The role of renal circadian biorhythms in lifelong LUTS.

INTRODUCTION: This article delves into the intricate relationship between kidney function, diuresis, and lower urinary tract symptoms (LUTS) throughout the transitions of the human lifespan. It explores circadian regulation of urine production, maturation of renal function from birth to adulthood, and effects of aging on kidney function and LUTS. The complex connections between these factors are highlighted, offering insights into potential interventions and personalized management strategies. METHODS: An international panel of seven experts engaged in online discussions, focusing on kidney function, diuresis, and LUTS throughout life. This manuscript summarizes expert insights, literature reviews, and findings presented during a webinar and subsequent discussions. RESULTS: Renal function undergoes significant maturation from birth to adulthood, with changes in glomerular filtration rate, diuresis, and tubular function. A circadian rhythm in urine production is established during childhood. Adolescents and young adults can experience persistent enuresis due to lifestyle factors, comorbidities, and complex physiological changes. In older adults, age-related alterations in kidney function disrupt the circadian rhythm of diuresis, contributing to nocturnal polyuria and LUTS. CONCLUSION: The interplay between kidney function, diuresis, and LUTS is crucial in understanding lifelong urinary health. Bridging the gap between pediatric and adult care is essential to address enuresis in adolescents and young adults effectively. For older adults, recognizing the impact of aging on renal function and fluid balance is vital in managing nocturia. This holistic approach provides a foundation for developing innovative interventions and personalized treatments to enhance quality of life for individuals with LUTS across all stages of life.

The effect of methylphenidate for giggle incontinence in children.

INTRODUCTION: Giggle incontinence (GI) is a rare form of urinary incontinence that occurs during or immediately after laughing due to involuntary and complete bladder emptying. Few studies in the literature report that methylphenidate can be effective in treatment of this condition. OBJECTIVE: The aim of this study is to characterize children with GI and evaluate their response to methylphenidate, as well as describe treatment duration, dosage of methylphenidate, relapse rates after discontinuation of medication, and side effects. METHODS: Medical records and 48-h frequency-volume charts from children treated with methylphenidate for GI in the period January 2011-July 2021 were retrospectively analyzed. RESULTS: Eighteen children were diagnosed with GI and fulfilled inclusion criteria. Fifteen patients were included in analysis, as 3 out of 18 children decided not to take the methylphenidate that was prescribed. In total, 14 out of the 15 GI patients treated with methylphenidate experienced clinical effect. All patients included in the study had methylphenidate prescribed in a dose range of 5-20 mg daily. Treatment duration ranged from 30 to 1001 days, with a median of 152 days (IQR 114, 243.5). Ten children experienced complete response and two of those reported symptom relapse after discontinuation of the methylphenidate. Only mild and short-lasting side effects were reported by two patients. DISCUSSION: Our study demonstrates that methylphenidate is an effective treatment in children diagnosed with GI. Side effects are mild and uncommon.

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.

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.

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.

Transcutaneous Electrical Nerve Stimulation Combined with Oxybutynin is Superior to Monotherapy in Children with Urge Incontinence: A Randomized, Placebo Controlled Study.

PURPOSE: We evaluated whether combination therapy with transcutaneous electrical nerve stimulation and oxybutynin results in a superior treatment response compared to either therapy alone in children with urge incontinence. MATERIALS AND METHODS: In this placebo controlled study 66 children with a mean ± SD age of 7.3 ± 1.6 years who were diagnosed with urge incontinence were randomized to 3 treatment groups. Group 1 consisted of 22 children undergoing transcutaneous electrical nerve stimulation plus active oxybutynin administration. Group 2 included 21 children undergoing active transcutaneous electrical nerve stimulation plus placebo oxybutynin administration. Group 3 consisted of 23 children undergoing active oxybutynin administration plus placebo transcutaneous electrical nerve stimulation. The children received active or placebo transcutaneous electrical nerve stimulation over the sacral S2 to S3 outflow for 2 hours daily in combination with 5 mg active or placebo oxybutynin twice daily. The intervention period was 10 weeks. Primary outcome was number of wet days weekly. Secondary outcomes were severity of incontinence, frequency, maximum voided volume over expected bladder capacity for age, average voided volume over expected bladder capacity for age and visual analogue scale score. RESULTS: Combination therapy was superior to oxybutynin monotherapy, with an 83% greater chance of treatment response (p = 0.05). Combination therapy was also significantly more effective than transcutaneous electrical nerve stimulation monotherapy regarding reduced number of wet days weekly (mean difference -2.28, CI -4.06 to -0.49), severity of incontinence (-3.11, CI -5.98 to -0.23) and daily voiding frequency (-2.82, CI -4.48 to -1.17). CONCLUSIONS: Transcutaneous electrical nerve stimulation in combination with oxybutynin for childhood urge incontinence was superior to monotherapy consisting of transcutaneous electrical nerve stimulation or oxybutynin, although the latter only reached borderline statistical significance. Furthermore, transcutaneous electrical nerve stimulation was associated with a decreased risk of oxybutynin induced post-void residual urine greater than 20 ml.

No immediate effect on urodynamic parameters during transcutaneous electrical nerve stimulation (TENS) in children with overactive bladder and daytime incontinence-A randomized, double-blind, placebo-controlled study.

AIM: To evaluate the immediate effect on natural fill urodynamic parameters and bladder function during transcutaneous electrical nerve stimulation (TENS) in children with overactive bladder (OAB) and daytime urinary incontinence (DUI). MEETHODS: In this double-blind, placebo-controlled study, 24 children with severe OAB and DUI (mean age 8.5 ± 1.2 years) underwent 48-h natural fill urodynamics. After 24 h of baseline investigation, the children were randomized to either active continuous TENS (n = 12) or placebo TENS (n = 12) over the sacral S2-S3 outflow. The urodynamic recordings were analyzed manually for three different bladder contraction patterns resulting in a void. The number of bladder contractions not leading to a void was also calculated. Maximum voided volume (MVV) and average voided volume (AVV) were identified for both the baseline and the intervention day. RESULTS: We found that TENS had no immediate objective effect on bladder capacity. The difference (before minus after treatment) in MVV/EBC in the active TENS group = 0.03 ± 0.23 versus placebo TENS group = -0.01 ± 0.10 (P = 0.61). Also, there was no significant difference in the proportion of different bladder contraction types between the two groups. TENS did not significantly influence the number of bladder contractions not leading to a void. Results are presented as mean ± SD. CONCLUSION: There is no immediate objective effect of TENS on bladder activity assessed by natural fill urodynamics in children with OAB and DUI.

Outcome of a standardized approach to childhood urinary symptoms-long-term follow-up of 720 patients.

AIMS: To investigate the relevance of enuresis subtyping for selection of treatment modality and for long-term outcome in a large consecutive patient cohort. MATERIALS AND METHODS: We included all patients referred for urinary incontinence during a 5-year period but excluding recurrent urinary tract infections (UTI). Type and severity of incontinence, prior history, results of examinations performed, number of visits, and effect of all treatments provided, were included in a clinical database. RESULTS: Seven hundred twenty children aged 4-16 years (mean 8.5 ± 2.2 years, 239 girls) were included in the analysis (42% with monosymptomatic (MNE), 55% with non-MNE, and 3% with isolated daytime incontinence). Initial evaluation revealed only few underlying causes (one neurological and eight anatomical). Investigations showed significant differences between MNE and non-MNE patients as both maximal voided volume and nocturnal urine volume was lower in non-MNE patients (P < 0.001). Follow-up for average 1,587 days (3.4 years) was performed in 660 (92%) patients. A higher number of visits and a longer treatment period were needed for non-MNE patients (on average 4.7 ± 2.8 visits) than MNE patients (3.1 ± 1.6 visits, P < 0.001). The most common treatment regimen that resulted in dryness in both MNE (40%) and non-MNE (36%) was the alarm system. Interestingly, of the 539 patients who initially were referred due to desmopressin resistance 177 (33%) of these were dry on desmopressin monotherapy. CONCLUSIONS: The study indicated that MNE and non-MNE are two distinct disease entities with different optimal treatments and showed that the latter patients are more difficult and time-consuming to manage.

The effect of desmopressin on renal water and solute handling in desmopressin resistant monosymptomatic nocturnal enuresis.

PURPOSE: We sought to evaluate the effect of desmopressin on renal water and solute handling in children with monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria compared to healthy controls. MATERIALS AND METHODS: A total of 12 patients with enuresis and nocturnal polyuria, normal bladder reservoir function and no response to desmopressin, and 10 age matched controls were enrolled in the study. Children were admitted to the hospital for a 48-hour protocol comprising urine collections and blood sampling. Sodium and water intake was standardized. During the second night children received 40 mug intranasal desmopressin. Parameters characterizing the renal water and solute handling were measured and compared between baseline nights and nights with desmopressin. RESULTS: Desmopressin markedly reduced nocturnal urine output in patients with enuresis, minimizing sodium, urea and overall solute excretion, despite the fact that these children were unresponsive to desmopressin at home. This effect on renal sodium handling was not mediated by atrial natriuretic peptide, angiotensin II, aldosterone or renin. Desmopressin did not influence urinary prostaglandin E(2) excretion. The antinatriuretic effect was seen only in patients with enuresis, and it was directly correlated with the reduction in urine output. CONCLUSIONS: Children with nocturnal enuresis and nocturnal polyuria who do not exhibit adequate response to desmopressin at home seem to respond well to the agent at the clinic. The effect of desmopressin in children with enuresis seems largely dependent on reductions in the amount of sodium excreted. Sodium regulating hormones remained unaffected by desmopressin, indicating a possible direct effect of the agent on renal sodium handling.