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Early diagnosis and treatment of congenital nephrogenic diabetes insipidus (CNDI) are essential due to the risk of intellectual disability caused by repeated episodes of dehydration and rapid rehydration. Timely genetic testing for disease-causing variants in the arginine vasopressin receptor 2 (AVPR2) gene is possible in at-risk newborns with a known family history of X-linked CNDI. In this study, a Swedish male with no family history was diagnosed with CNDI at 6 months of age during an episode of gastroenteritis. We analyzed the coding regions of AVPR2 by PCR and direct DNA sequencing and identified an 80-bp duplication in exon 2 (GenBank NM_000054.4; c.800_879dup) in the proband. This variant leads to a frameshift and introduces a stop codon four codons downstream (p.Ala294Profs*4). The variant gene product either succumbs to nonsense-mediated decay or is translated to a truncated nonfunctional vasopressin V2 receptor. This variant was absent in four unaffected family members, including his parents, as well as in 100 alleles from healthy controls, and is thus considered a novel de novo disease-causing variant. Identification of the disease-causing variant facilitated precise diagnosis of CNDI in the proband. Furthermore, it allows future genetic counseling in the family. This case study highlights the importance of genetic testing in sporadic infant cases with CNDI that can occur due to de novo variants in AVPR2 or several generations of female transmission of the disease-causing variant.

Udgivelsesdato: 2009-null OBJECTIVE: Renal involvement in Henoch-Schönlein purpura (HSP) constitutes a risk of end-stage renal disease (ESRD), especially in patients presenting with nephrotic syndrome. PATIENTS AND METHODS: The clinical courses of six patients (mean age 13.2 years; four boys and two girls) admitted from 2000 to 2007 with HSP and nephrotic syndrome were reviewed. Average follow-up was 44 months (28-59). Treatment protocols included oral prednisolone and in non-responders cyclosporin A, cyclophosphamide, mycophenolate mofetil or tacrolimus. Five patients were treated immediately after presentation of nephrotic syndrome/nephrotic range proteinuria (median 277 mg/m(2)/h). The last patient was treated locally with low-dose prednisolone (0.2-0.9 mg/kg/day) and 3 months of low-dose cyclophosphamide (1 mg/kg/day). RESULTS: All five patients treated promptly with high-dose immunosuppressant had normal estimated glomerular filtration rate (eGFR) (median 159 ml/min/1.73 m(2)) at follow-up. One obtained complete remission, two had positive dipstick proteinuria and two needed angiotensin-converting enzyme inhibitors to stay normotensive. The patient receiving low-dose immunosuppression at onset progressed to ESRD 44 months later. At initial presentation eGFR, blood pressure, renal biopsy grading, proteinuric range and plasma albumin were similar in all patients. CONCLUSION: Follow-up data from the patients suggest that an early aggressive immunosuppressive approach improves long-term renal outcome in HSP patients with nephrotic syndrome.

BACKGROUND: Obesity is associated with metabolic derangement and non-alcoholic fatty liver disease (NAFLD). Macrophages are involved in liver inflammation and fibrosis, and soluble (s)CD163 is a macrophage activation marker.OBJECTIVES: To associate sCD163 with parameters of paediatric obesity and NAFLD, as well as changes in these parameters during lifestyle intervention.METHODS: We studied 117 obese children during a 10-week lifestyle intervention; 71 completed the 12-month follow-up. We recorded clinical and biochemical data, and performed liver ultrasonography.RESULTS: Baseline sCD163 was higher in children with elevated alanine transaminase (ALT) (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1) , P = 0.03), steatosis (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1) , P = 0.01) and high paediatric NAFLD fibrosis index (2.3 ± 0.7 vs. 1.9 ± 0.6 mg L(-1) , P = 0.03). Baseline sCD163 was independently associated with ALT, cholesterol and high-sensitivity C-reactive protein (hs-CRP). The change in sCD163 during lifestyle intervention was associated with changes in ALT, homeostatic model assessment of insulin resistance (HOMA-IR), hs-CRP and cholesterol, and inversely associated with the change in high-density lipoprotein cholesterol.CONCLUSION: sCD163 was associated with markers of liver injury and metabolic parameters in obese children, and changes in these parameters during lifestyle intervention. This may suggest that activated macrophages play a role in NAFLD and sCD163 may serve as a marker of liver disease severity and treatment effect.

We investigated the influence of sex and puberty stage on circadian urine production and levels of antidiuretic hormone [arginine vasopressin (AVP)] in healthy children. Thirty-nine volunteers (9 prepuberty boys, 10 prepuberty girls, 10 midpuberty boys, and 10 midpuberty girls) were included. All participants underwent a 24-h circadian inpatient study under standardized conditions regarding Na+and fluid intake. Blood samples were drawn every 4 h for measurements of plasma AVP, serum 17-β-estradiol, and testosterone, and urine was fractionally collected for measurements of electrolytes, aquaporin (AQP)2, and PGE2. We found a marked nighttime decrease in diuresis (from 1.69 ± 0.08 to 0.86 ± 0.06 ml·kg−1·h−1, P < 0.001) caused by a significant nighttime increase in solute-free water reabsorption (TcH2O; day-to-night ratio: 0.64 ± 0.07, P < 0.001) concurrent with a significant decrease in osmotic excretion (day-to-night ratio: 1.23 ± 0.06, P < 0.001). Plasma AVP expressed a circadian rhythm ( P < 0.01) with a nighttime increase and peak levels at midnight (0.49 ± 0.05 pg/ml). The circadian plasma AVP rhythm was not influenced by sex ( P = 0.56) or puberty stage ( P = 0.73). There was significantly higher nighttime TcH2O in prepuberty children. This concurred with increased nighttime urinary AQP2 excretion in prepuberty children. Urinary PGE2exhibited a circadian rhythm independent of sex or puberty stage. Levels of serum 17β-estradiol and testosterone were as expected for sex and puberty stage, and no effect on the AVP-AQP2-TcH2O axis was observed. This study found a circadian rhythm of plasma AVP independent of sex and puberty stage, although nighttime TcH2O was higher and AQP2 excretion was more pronounced in prepuberty children, suggesting higher prepuberty renal AVP sensitivity.

AIMS: Desmopressin is a useful treatment for primary nocturnal enuresis (PNE), a common childhood condition that can persist into adolescence. This open-label, randomised, cross-over study evaluated the preference of children and adolescents with PNE for sublingual desmopressin oral lyophilisate (MELT) vs. tablet treatment, and the efficacy, safety, compliance and ease of use associated with each formulation. In total, 221 patients aged 5-15 years who were already receiving desmopressin tablets were randomised 1 : 1 to receive desmopressin treatment in the order MELT/tablet (n = 110) or tablet/MELT (n = 111) for 3 weeks each. Each formulation was administered in bioequivalent doses (0.2/0.4 mg tablets identical with 120/240 microg MELT). Following treatment, patients were questioned regarding treatment preference. Diary card data and 100 mm Visual Analogue Scale scores were also recorded. RESULTS: Overall, patients preferred the MELT formulation to the tablet (56% vs. 44%; p = 0.112). This preference was age dependent (p = 0.006); patients aged < 12 years had a statistically significant preference for desmopressin MELT (p = 0.0089). Efficacy was similar for both formulations (MELT: 1.88 +/- 1.94 bedwetting episodes/week; tablet: 1.90 +/- 1.85 episodes/week). Ease of use of both formulations was high. Compliance (> or = 80%) was 94.5% for MELT patients vs. 88.9% for the tablet (p = 0.059). No serious/severe adverse events were reported. CONCLUSIONS: There was an overall preference for the MELT, and a statistically significant preference for desmopressin MELT in children aged 5-11 years. Desmopressin MELT had similar levels of efficacy and safety at lower dosing levels than the tablet, and therefore facilitates early initiation of PNE treatment in children aged 5-6 years. Udgivelsesdato: 2007-Sep

The urine-concentrating mechanism performs one of the most essential functions in water and electrolyte metabolism and serves primarily to maintain extracellular osmolality within a very narrow range. The history of anti-diuresis dates back more than 100 years and includes the discovery of antidiuretic hormone (AVP), the renal AVP receptor, and most recently the water channel (aquaporin) proteins. Today, the mechanisms of antidiuresis are understood on a highly detailed molecular level including both short term and long-term regulation of AQP2 function. Furthermore, the background behind many acquired and inherited disturbances of water balance has now been revealed and has enabled a precise differential diagnosis. These include different forms of diabetes insipidus, nocturnal enuresis and nocturia in the elderly. Diabetes insipidus represents a dramatic but rare disturbance of water balance caused by deficient AVP secretion (neurogenic), reduced renal sensitivity to AVP (nephrogenic), an abnormally high fluid intake (primary polydipsia), or in rare cases by placental enzymatic degradation of AVP (gestational). Nocturnal enuresis and nocturia in the elderly represents much more common disturbances and share common pathogenic features including an abnormally high nocturnal urine production. This seems at least in part to be caused by abnormally low levels of plasma AVP during night. The increased understanding of such water balance disturbances have changed dramatically prior treatment practice by introducing antidiuresis as a treatment modality. The ongoing progress in our understanding of antidiuresis may provide the basis for the development of new antidiuretic compounds. Udgivelsesdato: 2007-Sep