Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome.

BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance. METHODS: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls. RESULTS: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6. CONCLUSIONS: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

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.

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.

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.

Very preterm birth is a risk factor for increased systolic blood pressure at a young adult age.

Children born very prematurely who show intrauterine growth retardation (IUGR) are suggested to be at risk of developing high blood pressure as adults. Renal function may already be impaired by young adult age. To study whether very preterm birth affects blood pressure in young adults, we measured 24-h ambulatory blood pressure (Spacelabs 90207 device) and renin concentration in 50 very premature individuals (<32 weeks of gestation), either small (SGA) or appropriate (AGA) for gestational age (21 SGA, 29 AGA), and 30 full-term controls who all were aged 20 years at time of measurement. The mean (standard deviation) daytime systolic blood pressure in SGA and AGA prematurely born individuals, respectively, was 122.7 (8.7) and 123.1 (8.5) mmHg. These values were, respectively, 3.6 mmHg [95% confidence interval (CI) -0.9 to 8.0] and 4.2 mmHg (95% CI 0.4-8.0) higher than in controls [119.6 (7.6)]. Daytime diastolic blood pressure and nighttime blood pressure did not differ between groups. We conclude that individuals born very preterm have higher daytime systolic blood pressure and higher risk of hypertension at a young adult age.

Reduced renal length and volume 20 years after very preterm birth.

Intrauterine growth retardation is presumed to be associated with decreased renal size and impaired renal function as a result of stunted kidney development and nephron deficit. To study whether very preterm birth also affects renal size at young adulthood, we sonographically measured bipolar kidney length and volume in 51 very premature individuals (<32 weeks of gestation), either small (SGA) or appropriate (AGA) for gestational age (22 SGA and 29 AGA), and 30 full-term controls 20 years after birth. Relative kidney length and volume were calculated. Both absolute and relative left kidney length and volume were significantly lower in SGA and AGA individuals, notably in women. Renal size did not differ between SGA and AGA individuals. In 70% of controls, the left kidney was larger than the right one compared with 40.9% in SGA [relative risk (RR) 1.7; 95% confidence interval (CI) 1.0-3.0] and 48.3% in AGA (RR 1.5; 95% CI 0.9-2.3) individuals. Renal structural anomalies were present in eight prematurely born participants only. Our data suggest that kidney growth is stunted after preterm birth, especially on the left side, and in the female gender.

Tracking and determinants of kidney size from fetal life until the age of 2 years: the Generation R Study.

BACKGROUND: An adverse fetal environment may lead to smaller kidneys and subsequently kidney disease and hypertension in adulthood. The aims of this study are to examine whether kidney size tracks from fetal life to childhood and whether maternal and fetal characteristics are associated with kidney size at the age of 2 years. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: The study was conducted in a group of 688 infants in Rotterdam, The Netherlands. Entry criteria were singleton, noncomplicated pregnancies, and Dutch ethnicity. PREDICTORS: The maternal characteristics age, height, and prepregnancy weight were measured in early pregnancy. Fetal growth, head circumference, abdominal circumference, femur length and estimated fetal weight, and placental characteristics were assessed in the second and third trimesters. OUTCOMES & MEASUREMENTS: Kidney size, defined as length, width, depth, and volume, was measured in the third trimester of pregnancy and at postnatal ages 6 and 24 months. RESULTS: Overall median gestational age was 40.3 weeks (95% range, 36.0 to 42.3 weeks), and mean birth weight was 3,536 +/- 524 (SD) g. Children tended to remain in the lowest and highest quartiles of kidney volume from the third trimester to the age of 2 years (odds ratio, 2.05; 95% confidence interval, 1.38 to 3.06; odds ratio, 3.29; 95% confidence interval, 2.22 to 4.87, respectively). Maternal height and prepregnancy weight were associated positively with kidney volume at the age of 2 years. Third-trimester fetal head circumference, abdominal circumference, and estimated weight and postnatal length were associated positively with kidney volume at the age of 2 years. Preferential fetal blood flow to the brain was associated with smaller kidneys. LIMITATIONS: Kidney measurements successfully performed in only 86% of children. CONCLUSIONS: Small kidney size in fetal life tends to persist in early childhood. Maternal anthropometrics and fetal biometrics and blood flow patterns are associated with kidney size in childhood. Follow-up studies are needed to examine whether these variations in kidney size are related to kidney function and blood pressure in later life.

Diastolic dysfunction in paediatric patients on peritoneal dialysis and after renal transplantation.

BACKGROUND: Cardiovascular disease is the leading cause of death in children with end-stage renal disease. We investigated the presence of cardiac systolic and diastolic dysfunction in patients on peritoneal dialysis or after renal transplantation. Methods and results. Fourteen patients on peritoneal dialysis for a mean of 1.4 years (range 0.1-5.3) and 39 patients with a functioning kidney transplant for a median time of 3.3 years (range 1.2-14.5) were studied. These patients were compared to 153 age-matched healthy controls. As assessed by echocardiography, both dialysis and transplant patients showed left ventricular dysfunction. Systolic tissue Doppler values were lower as compared to controls. Mitral E/A ratios were significantly lower as well, indicating diastolic dysfunction (transplant 1.82 +/- 0.58 versus 2.15 +/- 0.63, P < 0.01; dialysis patients 1.57 +/- 0.73 versus 2.31 +/- 0.52, P < 0.01). Also, tissue Doppler values were different, showing an increased E/E' ratio in the patients, indicating diastolic dysfunction (transplant 9.49 +/- 1.71 versus 7.50 +/- 1.60, P < 0.01; dialysis patients 11.90 +/- 2.11 versus 8.10 +/- 1.24, P < 0.01). The left ventricular mass index was increased in the transplant patients (controls 25 +/- 7 g/m(2.7); transplant 59 +/- 64 g/m(2.7); P < 0.01), as well as in the dialysis patients (controls 28 +/- 7 g/m(2.7); dialysis 43 +/- 11 g/m(2.7); P < 0.01) and was associated with systolic hypertension (R = 0.46, P < 0.05). High parathyroid hormone (PTH) levels, more prevalent in dialysis patients, were associated with abnormal E/A and E/E' ratios. CONCLUSIONS: Abnormalities in diastolic function are present in both peritoneal dialysis and renal transplanted patients. In the dialysis group, abnormalities in calcium-phosphate metabolism are associated with diastolic dysfunction. Cardiac hypertrophy was noted in both patient groups and was associated with systolic hypertension.

Six-minute walking test in children with ESRD: discrimination validity and construct validity.

The six-minute walking test (6MWT) may be a practical test for the evaluation functional exercise capacity in children with end-stage renal disease (ESRD). The aim of this study was to investigate the 6MWT performance in children with ESRD compared to reference values obtained in healthy children and, secondly, to study the relationship between 6MWT performance with anthropometric variables, clinical parameters, aerobic capacity and muscle strength. Twenty patients (13 boys and seven girls; mean age 14.1 +/- 3.4 years) on dialysis participated in this study. Anthropometrics were taken in a standardized manner. The 6MWT was performed in a 20-m-long track in a straight hallway. Aerobic fitness was measured using a cycle ergometer test to determine peak oxygen uptake (V O(2peak)), peak rate (W(peak)) and ventilatory threshold (VT). Muscle strength was measured using hand-held myometry. Children with ESRD showed a reduced 6MWT performance (83% of predicted, p < 0.0001), irrespective of the reference values used. The strongest predictors of 6MWT performance were haematocrit and height. Regression models explained 59% (haematocrit and height) to 60% (haematocrit) of the variance in 6MWT performance. 6MWT performance was not associated with V O(2peak), strength, or other anthropometric variables, but it was significantly associated with haematocrit and height. Children with ESRD scored lower on the 6MWT than healthy children. Based on these results, the 6MWT may be a useful instrument for monitoring clinical status in children with ESRD, however it cannot substitute for other fitness tests, such as a progressive exercise test to measure V O(2peak) or muscle strength tests.

Reliability of renal ultrasound measurements in children.

The aim of the investigation reported here was to assess the intraobserver and interobserver variability of renal measurements in children. The study comprised 56 paired measurements in 28 children (median age 7.5 years, range 3.0-15.0 years) without renal or ureterovesical anomalies. Intraobserver and interobserver reproducibility was assessed by repeated measurements of the left and right renal length, width, and thickness. Intraclass correlation coefficients (ICCs) with the corresponding 95% confidence interval (CI) were calculated. Bland and Altman plots were computed to assess the agreement of the measurements. Limits of agreement +/- 2 standard deviations (SD) for the mean differences in renal measurements were derived. Intraobserver ICCs ranged from 0.93 (left and right renal width and right renal thickness) to 0.99 (left renal length), and interobserver ICCs ranged from 0.64 (right renal thickness) to 0.90 (right renal length). Limits of agreement in the Bland and Altman plots ranged from -8.0 to 9.2% (intraobserver left renal width) to the widest limit from -18.0 to 19.2% (interobserver left renal length). Overall, this study demonstrated the good reproducibility and agreement of most renal dimensions in children measured by ultrasound (US). Based on these results, we conclude that US is an appropriate measure to assess renal dimensions in both clinical and epidemiological studies.

Pulmonary complaints and lung function after pediatric kidney transplantation.

Recently four of 38 children with a kidney transplant were diagnosed with bronchiectasis. The aim of the current study was to identify patients with increased risk for pulmonary damage. In this cross-sectional observational study, children with a functioning kidney graft in the Netherlands and Antwerp, Belgium, were screened with the use of a symptom checklist and spirometry. Maximum score for upper airway complaints was 21 (normal: <8), for lower airway complaints 28 (<10). Results of FVC, FEV(1) and MEF(25) were expressed as percentage predicted for height and sex. One hundred and thirty-five patients completed the interview (122) and/or spirometry (103); 91 did both. Lower airways symptoms were above acceptable levels in 18 (14%) patients. Forty-nine patients (48%) had an abnormal lung function test: in 12 concerning FVC%, in 11 FEV(1)%, in 24 MEF(25)% and in 36 FEV(1)/FVC. Of correlations between symptomatology or spirometry data, and clinical parameters, only that between GFR and MEF(25)% was statistically significant. Children with a kidney transplant are at increased risk for obstructive lung disease. We recommend to monitor lung function during the follow-up after renal transplantation.

Maintenance immunosuppression with mycophenolate mofetil and corticosteroids in pediatric kidney transplantation: temporary benefit but not without risk.

BACKGROUND: Aiming at reducing cyclosporine toxicity, we investigated safety and efficacy of mycophenolate mofetil (MMF) as an immunosuppressive drug in pediatric kidney transplantation compared with cyclosporine (CsA), both in combination with corticosteroids. METHODS: One year after kidney transplantation, children on triple immunosuppression, having experienced no more than one, steroid-sensitive, acute rejection episode, were randomized to withdrawal of either CsA or MMF and were followed for 2 yr. RESULTS: In each group, two patients had an acute rejection episode during withdrawal. Treatment failure occurred in 3 of 21 MMF and 5 of 23 CsA patients. Final analysis was for 18 patients in either group. A larger than 10 mL/min 1.73 m decrease in glomerular filtration rate was observed in more patients on CsA than on MMF (73% vs. 29%, P=0.019). No differences in blood pressure or nightly decrease of blood pressure were noted. Hypercholesterolism improved in the MMF (-16%), but not the CsA group (+5%, P<0.05), over the first, but not over both study years. Differences in triglycerid levels between groups were not shown. At study end, MMF patients tended to have lower hemoglobin levels than patients on CsA. Two MMF patients experienced a first acute rejection episode during the second study year, resulting in chronic transplant glomerulopathy with graft loss in one and deterioration of kidney function in the other. CONCLUSION: In pediatric kidney transplantation, maintenance immunosuppression with MMF together with corticosteroids has short-term benefits for kidney function and lipid pattern compared with CsA but is not without risk of complications.

Renal function and size at young adult age after intrauterine growth restriction and very premature birth.

BACKGROUND: Premature birth and intrauterine growth restriction may increase the risk of developing renal disease at adult age. Renal function may already be impaired at young adult age. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Very premature individuals (gestational age < 32 weeks) recruited from Project on Premature and Small for Gestational Age Infants and full-term-born controls (37 to 42 weeks) recruited from a children's hospital in Rotterdam, The Netherlands. All individuals were 20 years of age at the time of study. PREDICTORS: Gestational age and birth weight: premature and small for gestational age (SGA; n = 23), premature and appropriate for gestational age (n = 29), and controls (n = 30). OUTCOMES & MEASUREMENTS: Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction before and after renal stimulation with low-dose dopamine infusion and oral amino-acid intake. Urine albumin and renal ultrasound. RESULTS: Height, weight, kidney length and volume, GFR, and ERPF were significantly lower in the SGA group than in controls. After adjustment for body surface area, GFR did not differ significantly among groups. Mean ERPF was 71 mL/min/1.73 m(2) (95% confidence interval [CI], 3 to 139) less, but filtration fraction was only 1.3% (95% CI, -0.3 to 3.0) greater, in the SGA group than controls. Renal stimulation significantly increased GFR and ERPF and decreased filtration fraction in all groups. After renal stimulation, ERPF was 130 mL/min/1.73 m(2) (95% CI, 21 to 238) greater in the SGA group than controls, but GFR and filtration fraction did not differ significantly among groups. Microalbuminuria was present in 2 patients (8.7%) in the SGA group, but none in the appropriate-for-gestational-age group or controls. Renal function correlated with renal size. LIMITATIONS: Small sample size. CONCLUSIONS: Our findings do not fully support the hypothesis that preterm birth in combination with intrauterine growth restriction contributes to renal function alterations at young adult age. Larger studies are needed to evaluate this hypothesis.

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 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.

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.

Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies.

BACKGROUND: Membranous glomerulonephritis is an immune-mediated disease. In a recent case of antenatal membranous glomerulonephritis, we identified neutral endopeptidase (NEP) as the podocyte target antigen of circulating antibodies produced by the mother who failed to express NEP on granulocytes. We aimed to investigate whether the disease could affect other families, to search for mutations in the metallomembrane endopeptidase (MME) gene for NEP, and to analyse the outcome of the antenatal renal insult. METHODS: From three families with a case of neonatal membranous glomerulopathy, we detected mutations by direct sequencing of genomic PCR products. Single nucleotide polymorphism (SNP) analysis was undertaken with five SNPs located in the MME gene. IgG subclasses with anti-NEP activity were determined by western blotting. FINDINGS: In five mothers, we identified two compound heterozygous or homozygous mutations in the MME gene. The first, a 1342C-->T nonsense mutation, was detected in one family. The second, 446delC, was detected in all three families; all chromosomes bearing this mutation had the same alleles for the five SNPs. Severity of neonatal renal disease was determined by the mothers' IgG response to fetal NEP antigens expressed on glomerular podocytes. The oldest affected individual, now aged 20 years, has developed severe chronic renal failure. INTERPRETATION: Truncating mutations in the MME gene are the cause of alloimmunisation during pregnancy. Idiopathic renal failure in early adulthood might be caused by immune-mediated fetal nephron loss. We show that disease caused by fetomaternal alloimmunisation secondary to a genetic defect is not restricted to blood cells. RELEVANCE TO CLINICAL PRACTICE: During pregnancy, the absence of the NEP protein induces an alloimmunisation process against NEP presented by fetal cells, including syncytiotrophoblasts. The fetal podocyte insult and ensuing nephron loss could lead to chronic renal failure in early adulthood. Alloimmunisation against NEP should be considered as a leading cause of membranous glomerulopathy early in life. Concentrations of circulating anti-NEP antibodies should be carefully monitored during subsequent pregnancies, and specific therapeutic approaches developed. This new disease might also account for idiopathic chronic renal failure detected during adolescence, in individuals who can be identified by searching for anti-NEP antibodies in their mother and by MME gene mutation analysis. NEP deficiency should also be considered in patients developing de-novo membranous glomerulopathy after renal transplantation.