Development of a Novel Prediction Tool for Response to First-Line Treatments of Monosymptomatic Nocturnal Enuresis: A Randomized, Controlled, International, Multicenter Study (DRYCHILD).

PURPOSE: Nocturnal urine volume and bladder reservoir function are key pathogenic factors behind monosymptomatic nocturnal enuresis (MNE). We investigated the predictive value of these together with other demographic and clinical variables for response to first-line treatments in children with MNE. MATERIALS AND METHODS: A randomized, controlled, international, multicenter study was conducted in 324 treatment-naïve children (6-14 years old) with primary MNE. The children were randomized to treatment with or without prior consideration of voiding diaries. In the group where treatment choice was based on voiding diaries, children with nocturnal polyuria and normal maximum voided volume (MVV) received desmopressin (dDAVP) treatment, and children with reduced MVV and no nocturnal polyuria received an enuresis alarm. In the other group, treatment with dDAVP or alarm was randomly allocated. RESULTS: A total of 281 children (72% males) were qualified for statistical analysis. The change of responding to treatment was 21% higher in children where treatment was individualized compared to children where treatment was randomly selected (risk ratio = 1.21 [1.02-1.45], P = .032). In children with reduced MVV and no nocturnal polyuria (35% of all children), individualized treatment was associated with a 46% improvement in response compared to random treatment selection (risk ratio = 1.46 [1.14-1.87], P = .003). Furthermore, we developed a clinically relevant prediction model for response to dDAVP treatment (receiver operating characteristic curve 0.85). CONCLUSIONS: The present study demonstrates that treatment selection based on voiding diaries improves response to first-line treatment, particularly in specific subtypes. Information from voiding diaries together with clinical and demographic information provides the basis for predicting response. CLINICAL TRIAL REGISTRATION NO.: NCT03389412.

Exploring the Genetic Risk of Childhood Daytime Urinary Incontinence: A Genome-Wide Association Study.

PURPOSE: Childhood incontinence is stigmatized and underprioritized, and a basic understanding of its pathogenesis is missing. Our goal was to identify risk-conferring genetic variants in daytime urinary incontinence (DUI). MATERIALS AND METHODS: We conducted a genome-wide association study in the Danish iPSYCH2015 cohort. Cases (3024) were identified through DUI diagnosis codes and redeemed prescriptions for DUI medication in patients aged 5 to 20 years. Controls (30,240), selected from the same sample, were matched to cases on sex and psychiatric diagnoses, if any, and down-sampled to a 1:10 case:control ratio. Replication was performed in the Icelandic deCODE cohort (5475 cases/287,773 controls). Single-nucleotide polymorphism heritability was calculated using the genome-based restricted maximum likelihood method. Cross-trait genetic correlation was estimated using linkage disequilibrium score regression. Polygenic risk scores generated with LDpred2-auto and BOLT-LMM were assessed for association. RESULTS: Variants on chromosome 6 (rs12210989, odds ratio [OR] 1.24, 95% CI 1.17-1.32, P = 3.21 × 10-12) and 20 (rs4809801, OR 1.18, 95% CI 1.11-1.25, P = 3.66 × 10-8) reached genome-wide significance and implicated the PRDM13 and RIPOR3 genes. Chromosome 6 findings were replicated (P = .024, OR 1.09, 95% CI 1.01-1.16). Liability scale heritability ranged from 10.20% (95% CI 6.40%-14.00%) to 15.30% (95% CI 9.66%-20.94%). DUI and nocturnal enuresis showed positive genetic correlation (rg = 1.28 ± 0.38, P = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR 1.098, 95% CI 1.046-1.152, P < .0001) and BMI (OR 1.129, 95% CI 1.081-1.178, P < .0001) polygenic risk. CONCLUSIONS: Common genetic variants contribute to the risk of childhood DUI, and genes important in neuronal development and detrusor smooth muscle activity were implicated. These findings may help guide identification of new treatment targets.

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)."

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.

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.

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.

The influence of delay elimination communication on the prevalence of primary nocturnal enuresis-a survey from Mainland China.

AIMS: A pilot survey shows that primary nocturnal enuresis (PNE) prevalence has increased significantly during the past decade in Mainland China. Whether it is related to the delay of elimination communication (EC) is unclear. This study retrospectively investigated the influence of delayed EC on the PNE prevalence in children and adolescents in mainland China. METHODS: A cross-sectional study of PNE prevalence was performed by distributing 19 500 anonymous self-administered questionnaires to parents in five provinces of mainland China from July 2017 to October 2017. The questionnaires included sociodemographic data, family caregivers' information, and details about the disposable diapers (DD) usage, EC commencement date, psychological disorders, lower urinary tract symptoms, and family history of PNE in children and adolescents. The 2017 PNE prevalence was compared with that of 2006 in Mainland China. RESULTS: The total response rate was 97.04% (18 631 of 19 500) and 92.39% (18 016 of 19 500) qualified for statistical analysis. The PNE prevalence in 2017 has increased significantly compared to that of 2006 (7.30% vs 4.07%, P < 0.001). The PNE prevalence in children with EC starting before 6 months of age was significantly lower than those who start after 12 months of age. The longer DD were used and the later the beginning of EC, the higher the PNE prevalence was found. CONCLUSIONS: The PNE prevalence in Mainland China has increased significantly during the past 10 years. A longer use of DD and later onset of EC may be risk factors for PNE.

Transcutaneous Electrical Nerve Stimulation in Children with Monosymptomatic Nocturnal Enuresis: A Randomized, Double-Blind, Placebo Controlled Study.

PURPOSE: In a third of all children with monosymptomatic nocturnal enuresis their condition is refractory to first line treatments. Transcutaneous electrical nerve stimulation has been documented to be efficacious in children with daytime incontinence. We investigated the effect of transcutaneous electrical nerve stimulation in children with monosymptomatic nocturnal enuresis without nocturnal polyuria. MATERIALS AND METHODS: Children with monosymptomatic nocturnal enuresis (3 or more wet nights per week) and no nocturnal polyuria were randomized to treatment with active or sham transcutaneous electrical nerve stimulation involving 1-hour sessions twice daily for 10 weeks in a double-blind design. RESULTS: Of the 52 children with monosymptomatic nocturnal enuresis included in the study 47 completed treatment (mean age 9.5 ± 2.1 years, 38 males). None of the children experienced a full response with complete remission of enuresis. Treatment with transcutaneous electrical nerve stimulation did not lead to significant changes in number of wet nights, nocturnal urine production on wet or dry nights, maximum voided volume with and without first morning voided volume, or voiding frequency when comparing parameters before and after treatment. CONCLUSIONS: The present study demonstrates no anti-enuretic effect of transcutaneous electrical nerve stimulation in children with monosymptomatic nocturnal enuresis without nocturnal polyuria. Nocturnal urine production and bladder capacity remained unchanged during and after treatment with transcutaneous electrical nerve stimulation.

Transanal irrigation is effective in functional fecal incontinence.

Functional fecal incontinence (FFI) is divided into cases related to functional constipation (FC) and cases without concomitant constipation termed functional non-retentive fecal incontinence (FNRFI). Transanal irrigation (TAI) is widely used in children with neurogenic fecal incontinence but is less studied in children with functional defecation disorders. The aim was to evaluate the feasibility and efficacy of TAI in the treatment of FFI. A retrospective study in 72 children (mean age 9.2 ± 2.2 years, 47 males) with treatment-resistant FFI was performed. All children accepted treatment and 35% (n = 25) were titrated to daily sessions. Of the 63 children who fulfilled the Rome III criteria of constipation, 46 (73%) showed full response with complete remission of incontinence episodes. Eleven (17%) showed partial response (≥50% reduction). Of nine children with FNRFI, four (44%) showed full response whereas two (22%) showed partial response. We found no significant difference in the reduction of incontinence episodes between the children with FC (87%) and children with FNRFI (68%) (p = 0.11). CONCLUSION: TAI is an effective, well-tolerated, and safe choice in children with FC. No clinical parameters seemed to predict response to treatment. The number of children with FNRFI was low, but TAI seemed effective in this group of children. What is Known: • Functional fecal incontinence (FFI) is a frequent, chronic condition with significant impact on children's quality of life. • Transanal irrigation (TAI) is used in children with neurogenic bowel dysfunction but less studied in children with functional defecation disorders. What is New: • TAI seems an effective, well-tolerated, and safe choice in children with FFI due to functional constipation. • Albeit the number of children with functional non-retentive fecal incontinence was low in our study, TAI seems effective also in this group of children.

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.

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.

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.

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.

Milk Products in the Treatment of Hypophosphatemic Rickets: A Pilot Study.

BACKGROUND: Standard treatment of hypophosphatemic rickets (HR) is oral phosphate tablets plus vitamin D. Due to the rapid absorption of phosphate tablets, frequent daily doses are necessary, which is cumbersome and may cause fluctuations in plasma phosphate and risk of secondary hyperparathyroidism. It was hypothesized that phosphate from milk or cheese is less rapidly absorbed, and reduces fluctuations in plasma phosphate. OBJECTIVES: The current randomized, multiple crossover study aimed at investigating if an equivalent phosphate dose given as milk or cheese is comparable to phosphate tablets in patients with HR. METHODS: Seven females with HR were included. They went through three different four-day treatment sessions of either oral phosphate tablets consisting of 800 mg elemental phosphorus divided into five doses over the day or an equivalent phosphorus dose ingested as skimmed milk or cheese divided over five daily doses. Blood and urine samples were taken from patients after each treatment session. Except the usual doses of vitamin D, no phosphate or calcium-modifying treatments were allowed. Statistical analyses were performed using mixed models. RESULTS: Treatment feasibility was independent of the phosphorus source. The study demonstrated reduced plasma levels of parathyroid hormone (PTH), reduced fluctuations in plasma phosphate and plasma PTH, and reduced renal phosphate excretion when ingesting phosphorus supplementation as milk compared to phosphate tablets. The same trend was observed when administering phosphorus as cheese, though not statistically significant. CONCLUSIONS: Phosphorus supplements can be administered as phosphate tablets, milk or cheese when given in equimolar doses. The current study findings indicated that milk may be superior to phosphate tablets as the phosphate source in patients with HR.