Diagnostic value of nerve growth factor in detrusor overactivity: a study on women with mixed urinary incontinence.

OBJECTIVE: Urinary incontinence has a profound impact on women's quality of life. Studies have shown that changes in urinary protein levels could be a potential diagnostic biomarker in some urological diseases. The aim of present study is to determine the diagnostic value of nerve growth factor (NGF) in women with mixed urinary incontinence (MUI) as a diagnostic biomarkers of detrusor overactivity (DO). METHODS: Seventy women aged between 20 and 75 years with MUI were enrolled in this prospective study. All participants underwent urodynamic study. Urine NGF levels were measured using an ELISA method. NGF level was compared between groups using Mann-Whitney U test. Receiver Operator Characteristic (ROC) analysis was employed to evaluate the diagnostic performance of urinary NGF. RESULTS: The results showed that the median (min, max) of NGF in patients with DO was significantly higher in comparing to its level in women without DO [184.10 (31, 346.60) pg/ml vs. 151.80 (21, 210.70)], respectively (P = 0.035). Using receiver-operator characteristics analysis, the threshold urinary NGF value of 102.00 pg/ml provided a sensitivity of 88% and specificity of 40% in diagnosing DO, PPV of 39.1%, and NPV of 88.2%, positive likelihood ratio 2.18 and negative likelihood ratio of 0.45 (P = 0.02). CONCLUSION: Based on high sensitivity and low specificity, we can conclude that NGF can be a good tool for ruling out the OAB when the test is negative. However, the future investigations are needed to expand the observed correlation in larger groups of women with DO.

Urinary cytokines in women with refractory detrusor overactivity: A longitudinal study of rotating antibiotic versus placebo treatment.

Over 50% of women with detrusor overactivity (DO), who do not respond to therapy have been shown to have bacteriuria, which may stimulate the release of inflammatory cytokines than can enhance nerve signalling, leading to symptoms of urgency. This study made use of a consecutive series of urine samples collected from women with refractory DO, who participated in a clinical trial of rotating antibiotic therapy. The aim was to determine the effect of bacteriuria and antibiotic treatment on the levels of urinary cytokines, and to correlate the cytokine concentration with patient outcome measures relating to urgency or urge incontinence. The urinary cytokines chosen were IL-1α, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, CXCL10 (IP-10), MCP-1 and TNF-α. The presence of bacteriuria stimulated a significant increase in the concentrations of IL-1α (P 0.0216), IL-1 receptor antagonist (P 0.0264), IL-6 (P 0.0003), IL-8 (P 0.0043) and CXCL-10 (P 0.009). Antibiotic treatment significantly attenuated the release of IL-1α (P 0.005), IL-6 (P 0.0027), IL-8 (P 0.0001), IL-10 (P 0.049), and CXCL-10 (P 0.042), i.e. the response to the presence of bacteria was less in the antibiotic treated patients. Across the 26 weeks of the trial, antibiotic treatment reduced the concentration of five of the nine cytokines measured (IL-1α, IL-6, IL-8, IL-10 and CXCL-10); this did not reach significance at every time point. In antibiotic treated patients, the urinary concentration of CXCL-10 correlated positively with four of the six measures of urgency. This study has shown that cytokines associated with activation of the innate immune system (e.g. cytokines chemotactic for or activators of macrophages and neutrophils) are reduced by antibiotic therapy in women with refractory DO. Antibiotic therapy is also associated with symptom improvement in these women, therefore the inflammatory response may have a role in the aetiology of refractory DO.

Genetic variants and expression changes in urgency urinary incontinence: A systematic review.

AIM: To perform a systematic review summarizing the knowledge of genetic variants, gene, and protein expression changes in humans and animals associated with urgency urinary incontinence (UUI) and to provide an overview of the known molecular mechanisms related to UUI. METHODS: A systematic search was performed on March 2, 2020, in PubMed, Embase, Web of Science, and the Cochrane library. Retrieved studies were screened for eligibility. The risk of bias was assessed using the ROBINS-I (human) and SYRCLE (animal) tool. Data were presented in a structured manner and in the case of greater than five studies on a homogeneous outcome, a meta-analysis was performed. RESULTS: Altogether, a total of 10,785 records were screened of which 37 studies met the inclusion criteria. Notably, 24/37 studies scored medium-high to high on risk of bias, affecting the value of the included studies. The analysis of 70 unique genes and proteins and three genome-wide association studies showed that specific signal transduction pathways and inflammation are associated with UUI. A meta-analysis on the predictive value of urinary nerve growth factor (NGF) levels showed that increased urinary NGF levels correlate with UUI. CONCLUSION: The collective evidence showed the involvement of two molecular mechanisms (signal transduction and inflammation) and NGF in UUI, enhancing our understanding of the pathophysiology of UUI. Unfortunately, the risk of bias was medium-high to high for most studies and the value of many observations remains unclear. Future studies should focus on elucidating how deficits in the two identified molecular mechanisms contribute to UUI and should avoid bias.

Urinary Biomarkers in Women with Refractory Urgency Urinary Incontinence Randomized to Sacral Neuromodulation versus OnabotulinumtoxinA Compared to Controls.

PURPOSE: We measured urinary biomarker levels in women with refractory urgency urinary incontinence and controls at baseline and 6 months after treatment with sacral neuromodulation or intradetrusor injection of onabotulinumtoxinA. We also assessed the association of baseline biomarkers with posttreatment urgency urinary incontinence episodes and overactive bladder symptom bother outcomes. MATERIALS AND METHODS: First morning urine samples were collected from consented trial participants and age matched women without urgency urinary incontinence. Biomarkers reflecting general inflammation, neuroinflammation, afferent neurotransmitters and tissue remodeling were measured using standardized enzyme-linked immunosorbent assay and activity assays as appropriate. Symptom bother was assessed by the overactive bladder questionnaire and urgency urinary incontinence episodes were determined by bladder diary. Linear models were used to examine differences in mean biomarker levels and the change in urgency urinary incontinence episodes and symptom bother between baseline and 6 months. Modest evidence of a potential association was represented by p ≤0.01 and p ≤0.004 represented moderate evidence of an association with outcomes. RESULTS: Baseline biomarker levels differed little between cases and controls except tropoelastin (p = 0.001) and N-terminal telopeptide collagen type 1 (p <0.001). Changes in biomarker levels 6 months after intervention included decreases in collagenase (p <0.001) in both treatment groups and increases in interleukin-8 (p = 0.002) and matrix metalloprotease-9 (p <0.001) in the onabotulinumtoxinA group. Higher baseline calcitonin gene-related peptide across both treatments (p = 0.007) and nerve growth factor in the onabotulinumtoxinA arm (p = 0.007) were associated with less reduction in overactive bladder symptom bother. CONCLUSIONS: Refractory urgency urinary incontinence is a complex condition. These data suggest that matrix remodeling and neuropeptide mediation may be involved in its pathophysiological mechanisms and response to treatment.

Sacral nerve stimulation reduces elevated urinary nerve growth factor levels in women with symptomatic detrusor overactivity.

OBJECTIVES: To investigate changes in urinary nerve growth factor (uNGF) in women with symptomatic detrusor overactivity (DO) following peripheral nerve evaluation (PNE) for sacral neuromodulation vs controls. STUDY DESIGN: There were 23 subjects with overactive bladder symptoms and DO who failed management with anticholinergics and 22 controls consented to participate in this prospective pilot study. Urine specimens were collected from controls at baseline for evaluation of uNGF and creatinine. Subjects were evaluated at baseline and 5 days after a trial of sacral nerve stimulation referred to as a PNE. Each visit included urine collection for uNGF and, Incontinence Quality of Life Questionnaire, Urinary Distress Inventory Questionnaire, postvoid residual volume, and a 3-day voiding diary. uNGF levels were measured by enzyme-linked immunosorbent assay and expressed as uNGF pg/creatinine mg. RESULTS: Subjects with DO had significantly higher baseline uNGF levels (corrected for creatinine) compared with controls (19.82 pg/mg vs 7.88 pg/mg, P < .002). Seventeen DO subjects underwent PNE and were evaluated at the end of the testing period. There was a significant improvement in quality of life scores for subjects after PNE compared with baseline (Urinary Distress Inventory Questionnaire: 7.0 vs 13.7, P < .001; Incontinence Quality of Life Questionnaire: 87.3 vs 52.8, P < .0001). Concordantly, uNGF levels significantly decreased from 17.23 pg/mg to 9.24 pg/mg (P < .02) after PNE. CONCLUSION: uNGF levels decrease with symptomatic response in DO subjects undergoing PNE. DO subjects had significantly higher uNGF at baseline vs controls, and uNGF levels significantly decreased after only 5 days of sacral nerve stimulation. These findings support a larger study to validate the use of uNGF as an objective tool to assess therapeutic outcome in patients undergoing PNE for sacral neuromodulation.

Urinary nerve growth factor in women with overactive bladder syndrome.

OBJECTIVE: • To measure urinary nerve growth factor (NGF) in women with overactive bladder (OAB)-dry and OAB-wet and investigate the association of urinary NGF expression with these factors. PATIENTS AND METHODS: • Differentiation between OAB-wet and OAB-dry was based on symptoms and a 3-day voiding diary. • Urinary NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). • The urinary NGF levels were compared among controls, OAB-dry and OAB-wet subgroups, and also between OAB patients ≥ 55 years and < 55 years, as well as between patients with a body mass index (BMI, kg/m²) < 20, 20-30 and > 30. RESULTS: • A total of 113 women with OAB-dry, 106 with OAB-wet and 84 controls were enrolled. The urinary NGF/creatinine (Cr) levels were significantly highest in OAB-wet (2.13 ± 3.87) and second highest in OAB-dry (0.265 ± 0.59) compared to controls (0.07 ± 0.21). • Analysis of urinary NGF or NGF/Cr levels among controls, OAB-dry and OAB-wet groups by age and BMI showed no significant differences, except for the OAB-dry group. • Urinary NGF/Cr was not significantly correlated with age (P = 0.088) or BMI (P = 0.886) in women with OAB-dry and OAB-wet. CONCLUSIONS: • Urinary NGF levels were significantly higher in women with OAB-dry and even higher in women with OAB-wet. • The urinary NGF level was not associated with ageing, menopause or higher BMI either in controls or OAB patients.

Bacteriuria is associated with urge urinary incontinence in older women.

OBJECTIVE: To investigate the association between bacteriuria and frequency and type of urinary incontinence in elderly people living in the community. Bacteriuria and urinary incontinence are common conditions and often coexisting in this population; the authors have previously reported the prevalence of bacteriuria to be 22.4% in women and 9.4% in men. DESIGN: Cross-sectional study. SETTING: The catchment area of a primary healthcare centre in a Swedish middle-sized town. SUBJECTS: Residents, except for those in nursing homes, aged 80 and over. Participation rate: 80.3% (431/537). MAIN OUTCOME MEASURES: Urinary cultures and questionnaire data on urinary incontinence. RESULTS: In women the OR for having bacteriuria increased with increasing frequency of urinary incontinence; the OR was 2.83 (95% CI 1.35-5.94) for women who were incontinent daily as compared with continent women. Reporting urge urinary incontinence increased the risk of having bacteriuria: 3.36 (95% CI 1.49-7.58) in comparison with continent women while there was no significant association between stress urinary incontinence and bacteriuria. The prevalence of bacteriuria among men was too low to make any meaningful calculations about the association between bacteriuria and frequency and type of incontinence. CONCLUSION: Bacteriuria is associated with more frequent leakage and predominantly with urge urinary incontinence. The causes of this association and their clinical implications remain unclear. There might be some individuals who would benefit from antibiotic treatment, but further studies are warranted.