• Disturbance in the circadian rhythm of arginine vasopressin secretion is related to nocturnal polyuria in children with enuresis. • Desmopressin is recommended as a treatment for monosymptomatic nocturnal enuresis, working as a vasopressin analogue acting on V2 receptors in the collecting ducts of the kidney. What is New: • Other renal circadian rhythms might play a role in nocturnal polyuria, especially in desmopressin-resistant case.

The European Academy of Paediatrics urges national bodies, paediatric associations and paediatric teaching departments to adopt these training objectives and put them into practice, so that paediatricians will be better prepared in the future to meet the challenge of delivering appropriate and effective healthcare to adolescents.

Introduction: Desmopressin is used for nocturnal enuresis treatment in children. In this study, we investigated the pharmacokinetics of two formulations: a tablet and a lyophilisate, in both fasted and fed children.Methods: Previously published data from two studies (22 children aged 6 to 16 yr and 25 children aged 6 to 13 yr) were analyzed using population pharmacokinetic modeling. A 1-compartment model with first order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect.Results: The final model described the desmopressin plasma concentrations adequately.Formulation and fed state were included as covariates on the relative bioavailability. The lyophilisate was on average 32.1 % more available than the tablet, and fasted children exhibited an average increase in relative bioavailability of 101%, compared to fed children. Body weight was included as a covariate on distribution volume, using a power function with exponent 0.402.Simulations suggest both the formulation and the food effect are clinically relevant. Conclusions:Bioequivalence data of two formulations of the same drug in adults, cannot be readily extrapolated to children. This is the first study in children suggesting that the two desmopressin formulations in children are not bioequivalent at the currently approved dose levels.Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model. Key points Population pharmacokinetic modeling was applied to pediatric desmopressin PK data and used to extract more information out of existing pediatric drug data, generate new information and improve the collection of future information. In this study it was found that the established bioequivalence of desmopressin in adults might be different in the pediatric population. A profound food effect was also quantified. In order to make solid conclusions regarding desmopressin efficacy in children, PK and PD data should be gathered simultaneously in a well-designed study, for which some design suggestions are presented in this paper. Abbreviations

Patients referred to a tertiary enuresis center have a high incidence of hypercalciuria. However, the significant correlation between hypercalciuria and osmolar excretion and diuresis suggests that it is a comorbid factor rather than a primary pathogenic factor. As such, we cannot confirm the data from Italian studies relating nocturnal enuresis to primary hypercalciuria, and suggest instead an association with nutritional intake.

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We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to jumedia@elsevier.com. Abstract PURPOSEAlthough nocturnal polyuria in monosymptomatic enuresis (MNE) can largely be explained by the decreased nocturnal vasopressin secretion hypothesis, other circadian rhythms in the kidney also seem to play a role.Recently we documented an absent day/night rhythm in a subgroup of desmopressin (dDAVP) -refractory patients. The aim of this study was to explore the importance of abnormal circadian rhythm of glomerular filtration (GFR) and tubular (sodium, potassium) parameters in patients with MNE. MATERIALS AND METHODSThis retrospective study of a tertiary enuresis population collected data subsequent to a standardized screening (ICCS questionnaire, diary), 14 days diary for nocturnal enuresis and diuresis, and 24h concentration profile. The study population consisted of 139 children with nocturnal enuresis (NE) at least 5 years of age. The group of NMNE was used as control population for the children with MNE. RESULTSThere was a maintained circadian rhythm of GFR, sodium, osmotic excretion and diuresis-rate in both children with MNE and NMNE and there was no difference between the two groups. Secondary analysis revealed that in patients with nocturnal polyuria (both with MNE and NMNE), circadian rhythm of GFR, sodium, osmotic excretion and diuresis-rate was lost in contrast with patients without nocturnal polyuria (p<0.001). CONCLUSIONSCircadian rhythm of the kidney is not different between NMNE and MNE. However the subgroup of enuresis with nocturnal polyuria has a diminished circadian rhythm of nocturnal diuresis, sodiumexcretion and GFR in contrast with children without nocturnal polyuria. This observation cannot be explained by the vasopressin theory alone.

Urea is the most abundant and the largest contributing factor for urine osmolality. Urinary urea excretion is highly interrelated with dietary protein intake. Accordingly, an increase of urinary urea excretion due to high protein diet may lead to urea-induced osmotic diuresis. This study aims to explore the association between nocturnal polyuria (NP) and urea. This is a post hoc analysis of a prospective observational study of subjects who completed a renal function profile between October 2011 and February 2015 (n = 170). Each subject underwent a 24 h urine collection, which included 8 urine samples collected at 3 h intervals. Urine volume, osmolality, creatinine, urea and sodium were determined. Urinary urea excretion was used to estimate dietary protein intake. Compared to the control group, subjects with NP exhibited significantly higher nighttime urea and sodium excretion. Estimated evening dietary protein intake was correspondingly significantly higher amongst the NP subgroup. Nighttime diuresis rate was positively associated with age and nighttime free water clearance, creatinine clearance, sodium excretion, and urea excretion in NP subjects. Therefore, increased nocturnal urinary urea excretion may reflect an additional important mediator of nocturia owing to excess nocturnal urine production.