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.

Stimulation of the Tibial nerve Repetitively to Improve Incontinence in Parkinson's Electronically (STRIPE trial): a randomised control trial of tibial nerve stimulation for bladder symptoms in Parkinson's disease using a self-contained wearable device.

BACKGROUND: Bladder symptoms are common in Parkinson's disease (PD), affecting half of all individuals. These have significant impact on quality of life as well as implications for morbidity, contributing to falls and hospital admission. The treatment of bladder symptoms can be complicated by the tendency to side-effects in people with PD including cognitive impairment and gait instability with anti-muscarinics. The development of new, better treatments is therefore warranted. Tibial nerve stimulation is a form of neuromodulation demonstrated to improve overactive bladder symptoms in non-neurogenic cohorts. Previously requiring hospital attendance, we aim to explore the use of this intervention using a simple device that can be used by patients at home. METHODS: STRIPE is a phase II randomised control trial of tibial nerve stimulation delivered by the Geko™ device, a small, self-adhesive neuromuscular stimulation device currently used for thromboembolism prophylaxis post-surgery. Active tibial nerve stimulation will be compared to sham stimulation, with participants blinded to treatment allocation and undertaking outcome assessment whilst still blinded. Participants will be asked to self-administer stimulation at home twice per week, for 30 min per session, over the course of 3 months. Primary outcome measure will be the International Consultation on Incontinence Overactive Bladder Questionnaire (OAB) at week 12. Secondary outcomes will include pre- and post-intervention bladder diary (frequency, urgency episodes, nocturia), patient perception of global change, bowel function and bladder-related quality of life. Participants will be recruited from the Proactive Integrated Management and Empowerment (PRIME) cross-sectional trial in which participants have been screened for bladder symptoms and invited to take part, as well as clinician referral from around the region. DISCUSSION: This trial will involve a randomised control trial of a novel and easy to use method of delivering tibial nerve stimulation for PD in the patient's own home. This may potentially have huge benefit, avoiding the problems with side effects that can be seen with anti-muscarinics and providing a new potential modality of treatment. TRIAL REGISTRATION: ISRCTN11484954. Registered on 22 June 2021.

Synthetic sling or artificial urinary sphincter for men with urodynamic stress incontinence after prostate surgery: the MASTER non-inferiority RCT.

BACKGROUND: Stress urinary incontinence is common in men after prostate surgery and can be difficult to improve. Implantation of an artificial urinary sphincter is the most common surgical procedure for persistent stress urinary incontinence, but it requires specialist surgical skills, and revisions may be necessary. In addition, the sphincter is relatively expensive and its operation requires adequate patient dexterity. New surgical approaches include the male synthetic sling, which is emerging as a possible alternative. However, robust comparable data, derived from randomised controlled trials, on the relative safety and efficacy of the male synthetic sling and the artificial urinary sphincter are lacking. OBJECTIVE: We aimed to compare the clinical effectiveness and cost-effectiveness of the male synthetic sling with those of the artificial urinary sphincter surgery in men with persistent stress urinary incontinence after prostate surgery. DESIGN: This was a multicentre, non-inferiority randomised controlled trial, with a parallel non-randomised cohort and embedded qualitative component. Randomised controlled trial allocation was carried out by remote web-based randomisation (1 : 1), minimised on previous prostate surgery (radical prostatectomy or transurethral resection of the prostate), radiotherapy (or not, in relation to prostate surgery) and centre. Surgeons and participants were not blind to the treatment received. Non-randomised cohort allocation was participant and/or surgeon preference. SETTING: The trial was set in 28 UK urological centres in the NHS. PARTICIPANTS: Participants were men with urodynamic stress incontinence after prostate surgery for whom surgery was deemed appropriate. Exclusion criteria included previous sling or artificial urinary sphincter surgery, unresolved bladder neck contracture or urethral stricture after prostate surgery, and an inability to give informed consent or complete trial documentation. INTERVENTIONS: We compared male synthetic sling with artificial urinary sphincter. MAIN OUTCOME MEASURES: The clinical primary outcome measure was men's reports of continence (assessed from questions 3 and 4 of the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form) at 12 months post randomisation (with a non-inferiority margin of 15%). The primary economic outcome was cost-effectiveness (assessed as the incremental cost per quality-adjusted life-year at 24 months post randomisation). RESULTS: In total, 380 men were included in the randomised controlled trial (n = 190 in each group), and 99 out of 100 men were included in the non-randomised cohort. In terms of continence, the male sling was non-inferior to the artificial urinary sphincter (intention-to-treat estimated absolute risk difference -0.034, 95% confidence interval -0.117 to 0.048; non-inferiority p = 0.003), indicating a lower success rate in those randomised to receive a sling, but with a confidence interval excluding the non-inferiority margin of -15%. In both groups, treatment resulted in a reduction in incontinence symptoms (as measured by the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form). Between baseline and 12 months' follow-up, the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form score fell from 16.1 to 8.7 in the male sling group and from 16.4 to 7.5 in the artificial urinary sphincter group (mean difference for the time point at 12 months 1.30, 95% confidence interval 0.11 to 2.49; p = 0.032). The number of serious adverse events was small (male sling group, n = 8; artificial urinary sphincter group, n = 15; one man in the artificial urinary sphincter group experienced three serious adverse events). Quality-of-life scores improved and satisfaction was high in both groups. Secondary outcomes that showed statistically significant differences favoured the artificial urinary sphincter over the male sling. Outcomes of the non-randomised cohort were similar. The male sling cost less than the artificial sphincter but was associated with a smaller quality-adjusted life-year gain. The incremental cost-effectiveness ratio for male slings compared with an artificial urinary sphincter suggests that there is a cost saving of £425,870 for each quality-adjusted life-year lost. The probability that slings would be cost-effective at a £30,000 willingness-to-pay threshold for a quality-adjusted life-year was 99%. LIMITATIONS: Follow-up beyond 24 months is not available. More specific surgical/device-related pain outcomes were not included. CONCLUSIONS: Continence rates improved from baseline, with the male sling non-inferior to the artificial urinary sphincter. Symptoms and quality of life significantly improved in both groups. Men were generally satisfied with both procedures. Overall, secondary and post hoc analyses favoured the artificial urinary sphincter over the male sling. FUTURE WORK: Participant reports of any further surgery, satisfaction and quality of life at 5-year follow-up will inform longer-term outcomes. Administration of an additional pain questionnaire would provide further information on pain levels after both surgeries. TRIAL REGISTRATION: This trial is registered as ISRCTN49212975. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 36. See the NIHR Journals Library website for further project information.

Leakage of urine associated with physical exertion (e.g. sporting activities, sneezing or coughing) is common in men who have undergone prostate surgery, but it is difficult to improve. Many men still leak urine 12 months after their prostate surgery and may continue to wear protective pads or sheaths. The most common operation to improve incontinence is implantation of an artificial urinary sphincter. An artificial urinary sphincter is an inflatable cuff that is placed around the urethra, the tube that drains urine from the bladder. The cuff is inflated and compresses the urethra to prevent leaking. When the man needs to pass urine, he must deflate the cuff by squeezing a pump placed in his scrotum, which releases the compression on the urethra and allows the bladder to empty. Recently, a new device, the male sling (made from non-absorbable plastic mesh), has been developed. The sling, which is surgically inserted under the urethra, supports the bladder, but, in contrast to the artificial sphincter, it does not need to be deactivated by a pump and, therefore, the patient does not need to do anything to operate it. A sling is also easier for the surgeon to insert than a sphincter. However, in some men, the sling does not provide enough improvement in incontinence symptoms and another operation, to place an artificial urinary sphincter, is needed. The aim of this study was to determine if the male sling was as effective as the artificial urinary sphincter in treating men with bothersome incontinence after prostate surgery. The study took the form of a randomised controlled trial (the gold standard and most reliable way to compare treatments) in which men were randomised (allocated at random to one of two groups using a computer) to either a male sling or an artificial urinary sphincter operation. We asked men how they got on in the first 2 years after their operation. Regardless of which operation they had, incontinence and quality of life significantly improved and complications were rare. A small number of men did require another operation to improve their incontinence, and it was more likely that an artificial urinary sphincter was needed, rather than another sling operation, if a male sling was not successful. Satisfaction was high in both groups, but it was significantly higher in the artificial urinary sphincter group than in the male sling group. Those who received a male sling were less likely than those who received an artificial urinary sphincter to say that they would recommend their surgery to a friend.

Short-term efficacy and safety of second generation bipolar transurethral vaporization of the prostate (B-TUVP) for large benign prostate enlargement: Results from a retrospective feasibility study.

BACKGROUND: To investigate the efficacy and safety of a second-generation bipolar transurethral electro vaporization of the prostate (B-TUVP) with the new oval-shaped electrode for large benign prostatic enlargement (BPE) with prostate volume (PV) ≥100ml. MATERIALS AND METHODS: 100 patients who underwent second-generation B-TUVP with the oval-shaped electrode for male lower urinary tract symptom (LUTS) or urinary retention between July 2018 and July 2020 were enrolled in this study. The patients' characteristics and treatment outcome were retrospectively compared between patients with PV <100ml and ≥100ml. RESULTS: 17/41 (41.5%) cases of PV ≥100ml and 24/59 cases (40.7%) of PV <100ml were catheterised due to urinary retention. The duration of post-operative catheter placement and hospital-stay of PV ≥100ml (3.1±1.3 and 5.6±2.3 days) were not different from PV <100ml (2.7±1.2 and 5.0±2.4 days). In uncatheterised patients (N = 59), post-void residual urine volume (PVR) significantly decreased after surgery in both groups, however, maximum uroflow rate (Qmax) significantly increased after surgery only in PV <100ml but not in PV ≥100ml. Voiding symptoms and patients' QoL derived from International Prostate Symptom Score (IPSS), IPSS-QoL (IPSS Quality of Life Index) and BPH Impact Index (BII) scores, significantly improved after B-TUVP in both groups. Catheter free status after final B-TUVP among patients with preoperative urinary retention was achieved in 18/24 (75.0%) and 14/17 (82.1%) cases in patient with <100ml and ≥100ml, respectively. There was no significant difference in post-operative Hb after B-TUVP, which was 97.0±5.4% of baseline for PV <100ml and 96.9±6.1% for PV ≥100ml and no TUR syndrome was observed. CONCLUSIONS: This is the first study investigating short-term efficacy and safety of second-generation B-TUVP with the oval-shaped electrode on large BPE. B-TUVP appears to be effective and safe for treating moderate-to-severe lower urinary tract symptoms and urinary retention in patients with large BPE.

A Systematic Review of Patients' Values, Preferences, and Expectations for the Diagnosis and Treatment of Male Lower Urinary Tract Symptoms.

CONTEXT: Understanding men's values and preferences in the context of personal, physical, emotional, relational, and social factors is important in optimising patient counselling, facilitating treatment decision-making, and improving guideline recommendations. OBJECTIVE: To systematically review the available evidence regarding the values, preferences, and expectations of men towards the investigation and treatment (conservative, pharmacological, and surgical) of male lower urinary tract symptoms (LUTS). EVIDENCE ACQUISITION: We searched electronic databases until August 31, 2020 for quantitative and qualitative studies that reported values and preferences regarding the investigation and treatment of LUTS in men. We assessed the quality of evidence and risk of bias using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) and GRADE Confidence in the Evidence from Reviews of Qualitative Research (CERQual) approaches. EVIDENCE SYNTHESIS: We included 25 quantitative studies, three qualitative studies, and one mixed-methods study recruiting 9235 patients. Most men reported urodynamic testing to be acceptable, despite discomfort or embarrassment, as it significantly informs treatment decisions (low certainty evidence). Men preferred conservative and less risky treatment options, but the preference varied depending on baseline symptom severity and the risk/benefit characteristics of the treatment (moderate certainty). Men preferred pharmacological treatments with a low risk of erectile dysfunction and those especially improving urgency incontinence (moderate certainty). Other important preference considerations included reducing the risk of acute urinary retention or surgery (moderate certainty). CONCLUSIONS: Men prefer lower-risk management options that have fewer sexual side effects and are primarily effective at improving urgency incontinence and nocturia. Overall, the evidence was rated to be of low to moderate certainty. This review can facilitate the treatment decision-making process and improve the trustworthiness of guideline recommendations. PATIENT SUMMARY: We thoroughly reviewed the evidence addressing men's values and preferences regarding the management of urinary symptoms and found that minimising adverse effects is particularly important. Further research to understand other factors that matter to men is required.

Fibrosis and the bladder, implications for function ICI-RS 2017.

AIMS: Most benign bladder pathologies are associated with an increase of extracellular matrix (ECM-fibrosis) and may progress from formation of stiffer matrix to a more compliant structure. The aims were to summarize current knowledge of the origins of bladder fibrosis and consequences in bladder function. METHODS: A meeting at the International Consultation on Incontinence Research Society 2017 congress discussed the above aims and considered paradigms to reduce the extent of fibrosis. Discussants based their arguments on the basis of their own expertise, supplemented by review of the literature through PubMed. Proposals for future work were derived from the discussion. RESULTS: Altered urodynamic compliance when ECM deposition is increased is mirrored by changes in the elastic modulus of isolated tissue, whether compliance is decreased or increased. No changes to compliance or fibrosis have been reported after botulinum toxin injections. Several paracrine and autocrine agents increase ECM deposition, the role of TGF-ß was particularly emphasized. None of these agents has a net long-term effect on detrusor contractility and the reduction of contractile performance with increased ECM is due solely to a loss of detrusor mass. Several strategies to reduce fibrosis were described, ranging from potential therapeutic roles for vitamin-D or endostatin, manipulation of intracellular pathways that mediate myofibroblast differentiation and the potential role of the anti-fibrotic hormone relaxin. An understanding of epigenetic regulation of ECM deposition was also considered. CONCLUSIONS: The conclusion that reduced bladder contractile function with increased fibrosis is due largely to the replacement of detrusor with ECM offers a way forward for future research to consider approaches that will restore bladder function by reducing ECM deposition.

Male synthetic sling versus artificial urinary sphincter trial for men with urodynamic stress incontinence after prostate surgery (MASTER): study protocol for a randomised controlled trial.

BACKGROUND: Stress urinary incontinence (SUI) is a frequent adverse effect for men undergoing prostate surgery. A large proportion (around 8% after radical prostatectomy and 2% after transurethral resection of prostate (TURP)) are left with severe disabling incontinence which adversely effects their quality of life and many are reliant on containment measures such as pads (27% and 6% respectively). Surgery is currently the only option for active management of the problem. The overwhelming majority of surgeries for persistent bothersome SUI involve artificial urinary sphincter (AUS) insertion. However, this is expensive, and necessitates manipulation of a pump to enable voiding. More recently, an alternative to AUS has been developed - a synthetic sling for men which elevates the urethra, thus treating SUI. This is thought, by some, to be less invasive, more acceptable and less expensive than AUS but clear evidence for this is lacking. The MASTER trial aims to determine whether the male synthetic sling is non-inferior to implantation of the AUS for men who have SUI after prostate surgery (for cancer or benign disease), judged primarily on clinical effectiveness but also considering relative harms and cost-effectiveness. METHODS/DESIGN: Men with urodynamic stress incontinence (USI) after prostate surgery, for whom surgery is judged appropriate, are the target population. We aim to recruit men from secondary care urological centres in the UK NHS who carry out surgery for post-prostatectomy incontinence. Outcomes will be assessed by participant-completed questionnaires and 3-day urinary bladder diaries at baseline, 6, 12 and 24 months. The 24-h urinary pad test will be used at baseline as an objective assessment of urine loss. Clinical data will be completed at the time of surgery to provide details of the operative procedures, complications and resource use in hospital. At 12 months, men will also have a clinical review to evaluate the results of surgery (including another 24-h pad test) and to identify problems or need for further treatment. DISCUSSION: A robust examination of the comparative effectiveness of the male synthetic sling will provide high-quality evidence to determine whether or not it should be adopted widely in the NHS. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Registry: Number ISRCTN49212975 . Registered on 22 July 2013. First patient randomised on 29 January 2014.

Medical Treatment of Nocturia in Men with Lower Urinary Tract Symptoms: Systematic Review by the European Association of Urology Guidelines Panel for Male Lower Urinary Tract Symptoms.

CONTEXT: The treatment of nocturia is a key challenge due to the multi-factorial pathophysiology of the symptom and the disparate outcome measures used in research. OBJECTIVE: To assess and compare available therapy options for nocturia, in terms of symptom severity and quality of life. EVIDENCE ACQUISITION: Medical databases (Embase, Medline, Cochrane Systematic Reviews, Cochrane Central) were searched with no date restriction. Comparative studies were included which studied adult men with nocturia as the primary presentation and lower urinary tract symptoms including nocturia or nocturnal polyuria. Outcomes were symptom severity, quality of life, and harms. EVIDENCE SYNTHESIS: We identified 44 articles. Antidiuretic therapy using dose titration was more effective than placebo in relation to nocturnal voiding frequency and duration of undisturbed sleep; baseline serum sodium is a key selection criterion. Screening for hyponatremia (< 130 mmol/l) must be undertaken at baseline, after initiation or dose titration, and during treatment. Medications to treat lower urinary tract dysfunction (α-1 adrenergic antagonists, 5-α reductase inhibitors, phosphodiesterase type 5inhibitor, antimuscarinics, beta-3 agonist, and phytotherapy) were generally not significantly better than placebo in short-term use. Benefits with combination therapies were not consistently observed. Other medications (diuretics, agents to promote sleep, nonsteroidal anti-inflammatories) were sometimes associated with response or quality of life improvement. The recommendations of the Guideline Panel are presented. CONCLUSIONS: Issues of trial design make therapy of nocturia a challenging topic. The range of contributory factors relevant in nocturia makes it desirable to identify predictors of response to guide therapy. Consistent responses were reported for titrated antidiuretic therapy. For other therapies, responses were less certain, and potentially of limited clinical benefit. PATIENT SUMMARY: This review provides an overview of the current drug treatments of nocturia, which is the need to wake at night to pass urine. The symptom can be caused by several different medical conditions, and measuring its severity and impact varies in separate research studies. No single treatment deals with the symptom in all contexts, and careful assessment is essential to make suitable treatment selection.

Voiding dysfunction due to detrusor underactivity: an overview.

Detrusor underactivity (DUA) is defined as a voiding contraction of reduced strength and/or duration, which prolongs urination and/or prevents complete emptying of the bladder within a 'normal' period of time. This issue is associated with voiding and postmicturition urinary symptoms, and can predispose to urinary infections and acute urinary retention. The aetiology of DUA is influenced by multiple factors, including ageing, bladder outlet obstruction, neurological disease, and autonomic denervation. The true prevalence of this condition remains unknown, as most data come from referral populations. Urodynamic testing is used to diagnose the condition, either by assessing the relationship between bladder pressures and urinary flow, or by interrupting voiding to measure detrusor pressure change under isovolumetric conditions. Current treatments for DUA have poor efficacy and tolerability, and often fail to improve quality of life; muscarinic receptor agonists, in particular, have limited efficacy and frequent adverse effects. Bladder emptying might be achieved through Valsalva straining, and intermittent or indwelling catheterization, although sacral nerve stimulation can reduce dependency on catheterization. Novel stem-cell-based therapies have been attempted; however, new drugs that increase contractility are currently largely conceptual, and the complex pathophysiology of DUA, difficulty achieving organ specificity of treatment, the limited availability of animal models, and the subjective nature of current outcome measures must be addressed to facilitate the development of such agents.

Success rates for learning intermittent self-catheterisation according to age and gender.

PURPOSE: Voiding dysfunction becomes increasingly prevalent with ageing. Clean intermittent self-catheterisation (ISC) is associated with a lower morbidity than indwelling transurethral or suprapubic catheterisation. However, doctors and patients sometimes fail to consider ISC as an option because of a perception it will be unmanageable or poorly tolerated. This study aimed to determine how age and gender affect the success rates of patients being taught ISC. METHODS: Six years retrospective study (January 2004-January 2010) of non-neurogenic patients referred to be taught ISC by urology specialist nurses in a tertiary referral hospital. Patients were sent information about ISC in advance of their appointment, were given additional information at the appointment, received training under supervision and had access to follow-on support. Successful patients were those who continued to perform the technique independently at 6-week follow-up. RESULTS: Three hundred and nine patients (209 men, 100 women) with a mean age of 63 years (range 17-95 years) were taught ISC during the study period and had documented follow-up. The main reasons for needing ISC were incomplete bladder emptying (46%), urethral stricture disease (20%) and inability to void (18%). The overall ISC success rate was 84% for all age groups, 86% for patients under the age of 65 and 82% for those aged 65 years and over. Men had a higher success rate than women (88 and 76%, respectively). CONCLUSIONS: Older patients can successfully be taught ISC in a high proportion, and it can be offered as an alternative to an indwelling catheter irrespective of age.

Emerging drugs for treatment of overactive bladder and detrusor overactivity.

BACKGROUND: Overactive bladder (OAB) signifies the presence of urinary urgency and can have major effects on quality of life and social functioning. Standard antimuscarinic drugs have good initial response rates but substantial adverse effects and long-term compliance problems. OBJECTIVES: To review the complexities of the mechanisms underlying OAB and the current drugs available for treating its symptoms. METHODS: The literature was reviewed to define current therapies and drugs in clinical trials. Articles were identified by means of a computerised PubMed and Cochrane Library search (using the following keywords: overactive bladder, detrusor overactivity, urgency and bladder), supported by a search of the PharmaProjects database. CONCLUSIONS: New drug classes, such as beta-3 adrenergic agonists, may work by reducing contractility or excitability of bladder muscle. Moderation of afferent activity may allow improved OAB symptoms, with lower risk of affecting voiding function. Agents acting on the CNS could influence OAB favourably, but target selection and adverse effects are an issue. The recognition of the functional contribution of the urothelium and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of OAB pathophysiology.