Discontinuing absorbent pants in children with bedwetting: a randomized controlled trial.

The objective of this study is to examine the effect of discontinuing wearing protective garments (absorbent pyjama pants - APP) in children with severe childhood nocturnal enuresis (NE). The study employs a multicenter, parallel, randomized controlled trial. Following a 4-week run-in period, participants were randomly allocated in a 2:1 group allocation to discontinue or continue using APP. The research was conducted across seven European pediatric incontinence centers. The study included treatment-naïve children aged 4-8 years with severe (7/7 wet nights per week) mono-symptomatic NE, who had used nighttime protection for at least 6 months prior to the study. The study consisted of a 4-week run-in period (± 7 days), where all children slept wearing APP (DryNites®). At week 4 (± 7 days), if meeting randomization criteria (7/7 wet nights during the last week of run-in), participants were randomized to continue to sleep in APP or to discontinue their use for a further 4 weeks, with the option of another 4 weeks in the extension period. The primary outcome was the difference between groups of wet nights during the last week of intervention. Quality of life (QoL) and sleep were secondary endpoints. In total, 105 children (43 girls and 62 boys, mean age 5.6 years [SD 1.13]) were randomized (no-pants group n = 70, pants group n = 35). Fifteen children (21%) in the no-pants group discontinued early due to stress related to the intervention. Children in the no-pants group experienced fewer wet nights compared to the pants group during the last week (difference 2.3 nights, 95% CI 1.54-3.08; p < 0.0001). In the no-pants group, 20% responded to the intervention, of whom 13% had a full response. Clinical improvement was detected within 2 weeks. Sleep and QoL were reported as negatively affected by APP discontinuation in the extension period but not in the core period.    Conclusion: A ~ 10% complete resolution rate was associated with discontinuing APP. While statistically significant, the clinical relevance is debatable, and the intervention should be tried only if the family is motivated. Response was detectable within 2 weeks. Discontinuing APP for 4-8 weeks was reported to negatively affect QoL and sleep quality. No severe side effects were seen.Trial registration: Clinicaltrials.gov Identifier: NCT04620356; date registered: September 23, 2020. Registered under the name: "Effect of Use of DryNites Absorbent Pyjama Pants on the Rate of Spontaneous Resolution of Paediatric Nocturnal Enuresis (NE)."

GFR measurements and ultrasound findings in 154 children with a congenital solitary functioning kidney.

BACKGROUND: Multicystic dysplastic kidney (MCDK) and unilateral renal agenesis (URA) are the most common reasons for a congenital solitary functioning kidney (SFK). We aimed to assess the presence of abnormalities in the congenital SFK and evaluate kidney function using chrome EDTA (CrEDTA) measurements. METHODS: We retrospectively reviewed the medical records of 154 children with MCDK and URA in the period from 2005 to 2022 to analyze results from ultrasound scans and CrEDTA glomerular filtration rate (GFR) examinations. RESULTS: Of 154 children with a solitary kidney due to MCDK (62%) or URA (38%), abnormalities on the congenital SFK were found in 13 children (8%). The abnormalities spontaneously resolved in 6 children (46%). The most common abnormality was hydronephrosis. Compensatory hypertrophy was found in 17% of the children within the first 6 months of life. 116 children (90%) had a standard GFR (sdGFR) above 75% of expected for the age. Out of those with a sdGFR below 75% of expected, 3 (23%) had abnormalities in the congenital SFK. There was no difference in sdGFR between children with MCDK and URA. CONCLUSIONS: Our study is the first using CrEDTA for GFR measurements and suggests that most children with a congenital SFK due to MCDK or URA have a kidney function within expected for the age. Compensatory hypertrophy of the SFK is found in a minority of children within the first six months of life, suggesting that this process is developing over time. The prevalence of abnormalities in the SFK seems low, however those with abnormalities (e.g. hydronephrosis) are at higher risk of reduced sdGFR.

Differences in the urinary metabolome and proteome between wet and dry nights in children with monosymptomatic nocturnal enuresis and nocturnal polyuria.

BACKGROUND: Nocturnal enuresis (NE) is a common disease with multiple pathogenic mechanisms. This study aimed to compare levels of metabolites and proteins between wet and dry nights in urine samples from children with monosymptomatic NE (MNE). METHODS: Ten boys with MNE and nocturnal polyuria (age: 7.6 ± 1.3 years) collected their total nighttime urine production during a wet and a dry night. Untargeted metabolomics and proteomics were performed on the urine samples by liquid chromatography coupled with high-mass accuracy tandem mass spectrometry (LC-MS/MS). RESULTS: On wet nights, we found reduced urine osmolality (P = 0.025) and increased excretion of urinary potassium and sodium by a factor of, respectively, 2.1 (P = 0.038) and 1.9 (P = 0.19) compared with dry nights. LC-MS identified 59 metabolites and 84 proteins with significantly different levels between wet and dry nights (fold change (FC) < 0.67 or > 1.5, P < 0.05). Some compounds were validated by different methodologies. During wet nights, levels of compounds related to oxidative stress and blood pressure, including adrenalin, were increased. We found reduced levels of aquaporin-2 on wet nights. The FCs in the 59 metabolites were positively correlated to the FCs in the same metabolites identified in urine samples obtained during the evening preceding wet and dry nights. CONCLUSIONS: Oxidative stress, which in the literature has been associated with nocturia and disturbances in sleep, might be increased during wet nights in children with MNE. We further found evidence of increased sympathetic activity. The mechanisms related to having wet nights in children with MNE seem complex, and both free water and solute handling appear to be important. A higher resolution version of the Graphical abstract is available as Supplementary information.

Successful low-dose immunotherapy after kidney transplantation in a 10-year-old girl with Schimke immuno-osseous dysplasia.

BACKGROUND: This case report highlights a successful steroid-free, low-dose immunosuppressive protocol for renal transplantation in a pediatric patient with Schimke immuno-osseous dysplasia with excellent 7-year patient and graft survival. Schimke immuno-osseous dysplasia is a rare multisystem disorder involving the kidney. Renal transplantation is a therapeutic option, but posttransplant mortality is high due to severe infections and posttransplant lymphoproliferative disease. METHODS: A 10-year-old girl diagnosed with Schimke immuno-osseous dysplasia and end-stage renal disease underwent an AB0-compatible living-related kidney transplantation, with no donor-specific antibodies. Our standard immunosuppression protocol was modified due to the risk of infection. Basiliximab was used as induction therapy, and a reduced dose of mycophenolate mofetil and tacrolimus was initiated following transplantation, maintaining the patient on a low tacrolimus target (3-5 µg/L). Mycophenolate mofetil was discontinued after 8 weeks due to neutropenia and the patient was kept on tacrolimus as monotherapy. Five years posttransplant the patient developed acute onset of neurological symptoms, consisting of ataxia, lack of voluntary coordination, balance, aphasia and dysphagia, and diplopia. She recovered without neurological deficits within 6 weeks. Extensive evaluation revealed no pathology. To avoid a possible a component of tacrolimus-induced cerebral vasoconstriction, the immunosuppressive therapy was changed to everolimus. RESULTS: Seven years posttransplant, the patient has experienced no serious infections, no rejections, and had excellent graft function, and no de novo donor-specific antibodies. CONCLUSIONS: The present results indicate that low-dose immunosuppressive therapy after renal transplantation with low immunological risk should be considered for patients with Schimke immuno-osseous dysplasia.

The genetics of incontinence: A scoping review.

The genetic causes underlying incontinence in both children and adults have begun to be unravelled during the last decades. The aim of this scoping review is to synthesize current knowledge on the genetics of childhood and adult urinary and faecal incontinence, identify similarities between different incontinence subgroups, and identify knowledge gaps to aid future research. PRISMA-ScR was used, and 76 studies were included. Early epidemiological family and twin studies suggest high heritability of incontinence. Linkage studies provide evidence for the existence of rare genetic variants; however, these variants have not been identified. Later candidate gene association studies and recent genome-wide association studies provide the first preliminary evidence that common risk variants also play a role. The genetics of incontinence in children and adults has predominantly been studied separately, but this review identifies for the first time the endothelin system as a potential common pathophysiological pathway. Overall, these findings strengthen the hypothesis that genetic variants play a prominent role in the pathogenesis of incontinence. Future research should include hypothesis-free studies of rare and common variants in large well-characterized cohorts with incontinence. Studies should include different age groups and ethnicities and both sexes to fully reveal the genetics of incontinence.

The efficacy of standard urotherapy in the treatment of nocturnal enuresis in children: A systematic review.

INTRODUCTION: Standard urotherapy in children with nocturnal enuresis (NE) is first-line treatment according to the current International Children's Continence Society (ICCS) guidelines. ICCS defines standard urotherapy as information and demystification, instruction in how to resolve lower urinary tract dysfunction, lifestyle advice, registration of symptoms and voiding habits, and support and encouragement. These interventions often are time consuming and some aspects of urotherapy, such as fluid restrictions, can be a frustrating process for a child, which emphasizes the importance of clarifying their relevance. The purpose of this review is to perform a systematic search in literature to evaluate the use of standard urotherapy in the treatment of children with primary NE (PNE). STUDY DESIGN: A systematic literature search was conducted in MEDLINE, Embase, and CENTRAL based on the key concepts of standard urotherapy and NE. We identified 2,476 studies. After a systematic selection process using the Covidence tool, 39 studies were included. The quality of the studies was assessed by the QualSyst Checklist. Our protocol adheres to the PRISMA statement and was registered in PROSPERO database (CRD42020185611). RESULTS: Most of the 39 included studies scored low in quality. All studies combined several urotherapy interventions and studied different study populations. Twenty-two randomized controlled trials (RCTs) were included, which reported 0-92% of children being dry after urotherapy treatment. Three RCTs, all individualizing and optimizing drinking and voiding during the day and practicing optimal toilet posture, scored higher in quality based on the QualSyst score, and reported few children experiencing complete resolution of NE (5-33%). Eight studies compared the efficacy of urotherapy to a control group, however, conflicting results were found. DISCUSSION: This systematic review presents available literature in the field of standard urotherapy in the treatment of children with PNE. One possible explanation for low efficacy rates of urotherapy in NE is the large heterogeneity of the study populations and interventions. Additionally, the intervention period and the intensity of intervention can have an impact on the outcome. CONCLUSION: The number of clinical studies on standard urotherapy in children with NE is limited and many of them are of poor quality. High quality research in a well-defined NE population is needed to establish the role of standard urotherapy in first-line treatment of children with NE or as an add-on to other first line treatments. We conclude that at present there is insufficient evidence for recommending standard urotherapy to children with PNE as a first line treatment modality.

Effects of lifestyle intervention on IGF-1, IGFBP-3, and insulin resistance in children with obesity with or without metabolic-associated fatty liver disease.

Obesity is a strong predictor for metabolic associated fatty liver disease (MAFLD), which has been associated with decreased insulin like growth factor 1 (IGF-1). In obesity, weight loss increases growth hormone secretion, but this is not unequivocally associated with increases in serum IGF-1 and IGF binding protein-3 (IGFBP-3). We studied the changes in the IGF axis in relation to weight loss and improvement in insulin resistance in children with or without MALFD after 10 weeks of lifestyle intervention at a weight loss camp (WLC). We investigated 113 (66 females) Caucasian children with obesity, median age 12.4 (range 7.3-14.6) years, before and after 10 weeks of lifestyle intervention at a WLC. We investigated children who was either MAFLD positive (n = 54) or negative (n = 59) before and after WLC. Children with MAFLD had lower baseline IGF-1 (249 ± 112 vs 278 ± 107 µg/l, P = 0.048), whereas the IGF-1/IGFBP-3 molar ratio was similar to children without MAFLD (19.4 ± 6.6 vs. 21.8 ± 6.6%, P = 0.108). When all children were considered as one group, WLC decreased SDS-BMI and HOMA-IR (P < 0.001, both) and increased IGF-1 (264 ± 110 vs 285 ± 108 µg/l, P < 0.001) and the IGF/IGFBP-3 molar ratio (20.7 ± 6.7 vs 22.4 ± 6.1%, P < 0.001). When categorized according to liver status, IGF-1 increased significantly in children with MAFLD (P = 0.008) and tended to increase in children without MAFLD (P = 0.052).   Conclusions: Ten weeks of lifestyle intervention decreased insulin resistance and improved the IGF axis. We observed slight differences in the IGF axis in relation to MAFLD status. This suggests that the IGF axis is primarily influenced by insulin resistance rather than MAFLD status. What is New: • Weight loss decreases insulin resistance and subsequently increases the IGF axis in children with obesity. • Children with MAFLD had an aberration in the IGF axis compared to their MAFLD negative counter parts and the IGF axis was primarily influenced by the decreased BMI-SDS and insulin resistance, rather than MAFLD status. What is Known: • NAFLD has previously been associated with reduced serum IGF-1 concentrations. • Data on the impact of MAFLD and aberrations in the growth hormone and IGF axis and the effects of lifestyle interventions in children are limited.

Two nights of home polysomnography in healthy 7-14-year-old children - Feasibility and intraindividual variability.

OBJECTIVE: Attended polysomnography (PSG) is the gold standard for childhood sleep evaluation. There is, however, only limited information regarding repeated ambulatory PSG in children. We aimed to test whether in hospital attached level 2 home PSG is feasible and reproducible in healthy children. METHODS: We recruited healthy children aged 7-14 years to undergo two nights of full level 2 PSG. The PSG equipment was attached at the hospital on the day of the sleep test and all recordings were performed at home. Subjective sleep quality, nocturnal urine production, sleep time and number of awakenings were documented for a week in connection to the first PSG night. RESULTS: Thirty-three children were recruited of whom 32 children (aged 11 ± 2.1 years) underwent two nights of PSG. All 64 PSGs were technically adequate for sleep evaluation. We found mean sleep efficiency of 94% and mean total sleep time of 8.4 h. Sleep stages distribution with 5.9% N1, 46.8% N2, 24.3% N3 and 22.8% REM sleep. We found poorer subjective sleep quality, more self-reported awakenings, and shorter total sleep time on nights with PSG compared to nights without PSG with no differences between PSG study nights. No differences in nocturnal urine production were found between nights with and without PSG. The comparison of PSG variables between the two PSG nights revealed no first night effect. CONCLUSIONS: Type 2 PSG recording is feasible for sleep evaluation in children 7-14 years of age producing good data quality. We found no first night effect on PSG variables. www. CLINICALTRIALS: gov Registration number: NCT03477812.

Transcutaneous electrical nerve stimulation as add-on therapy in children receiving anticholinergics and/or mirabegron for refractory daytime urinary incontinence: A retrospective cohort study.

AIMS: To investigate if children with daytime urinary incontinence (DUI) and overactive bladder (OAB) refractory to standard urotherapy and medicinal treatment, would experience improvement in symptoms after add-on treatment with transcutaneous electrical nerve stimulation (TENS). METHODS: Children were retrospectively enrolled from tertiary referral centers at Aarhus and Aalborg University Hospitals. All data were retrieved from the patients' journals. All children were prescribed TENS as an add-on treatment to the highest-tolerable dose of medicinal treatment in a standardized regime of 2 h a day for around 3 months. Primary endpoints were the number of wet days per week (WDPW) and incontinence episodes per day. Effect of treatment was defined as greater or equal to 50% reduction in the frequency of DUI episodes. Secondary endpoints were to establish predictive factors for the effect of treatment using logistic regression. RESULTS: Seventy-six children diagnosed with DUI and OAB refractory to treatment with standard urotherapy and pharmacological treatment, at the age of 5-16 years were included from February 2017 to February 2020. A reduction in WDPW (from 6.31 [5.86-6.61] to 4.27 [3.45-4.90], p < 0.05) and incontinence episodes per day (from 2.45 [1.98-2.91] to 1.43 [1.07-1.80], p < 0.05) was observed. Twelve patients became completely dry. At 6 months follow-up, seven of the 12 complete responders had relapsed while five remained dry. A history of constipation before TENS was a predictor of poor treatment response (p = 0.016). CONCLUSIONS: TENS as add-on to anticholinergic treatment seems effective in a number of children with treatment-refractory DUI.

The efficacy of physiotherapeutic intervention with biofeedback assisted pelvic floor muscle training in children with dysfunctional voiding.

INTRODUCTION: Dysfunctional voiding (DV) in children is a common issue, which can be found in up to 30% of children with wetting problems. Biofeedback assisted pelvic floor muscle training (PFMT) is an established nonpharmacological method to treat DV. The aim of the present study was to evaluate the efficacy of physiotherapeutic intervention with biofeedback assisted PFMT in children with DV. STUDY DESIGN: Children referred with DV, unresponsive to standard urotherapy were included in this study. All children underwent biofeedback assisted PFMT sessions with a physiotherapist. Uroflowmetries and measurements of post-void residual (PVR) urine were performed before and after the treatment, and the following parameters were registered; daytime incontinence (DI), nocturnal enuresis (NE), constipation, faecal incontinence (FI), and recurrent urinary tract infections (UTI). Other concomitant treatments were noted. The primary outcomes were the resolution of DV evaluated by uroflow curve configuration and PVR. Secondary outcomes were the resolution of DI, NE and the reduction of recurrent UTIs. RESULTS: Forty-six children (mean age 9.6 ± 2.4 years, 38 girls) were included in the analysis. The median period of treatment was 9.0 ± 8.5 months (2-9 visits). Twenty-seven (59%) children responded to treatment according to one or both primary outcomes; uroflow configuration (50%) and PVR (28%). DI resolved in 12 (26%) children and 27 of the 32 children, who prior to the treatment had recurrent UTIs experienced no UTIs during the follow up period. The use of anticholinergics was a significant negative predictor for response to treatment. We found that almost half of the responders (48%) reached effect prior to the fourth visit. DISCUSSION: Biofeedback assisted PFMT can improve the symptoms in children with DV. When comparing to existing literature we find a less pronounced effect of the intervention. A possible explanation may be that the children enrolled in this study were recruited from a tertiary referral centre and were all refractory to standard urotherapy. Moreover, the difference in patient characteristics and treatment protocols between different studies make direct comparisons of efficacy difficult. CONCLUSION: Physiotherapeutic intervention with biofeedback assisted PFMT seems to lead to better uroflow patterns in approximately 60% of cases in DV improving the uroflow curves and PVR, however improvement in uroflowmetry patterns is not necessarily reflected in the resolution of incontinence or UT symptoms. The use of anticholinergics seems to be a negative predictor for response to treatment.

Pitfalls in Diagnosing Urinary Tract Infection in Children below the Age of 2: Suprapubic Aspiration vs Clean-Catch Urine Sampling.

PURPOSE: Reliable urine samples are of eminent importance when diagnosing urinary tract infections (UTIs) in children. Noninvasive procedures are convenient but likely to be contaminated. This study aimed to compare the diagnostic accuracy of urine samples obtained by the midstream clean-catch method (CCU) to urine obtained by suprapubic aspiration (SPA) and to evaluate the ability of urinary dipstick to predict true infection. MATERIALS AND METHODS: Retrospectively, data on children <2 years of age seen at our center for suspicion of UTI who had a CCU and a SPA performed the same day were included. Any growth in SPA was considered significant, whereas for CCU we tested 2 cutoff values of 104 and 105 CFU/ml, along with urinary dipstick results. RESULTS: A total of 223 children were included. Using a cutoff of ≥104 CFU/ml, 16.6% of the cohort (37 cases) would be misdiagnosed if relying only on CCU. Using ≥105 CFU/ml, the rate was 24.6% (55 cases). Evaluating leukocyte esterase on urinary dipstick, a large difference between using CCU (sensitivity 94.7%, specificity 14.4%) and SPA (sensitivity 78.9%, specificity 82.2%) became obvious. CONCLUSIONS: A large number of children will be misdiagnosed if relying on CCU specimens compared to SPA. Relying on a negative leukocyte esterase dipstick test to rule out a UTI is not sufficient in a child with high suspicion of such an infection. SPA is a safe procedure, and we thus recommend its use to avoid delay of treatment and unnecessary invasive followup investigations.

Dissatisfaction with school toilets is associated with bladder and bowel dysfunction.

Poor quality of school toilets is reportedly an issue in many countries and has been correlated with toilet refusal in children. The aim of this study was to evaluate the association between perceived school toilet quality, behaviour regarding toilet visits, and symptoms of bladder and bowel dysfunction (BBD). Pupils in Danish schools were invited to complete online questionnaires regarding toilet behaviour, perception of school toilet standards/quality, and symptoms of BBD. Teachers at the same schools were asked about the quality of the toilets. We recruited 19,577 children from 252 different schools. More than half of the children (50% boys and 60% girls) were dissatisfied with the toilet facilities. One-fourth of the children (28% of girls, 23% of boys) reported avoiding the use of school toilets. We found a strong correlation between being dissatisfied with school toilets, toilet avoidance, and symptoms of BBD.Conclusion: The majority of Danish children are unhappy with their school toilet facilities. Symptoms of BBD are associated with subjective toilet dissatisfaction and toilet visit postponement. Because children spend a significant part of their day at school, access to satisfactory toilet facilities is of utmost importance for their well-being. What is Known • Bladder and bowel dysfunction is common in childhood with urinary incontinence, constipation, and faecal incontinence being cardinal symptoms. • Behaviour regarding toilet visits contributes to the aetiology, and we know that toilet avoidance can lead to abnormal bladder and bowel function. What is New • Most children are not satisfied with their school toilets, and many avoid toilet visits. • Dissatisfaction with the school toilets is related to toilet avoidance and bladder and bowel dysfunction in school children regardless of age and gender.

Prevalence, Risk Factors, and Psychological Effects of Primary Nocturnal Enuresis in Chinese Young Adults.

PURPOSE: This study aimed to investigate the prevalence, risk factors, and effects of primary nocturnal enuresis (PNE) on physical and mental health in young adults in mainland China. METHODS: An anonymous questionnaire was used to collect information including the sociodemographic characteristics, history of PNE, family history, daytime voiding symptoms, Pittsburgh Sleep Quality Index (PSQI) scores, Self-Esteem Scale (SES), and Self-Rating Depression Scale (SDS). A total of 22,500 university students from 23 provinces and 368 cities in mainland China were included. RESULTS: In total, 21,082 questionnaires were collected, and 20,345 of them qualified for statistical analysis. The PNE prevalence was 1.17%, and the distribution of monosymptomatic nocturnal enuresis (MNE) and nonmonosymptomatic nocturnal enuresis (NMNE) was 66.1% and 33.9%, respectively. In total, 28% of respondents with PNE reported bedwetting daily, 31.6% between 1 and 7 times weekly, and 40.4% between 1 and 4 times monthly; 80% of PNE cases had no history of treatment. The prevalence of PNE in patients with a family history, frequency, urgency, urinary incontinence, and recurrent urinary tract infections was significantly higher than in those without these conditions (P<0.001). PNE was significantly correlated with the PSQI total score (sleep quality) (P=0.011). The SES score was lower and the SDS was higher (P<0.001) in the PNE group than in those without PNE. CONCLUSION: In mainland China, the PNE prevalence among young adults was found to be high, and PNE had significant effects on physical and mental health. Risk factors included a family history, daytime voiding symptoms, and lack of treatment.

Efficacy and safety of multimodal treatment in nocturnal enuresis - A retrospective cohort study.

INTRODUCTION AND AIM OF THE STUDY: Most treatments of nocturnal enuresis (NE) are targeting the main pathophysiological mechanisms, i.e., excess nocturnal urine production, bladder reservoir dysfunction and inability to awaken to a full bladder. Although many children can be effectively treated with only one treatment modality, there is a significant number of treatment-refractory cases. We experience an increasing tendency to combine treatment modalities in those children. However, there is limited evidence regarding the efficacy and safety of such strategies. MATERIALS AND METHODS: We reviewed files from all NE children seen in our outpatient incontinence clinic between January 1st and December 31st 2017 and identified children refractory to first line treatment receiving a combination of at least two treatment modalities concurrently. Age, gender, wet nights per week before treatment, follow-up time, previous treatment with desmopressin or alarm, phenotype of NE, number of simultaneous treatments tried and response as well as registered side effects during treatment was noted. We registered the outcomes and safety of the treatment modalities and evaluated prognostic factors. RESULTS: We identified 59 children (13 girls) aged 6-15 yrs (mean 9.6 yrs) of whom 30 were monosymptomatic NE (MNE) and 29 were non-monosymptomatic NE (NMNE) patients. They all suffered at least three wet nights per week before treatment. In total, 38 children (61%) became dry on multimodal therapy. Eighteen children (30%) became dry on a combination of two treatment modalities, 16 (27%) on three modalities, and two (3%) on four modalities. Nine children (15%) achieved partial response whereas three (5%) showed no response despite multiple tries with combination therapies. A total of 18 children (30%) reported side effects to one or more of the modalities tried. Side effects that led to discontinuation of the treatment were uncommon (three patients). CONCLUSIONS: Treatment refractory NE represents a challenge for the clinician. Although it seems possible to adequately treat refractory NE patients with multimodal treatment one should be aware of side effects as well as inform the families of the challenges in the treatment of refractory enuresis patients. Future RCT's should focus on providing further evidence for the role of multimodal therapy in NE treatment.

Risk factors for kidney scarring and vesicoureteral reflux in 421 children after their first acute pyelonephritis, and appraisal of international guidelines.

BACKGROUND: Acute pyelonephritis (AP) is a common bacterial infection in childhood. Follow-up guidelines on these children are controversial. This study aimed to identify risk factors for kidney scarring and vesicoureteral reflux (VUR). Furthermore, international follow-up guidelines were used for simulation to evaluate sensitivity and specificity. METHODS: Urinary culture-confirmed first-time AP patients (aged 0-14 years) were enrolled (n = 421) from review of patient charts. All underwent kidney ultrasound (US) and a technetium-99m-dimercaptosuccinic acid (DMSA) scan or technetium-99m-mercaptoacetyltriglycine scinti-renography (MAG3) at 4-6 months of follow-up. The international guidelines used for simulation were from the National Institute of Health UK (NICE), the American Association of Paediatrics (AAP) and the Swedish Paediatric Society (SPS). RESULTS: 17.8% presented with an abnormal DMSA/MAG3 at follow-up, 7.1% were diagnosed with VUR grades III-V and 4.7% were admitted for surgery. Non-Escherichia coli infections, abnormal kidney US, elevated creatinine and delayed response to treatment (>48 h) were risk factors for abnormal DMSA findings and VUR grades III-V. NICE and SPS guidelines showed best sensitivity in diagnosing VUR grades III-V (75%) compared with AAP (56%). CONCLUSIONS: Risk factors are helpful in identifying the children in need of further investigations and minimizing invasive work-up for the rest. International guidelines on follow-up detect a varying number of children with kidney damage and/or significant VUR. Future work must focus on identifying more specific risk factors, better imaging, or specific biomarkers, to enhance sensitivity and specificity in detecting the children at high risk for developing recurrent infections and/or nephropathy.

Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study.

BACKGROUND: Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. METHODS: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. FINDINGS: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10-8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10-11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10-8). All associated variants in the chromosome 6 locus were replicated (p<8 × 10-3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. INTERPRETATION: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. FUNDING: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.

Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics.

OBJECTIVE: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability. DESIGN: Open label, non-randomised, interventional PK and PD trial. SETTING: Single-centre study. PATIENTS: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month. INTERVENTIONS: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration. MAIN OUTCOME MEASURES: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated. RESULTS: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (Vd/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated. CONCLUSIONS: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated. TRIAL REGISTRATION NUMBER: NTC02584231.

[Copeptin is a new diagnostic biomarker for diabetes insipidus].

Differential diagnosis of diabetes insipidus is challenging. The water deprivation test is the current gold standard, but the test is cumbersome, and the diagnostic performance is poor. Copeptin, which is a split product of the vasopressin pre-propeptide, appears to be a robust biomarker in the circulation and a promising tool for the diagnosis of patients with polyuria and polydipsia, especially when measured in conjunction with intravenous infusion of arginine, as summarised in this review.