Recent Investigations of Urinary Nerve Growth Factor as a Biomarker for Overactive Bladder Syndrome

Hann-Chorng Kuo 대한비뇨의학회 2009 Investigative and Clinical Urology Vol.50 No.9

Purpose: Overactive bladder (OAB) is a symptom syndrome and is usually diagnosed by subjective symptoms of urgency with or without urgency incontinence. However, because urgency symptoms are so subjective, it is difficult to objectively grade symptoms of urgency. Although urodynamic study can detect detrusor overactivity (DO) objectively, not all patients with OAB are found to have DO. Therefore, recent research interests have focused on urinary and image biomarkers in the assessment of OAB. Materials and Methods: Investigating articles from the literature and recent published works were reviewed. Results: The urinary nerve growth factor (NGF) level is found to increase in patients with OAB-wet, bladder outlet obstruction, mixed urinary incontinence, and urodynamic DO. NGF levels are correlated with OAB symptoms and return to normal after treatment. However, urinary NGF is not increased only in patients with OAB and DO. It also increases in patients with interstitial cystitis/painful bladder syndrome (IC/PBS) and other lower urinary tract diseases such as urinary tract stones, bacterial infection, and urothelial tumor. Thirty percent of OAB patients have a low urinary NGF level. Nevertheless, antimuscarinic or botulinum toxin treatment can decrease the urinary NGF level, and changes in the NGF level are correlated with the urgency severity scale. Conclusions: It is therefore possible to use urinary NGF levels as a biomarker for assessment of therapeutic outcome in patients with OAB. Further research on combined multiple biomarkers to differentiate OAB and IC/PBS is necessary. Purpose: Overactive bladder (OAB) is a symptom syndrome and is usually diagnosed by subjective symptoms of urgency with or without urgency incontinence. However, because urgency symptoms are so subjective, it is difficult to objectively grade symptoms of urgency. Although urodynamic study can detect detrusor overactivity (DO) objectively, not all patients with OAB are found to have DO. Therefore, recent research interests have focused on urinary and image biomarkers in the assessment of OAB. Materials and Methods: Investigating articles from the literature and recent published works were reviewed. Results: The urinary nerve growth factor (NGF) level is found to increase in patients with OAB-wet, bladder outlet obstruction, mixed urinary incontinence, and urodynamic DO. NGF levels are correlated with OAB symptoms and return to normal after treatment. However, urinary NGF is not increased only in patients with OAB and DO. It also increases in patients with interstitial cystitis/painful bladder syndrome (IC/PBS) and other lower urinary tract diseases such as urinary tract stones, bacterial infection, and urothelial tumor. Thirty percent of OAB patients have a low urinary NGF level. Nevertheless, antimuscarinic or botulinum toxin treatment can decrease the urinary NGF level, and changes in the NGF level are correlated with the urgency severity scale. Conclusions: It is therefore possible to use urinary NGF levels as a biomarker for assessment of therapeutic outcome in patients with OAB. Further research on combined multiple biomarkers to differentiate OAB and IC/PBS is necessary.

Pathomechanism of Interstitial Cystitis/Bladder Pain Syndrome and Mapping the Heterogeneity of Disease

Jia-Fong Jhang,Hann-Chorng Kuo 대한배뇨장애요실금학회 2016 International Neurourology Journal Vol.20 No.S1

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous syndrome which is usually characterized by urinary frequency, nocturia, and bladder pain. Several pathomechanisms have been proposed, including uroepithelial dysfunction, mast cell activation, neurogenic inflammation, autoimmunity, and occult urinary tract infections. It is possible that an inflammatory process alters regulation of urothelial homeostasis and results in dysfunction of the bladder epithelium. Different phenotypes of IC/BPS have been explored including Hunner and non-Hunner type IC, hypersensitive bladder, and bladder pain both with and without functional somatic syndrome. Different gene expressions have also been found in different IC phenotypes. Abnormal expressions of uroplakin, chondroitin sulfate and adhesive protein E-cadherin, tight junction protein zonula occludens-1 in IC/BPS bladder suggest abnormal epithelial differentiation in this bladder disease. Analysis of inflammatory proteins, or cytokines in the urine or serum provides another diagnostic foundation forIC/BPS subtypes. The involvement of IC/BPS in systemic functional somatic syndrome and other pelvic organ diseases might also subdivide subtypes of IC/BPS. Chronic inflammation, increased urothelial apoptosis, and abnormal urothelial function are closely associated in IC bladders. This article reviews recent research on the pathomechanisms of IC, which might help us in mapping the heterogeneity of the disease.

Practical Aspects of Botulinum Toxin-A Treatment in Patients With Overactive Bladder Syndrome

Chun-Hou Liao,Hann-Chorng Kuo 대한배뇨장애요실금학회 2015 International Neurourology Journal Vol.19 No.4

Intravesical onabotulinumtoxinA (BoNT-A) injection is an effective treatment for overactive bladder syndrome (OAB) that is refractory to antimuscarinics. An injectable dose of 100 U has been suggested to achieve the optimal balance of benefit and safety in patients with OAB. BoNT-A (total volume of 10 mL) was administered as evenly distributed intradetrusor injections (5 U) across 20 sites approximately 1 cm apart (0.5 mL per site) using a flexible or rigid cystoscope. Treatment with BoNT-A was generally well tolerated by most patients, and most treatment-related adverse events were localized to the urinary tract. The prevalence of OAB increases with age, and elderly patients are more vulnerable to complications. The short-term efficacy of intravesical BoNT-A injection for refractory OAB with no treatment-related complications in the elderly population has been documented. Frail elderly patients can experience the same treatment results, such as significantly improved urgent urinary incontinence and quality of life, as young and nonfrail elderly patients with 100-U BoNT-A injections. However, increased risk of larger postvoid residual (PVR) urine and lower long-term success rates were noted in frail elderly patients; around 11% had acute urinary retention, while 60% had PVR urine volume >150 mL after treatment. In addition, intravesical injection of BoNT-A effectively decreased urgency symptoms in elderly patients with OAB and central nervous system lesions. The adverse effects were acceptable, while the long-term effects were comparable to those in patients with OAB without central nervous system lesions. Nonetheless, the possibility of longstanding urinary retention and chronic catheterization in this vulnerable population requires careful evaluation before treatment with intravesical BoNT-A. In conclusion, the current findings indicate that intravesical BoNT-A is an effective and safe treatment for OAB in elderly patients.

Comparative Study Between Behavior Therapy and Behavior Therapy Plus Mirabegron 50 mg in Sexually Active Men With Bothersome Overactive Bladder Symptoms – A Multicenter, Randomized Study

Chih-Chieh Lin,Hann-Chorng Kuo,Jian-Ri Li,Yao-Chi Chuang 대한배뇨장애요실금학회 2023 International Neurourology Journal Vol.27 No.3

Purpose: We evaluated the therapeutic effects on overactive bladder (OAB) symptoms and sexual function of behavioral therapy with or without mirabegron in sexually active male patients with OAB. Mirabegron, a selective β3 adrenoceptor agonist for the treatment of OAB, has been shown to induce corpus cavernosum relaxation. Methods: In this 4-site, randomized controlled trial, 150 sexually active men with OAB were enrolled between June 2020 and May 2022. Participants were randomly allocated (1:2) into 2 treatment groups: (1) behavioral therapy alone (n=50) and (2) a combination of mirabegron 50 mg daily and behavioral therapy (n=100). The evaluation was based on the overactive bladder symptoms score (OABSS), the International Index of Erectile Function, the ejaculatory domain short form, the International Prostate Symptom Score, patient perception of bladder condition, quality of life, and urodynamic parameters. The therapeutic outcomes were assessed at baseline, 4 weeks, and 12 weeks. Results: There were 65 patients (65%) in the combination subgroup and 36 patients in the behavioral therapy who completed all 12 weeks of treatment. Both groups had a statistically significant improvement in OABSS after 12 weeks of treatment. The combination therapy group achieved a statistically significant improvement in all 4 subscores of OABSS, however, the urinary frequency (P=0.120) and urinary incontinence (P=0.234) subscores in the behavioral therapy only group did not show a significant change. Additionally, the combination group had a significant improvement in functional bladder capacity, which was not seen in the behavioral therapy group. However, both groups did not have a significant change in erectile or ejaculatory function. Conclusions: Behavioral therapy combined with mirabegron had more significant impact on the improvement of OAB than behavior therapy alone. However, both groups did not have significant changes in erectile or ejaculatory function.

Clinical application of intravesical botulinum toxin type A for overactive bladder and interstitial cystitis

Jing-Liang Chen,Hann-Chorng Kuo 대한비뇨의학회 2020 Investigative and Clinical Urology Vol.61 No.-

After decades of clinical and basic science research, the clinical application of botulinum toxin A (Botox) in urology has been extended to neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity, refractory overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), lower urinary tract symptoms, benign prostatic hyperplasia, and neurogenic or non-neurogenic lower urinary tract dysfunction in children. Botox selectively disrupts and modulates neurotransmission, suppresses detrusor overactivity, and modulates sensory function, inflammation, and glandular function. In addition to motor effects, Botox has been found to have sensory inhibitory effects and anti-inflammatory effects; therefore, it has been used to treat IC/BPS and OAB. Currently, Botox has been approved for the treatment of NDO and OAB. Recent clinical trials on Botox for the treatment of IC/BPS have reported promising therapeutic effects, including reduced bladder pain. Additionally, the therapeutic duration was found to be longer with repeated Botox injections than with a single injection. However, the use of Botox for IC/BPS has not been approved. This paper reviews the recent advances in intravesical Botox treatment for OAB and IC/BPS.

Urothelial Dysfunction and Chronic Inflammation are Associated With Increased Bladder Sensation in Patients With Chronic Renal Insufficiency

Sheng-Fu Cheng,Yuan-Hong Jiang,Hann-Chorng Kuo 대한배뇨장애요실금학회 2018 International Neurourology Journal Vol.22 No.S2

Purpose: Chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients usually have lower urinary tract symptoms, such as frequency and urgency. Additionally, they frequently suffer from urinary tract infections. This study investigated dysfunction and chronic inflammation of the bladder urothelium in ESRD/CKD patients. Methods: This study enrolled 27 patients with CKD (n=13) or ESRD (n=14) for urodynamic studies and bladder biopsies. Patients presented with detrusor underactivity (DU; n=8) or bladder oversensitivity (BO; n=19). Bladder biopsies were performed in these patients and in 20 controls. The bladder mucosa was examined for E-cadherin and zonula occludens-1 (ZO-1) expression, activated mast cell count (through tryptase staining), and urothelial apoptosis (through terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling [TUNEL]). The urodynamic parameters were also compared with variables regarding urothelial dysfunction. Results: The bladder mucosa samples of ESRD and CKD patients revealed significantly higher mast cell counts, more urothelial apoptosis, and lower levels of ZO-1 expression than the control samples. E-cadherin expression was significantly reduced in ESRD/CKD patients with DU, but not in ESRD/CKD patients with BO. Increased mast cell and apoptotic cell counts were also associated with ESRD/CKD with BO. Less expression of ZO-1 and E-cadherin was significantly associated with increased bladder sensation and a small bladder capacity. Conclusions: Bladder urothelial dysfunction and chronic inflammation were present to a noteworthy extent in patients with ESRD or CKD. Increased inflammation and defective barrier function were more notable in ESRD/CKD bladders with BO than in those with DU. The clinical characteristics of these patients may involve urothelial pathophysiology.

Long-term Combination Therapy With α-Blockers and 5α-Reductase Inhibitors in Benign Prostatic Hyperplasia: Patient Adherence and Causes of Withdrawal From Medication

Hueih Ling Ong,Chun-Hou Liao,Hann-Chorng Kuo 대한배뇨장애요실금학회 2016 International Neurourology Journal Vol.20 No.4

Purpose: To investigate long-term therapeutic effects and patient adherence to a combination therapy of a 5α-reductase inhibitor and an α-blocker and to identify causes of withdrawal from medication in patients with clinical benign prostatic hyperplasia (BPH). Methods: BPH patients with lower urinary tract symptoms (LUTS) receiving combination therapy with follow-ups for 1–12 years were retrospectively analyzed. Therapeutic effects were assessed at baseline and annually by measuring International Prostatic Symptoms Score, quality of life index, total prostate volume (TPV), maximal flow rate, voided volume, postvoid residual volume and prostate-specific antigen level. Causes of discontinued combination therapy were also investigated. Results: A total of 625 patients, aged 40–97 years (mean, 73 years) were retrospectively analyzed. All measured parameters showed significant improvements after combination therapy. Three hundred sixty-nine patients (59%) discontinued combination therapy with a mean treatment duration of 2.2 years. The most common reasons for discontinued treatment were changing medication to monotherapy with α-blockers or antimuscarinics (124 patients, 19.8%), receiving surgical intervention (39 patients, 6.2%), and LUTS improvement (53 patients, 8.5%). Only 64 patients (10.2%) were loss to follow-up and 6 (1.0%) discontinued combined treatment due to adverse effects. Smaller TPV after short-term combination treatment caused withdrawal from combination therapy. Conclusions: BPH patients receiving long-term combination therapy showed significant improvement in all measured parameters. Changing medication, improved LUTS and choosing surgery are common reasons for discontinuing combination herapy. A smaller TPV after short-term combination treatment was among the factors that caused withdrawal from combination therapy.

Lower Levels of Urinary Nerve Growth Factor Might Predict Recurrent Urinary Tract Infections in Women

Fei-Chi Chuang,Hsin-Tzu Liu,Hann-Chorng Kuo 대한배뇨장애요실금학회 2016 International Neurourology Journal Vol.20 No.1

Purpose: To investigate the changes in urinary nerve growth factor (uNGF) levels after acute urinary tract infection (UTI) and to assess the role of uNGF in predicting UTI recurrence in women. Methods: Women with uncomplicated, symptomatic UTIs were enrolled. Cephalexin 500 mg (every 6 hours) was administered for 7–14 days to treat acute UTIs. Subsequently, the patients were randomized to receive either sulfamethoxazole/trimethoprim 800 mg/160 mg daily at bedtime, or celecoxib 200 mg daily for 3 months and were monitored for up to 12 months. NGF levels in the urine were determined at baseline, 1, 4, and 12 weeks after the initiation of prophylactic therapy, and were compared between women with first-time UTIs and recurrent UTIs, sulfamethoxazole/trimethoprim and celecoxib-treated women, and no UTI recurrence and UTI recurrence that occurred during the follow-up period. Twenty women free of UTIs served as controls. Results: A total of 139 women with UTI and 20 controls were enrolled in the study, which included 50 women with a firsttime UTI and 89 women with recurrent UTIs. Thirty-seven women completed the study. Women with recurrent UTIs (n=23) had a trend of lower uNGF levels than women with first-time UTIs (n=14). During follow-up, 9 women had UTI recurrence. The serial uNGF levels in women with UTI recurrence were significantly lower than those in women who did not have UTI recurrence during the follow-up period. Conclusions: The lower levels of uNGF in women with recurrent UTI and the incidence of UTI recurrence during follow-up suggest that lower uNGF might reflect the defective innate immunity in women with recurrent UTI.

Therapeutic Efficacy of Urethral Sphincter Injections of Platelet- Rich Plasma for the Treatment of Stress Urinary Incontinence due to Intrinsic Sphincter Deficiency: A Proof-of-Concept Clinical Trial

Yuan-Hong Jiang,Ping-Jui Lee,Hann-Chorng Kuo 대한배뇨장애요실금학회 2021 International Neurourology Journal Vol.25 No.1

Purpose: The aim of this study was to investigate the efficacy of autologous platelet-rich plasma (PRP) in the treatment of stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD) refractory to medical treatment. Methods: Thirty-five patients with SUI due to urodynamically proven ISD were prospectively enrolled. Five milliliters of PRP (2.5–5 times the platelet concentration in peripheral blood) was injected into the external sphincter at 5 sites; all patients received 4 injections at monthly intervals. The primary end-point was the change in SUI severity as assessed by a visual analogue scale (VAS of SUI). The secondary-endpoints were the Global Response Assessment score and changes in urodynamic parameters from baseline to 3 months after treatment. Results: The mean age of patients was 68.7±12 years; the median duration of SUI was 4 years. Five patients had neurogenic SUI, while 30 had nonneurogenic SUI (21 with postprostatectomy incontinence, 6 with previous radical cystectomy, and 3 with other etiologies). Complete dryness was achieved in 7 patients (20.0%) while moderate improvement was observed in 14 (40.0%). The mean VAS of SUI score decreased significantly from 6.57±1.89 to 3.77±2.41 after treatment. The abdominal leak point pressure (ALPP) increased significantly from 98.3±55.8 to 157.3±79.3 cm H2O. There was no increase of ALPP in neurogenic SUI and less increase of ALPP in patients with failed treatment outcomes. No perioperative adverse events or severe complications occurred. Conclusions: Urethral PRP injection is safe and effective in increasing urethral resistance and improving SUI. PRP could be an alternative treatment modality for male and female patients with moderate SUI due to nonneurogenic causes.

Therapeutic Efficacy of a New Procedure for Male Urinary Incontinence Combining a Suburethral Polypropylene Mesh and Cardiovascular Patch

Shu-Yu Wu,Yuan-Hong Jiang,Hann-Chorng Kuo 대한배뇨장애요실금학회 2017 International Neurourology Journal Vol.21 No.1

Purpose: Stress urinary incontinence (SUI) in men is a complication secondary to prostatectomy or resulting from neurological lesions. This study presents our experiences with male suburethral slings over the past decade. Methods: In this study, we considered patients who presented with SUI and were diagnosed with an intrinsic sphincteric deficiency due to postprostatectomy incontinence (PPI) or other causes (non-PPI). Patients who underwent the suburethral sling procedure using a polypropylene mesh and a cardiovascular patch were retrospectively included. An urodynamic study was performed before and after the operation. Global response assessment (GRA) and SUI grading were used for surgical outcome. The revision rate and the infection rate were also evaluated. Results: A total 31 patients were enrolled in this study; the mean patient age was 59.5±18.9 years, and the mean follow-up period was 36.9±29.4 months. Fourteen patients comprised the non-PPI group and 17 were in the PPI group. The preoperative SUI of all patients were categorized as a moderate to severe problem according to the SUI grade, with a mean score of 2.32±0.48 before the operation and 0.48±0.57 after the operation. With a mean score of 2.35±0.71, GRA showed that the patients were satisfied with the treatment. After the sling procedure, 4 patients (13%) reported a mild improvement, 12 (38.7%) a moderate improvement, while 15 (48.4%) reported an excellent improvement. Six patients (19.4%), including 5 from the non-PPI group (35.7%) and 1 (5.9%) from the PPI group (P=0.037), underwent sling removal because of infection. Conclusions: The male suburethral sling procedure using a polypropylene mesh and a cardiovascular patch is a safe, efficacious, and inexpensive surgical procedure for PPI. In cases of neurological incontinence, however, the higher infection rate in non-PPI patients means that they should be carefully managed.