-preterm infants with and without nephrocalcinosis than expected had low values for plasma bicarbonate and early-morning urine osmolality compared with healthy children. Kidney length of ex-preterm infants with and without nephrocalcinosis was significantly smaller than expected in healthy children of the same height. Nephrocalcinosis persisted long-term in 4 of 42 children but was not related to blood pressure, kidney length, or renal function. CONCLUSIONS: Nephrocalcinosis in preterm neonates can have long-term sequelae for glomerular and tubular function. Furthermore, prematurity per se is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. Long-term follow-up of blood pressure and renal glomerular and tubular function of preterm neonates, especially with neonatal nephrocalcinosis, seems warranted.

Evaluation of furosemide regimens in neonates treated with extracorporeal membrane oxygenation.

INTRODUCTION: Loop diuretics are the most frequently used diuretics in patients treated with extracorporeal membrane oxygenation (ECMO). In patients after cardiopulmonary bypass (CPB) surgery, the use of continuous furosemide infusion is increasingly documented. Because ECMO and CPB are 'comparable' procedures, continuous furosemide infusion is used in newborns on ECMO. We report on the use of continuous intravenous furosemide in neonates treated with ECMO. METHODS: This was a retrospective observational study in neonates treated with continuous intravenous furosemide during ECMO. RESULTS: Thirty-one patients were included in the study. A median of 25 (9-149) hours after the start of ECMO, continuous furosemide therapy was started at a median rate of 0.08 (0.02-0.17) mg/kg per hour. The continuous furosemide dose was not changed in the individual patient. Seven patients received a furosemide bolus prior to, and five patients received additional loop diuretics during, the continuous infusion. Urine production before continuous furosemide therapy was not significantly different between patients who received a furosemide bolus prior to the infusion and those who did not receive this bolus (P = 0.2879). Although a positive effect of the 'loading' bolus was observed in urine output in the first 24 hours, there was no statistically significant difference in urine output (P = 0.0961) or in time (P = 0.1976) to reach a urine output of 6 ml/kg per hour between patients. After 24 hours, urine production remained a median of 6.2 ml/kg per hour irrespective of furosemide boluses. The forced diuresis was well tolerated as illustrated by stable haemodynamic parameters and a decrease in ECMO flow and vasopressor score over the observation period. CONCLUSION: This is the first report on continuous intravenous furosemide therapy in newborns treated with ECMO. The furosemide regimens used in this study varied widely in continuous and intermittent doses. However, all regimens achieved adequate urine output. An advantage of continuous, over intermittent, intravenous furosemide could not be documented. Furosemide dosing regimens should be developed for neonates treated with ECMO. In addition, therapeutic drug-monitoring studies are required to prevent furosemide toxicity because so far no data are available on serum furosemide levels in neonates treated with ECMO.

Outcome of renal transplantation for Wilms' tumor and Denys-Drash syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study.

In some children with bilateral Wilms' tumor, reduction of tumor burden cannot be accomplished without total nephrectomy. In Denys-Drash syndrome, nephrectomy is required for associated Wilms' tumor or after progression to end stage renal disease secondary to diffuse mesangial sclerosis because of risk of development of Wilms' tumor. Current recommendation is to wait at least 1-2 yr after completion of chemotherapy for Wilms' tumor before renal transplantation. The North American Pediatric Renal Transplant Cooperative Study dialysis (1992-2001) and transplant registries (1987-2002) were analyzed, comparing children 0-18 yr old with Wilms' tumor and Denys-Drash syndrome to other primary diagnoses. There were 37 children with Wilms' tumor and 33 with Denys-Drash syndrome in the dialysis registry. Of these, 10 children with Wilms' tumor and three with Denys-Drash syndrome did not receive a renal transplant and all died. The cause of death was Wilms' tumor in eight children with Wilms' tumor and in one with Denys-Drash syndrome. The transplant registry included 43 children with Wilms' tumor, 43 children with Denys-Drash syndrome, and 7469 patients with other diagnoses. Acute rejection, graft and patient survival profiles from all three groups at 6 months, 1 and 3 yr post-transplant were comparable. There were no graft failures or deaths because of recurrent Wilms' tumor in the Drash group. There was one death with Wilms' tumor in the Wilms' group - a 2.5-yr-old child transplanted after 6 months of dialysis who died of Wilms' <6 months after renal transplantation. In conclusion, most children dialyzed because of Wilms' tumor and Denys-Drash syndrome who did not receive a renal transplant died of Wilms' tumor. However, the outcomes of children with Wilms' tumor and Denys-Drash syndrome who proceeded to renal transplantation are comparable with children with other diagnoses, with no graft failures because of recurrence and only one death from Wilms' tumor in a Wilms' patient who received only a short course of dialysis prior to transplantation. Current practices in children with Wilms' tumor and Denys-Drash syndrome appear to be on target to portend good outcome following renal transplantation.