Pathophysiology of hypertension in obese children: a systematic review.

Hypertension is increasingly common in overweight and obese children. The mechanisms behind the development of hypertension in obesity are complex, and evidence is limited. In order to effectively treat obese children for hypertension, it is important to have a deeper understanding of the pathophysiology of hypertension in obese children. The present review summarizes the main factors associated with hypertension in obese children and discusses their potential role in its pathophysiology. Systematic searches were conducted in PubMed and EMBASE for articles published up to October 2014. In total, 60 relevant studies were included. The methodological quality of the included studies ranged from weak to strong. Several factors important in the development of hypertension in obese children have been suggested, including endocrine determinants, such as corticosteroids and adipokines, sympathetic nervous system activity, disturbed sodium homeostasis, as well as oxidative stress, inflammation and endothelial dysfunction. Understanding the pathophysiology of hypertension in overweight and obese children is important and could have implications for its screening and treatment. Based on solely cross-sectional observational studies, it is impossible to infer causality. Longitudinal studies of high methodological quality are needed to gain more insight into the complex mechanisms behind the development of hypertension in obese children.

Disease activity patterns in juvenile systemic lupus erythematosus and its relation to early aggressive treatment.

This study aimed to determine disease activity patterns in juvenile systemic lupus erythematosus (jSLE) and its relation to early treatment. All jSLE patients who visited the outpatient departments of three Dutch university hospitals for at least 6 months were included. Data were retrospectively collected from each patient visit and hospitalization. Patient characteristics, clinical and laboratory findings categorized in organ systems, flare rate, medication use and disease course were analysed. Included were 35 patients (female 77%; White 47%) with a total follow-up of 142 years. Median age at diagnosis was 12.8 years. Flare rate was 0.45/ patient-year. An organ system not earlier involved was affected in 34% of flares. Identifiable disease activity patterns were: chronic active (49%), relapse remitting (14%) and long quiescence (37%), with no significant difference in organ involvement at diagnosis. Positive anti-Sm and non-White ethnicity were significantly associated with a chronic active pattern. In 14 patients with severe symptoms at diagnosis, treatment with intravenous cyclophosphamide and/or biologics and/or intravenous methylprednisone in the first 6 months resulted in a long quiescence pattern in seven patients. In conclusion, distinct disease activity patterns are identifiable in children. Suppression of disease with early aggressive treatment may decrease the rate of progression.

Is screening for renal anomalies warranted in neonates with isolated single umbilical artery?

AIM: To determine the prevalence of renal anomalies in patients with an isolated single umbilical artery (SUA). METHODS: We performed a retrospective study of all renal ultrasound examinations assessed at our centre between January 1998 and December 2008 in neonates with SUA with or without associated anomalies. RESULTS: Renal ultrasound examination was performed in 65 neonates with SUA (57 neonates with isolated SUA and 8 neonates with nonisolated SUA). The prevalence of renal anomalies in the group with and without isolated SUA was 2% (1/57) and 38% (3/8), respectively. Only one patient with isolated SUA had a mild renal abnormality without clinical consequences. CONCLUSIONS: The prevalence of renal anomalies in neonates with isolated SUA is low. We suggest that routine ultrasound screening for renal anomalies is not warranted in neonates with isolated SUA.

A 3-year old girl with seizures, hypokalemia and metabolic alkalosis.

A 3-year-old girl presented to the emergency department with seizures, low-grade fever and vomiting. She had tachycardia and a slow capillary refill. Blood pressure could not be measured. Because of suspected sepsis and/or meningo-encephalitis, broad spectrum antibiotics and antiviral medication were given together, along with volume expansion and anticonvulsive therapy. A few hours later, after a second seizure, the blood pressure was extremely high (156/116 mm Hg). The girl was treated with anticonvulsants and intravenous antihypertensive agents. MRI of the brain showed signs of posterior reversible encephalopathy syndrome. Cultures of blood and cerebrospinal fluid remained sterile. Further investigation into the cause of the malignant hypertension revealed hypokalemia, metabolic alkalosis and extremely high plasma renin activity, caused by a rare renal abnormality: bilateral renal segmental hypoplasia or Ask-Upmark kidneys.

Long-term renal function after hemopoietic stem cell transplantation in children.

Glomerular function of all long-term survivors who underwent hemopoietic stem cell transplantation (HSCT) from 1991 to 1998 (study I, n=121) was studied retrospectively. In addition, we prospectively analyzed glomerular and tubular function of all long-term surviving children who received an HSCT between 1998 and 2000 (study II, n=41). We found a lower prevalence of children with chronic renal failure (CRF) post-HSCT in our more recent cohort (study II: 10%) as compared to the older cohort (study I: 24%) 5.0 (0.7 s.d.) and 7.6 (2.4 s.d.) year's post-HSCT, respectively. Furthermore, it seems that renal function may stabilize after 1-year post-HSCT. None of the patients required dialysis or antihypertensive medication at long-term follow-up. The sole predictor of CRF in our study was high serum creatinine pre-HSCT (P=0.007), while acute renal failure within 3 months after HSCT (P=0.08) only showed a trend towards predicting CRF. We could not confirm a relation of conditioning with irradiation with CRF post-HSCT, as was shown in several other pediatric and adult studies. Proximal and distal tubular dysfunction only occurred in a minority of long-time survivors of HSCT (3-12 and 9-13%, respectively) and had no clinical consequences.

Modulation of calcium oxalate monohydrate crystallization kinetics by urine of preterm neonates.

Preterm neonates frequently develop nephrocalcinosis (NC). However, the cause has not yet been elucidated. This study focuses on the effects of urine from preterm neonates on crystallization kinetics. Urine samples were collected and renal ultrasound examinations of preterm neonates (gestational age < 32 weeks) were performed during the first weeks of life, at term, and ages 6, 12, and 24 months. The effect of urine on crystallization was determined using a seeded crystal growth system, which measures the square root of solubility product ( radicalLc), percentage of growth inhibition (GI), and agglomeration inhibition ([tm]) of calcium oxalate crystals. Data for preterm neonates in the first weeks of life (n = 19) were compared with those for full-term neonates (n = 17) and healthy adults. Moreover, the correlation between [tm] and urinary (U)citrate level was studied. Mean radicalLc (0.27 +/- 0.1 versus 0.36 +/- 0.08 mmol/L) and mean [tm] (81 +/- 32 versus 143 +/- 97 minutes) were lower and mean Ucalcium-creatinine (2.20 +/- 1.74 versus 0.46 +/- 0.73 mol/mol) and Uoxalate-creatinine ratios (0.39 +/- 0.21 versus 0.16 +/- 0.09 mol/mol) were greater in preterm neonates in the first weeks of life compared with full-term neonates (p < 0.05). Furthermore, [tm] was less than the lower limit for healthy adults for all but one preterm neonate; [tm] increased and Ucalcium-creatinine and Uoxalate-creatinine ratios decreased with age (p < 0.005). There was a correlation between [tm] and citrate excretion (coefficient of 38; P < 0.001). Patients with and without NC at term did not differ statistically in mean radicalLc, percentage of GI, or [tm]. In conclusion, urine from preterm neonates in the first weeks of life is highly supersaturated and has a defective ability to inhibit calcium oxalate crystal agglomeration. This ability improves with age and is citrate mediated. We suggest that both the high level of supersaturation and defective ability to inhibit calcium oxalate crystal agglomeration contribute to the high incidence of NC.

Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery.

OBJECTIVE: The commonly used continuous intravenous (i.v.) furosemide dosing schedule after cardiac surgery in children is largely empirical and may not be optimal. This may even be more marked in children after cardiac surgery who are haemodynamically unstable, and in whom transient renal insufficiency may occur. A study was performed to obtain an impression regarding which clinically applicable measures may be used to design a rational scheme for continuous i.v. furosemide therapy in children after cardiac surgery. SUBJECTS AND METHODS: Twelve paediatric patients (5F/7 M, age 0-33 weeks) post-cardiac surgery, who were to receive 3 days of continuous i.v. furosemide treatment, were included in an open study. Blood and urine samples were taken for furosemide, creatinine, and electrolyte levels, and fractionated urinary output was measured. Furosemide in blood and urine was measured using high performance liquid chromatography (HPLC). RESULTS: The mean starting dose of continuous i.v. furosemide was 0.093 (+/- 0.016) mg/kg per hour. The mean dose was increased to 0.175 (+/- 0.045) mg/kg per hour per hour on day 2, and changed to 0.150 (+/- 0.052) mg/kg per hour on day 3. Infusion rates were increased from day 1 to day 2 in ten cases, and decreased from day 2 to day 3 in three cases. Serum furosemide levels never exceeded ototoxic levels. The urinary furosemide excretion rate was inversely related to serum creatinine levels. CONCLUSIONS: This study extends the observation of the beneficial effects of continuous i.v. furosemide also to those children who are haemodynamically unstable after cardiac surgery. However, as the effects of furosemide are dependent on renal function, it can be hypothesised that the dosing schedule may be optimised. Contrary to the currently used dosage schedule in which the dose of furosemide is gradually increased over time, it may be more rational to start with a higher dose and adapt this dose (downward) guided by the observed effect (urine output). Because the infusion rate was increased to 0.2 mg/kg per hour in nine out of 12 patients on day 2 and was never increased further, this suggests that a starting rate of 0.2 mg/kg per hour may be optimal.

Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo.

We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.

Etiology of nephrocalcinosis in preterm neonates: association of nutritional intake and urinary parameters.

BACKGROUND: Nephrocalcinosis (NC) in preterm neonates has been described frequently, and small-scale studies suggest an unfavorable effect on renal function. The etiologic factors have not yet been fully clarified. We performed a prospective observational study to identify factors that influence the development of NC. METHODS: The study population consisted of 215 preterm neonates with a gestational age <32 weeks. Clinical characteristics and intake in the first four weeks of calcium, phosphorus, vitamin D, protein, and ascorbic acid were noted. Serum calcium, phosphate, vitamin D, magnesium, uric acid, creatinine, urea and urinary calcium, phosphate, oxalate, citrate, magnesium, uric acid, and creatinine were assessed at four weeks of age and at term. Renal ultrasonography (US) was performed at four weeks and at term. At term was defined as a postconceptional age of 38 to 42 weeks. RESULTS: NC was diagnosed by means of US in 33% at four weeks and in 41% at term. Patients with NC at four weeks had a significantly higher mean intake of calcium (P < 0.05), phosphorus (P < 0.05), and ascorbic acid (P < 0.01) than patients without NC. They had a higher mean serum calcium (2.55 vs. 2.46 mmol/L, P < 0.01) and a higher mean urinary calcium/creatinine ratio (2.6 vs. 2.1 mmol/mmol, P < 0.05). Patients with NC at term had a lower birth weight (1142 vs. 1260 g, P < 0.05) and a lower gestational age (28.8 vs. 29.4 weeks, P < 0.05), were treated significantly longer with furosemide, dexamethasone, theophylline, and thiazides, developed chronic lung disease more frequently (40 vs. 16%, P < 0.001), and had a higher mean urinary calcium/creatinine ratio (2.7 vs. 2.3 mmol/mmol, P < 0.05) and a lower mean urinary citrate/calcium ratio (1.1 vs. 1.7 mmol/mmol, P = 0.005). CONCLUSIONS: NC develops as a result of an imbalance between stone-inhibiting and stone-promoting factors. A high intake of calcium, phosphorus, and ascorbic acid, a low urinary citrate/calcium ratio, a high urinary calcium/creatinine ratio, immaturity, and medication to prevent or treat chronic lung disease with hypercalciuric side effects appear to contribute to the high incidence of NC in preterm neonates.

Ultrasonographic features of nephrocalcinosis in preterm neonates.

Nephrocalcinosis (NC) in preterm neonates has been reported frequently and small studies suggest an unfavourable effect on renal function. Data on ultrasonic features are limited and the reproducibility of ultrasonography (US) in detecting NC in preterm neonates is unknown. In this study, interobserver and intraobserver agreement of US was determined through videotape recordings of US examinations of preterm neonates. Furthermore, a prospective US study was performed in 215 preterm neonates (gestational age < 32 weeks) to evaluate ultrasonic characteristics, incidence, time course and effect on kidney length of NC. Patients were studied at 4 weeks after birth and at term. Patients with NC were followed for 2 years. NC was defined as bright reflections in the medulla or cortex seen in both transverse and longitudinal direction. The length of the kidneys was noted. The kappa value was 0.84 for intraobserver and 0.46 for interobserver agreement, whereas the overall agreement was 73%. NC was found in 50 of 150 (33%) patients at 4 weeks and in 83 of 201 patients (41%) at term. NC was localized mainly in the medulla. At 1 and 2 years, NC had persisted in 36% and 26%, respectively, of the patients with NC at term. Kidney length was comparable with normal values. In conclusion, US has a very good intraobserver agreement but a moderate interobserver agreement in detecting NC. Medullary NC is common among preterm neonates. During the first 2 years of life, the incidence decreases spontaneously and NC does not influence kidney length.

[Dehydration due to gastro-enteritis in children]. / Dehydratie ten gevolge van gastro-enteritis bij kinderen.

Gastroenteritis is the commonest cause of dehydration in children. Infants and young children dehydrate more easily than adults if fluid intake is insufficient or fluid loss too high because of the combination of a large extracellular volume, a large insensible loss and a mediocre concentrating capacity of the kidney. Fluid loss due to gastroenteritis is often accompanied by electrolyte and acid-base disturbances. Oral rehydration with oral rehydration salts (ORS) is nearly always possible. Re-evaluation after 6 hours is advised especially in young children. Early (< 6-24 hours) resumption of feeding is important. If rehydration with frequent small amounts of ORS at home fails, continuous nasogastric tube feeding in the hospital is a good alternative. In dehydration exceeding 10% of body weight intravenous rehydration is necessary.

Bone marrow transplantation in children: consequences for renal function shortly after and 1 year post-BMT.

The aim of this study was to investigate the effect of a bone marrow transplantation (BMT) on renal function in children. In a 5-year period, 142 children received a BMT at the Department of Pediatrics of the University Hospital Leiden. The study was performed retrospectively using the estimated glomerular filtration rate before and 1 year after BMT, and weekly measurements of serum creatinine during the first 3 months after BMT for assessment of renal function. Patient characteristics (sex, age, diagnosis), conditioning regimen, type of BMT, major complications (sepsis, veno-occlusive disease and graft-versus-host disease (GVHD)) and the use of nephrotoxic medication were listed. In the first 3 months after BMT 17 (12%) patients died, 13 from transplant-related complications other than renal failure and four from relapse of the disease. Forty-eight children (34%) had a period with acute renal insufficiency. A high pre-BMT serum creatinine, transplantation with either a non-HLA-identical related or a matched unrelated donor were risk factors for acute renal insufficiency after BMT. Sepsis and the use of intravenous vancomycin were risk factors for acute renal insufficiency only for patients with a high pre-BMT serum creatinine. GVHD seemed to have a beneficial effect on renal function of BMT recipients. One year after BMT a total of 35 (25%) patients had died, 16 from transplant-related complications and 19 from relapse of the disease; another 17 patients could not be evaluated. Twenty-five of 90 evaluable children (28%) had chronic renal insufficiency. Chronic renal insufficiency 1 year after BMT was correlated with a high serum creatinine in the first 3 months after BMT. None of the children of this retrospective study on renal function after BMT needed dialysis.

Bone mineral density, bone metabolism and body composition of children with chronic renal failure, with and without growth hormone treatment.

OBJECTIVE: Osteopenia has been reported in adult patients with chronic renal failure (CRF). Only a few studies have been performed in children. The objective of this study was to evaluate bone mineral density (BMD), bone turnover, body composition in children with CRF and to study the effect of GH on these variables. DESIGN: Two groups were identified: patients with growth retardation who received GH (GH-group) and patients most of whom were not growth retarded who did not receive GH (no-GH-group). After an observation period of 6 months, the patients in the GH-group started GH treatment. Patients were studied every 6 months during 18 months. PATIENTS: Thirty-six prepubertal patients (27 boys and 9 girls), mean age 7.9 years, with CRF participated in the study. The GH-group consisted of 17 patients of whom 14 completed one year treatment. The no-GH-group consisted of 19 patients, of whom 16 were followed for 6 months, 14 for 12 months and 13 for 18 months. MEASUREMENTS: Lumbar spine BMD, total body BMD and body composition were assessed by dual energy X-ray absorptiometry, compared to age-and sex-matched reference values of the same population and expressed as standard deviation scores (SDS). BMD of appendicular bone was measured by quantitative microdensitometry (QMD). Blood samples were obtained to assess bone metabolism and growth factors. RESULTS: Baseline mean lumbar spine and total body BMD SDS of all patients were not significantly different from normal. Mean lumbar spine and total body BMD SDS did not change significantly in the GH-group during GH treatment. The change of QMD at the midshaft during the first 6 months of GH treatment was significantly smaller than during the observation period (P < 0.01). Height SDS and biochemical markers of both bone formation and bone resorption increased significantly during GH treatment; 1,25-dihydroxyvitamin D remained stable. Lean tissue mass increased (P < 0.001) and percentage body fat decreased (P < 0.01) during GH treatment. BMD, the biochemical markers of bone turnover which are independent of renal function, and body composition remained stable in the no-GH-group. CONCLUSIONS: Mean lumbar spine and total body BMD of children with chronic renal failure did not differ from healthy controls. The lack of a GH-induced increase in 1,25-dihydroxyvitamin D levels, probably due to treatment with alpha-calcidol, might be linked to the absence of a response in BMD during GH treatment in children with chronic renal failure.