Copeptin improves prediction of treatment response in children with monosymptomatic nocturnal enuresis.

OBJECTIVE: One of the main medical treatment options for monosymptomatic nocturnal enuresis (MNE) is the vasopressin analog desmopressin. But not all children respond to desmopressin treatment, and no reliable treatment predictor has yet been established. We hypothesize that plasma copeptin, a surrogate marker for vasopressin, can be used to predict treatment response to desmopressin in children with MNE. DESIGN/METHODS: In this prospective observational study, we included 28 children with MNE. At baseline, we assessed the number of wet nights, morning, and evening plasma copeptin, and plasma sodium and started treatment with desmopressin (120 µg daily). Desmopressin was increased to 240 µg daily if clinically necessary. The primary endpoint was reduction in the number of wet nights following 12 weeks of treatment with desmopressin using plasma copeptin ratio (evening/morning copeptin) at baseline. RESULTS: Eighteen children responded to desmopressin treatment at 12 weeks, while 9 did not. A copeptin ratio cutoff of 1.34 (sensitivity 55.56%, specificity 94.12%, area under the curve 70.6%, P = .07) was best at predicting treatment response, with a lower ratio indicating a better treatment response. In contrast, neither the number of wet nights at baseline (P = .15) nor serum sodium (P = .11) alone or in combination with plasma copeptin improved outcome prediction. CONCLUSIONS: Our results indicate that, of our investigated parameters, plasma copeptin ratio is the best predictor for treatment response in children with MNE. Plasma copeptin ratio could thus be useful to identify children with the highest benefit of desmopressin treatment and improve individualized treatment of MNE.

Randomised placebo-controlled multicentre effectiveness trial of adjunct betamethasone therapy in hospitalised children with community-acquired pneumonia: a trial protocol for the KIDS-STEP trial.

INTRODUCTION: Community-acquired pneumonia (CAP) causes around 10 hospitalisations per 1000 child-years, each associated with an average 13 non-routine days experienced and more than 4 parent workdays lost. In adults, steroid treatment shortens time to clinical stabilisation without an increase in complications in patients with CAP. However, despite promising data from observational studies, there is a lack of high-quality evidence for the use of steroids. METHODS AND ANALYSIS: The KIDS-STEP trial is a multicentre, randomised, double-blind, placebo-controlled superiority trial of betamethasone treatment on outcome of hospitalised children with CAP. Children are enrolled in paediatric emergency departments of hospitals across Switzerland and randomised to adjunct oral betamethasone for 2 days or matching placebo in addition to standard of care treatment. The co-primary outcomes are the proportion of children clinically stable 48 hours after randomisation and the proportion of children with CAP-related readmission within 28 days after randomisation. Secondary outcomes include length of hospital stay, time away from routine childcare and healthcare utilisation and total antibiotic prescriptions within 28 days from randomisation.Each of the co-primary outcomes will be analysed separately. We will test clinical stability rates using a proportion test; to test non-inferiority in readmission rates, we will construct 1-α % CI of the estimated difference and test if it contains the pre-defined margin of 7%. Success is conditional on both tests. A simulation-based sample size estimation determined that recruiting 700 patients will ensure a power of 80% for the study. ETHICS AND DISSEMINATION: The trial protocol and materials were approved by ethics committees in Switzerland (lead: Ethikkommission Nordwest und Zentralschweiz) and the regulatory authority Swissmedic. Participants and caregivers provide informed consent prior to study procedures commencing. The trial results will be published in peer-reviewed journals and at national and international conferences. Key messages will also be disseminated via press and social media where appropriate. TRIAL REGISTRATION NUMBER: NCT03474991 and SNCTP000002864.

Copeptin Kinetics and Its Relationship to Osmolality During Rehydration for Diabetic Ketoacidosis in Children.

CONTEXT: Copeptin is a surrogate marker for arginine vasopressin (AVP) release in response to hyperosmolal stimuli such as diabetic ketoacidosis (DKA). OBJECTIVE: The objective of this work is to characterize kinetics of copeptin and osmolality, and their dynamic relationship during rehydration and insulin therapy in children with type 1 diabetes (T1D) and DKA. DESIGN AND SETTING: A prospective, observational, multicenter study was conducted. PATIENTS AND INTERVENTION: Children with T1D admitted for DKA underwent serial serum copeptin and osmolality measurements from start of rehydration at 14 time points during 72 hours. MAIN OUTCOME MEASURES: Measurements included temporal course of copeptin and osmolality (kinetics), relationship between both (dynamics), and association between-subject variability (BSV) (coefficient of variation, CV%). RESULTS: Twenty-eight children (20 newly diagnosed T1D) aged 1 to 16 years were included. Copeptin decreased from 95 pmol/L (95% CI, 55-136 pmol/L) (CV%, 158%) to 9.7 pmol/L (95% CI, 8.1-11.4 pmol/L) (CV%, 31%) with a 50% recovery time (t1/2) of 7.1 hours (range, 5.1-11.5 hours) (114%). Serum osmolality decreased from 321 mOsm/kg (range, 315-327 mOsm/kg) (4%) to 294 mOsm/kg (range, 292-296 mOsm/kg) (1%) with a t1/2 of 4.3 hours (range, 3.0-5.6 hours) (64%). Copeptin levels doubled with each osmolality increase by 15 mOsm/kg (range, 10-21 mOsm/kg) (59%), from 9.8 pmol/L (range, 7.3-12.3 pmol/L) (48%) to 280 mOsm/kg. Copeptin kinetics differed between newly diagnosed and known T1D patients (P = .001), and less between mild vs moderate-severe DKA (P = .04). CONCLUSIONS: First, this study characterized for the first time copeptin kinetics and dynamics in the high hyperosmolar range in children with DKA. Second, it revealed significant differences in copeptin kinetics between newly diagnosed and known T1D patients that may be explained by changes at the osmoreceptor and renal AVP receptor level due to longstanding osmotic diuresis and DKA.

The Circadian Rhythm of Copeptin, the C-Terminal Portion of Arginine Vasopressin.

BACKGROUND: Several studies have investigated copeptin as a prognostic marker of different acute diseases and as a diagnostic marker in disorders of water and salt homeostasis. However, no data of the normal circadian rhythm of copeptin in healthy subjects are available. AIM: To investigate the circadian rhythm of copeptin in healthy subjects under standardized conditions. METHODS: 19 healthy volunteers aged 18 to 53 years, male and female, were studied in a prospective observational study. In all 19 participants, blood samples for copeptin were taken in regular intervals of 30 minutes for 24 hours after a fasting period of minimum 8 hours. RESULTS: The mean values of copeptin showed a circadian rhythm, similar to that described for AVP release, with a trend towards higher levels (5.9 ± 1 pmol/L) at night and early morning between 4 am and 6 am and lowest levels (2.3 ± 0.2 pmol/L) in the late afternoon between 5 pm and 7 pm. This finding was only observed in individuals with initial higher copeptin levels, whereas in individuals with lower basal copeptin levels no circadian rhythm was observed. CONCLUSION: There is evidence for a circadian rhythm in copeptin release during 24 hours, however, of minor extent. These findings suggest that copeptin levels can be determined irrespectively of the time of the day.

Effect of a test meal on meal responses of satiation hormones and their association to insulin resistance in obese adolescents.

OBJECTIVE: The role of gastrointestinal (GI) hormones in the pathophysiology of obesity is unclear, although they are involved in the regulation of satiation and glucose metabolism. To (i) examine glucagon-like peptide 1 (GLP-1), amylin, ghrelin, and glucagon responses to a meal in obese adolescents and to (ii) test which GI peptides are associated with insulin resistance are presented. METHODS: A total of 16 obese (body mass index (BMI) ≥ 97th percentile for age and gender) and 14 control (BMI between 25th and 75th percentiles) adolescents were included. Subjects were instructed to eat a test meal (490 kcal). Plasma samples were collected for hormone and glucose analysis. RESULTS: Obese adolescents were insulin resistant as expressed by the Homeostasis Model Assessment (HOMA) index and had significantly increased fasting glucagon and amylin levels compared to the control group (P = 0.003 and 0.044, respectively). In response to the meal, the increase in GLP-1 levels was reduced in obese adolescents (P < 0.001). In contrast, amylin secretion was significantly increased in the obese population compared to the control group (P < 0.005). CONCLUSIONS: Obese adolescents have increased fasting glucagon and amylin levels and attenuated post-prandial GLP-1 concentrations compared with the control group. These factors could contribute to the metabolic syndrome.

Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion.

CONTEXT: Glucagon-like peptide-1 (GLP-1) is produced by specialized cells in the gut and secreted in response to carbohydrates and lipids. The mechanisms regulating fat-stimulated GLP-1 release have, however, not been clarified in detail. AIM: We aimed to investigate the effect of intraduodenal (ID) fat hydrolysis on GLP-1 release and test whether the signal is mediated through cholecystokinin (CCK)-1 receptors. DESIGN AND SETTING: Thirty-four healthy, male ambulatory volunteers were studied in three consecutive, randomized, double blind, crossover studies. INTERVENTION: There were three interventions: 1) 12 subjects received an ID fat infusion with or without orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison with vehicle; 2) 12 subjects received ID sodium oleate (C18:1), ID sodium caprylate (C8:0), or ID vehicle; and 3) 10 subjects received ID sodium oleate with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). The effect of these treatments on GLP-1 concentrations and CCK release was quantified. RESULTS: The following results were reached: 1) ID fat induced significant increase in GLP-1 concentrations (P < 0.004), and inhibition of fat hydrolysis by orlistat abolished this effect; 2) sodium oleate significantly stimulated GLP-1 release (P < 0.008), whereas sodium caprylate was ineffective compared with controls; and 3) dexloxiglumide administration abolished the effect of sodium oleate on GLP-1. ID fat or sodium oleate significantly stimulated plasma CCK (P < 0.006 and P < 0.004) compared with saline, whereas sodium caprylate did not. CONCLUSION: Generation of long-chain fatty acids through hydrolysis of fat is a critical step for fat-induced stimulation of GLP-1 in humans; the signal is mediated via CCK release and CCK-1 receptors.