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) 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 (RR = 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 (RR = 1.46 (1.14-1.87), P = .003). Furthermore, we developed a clinically relevant prediction model for response to dDAVP treatment (ROC 0.85). CONCLUSIONS: The present study demonstrates that treatment selection based on voiding diaries improve 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.

Transition in enuresis patients: Identifying the gaps and opportunities for the future.

BACKGROUND: Nocturnal enuresis is generally considered a children's condition, yet it may persist 1%-2% in adolescence and early adulthood. Refractory patients often demand follow-up by multidisciplinary teams, which is only restricted to some of the expert tertiary centers. However, there are no standardized transition programs/guidelines when follow-up must be passed from pediatric to adult healthcare providers. AIM, MATERIALS & METHODS: To investigate this issue, we conducted a literature search on enuresis transition, which resulted in no articles. We, therefore, proceeded in a rescue search strategy: we explored papers on transition programs of conditions that may be related and/or complicated by enuresis, nocturia, or other urinary symptoms (chronic diseases, CKD, bladder dysfunction, kidney transplant, neurogenic bladder). RESULTS: These programs emphasize the need for a multidisciplinary approach, a transition coordinator, and the importance of patient and parent participation, practices that could be adopted in enuresis. The lack of continuity in enuresis follow-up was highlighted when we investigated who was conducting research and publishing on enuresis and nocturia. Pediatric disciplines (50%) are mostly involved in children's studies, and urologists in the adult ones (37%). DISCUSSION: We propose a stepwise approach for the transition of children with enuresis from pediatric to adult care, depending on the clinical subtype: from refractory patients who demand more complex, multidisciplinary care and would benefit from a transition coordinator up to children/young adults cured of enuresis but who persist in having or present lower urinary tract symptoms (LUTS)/nocturia later on. In any case, the transition process should be initiated early at the age of 12-14 years, with adequate information to the patient and parents regarding relapses or LUTS/nocturia occurrence and of the future treating general practitioner on the enuresis characteristics and comorbidities of the patient.

First uninterrupted sleep period in children and adolescents with nocturnal enuresis: Added value in diagnosis and follow-up during therapy.

BACKGROUND: The first uninterrupted sleep period (FUSP, time up to the first episode of enuresis/nocturia after falling asleep) is a frequently investigated parameter in adults with nocturia, as it correlates with quality of life. However, it has not been included in pediatric enuresis studies. AIM: Investigate FUSP, circadian renal water and sodium handling, as well as sleep quality before and after desmopressin therapy in enuresis. MATERIALS AND METHODS: We conducted a post hoc analysis of a prospective study in 30 treatment-naïve children with enuresis who underwent a video-polysomnography and a 24-h urine concentration profile before and after 6 months of desmopressin therapy. We analyzed FUSP, periodic limb movements in sleep (PLMS), and arousal indexes and their correlations with the urinary parameters. RESULTS: Sixteen children with a mean age of 10.9 ± 3.1 years had full registrations and were included in this subanalysis. After therapy, FUSP was significantly longer (p < 0.001), and the PLMS index was lower (p = 0.023). Significant differences in the circadian rhythm of diuresis (night/day diuresis, p = 0.041), nocturnal urinary osmolality (p = 0.009), and creatinine (p = 0.001) were found, demonstrating the increase of urinary concentration overnight by desmopressin, as well as a significant antidiuretic effect (diuresis [p = 0.013] and diuresis rate (p = 0.008). There was no correlation between the difference of FUSP, PLMS index, and urinary parameters. Nevertheless, despite this study being underpowered, there are indications of a correlation between nocturnal diuresis and diuresis rate. RESULTS: Our results support the need for further research regarding FUSP in children with enuresis, in accordance with nocturia studies in adults, as this parameter could be valuable in the follow-up and evaluation of therapeutic strategies for enuresis.

Circadian rhythm of water and solute excretion in nocturnal enuresis.

BACKGROUND: Nocturnal polyuria (NP) due to a suppressed vasopressin circadian rhythm is a well-documented pathogenetic mechanism in enuresis, mainly studied in monosymptomatic enuresis. A substantial percentage of patients do not respond to desmopressin. This suggests that NP may not only be related to vasopressin, but that other kidney components play a role. Solute handling and osmotic excretion have been investigated in the past, especially in refractory patients. Nevertheless, data in treatment-naïve populations with information on timing overnight are sparse. This study aims to investigate the diuresis and solute excretion in treatment-naïve patients with or without NP, with emphasis on circadian rhythms. METHODS: Retrospective analysis of 403 treatment-naïve children 5-18 years with severe enuresis (> 8 nights/2 weeks). Circadian rhythms were evaluated by a 24-h urine collection in 8 timed portions (4 day, 4 nighttime) at in-home settings. Urine volume, osmolality, and creatinine were measured. Patients were subdivided into three groups according to nocturnal diuresis (ND) and Expected Bladder Capacity (EBCage) ratio: (a) < 100%, (b) 100-129%, (c) > 130%. RESULTS: All groups maintained circadian rhythm for diuresis and diuresis rates. Patients with higher ND (100-129% and > 130% EBCage) had higher daytime volumes and less pronounced circadian rhythm. In the ND group > 130% EBCage, the ND rate was higher during the first night collection and osmotic excretion was significantly higher overnight. CONCLUSIONS: Overall 24-h fluid intake (reflected by 24-h diuresis) and nutritional intake (24-h osmotic excretion) might play a role in enuresis. Increased diuresis rate early in the night can be important in some patients, whereas the total night volume can be important in others. A higher resolution version of the Graphical abstract is available as Supplementary Information.

Epidemiology and clinicopathological characteristics of native kidney disease in children in Flanders, Belgium.

BACKGROUND: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry is a population-based kidney biopsy registry that has been including all native kidney biopsies performed in children in Flanders (Belgium), since 2017. METHODS: From 2017 to 2020, 148 pediatric (< 18 years) native kidney biopsies were included. Each biopsy received a histopathological and final nephrological diagnosis, and concordance between both was assessed. Disease chronicity, summarized by the Mayo Clinic Chronicity Score, was determined on 122 biopsies with > 5 glomeruli. RESULTS: Kidney biopsy rate was high (29.0 biopsies per million children per year), median age was 10.0 years (IQR 5.8-14.7), and boys predominated (56.1% males). A total of 140 biopsies (94.6%) showed a representative pathology result. Glomerular disease was most prevalent, with IgA nephropathy/IgA vasculitis (43 biopsies, 29.1%) and minimal change disease (MCD) (29 biopsies, 19.6%) being the overall most frequent diagnoses. In general, diagnostic concordance was high (80.7%). In Alport syndrome and focal segmental glomerulosclerosis (FSGS), concordance was lower, as the nephrological diagnosis was often determined by results of genetic analysis. Nephrotic syndrome was the most frequent indication for kidney biopsy (31.8%) and was mainly caused by MCD and FSGS. The degree of disease chronicity on kidney biopsies was generally low, although 27.3% of biopsies with a diagnosis of FSGS showed moderate-to-severe chronic damage. CONCLUSIONS: The presented epidemiological findings validate data from previous European registry studies and may inspire kidney biopsy registries worldwide to implement novel features such as clinicopathological concordance and chronicity grading. A higher resolution version of the Graphical abstract is available as Supplementary information.

Impact of New vs. Old International Children's Continence Society Standardization on the Classification of Treatment Naïve Enuresis Children at Screening: The Value of Voiding Diaries and Questionnaires.

Expert consensus papers recommend differentiating enuresis using questionnaires and voiding diaries into non- (NMNE) and monosymptomatic enuresis (MNE) is crucial at intake to decide the most appropriate workout and treatment. This national, Belgian, prospective study investigates the correlation, consistency, and added value of the two methods, the new against the old International Children's Continence Society (ICCS) definitions, and documents the prevalence of the two enuresis subtypes in our population. Ninety treatment-naïve enuretic children were evaluated with the questionnaire, and the voiding diary and the two clinical management tools were compared. Almost 30% of the children had a different diagnosis with each method, and we observed inconsistencies between them in registering Lower Tract Symptoms (κ = -0.057-0.432 depending on the symptom). Both methods had a high correlation in identifying MNE (rs = 0.612, p = 0.001) but not for NMNE (rs = 0.127, p = 0.248). According to the latest ICCS definitions, the incidence of MNE was significantly lower (7 vs. 48%) with the old standardization. Conclusion: The voiding diary and the questionnaire, as recommended by the ICCS at the screening of treatment-naïve enuretic patients, are considerably inconsistent and have significantly different sensitivities in identifying LUTS and thus differentiating MNE from NMNE. However, the high incidence of LUTS and very low prevalence of MNE suggest that differentiating MNE from NMNE to the maximum might not always correlate with different therapy responses.