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.

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.

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.

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.

Randomized controlled trial of intravesical electrical stimulation for underactive bladder.

AIM: To evaluate the efficacy and safety of intravesical electrical stimulation (IVES) performed with a novel device in patients with underactive bladder (UAB). PATIENTS AND METHODS: This was a multicentre, prospective, single-blind, randomized controlled clinical trial of patients with UAB in China. Eligible patients were randomly assigned in a 1:1 ratio to receive conventional IVES (n = 38) or IVES with an open circuit (n = 38). The primary efficacy measure was change from baseline in post-void residual urine volume (PVR) after 4 weeks of treatment. Secondary efficacy measures included changes in maximum urinary flow rate (Qmax ), bladder voiding efficiency (BVE), number of 24-h clean intermittent catheterization (CIC) procedures, and Patient Perception of Bladder Condition-Scale (PPBC-S) and American Urological Association Symptom Index Quality of Life (AUA-SI-QoL) scores from baseline after 4 weeks of treatment. Adverse events (AEs) were monitored throughout the trial. RESULTS: In the full analysis set (FAS), the mean (sd) PVR changes in the trial and control groups at 4 weeks were -97.1 (107.5) mL and -10.5 (86.7) mL, respectively (P < 0.01). Similar results were obtained in the per-protocol set (PPS): -102.9 (100.0) mL vs 0.7 (82.5) mL (P < 0.01). In the FAS and PPS, Qmax improved significantly at 4 weeks (P = 0.04 and P = 0.03). In the FAS and PPS, BVE was significantly improved at 4 weeks in the two groups (P < 0.01 and P < 0.01), whereas no significant differences in the number of 24-h CIC procedures, PPBC-S score or AUA-SI-QoL score were observed between the groups. Six possible therapy-related AEs occurred in six patients (four in the trial group and two in the control group; P = 0.67), all of which were urinary tract infections. No severe AEs were reported. CONCLUSIONS: The results of this clinical study strongly demonstrate that UAB patients benefit from this novel IVES device. More research is needed to validate the clinical utility of this device.

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.

Two types of detrusor underactivity in men with nonneurogenic lower urinary tract symptoms.

AIMS: To clarify the clinical features of men with nonneurogenic detrusor underactivity (DU) by focusing on storage dysfunction (SD). METHODS: We retrospectively reviewed the clinical and urodynamic data of men with nonneurogenic DU. Patients were divided into two groups according to the presence or absence of SD, such as detrusor overactivity (DO) and reduced bladder compliance (BC). Patient characteristics, lower urinary tract symptoms (LUTS), and urodynamic parameters were compared. DU was defined as bladder contractility index (BCI) ≤ 100 and bladder outlet obstruction index (BOOI) ≤ 40. RESULTS: Of 212 men with DU, 123 (58.0%) had concomitant SD (SD + DU group), and 89 (42.0%) had only DU (DU-only group). Age, prostate volume, and severity of storage symptoms were significantly higher in the SD + DU group. Particularly, >80% of men in the SD + DU group met the diagnostic criteria for overactive bladder in Japan, which was significantly higher than the 26% of men in the DU-only group. The frequency of urinary urgency incontinence (UUI) was also significantly higher in the SD + DU group (65% vs. 12% in DU-only group). In contrast, voiding symptoms, including straining, were more severe in the DU-only group. Regarding the urodynamic parameters, compared to the DU-only group, bladder capacity was significantly smaller and BOOI and BCI were significantly higher in the SD + DU group. However, there was no significant difference in the maximum flow rate and bladder voiding efficiency. CONCLUSIONS: Approximately 60% of men with DU had SD, such as DO and/or reduced BC, whereas the remaining 40% had increased bladder capacity without an increase in detrusor pressure during the storage phase. There were significant differences in the storage and voiding symptoms between the groups. It is important to divide patients with DU based on SD to accurately clarify the clinical picture of DU.

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.

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.

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.

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.

[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.

Efficacy of TAC-302 for patients with detrusor underactivity and overactive bladder: a randomized, double-blind, placebo-controlled phase 2 study.

PURPOSE: This multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluated the efficacy and safety of TAC-302, a novel drug that restores neurite outgrowth, in patients with detrusor underactivity (DU) and overactive bladder (OAB). METHODS: After 2-4 weeks of observation, patients were randomized 2:1 to receive oral TAC-302 200 mg or placebo twice daily for 12 weeks. The primary endpoint was detrusor contraction strength, estimated by bladder contractility index (BCI) for males and projected isovolumetric pressure 1 (PIP1) for females. Secondary endpoints included changes in bladder voiding efficiency (BVE) and safety. RESULTS: Seventy-six patients were included (TAC-302, n = 52; placebo, n = 24). The mean (standard deviation [SD]) BCI for males was 64.6 (16.6) at baseline and 75.2 (21.1) at week 12 (p < 0.001) with TAC-302 (n = 27), and 61.3 (16.6) and 60.5 (16.7) (p = 0.82) with placebo (n = 11). The respective mean (SD) PIP1 for females was 18.8 (6.6) and 29.4 (9.4) (p < 0.001) with TAC-302 (n = 15), and 20.6 (7.5) and 25.5 (9.6) (p = 0.14) with placebo (n = 7). TAC-302 significantly increased BCI in males and BVE in both sexes. TAC-302 efficacy on OAB was not clearly shown. The incidences of adverse events (AEs), serious AEs, and AEs leading to dose interruption were similar between groups; no adverse drug reactions occurred. CONCLUSION: Considering the significant effects on BCI in males and BVE in both sexes, TAC-302 may benefit patients with DU. REGISTRATION: ClinicalTrials.gov Identifier NCT03175029 registered 6/5/2017.

Sacral neuromodulation in patients with detrusor underactivity: Is biological sex an indicator?

OBJECTIVES: This study aimed to report sacral neuromodulation (SNM) outcomes in detrusor underactivity (DU). METHODS: A multicentric, multinational, retrospective case series was conducted between March 2017 and June 2021 in three different referral centers. Initial test phase stimulation included either a percutaneous nerve evaluation (PNE) or an advanced lead evaluation test phase (ALTP) before permanent SNM implantation. The test phases were performed under local anesthesia, either in the outpatient (PNE) or operating room (ALTP), in the prone position, which was implanted in the third or fourth sacral foramina under fluoroscopic guidance. Patients with favorable response to the initial test phase during the first 2 weeks underwent the implantable pulse generator (IPG) implantation (Medtronic neurostimulation generator device InterStim™). Favorable response was defined as ≥ 50% improvement in symptoms, frequency of clean intermittent catheterization (CIC) and/or decrease in postvoid residual (PVR), increase in voided volume, or improvement in bladder voiding efficiency (BVE) based on the bladder diary. RESULTS: Fifty-eight patients were recruited with a mean age of 39.95 ± 15.28 years. Among the 58 cases, 36 (62.1%) patients responded to the initial stage. Of these, 12 patients (30.8%) with non-neurogenic etiology and nine patients (52.9%) with neurologic etiology did not respond to the initial test phase; thus, they did not undergo full implantation (p = 0.141). Voided volume, PVR, and the median maximum flow rate (Qmax) improved significantly (p < 0.001) in both sexes; however, there was no statistical difference between both genders. Most female cases (78.3%), and nearly half of the men (51.4%), responded to the test phase and were candidates for the IPG phase. Among the 35 cases who underwent IPG, 27 patients (72.2% of males, and 77.8% of females; p = 0.700) had a favorable response to IPG. 46.6% of patients had a successful outcome at the end of the study. CONCLUSION: This multicentric study showed that SNM effectively and safely provided symptom improvement in refractory DU in males similar to females which is an important finding as previously it has been suggested that SNM works better in nonobstructive urinary retention in women and not in women.

Muscarinic-3-receptor positive allosteric modulator ASP8302 in patients with underactive bladder. A randomized controlled trial.

AIM: The aim of this study is to evaluate safety and efficacy of ASP8302, a novel positive allosteric modulator for the muscarinic M3 receptor (M3-PAM), in patients with underactive bladder (UAB). METHODS: A randomized, double-blind, placebo-controlled multicenter study was performed in adult male/female subjects with UAB, defined as incomplete bladder emptying (postvoid residual volume [PVR] > 100 ml) without significant bladder outlet obstruction and/or overactive bladder. Subjects were randomized (1:1) to receive 4-week oral once-daily administration of 100 mg ASP8302 or matching placebo. Primary endpoint was a change from baseline in PVR measured by catheterization after standardized bladder filling (PVRC2 ). Other endpoints included PVR and bladder voiding efficiency (BVE) measured in various ways, uroflowmetry, bladder diary, and questionnaires. Pressure-flow studies were performed in a subgroup. RESULTS: One hundred and thirty-five patients were randomized (ASP8302 group: 65 patients, placebo group: 70 patients). The median change in PVRC2 was -40.0 ml (ASP8302) versus -35.0 ml (placebo) and the difference between groups was -5.0 ml (p = 0.960). In males, functional and symptomatic outcomes improved, for example, maximum urine flow rate (Qmax ) and detrusor pressure at Qmax (Pdet.Qmax ) increased (mean difference in change ASP8302 vs. placebo: 3.8 ml/s, p = 0.031 and 12.7 cm H2 O, p = 0.034, respectively). Urinary incontinence episodes/24 h decreased in males with preexisting incontinence (mean difference: -0.35; p = 0.028). The incidence of adverse events was similar between study groups (ASP8302: 33.3%, placebo: 31.4%). In the included subjects, both baseline urine flow and bladder voiding pressure was low. Compared with PVR, simultaneous BVE measurements were more consistent between various methods (spontaneous vs. standardized bladder filling, catheterization vs. ultrasound [US]). CONCLUSIONS: ASP8302 was safe and well tolerated in patients with UAB identified by nonurodynamic clinical criteria, but it did not show efficacy in the primary endpoint. However, in males it showed improvement of symptoms and functional parameters. BVE (using US) is a more optimal outcome measure than PVR in UAB.

Urinary adenosine triphosphate and nitric oxide levels in patients with underactive bladder: a preliminary study.

INTRODUCTION: Various in vitro and in vivo animal studies have shown that adenosine triphosphate (ATP) has a stimulatory role and nitric oxide (NO) has an inhibitory role in modulating bladder contractility. However, it is not known what happens to the urinary levels of ATP and NO in humans with underactive bladder (UAB). METHODS: In this prospective case-control study, we compared ATP and NO levels in twenty six male patients of UAB with a bladder contractility index (BCI) of < 100 and 18 healthy male volunteers without any lower urinary tract symptoms (LUTS). RESULTS: The mean urinary ATP levels were significantly lower in cases compared to controls (546.1 ± 37.3 pg/µl vs. 610.7 ± 24.9 pg/µl, p value < 0.001) and the mean NO levels were significantly higher in cases compared to controls (1233.4 ± 91.2 pg/µl vs. 1126.3 ± 91.3.4 pg/µl, p value < 0.001). The mean NO/ATP ratio in cases was significantly higher than that of controls (2.26 ± 0.2 vs. 1.84 ± 0.18, p value < 0.000). Using receiver operating curve (ROC) analysis, we noted the area under the curve (AUC) for NO/ATP ratio to be 0.91 in the diagnosis of cases. A cut-off value of 2.06 for NO/ATP ratio had sensitivity, specificity and diagnostic accuracy of 88.5%, 88.9% and 88.6%, respectively, in diagnosing patients with UAB. CONCLUSION: Patients with UAB have significantly higher levels of urinary NO and decreased levels of urinary ATP. Urinary NO/ATP levels can be considered as a noninvasive alternate test for diagnosing bladder underactivity.

Evaluation of pre-operative bladder contractility as a predictor of improved response rate to a staged trial of sacral neuromodulation in patients with detrusor underactivity.

PURPOSE: Sacral neuromodulation (SNM) is one of the few management options shown to improve outcomes in patients with detrusor underactivity (DU). This original research will investigate if preserved bladder contractility can predict a successful treatment with SNM. METHODS: This is a retrospective study of a prospectively collected database of consecutive patients with DU, who had a staged SNM trial from January 2013 to December 2018, with a minimum of 12 months follow-up. The primary outcome was the success of stage 1 SNM trial. RESULTS: In total, 69 patients with DU were followed. The median age was 67 [interquartile range (IQR) 74-55], median baseline bladder contractility index (BCI) 18 (IQR 67-0), and median post-void residual 200 mL (IQR 300-130). There were 35 patients (51%) that responded to a SNM trial. At a median follow-up of 23 months (IQR 39-12), three were removed for poor efficacy. In patients with detrusor acontractility (DAC), six responded (33%), compared to 29 patients (57%) with BCI > 0. This was statistically significant, p value 0.03. Younger age was also a predictive factor for SNM response, p value 0.02. There were no differences noted in those with gender, neurogenic history, previous pelvic surgery, diabetes, or pre-operative voiding history. CONCLUSION: Our study showed that patients with preserved bladder contractility are more likely to respond to a trial of SNM compared with those that have DAC. Younger age was also predictive of SNM response. UDS is the only method to accurately identify DAC patients. This information will help in patient selection and pre-operative counselling.

Trends in the use and costs of intermittent urinary catheters in the Netherlands from 1997 to 2018: A population-based observational study.

AIM: To obtain insight into the the use and costs of clean intermittent catheterization (CIC) in the Netherlands from 1997 to 2018. METHODS: For this population-based study, data on the use and costs of disposable catheters were provided by the Drug Information Project database. This database contains information about the Dutch insured population, which increased from 9.9 to 17.1 million persons between 1997 and 2018 (64%-100% of the Dutch population). The following trends were evaluated: (1) CIC users, (2) distribution of users by gender and age-group, (3) distribution of users by neurogenic and non-neurogenic cause for CIC, (4) total costs, and (5) costs per user. Total users are adjusted for the Dutch population. Costs are corrected for inflation and expressed in euros. RESULTS: Extramural use of CIC increased from 14,258 users in 1997 to 45,909 users in 2018. CIC users per 100,000 persons nearly tripled from 92 users to 267 users. Male CIC users almost quadrupled from 92 to 334 per 100,000 insured persons, whereas female users more than doubled from 91 to 201 per 100,000 insured persons. In 2018, 49% of the users had a non-neurogenic cause for CIC. Total costs increased from 16.4 million euros in 1997 to 74.6 million euros in 2018. Costs per user rose from 1151 to 1624 euros (41.1%). CONCLUSIONS: The use and costs of disposable catheters in the Netherlands increased substantially over the past two decades. Non-neurogenic bladder patients represent 49% of the population on CIC, which has not been described before in the literature.

Sensitivity of urethral flow-evoked voiding reflexes decline with age in the rat: insights into age-related underactive bladder.

The prevalence of underactive bladder (UAB) increases with age, suggesting a link between age-related processes and lower urinary tract (LUT) symptoms; however, the underlying mechanisms of age-related UAB are poorly understood. Understanding how aging affects LUT reflexes may help in the development of new treatments by identifying mechanistic targets. In this work, we studied the relationship between age and systems-level function of the LUT and tested the hypothesis that aging is related to weakening of reflexes that control voiding. Three groups of anesthetized female rats, young (4-7 mo old), mature (11-14 mo old), and old (18-24 mo old), were used to quantify the effect of aging on LUT reflexes. A double-lumen catheter enabled us to control the bladder volume and urethral flow rate independently, under quasi-isovolumetric bladder conditions. We systematically investigated the reflex bladder contractions evoked by combinations of rates of urethral infusion and bladder fill volumes as a function of age. Urethral infusion with the same flow rate evoked bladder contractions (via the augmenting reflex) in old animals less often than in younger animals. Furthermore, old animals needed more fluid in their bladders (relative to their bladder capacity) before urethra flow-evoked bladder contractions could be triggered at all, suggesting a delay in the switch of the LUT to "voiding mode." Old rats also showed longer and weaker bladder contractions than young or mature rats. Taken together, this suggests there is an age-related functional weakening and loss of sensitivity in LUT reflexes, which may contribute to age-related UAB symptoms.