Pirfenidone improves voiding function by suppressing bladder fibrosis in underactive bladder rats.

Underactive bladder (UAB), characterized by a complex set of symptoms with few treatment options, can significantly reduce the quality of life of affected people. UAB is characterized by hyperplasia and fibrosis of the bladder wall as well as decreased bladder compliance. Pirfenidone is a powerful anti-fibrotic agent that inhibits the progression of fibrosis in people with idiopathic pulmonary fibrosis. In the current study, we evaluated the efficacy of pirfenidone in the treatment of bladder fibrosis in a UAB rat model. UAB was induced by crushing damage to nerve bundles in the major pelvic ganglion. Forty-two days after surgery, 1 mL distilled water containing pirfenidone (100, 300, or 500 mg/kg) was orally administered once every 2 days for a total of 10 times for 20 days to the rats in the pirfenidone-treated groups. Crushing damage to the nerve bundles caused voiding dysfunction, resulting in increased bladder weight and the level of fibrous related factors in the bladder, leading to UAB symptoms. Pirfenidone treatment improved urinary function, increased bladder weight and suppressed the expression of fibrosis factors. The results of this experiment suggest that pirfenidone can be used to ameliorate difficult-to-treat urological conditions such as bladder fibrosis. Therefore, pirfenidone treatment can be considered an option to improve voiding function in patient with incurable UAB.

Underactive bladder, Fowler's syndrome are potentially curable by uterosacral ligament repair.

Underactive bladder (UAB) is essentially an inability of the bladder to properly empty. UAB symptoms, when they co-occur with posterior fornix syndrome (PFS) symptoms (urge, frequency, nocturia, chronic pelvic pain), can be cured/improved, surgically by uterosacral ligament (USL) repair, non-surgically, by devices which give mechanical support of the USLs or strengthening pelvic muscle and ligaments with squatting-based exercises. The pathogenic pathway from weak USLs to UAB (and PFS) is that, when the muscles which externally open the posterior wall of the urethra contract against lax USLs, their contractile force weakens, and they cannot open the urethra adequately. The detrusor then contracts against a relatively unopened urethra to cause obstructive symptoms (i.e., UAB) such as slow stream, intermittent stream (stopping and starting), hesitancy (difficulty starting), feeling of incomplete emptying, and post-micturition dribble. Co-occurrence of PFS symptoms indicates that UAB may be part of the PFS, with USL causation, which can be tested by a tampon or probe in the posterior fornix. If the emptying (and other) PFS symptoms improve, it is a sign that UAB, and Fowler's syndrome (FS) can potentially be cured or improved by USL repair. Following USL repair, many studies have recorded very significant improvement in emptying symptoms, and objective tests, for example, postvoid residual (PVR), decreased natural bladder volume, and decreased emptying time. FS and UAB are most likely a part of the PFS and, therefore, potentially curable by USL repair.

Summary Paper on Underactive Bladder from the European Association of Urology Guidelines on Non-neurogenic Male Lower Urinary Tract Symptoms.

BACKGROUND AND OBJECTIVE: The European Association of Urology (EAU) Guidelines Panel on non-neurogenic male lower urinary tract symptoms (LUTS) aimed to develop a new subchapter on underactive bladder (UAB) in non-neurogenic men to inform health care providers of current best evidence and practice. Here, we present a summary of the UAB subchapter that is incorporated into the 2024 version of the EAU guidelines on non-neurogenic male LUTS. METHODS: A systematic literature search was conducted from 2002 to 2022, and articles with the highest certainty evidence were selected. A strength rating has been provided for each recommendation according to the EAU Guideline Office methodology. KEY FINDINGS AND LIMITATIONS: Detrusor underactivity (DU) is a urodynamic diagnosis defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span. UAB is a terminology that should be reserved for describing symptoms and clinical features related to DU. Invasive urodynamics is the only widely accepted method for diagnosing DU. In patients with persistently elevated postvoid residual (ie, >300 ml), intermittent catheterization is indicated and preferred to indwelling catheters. Alpha-adrenergic blockers are recommended before more invasive techniques, but the level of evidence is low. In men with DU and concomitant benign prostatic obstruction (BPO), benign prostatic surgery should be considered only after appropriate counseling. In men with DU and no BPO, a test phase of sacral neuromodulation may be considered. CONCLUSIONS AND CLINICAL IMPLICATIONS: The current text represents a summary of the new subchapter on UAB. For more detailed information, refer to the full-text version available on the EAU website (https://uroweb.org/guidelines/management-of-non-neurogenic-male-luts). PATIENT SUMMARY: The European Association of Urology guidelines on underactive bladder in non-neurogenic adult men are presented here. Patients must be fully informed of all relevant options and, together with their treating physicians, decide on the most optimal management for them.

Novel clinical diagnostic criteria based on noninvasive examination findings to predict the presence of urodynamic detrusor underactivity in men.

AIMS: To investigate the usefulness of novel clinical diagnostic criteria based on noninvasive examination findings to diagnose urodynamic detrusor underactivity (DU) in men. METHODS: We developed clinical diagnostic criteria to predict the presence of urodynamic DU in men as follows: (a) bladder voiding efficiency <70% on uroflowmetry, (b) existence of "sawtooth and interrupted waveforms" on uroflowmetry, and (c) ultrasonography-documented intravesical prostatic protrusion <10 mm. We analyzed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these clinical criteria for diagnosing urodynamic DU in men aged 50 years or above with lower urinary tract symptoms who underwent urodynamic studies. RESULTS: Of the 314 men analyzed (mean age, 72.4 years; mean detrusor contraction index [DCI], 98.8; and mean bladder outlet obstruction index [BOOI], 43.9), 89 men met this clinical DU diagnostic criteria. Of these, 79 men (88.8%) had urodynamic DU (DCI < 100 and BOOI < 40), nine (10.1%) had DU + BOO (DCI < 100 and BOOI ≥ 40), and one (1.1%) had normal voiding functions. None of the men with urodynamic BOO (DCI ≥ 100 and BOOI ≥ 40) met the clinical DU diagnostic criteria. The sensitivity, specificity, PPV, and NPV of these clinical diagnostic criteria for urodynamic DU were 69.3%, 95.0%, 88.8%, and 84.4%, respectively. CONCLUSION: The proposed clinical DU diagnostic criteria showed a high PPV (88.8%) for diagnosing urodynamic DU. None of the patients with BOO met the clinical diagnostic criteria for DU. These clinical DU diagnostic criteria may be useful in identifying men with urodynamic DU in clinical practice.

How do we make progress in phenotyping patients with LUT such as OAB and underactive detrusor, including using urine markers and microbiome data, in order to personalize therapy? ICI-RS 2023: Part 1.

INTRODUCTION: Overactive bladder (OAB) and Underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction. OBJECTIVES: The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment. METHODS: A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU investigating metabolic, neurogical, psychological and gastrointestinal aspects with the aim to personalize the treatment. RESULTS AND CONCLUSIONS: The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract symptoms, such as OAB and UAB. The intricate interplay between the lower urinary tract and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one-size-fits-all approach.

How do we make progress in phenotyping patients with lower urinary tract such as overactive bladder and underactive detrusor, including using urine markers and microbiome data, to personalize therapy? ICI-RS 2023-Part 2.

INTRODUCTION: Overactive bladder (OAB) and underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction. OBJECTIVES: The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment. METHODS: A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU using urodynamic tests, functional neuro-imaging, urinary markers, and microbiome. RESULTS AND CONCLUSIONS: The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract (LUT) symptoms, such as OAB and UAB. The intricate interplay between the LUT and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one-size-fits-all approach.

Regional variation in urinary catheter use in the Netherlands from 2012 to 2021: a population-based cohort.

Objectives: Our aim was to evaluate trends and regional differences in the use of indwelling and intermittent urinary catheters in the community setting in the Netherlands from 2012 to 2021. Design and methods: For this population-based cohort study, data on catheter use was collected from the Drug and Medical Devices Information System of the National Healthcare Institute of the Netherlands. This database contains information on the Dutch insured population, which was 100% of the total population in 2018. Users were divided into 12 provinces according to the Nomenclature of Territorial Units for Statistics codes. The number of catheter users was adjusted for the total population of the provinces by sex and age, and was expressed by users per 100,000 people. Negative binomial regression (NBR) was used to test for differences in clean intermittent catheter (CIC) and indwelling catheter (IDC) users across Dutch provinces. Results: Between 2012 and 2021, IDC users increased by 44.6% from 41,619 to 60,172, and CIC users increased by 27.3% from 34,204 to 43,528. The greatest increases were mainly observed among IDC users over 85 years old and male CIC users over 65 years old. NBR showed significant differences for IDC and CIC users between the 12 provinces. CIC incidence was higher in Drenthe and Groningen (Northern Netherlands) compared to Zuid-Holland (Southern Netherlands). IDC incidence was higher in seven provinces dispersed throughout the Netherlands compared to Noord-Holland. Conclusion: CIC and IDC users have continued to increase in recent years; this was especially observed among older men. In addition, there were regional differences in the number of CIC and IDC users; CIC was more prominent in the northern region of the Netherlands, and IDC varied between multiple provinces. Practice variation in urinary catheterization may result from patient population differences or healthcare provider preferences and their alignment with guidelines.

Underactive Bladder and Detrusor Underactivity: New Advances and Prospectives.

Underactive bladder (UAB) is a prevalent but under-researched lower urinary tract symptom that typically occurs alongside detrusor underactivity (DU). Unlike UAB, DU is a urodynamic diagnosis which the International Continence Society (ICS) defines as "a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span". Despite the widespread prevalence of UAB/DU, there are significant gaps in our understanding of its pathophysiological mechanisms, diagnosis, and treatment compared with overactive bladder (OAB) and detrusor overactivity (DO). These gaps are such that clinicians regard UAB/DU as an incurable condition. In recent years, the understanding of UAB has increased. The definition of UAB has been clarified, and the diagnostic criteria for DU have been considered more comprehensively. Meanwhile, a number of non-invasive diagnostic methods have also been reported. Clinical trials involving novel drugs, electrical stimulation, and stem cell therapy have shown promising results. Therefore, this review summarizes recent reports on UAB and DU and highlights the latest advances in their diagnosis and treatment.

Can we define the optimal postvoid residual volume at which intermittent catheterization should be recommended, and are there other measures that could guide an intermittent catheterization protocol: ICI-RS 2023.

AIMS: The postvoid residual (PVR) volume of urine in the bladder is widely used in clinical practice as a guide to initiate treatment, including clean-intermittent self-catheterization (CISC). It is often believed that an elevated PVR causes complications such as recurrent urinary tract infections (UTI) and renal failure. However, evidence for this is limited and identifying alternative measures to guide treatment decisions may optimize patient care. At the International Consultation on Incontinence Research Society (ICI-RS) meeting in 2023 a Think Tank addressed the question of whether we can define the optimal PVR at which CISC should be recommended, and whether there are other measures that could guide a CISC protocol. METHODS: The Think Tank conducted a literature review and expert consensus meeting focusing on current limitations in defining and measuring PVR, and highlighting other measures that may optimize selection for, and persistence with, CISC. RESULTS: There is no consensus on the threshold value of PVR that is considered "elevated" or "significant." There is a lack of standardization on terminology, and the normal range of PVR in different populations of different ages remains to be well-studied. The measurement of PVR is influenced by several factors, including intraindividual variation, timing and method of measurement. Furthermore, the evidence linking an elevated PVR with complications such as UTI and renal failure is mixed. Other measures, such as bladder voiding efficiency or urodynamic parameters, may be better at predicting such complications, and therefore may be more relevant at guiding a CISC protocol. CONCLUSIONS: There is a lack of high quality evidence to support PVR as a predictor for complications of UTI or renal failure. Threshold values for normal PVR in different populations are unknow, and so threshold values for "elevated" or "significant" PVR cannot be determined. Other factors, such as urodynamic findings, may be better at predicting complications and therefore guiding management decisions, and this remains to be studied. Areas for further research are proposed.

Transcriptomics Reveals Molecular Features of the Bilateral Pelvic Nerve Injury Rat Model of Detrusor Underactivity.

The pathogenesis of detrusor underactivity (DU) is unclear, and the available therapeutic effects are unsatisfactory. We propose to find key molecules and pathways related to DU based on transcriptome sequencing. A rat model of bilateral pelvic nerve injury (BPNI) was established. Bladder tissues from the sham-operated group, 3 and 28 days after BPNI mapping, were taken for urodynamics, histopathology, and RNA-seq. An enrichment analysis of the screened differential expression genes was performed. Three days after BPNI, the results showed urodynamic features of overflow incontinence, while there was a recovery at 28 days after the operation. Masson staining revealed collagen deposition accompanied by progressive thickening of the smooth muscle layer as DU progressed. RNA-seq results suggested that a total of 1808 differentially expressed genes (DEGs) differed among the groups. RNA-seq and subsequent analysis confirmed that the cell cycle and immune response were significantly activated 3 days after BPNI, while extracellular matrix remodeling occurred 28 days after BPNI. Partial DEGs and pathways were verified by qRT-PCR. Validation of key proteins involved in cell cycle, inflammation, and fibrosis was performed by immunohistochemical staining and western blot, respectively. These molecular expression patterns at different time points after BPNI injury provide valuable insights into the search for therapeutic targets for DU.

Retropubic tape surgery for stress urinary incontinence: can women be cured without voiding dysfunction?

PURPOSE: Retropubic tension free vaginal tape (RP-TVT) has become the gold standard for surgical management of female stress urinary incontinence but is associated with voiding dysfunction (VD). We developed for more than 10 years a reproductible and totally tension free tape procedure. Our goal is to determine efficiency of this technique compared to the incidence of VD. METHODS: We retrospectively reviewed patients who underwent RP-TVT in our center between 2011 and 2019. Subjective cure, VD (determined as maximum urinary flow rate (Qmax) < 15 mL/s or post void residual (PVR) volume > 150 mL, or tape's section or resection requirement for underactive bladder (UB) with significant PVR) was assessed at 1 year. The main objective was the evaluation of subjective cure and VD at 1 year. RESULTS: On the 319 patients reviewed, 93% of the patients were dry and 10.9% presented VD at one year. UB (OR = 5.01 [1.55-16.44], p = 0.008), preoperative Qmax < 15 mL/s (OR = 0.89 [0.84-0.95], p = 0.001) and previous incontinence surgery (OR = 4.20 [1.54-11.46], p = 0.005) were associated with VD. Acute urinary retention concerned 4.7% of the population and all were resolved after 6 weeks postoperatively. We reported 0.3% of de novo urgency and patients without VD showed a significant decrease of their voiding time at 1 year. CONCLUSION: The placement of RP-TVT without intraoperative tightening seems to be a safe technique ensuring a high cure rate and low occurrences of bladder outlet obstruction.

Characteristics of uroflowmetry patterns in men with detrusor underactivity revealed by artificial intelligence.

OBJECTIVES: To elucidate the characteristics of uroflowmetry (UFM) observed in men with detrusor underactivity (DU) using our developed artificial intelligence (AI) diagnostic algorithm to distinguish between DU and bladder outlet obstruction (BOO). METHODS: Subjective and objective parameters, including four UFM parameters (first peak flow rate, time to first peak, gradient to first peak, and the ratio of first peak flow rate to maximum flow rate [Qmax ]) selected by analyzing the judgment basis of the AI diagnostic system, were compared in 266 treatment-naive men with lower urinary tract symptoms (LUTS). Patients were divided into the DU (70; 26.32%) and non-DU (196; 73.68%) groups, and the UFM parameters for predicting the presence of DU were determined by multivariate analysis and receiver operating characteristic (ROC) curve analysis. Detrusor underactivity was defined as a bladder contractility index <100 and a BOO index <40. RESULTS: Most parameters on the first peak flow of UFM were significantly lower in the DU group. On multivariate analysis, lower first peak flow rate and lower ratio of first peak flow rate to Qmax were significant parameters to predict DU. In the ROC analysis, the ratio of the first peak flow rate to Qmax showed the highest area under the curve (0.848) and yielded sensitivities of 76% and specificities of 83% for DU diagnosis, with cutoff values of 0.8. CONCLUSIONS: Parameters on the first peak flow of UFM, especially the ratio of the first peak flow rate to Qmax , can diagnose DU with high accuracy in men with LUTS.

Wireless, Fully Implantable and Expandable Electronic System for Bidirectional Electrical Neuromodulation of the Urinary Bladder.

Current standard clinical options for patients with detrusor underactivity (DUA) or underactive bladder─the inability to release urine naturally─include the use of medications, voiding techniques, and intermittent catheterization, for which the patient inserts a tube directly into the urethra to eliminate urine. Although those are life-saving techniques, there are still unfavorable side effects, including urinary tract infection (UTI), urethritis, irritation, and discomfort. Here, we report a wireless, fully implantable, and expandable electronic complex that enables elaborate management of abnormal bladder function via seamless integrations with the urinary bladder. Such electronics can not only record multiple physiological parameters simultaneously but also provide direct electrical stimulation based on a feedback control system. Uniform distribution of multiple stimulation electrodes via mesh-type geometry realizes low-impedance characteristics, which improves voiding/urination efficiency at the desired times. In vivo evaluations using live, free-moving animal models demonstrate system-level functionality.

[Uroflowmetry: A follow-up tool for neurogenic bladder patients treated by transcutaneous tibial posterior stimulation?] / Débitmétrie : outil de suivi chez les patients avec vessie neurologique traités par neurostimulation tibiale postérieure ?

OBJECTIVE: Neurogenic bladders can suffer from overactivity, underactivity or dyssynergia depending on the level of the initial lesion. These symptoms can lead to severe alterations of the upper urinary tract. One of the first-line treatments is the transcutaneous tibial posterior stimulation (TTNS), which was demonstrated to be efficient on urodynamics. But it is an invasive, expensive and sometimes not patient-accepted examination, contrary to the uroflowmetry. The aim of this study is to assess the feasibility of a follow-up with a uroflowmetry when treated by TTNS and show that the maximum flow rate increased after treatment, displaying a better detrusor contraction. METHODS: In total, 38 patients with neurogenic bladder undergoing a 12-weeks TTNS treatment and with 2 uroflowmetries interpretable before and after treatment were included. The maximum flow rate (Qmax), the urinated volume and the post-void residual (PVR) were retrieved from the uroflowmetry, and the USP-score and the urinary discomfort were asked at each appointment. RESULTS: Qmax is increased from 17,53ml/s to 18,26ml/s, as well as the PVR (from 76,97ml to 79,16ml). Urinated volume is decreased from 241,4ml to 193,66ml. Patients feel enhanced after TTNS according to the decrease in the USP-score and the urinary discomfort scale. CONCLUSION: The increase of the cystomanometric capacity and the delay of the detrusor overactivity due to TTNS explains the reduction of the urinated volume and the increase of PVR. Increased Qmax might show a better voluntary bladder contraction, with a restraint due to the lack of abdominal pressure measurement during voiding.

The role of transurethral resection of prostate (TURP) in patients with underactive bladder: 12 months follow-up in different grades of detrusor contractility.

INTRODUCTION AND OBJECTIVE: Male detrusor underactivity (DUA) definition remains controversial and no effective treatment is consolidated. Transurethral resection of the prostate (TURP) is one of the cornerstones surgical treatments recommended in bladder outlet obstruction (BOO). However, the role of prostatic surgery in male DUA is not clear. The primary endpoint was the clinical and voiding improvement based on IPSS and the maximum flow rate in uroflowmetry (Qmax) within 12 months. MATERIALS AND METHODS: We analyzed an ongoing prospective database that embraces benign prostata hyperplasia (BPH) male patients with lower urinary tract symptoms who have undergone to TURP. All patients were evaluated pre and postoperatively based on IPSS questionnaires, prostate volume measured by ultrasound, postvoid residual urine volume (PVR), Prostate Specific Antigen measurement and urodynamic study (UDS) before the procedure. After surgery, all patients were evaluated at 1-, 3-, 6- and 12-months. Patients were categorized in 3 groups: Group 1-Detrusor Underactive (Bladder Contractility Index (BCI) [BCI] < 100 and BOO index [BOOI] < 40); Group 2-Detrusor Underactive and BOO (BCI < 100 and BOOI ≥ 40); Group 3-BOO (BCI ≥ 100 and BOOI ≥ 0). RESULTS: It was included 158 patients underwent monopolar or bipolar TURP since November 2015 to March 2021. According to UDS, patients were categorized in: group 1 (n = 39 patients); group 2 (n = 41 patients); group 3 (n = 77 patients). Preoperative IPSS was similar between groups (group 1-24.9 ± 6.33; group 2-24.8 ± 7.33; group 3-24.5 ± 6.23). Qmax was statistically lower in the group 2 (group 1-5.43 ± 3.69; group 2-3.91 ± 2.08; group 3-6.3 ± 3.18) as well as greater PVR. The 3 groups presented similar outcomes regard to IPSS score during the follow-up. There was a significant increase in Qmax in the 3 groups. However, group 1 presented the lowest Qmax improvement. CONCLUSION: There were different objective outcomes depending on the degree of DUA at 12 months follow-up. Patients with DUA had similar IPSS improvement. However, DUA patients had worst Qmax improvement than men with normal bladder contraction.

The Efficacy of Transvaginal Ultrasound-Guided BoNT-A External Sphincter Injection in Female Patients with Underactive Bladder.

Owing to the diverse treatment outcomes after a botulinum toxin A (BoNT-A) injection to the external sphincter, this study aimed to develop a new technique: an ultrasound-guided BoNT-A external sphincter injection. This single-center prospective cohort study was conducted at a tertiary medical center in Taichung, Taiwan. From December 2020 to September 2022, 12 women were enrolled. The patients were evaluated for lower urinary tract syndrome using patient perception of bladder condition (PPBC), international prostate symptom score (IPSS), uroflowmetry, post-void residual volume (PVR), cystometry, and external sphincter electromyography. We evaluated the patients the day before surgery and 1 week after the BoNT-A injection. For the patients requiring self-catheterization, we recorded the number of times they required clean intermittent catheterization (CIC) per day before the procedure and 1 month after the procedure. The IPSS, PPBC, and PVR were significantly better after the transvaginal ultrasound-guided BoNT-A external sphincter injection. The number of times the patients required daily CIC was also reduced after the injection. Only one patient developed de novo urge urinary incontinence. Our results demonstrated that a transvaginal ultrasound-guided BoNT-A injection was efficacious and safe in the treatment of underactive bladder.

The role of intracellular calcium and Rho kinase pathways in G protein-coupled receptor-mediated contractions of urinary bladder urothelium and lamina propria.

The influence of extracellular and intracellular calcium on smooth muscle contractile activity varies between organs. In response to G protein-coupled receptor (GPCR) stimulation, the urinary bladder detrusor muscle has shown a 70% dependence on extracellular calcium, whereas the urothelium and lamina propria (U&LP) has a 20%-50% dependence. However, as this only accounts for partial contractile activity, the contribution of intracellular calcium and calcium sensitization pathways remains unclear. This study assessed the role of intracellular signaling pathways on GPCR-mediated urinary bladder U&LP contraction. Porcine U&LP responses to activation of the Gq/11-coupled muscarinic, histamine, 5-hydroxytryptamine (serotonin), neurokinin, prostaglandin, and angiotensin II receptors were assessed with three selective inhibitors of store-released intracellular calcium, 2-aminoethyl diphenylborinate (2-APB), cyclopiazonic acid (CPA), and ruthenium red, and three Rho kinase inhibitors, fasudil, Y-27632, and GSK269962. There was no discernible impact on receptor agonist-induced contractions of the U&LP after blocking intracellular calcium pathways, suggesting that this tissue is more sensitive to alterations in the availability of extracellular calcium. However, an alternative mechanism of action for GPCR-mediated contraction was identified to be the activation of Rho kinase, such as when Y-27632 significantly reduced the GPCR-mediated contractile activity of the U&LP by approximately 50% (P < 0.05, n = 8). This suggests that contractile responses of the bladder U&LP do not involve a significant release of calcium from intracellular stores, but that Gq/11-coupled receptor activation causes calcium sensitization via Rho kinase. This study highlights a key role for Rho kinase in the urinary bladder, which may provide a novel target in the future pharmaceutical management of bladder contractile disorders.

Prospective, Randomized, Double-blind, Placebo-controlled, Pilot Study of Extracorporeal Shock Wave Therapy for Detrusor Underactivity/Underactive Bladder.

BACKGROUND: Detrusor underactivity/underactive bladder (DU/UAB) is a disease with great unmet needs and no current approved drug treatment. Extracorporeal shock wave therapy (ESWT) has been shown to improve regeneration of tissue and increase detrusor contractility in preclinical studies of DU/UAB. OBJECTIVE: To assess ESWT as a treatment of DU/UAB. DESIGN, SETTING, AND PARTICIPANTS: Patients with DU/UAB were enrolled in this phase 2 randomized, double-blind, placebo-controlled, physician-initiated study. INTERVENTION: The patients were assigned to ESWT (N = 6, 2500 shocks, frequency of four pulses per second, and maximum total energy flow density of 0.25 mJ/mm2) once a week for 6 wk at the suprapubic bladder area or to placebo (N = 5, shock wave setting without energy transmission). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the average changes in postvoid residual urine (PVR) from baseline to 4 wk after treatment. Other endpoints included the average changes in 3-d voiding diary, global response assessment of patient satisfaction, Underactive Bladder Questionnaire (UAB-Q) score, and urodynamic evaluation. RESULTS AND LIMITATIONS: The difference in improvement in PVR was -157.8 ml (95% confidence interval [CI]: -380.1, 64.4) versus -6.6 ml (95% CI: -178.1, 164.9) and -77.5 ml (95% CI: -242.1, 87.1) versus 81.8 ml (95% CI: -137.2, 300.7) for ESWT versus placebo (p = 0.116 and 0.056) at 4 and 12 wk, respectively. The ESWT group exhibited a significant reduction in the UAB-Q score (-4.3; 95% CI: -9.1, 0.4) compared with the placebo group (-0.4; 95% CI: -1.8, 1.0) at 4 wk after treatment (p = 0.025), and the effects were decreased at 12 wk (p = 0.091). This study was limited by small sample size. CONCLUSIONS: ESWT was well tolerated with a statistically significant decrease of DU/UAB symptoms and a trend to decrease PVR versus placebo. These results indicate that ESWT may be a promising treatment for DU/UAB and multicenter studies are needed. PATIENT SUMMARY: Bladder shock wave therapy was studied in this randomized, double-blind, placebo-controlled study in patients with inadequate bladder emptying (underactive bladder). Bladder shock wave therapy was found to be well tolerated with an improvement in bladder emptying. These results indicate that bladder shock wave therapy may be a promising treatment for patients who cannot empty their bladder adequately.

Two-Staged Sacral Neuromodulation for the Treatment of Nonobstructive Urinary Retention: A Multicenter Study Assessing Predictors of Success.

OBJECTIVES: The aims of this study were to 1) determine the success rate of the tined lead test phase in patients with nonobstructive urinary retention (NOUR), 2) determine predictive factors of a successful test phase in patients with NOUR, and 3) determine long-term treatment efficacy and satisfaction in patients with NOUR. MATERIALS AND METHODS: The first part was a multicenter retrospective study at two centers in The Netherlands. Patients with NOUR received a four-week tined lead test phase. Success was defined as a ≥50% reduction of clean intermittent catheterization frequency or postvoid residual. We analyzed possible predictors of success with multivariable logistic regression. Second, all patients received a questionnaire to assess efficacy, perceived health (Patient Global Impression of Improvement), and treatment satisfaction. RESULTS: This study included 215 consecutive patients (82 men and 133 women) who underwent a tined lead test phase for the treatment of NOUR. The success rate in women was significantly higher than in men, respectively 62% (83/133) and 22% (18/82, p < 0.001). In women, age per ten years (odds ratio [OR] 0.74, 95% CI: 0.59-0.93) and a history of psychiatric illness (OR 3.92, 95% CI: 1.51-10.2), including posttraumatic stress disorder (PTSD), significantly predicted first stage sacral neuromodulation (SNM) success. In men, age per ten years (OR 0.43, 95% CI: 0.25-0.72) and previous transurethral resection of the prostate and/or bladder neck incision (OR 7.71, 95% CI: 1.43-41.5) were significant predictors of success. Conversely, inability to void during a urodynamic study (for women, OR 0.79, 95% CI: 0.35-1.78; for men, OR 3.06, 95% CI: 0.83-11.3) was not predictive of success. Of the patients with a successful first stage, 75% (76/101) responded to the questionnaire at a median follow-up of three years. Of these patients, 87% (66/76) continued to use their SNM system, and 92% (70/76) would recommend SNM to other patients. CONCLUSIONS: A history of psychiatric illness, including PTSD, in women with NOUR increased the odds of first stage SNM success 3.92 times. A previous transurethral resection of the prostate and/or bladder neck incision in men increased the odds of success 7.71 times. In addition, a ten-year age increase was associated with an OR of 0.43 in men and 0.74 in women, indicating a 2.3- and 1.3-times decreased odds of success, respectively.