Urinary Biomarkers of Overactive Bladder: Nerve Growth Factor and Brain-Derived Neurotrophic Factor in Diagnosis and Severity Assessment
Overactive bladder (OAB) is a prevalent voiding dysfunction disorder characterized by urinary urgency, often accompanied by frequency, nocturia, and urge urinary incontinence (UUI). In China, the incidence of OAB rises from 5.9% in adults over 18 years to 11.3% in those over 40 years, significantly impacting patients’ quality of life and contributing to physiological, psychological, and social challenges. Current diagnostic methods rely on subjective symptom reporting, urodynamic studies, bladder diaries, and questionnaires, which lack objectivity. Recent research has focused on identifying reliable biomarkers to improve diagnostic accuracy and assess disease severity. Among potential candidates, urinary nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), normalized to creatinine (Cr), have emerged as promising biomarkers. This study investigates their diagnostic utility, correlation with symptom severity, and clinical thresholds for OAB.
Study Design and Participant Characteristics
The study enrolled 30 untreated female OAB patients (mean age: 62.0 ± 15.5 years) and 25 age-matched female controls (mean age: 66.6 ± 11.8 years) between August 2014 and February 2015. OAB diagnosis was based on clinical criteria, including the Overactive Bladder Symptom Score (OABSS), with a mean total score of 8.9 ± 3.5 in the OAB group versus 1.7 ± 1.6 in controls (P < 0.01). Urinary NGF/Cr and BDNF/Cr levels were measured using standardized assays, adjusting for urine concentration via Cr.
Elevated Biomarker Levels in OAB Patients
Urinary NGF/Cr and BDNF/Cr levels were significantly higher in the OAB group than in controls (P = 0.04 and P < 0.01, respectively). The mean urinary NGF/Cr in OAB patients was 26.32 pg/mg (range: 2.6–63.0), compared to lower values in controls. Similarly, BDNF/Cr levels in OAB patients were approximately 21.2 times higher than NGF/Cr levels, demonstrating their substantial elevation in pathological conditions.
Correlation with Symptom Severity
Participants were stratified into mild (OABSS 1–5, n = 7), moderate (OABSS 6–10, n = 13), and severe (OABSS 11–15, n = 10) subgroups. Urinary NGF/Cr levels in the severe subgroup were markedly higher than in controls (P < 0.01) and the mild subgroup (P < 0.01). BDNF/Cr levels in controls were significantly lower than in moderate (P = 0.03) and severe (P < 0.01) subgroups. Both biomarkers exhibited strong positive correlations with total OABSS (NGF/Cr: r = 0.55, P < 0.01; BDNF/Cr: r = 0.43, P = 0.02).
Subgroup analysis of dry OAB (without UUI, n = 9) versus wet OAB (with UUI, n = 21) revealed significantly higher NGF/Cr and BDNF/Cr levels in the wet subgroup compared to controls (P < 0.05) and the dry subgroup (P < 0.05). This underscores the association between biomarker elevation and symptom complexity.
Symptom-Specific Correlations
Urinary urgency and UUI severity showed the strongest correlations with biomarker levels. For urgency, NGF/Cr (r = 0.55, P < 0.01) and BDNF/Cr (r = 0.43, P = 0.02) were significantly elevated. Similarly, UUI severity correlated with NGF/Cr (r = 0.59, P < 0.01) and BDNF/Cr (r = 0.52, P < 0.01). No significant correlations were observed for frequency or nocturia, highlighting the specificity of these biomarkers to urgency-driven pathophysiology.
Diagnostic Accuracy and Thresholds
Receiver operating characteristic (ROC) analysis evaluated the diagnostic performance of NGF/Cr and BDNF/Cr. For NGF/Cr, the area under the curve (AUC) was 0.793 (P < 0.01), with a sensitivity of 93.3% and specificity of 64.0% at a cutoff of 26.32 pg/mg. BDNF/Cr showed an AUC of 0.739 (P = 0.01), with lower sensitivity (76.7%) and specificity (68.0%). These results position NGF/Cr as the superior diagnostic biomarker, though BDNF/Cr remains a viable secondary indicator.
Phenotypic Variability and Pathophysiological Implications
The study identified four biomarker phenotypes in OAB patients:
- Elevated NGF/Cr and BDNF/Cr (n = 20),
- Elevated BDNF/Cr only (n = 4),
- Elevated NGF/Cr only (n = 1),
- No elevation (n = 5).
This heterogeneity suggests divergent pathophysiological mechanisms underlying OAB. For instance, patients with isolated BDNF/Cr elevation might exhibit distinct bladder afferent sensitization patterns compared to those with dual biomarker elevation. Further research is needed to elucidate these mechanisms and their clinical implications.
Clinical and Therapeutic Relevance
Prior studies support the utility of NGF/Cr and BDNF/Cr in monitoring treatment response. Antimuscarinic therapy has been shown to reduce urinary NGF/Cr levels alongside symptom improvement, reinforcing its role as a dynamic biomarker. Similarly, intravesical botulinum toxin A injections correlate with decreased NGF/Cr in responders. While this study did not assess post-treatment biomarker changes, its findings align with the hypothesis that NGF/Cr and BDNF/Cr reflect real-time pathological activity.
Limitations and Future Directions
The study’s limitations include its small sample size, exclusion of males and secondary OAB cases, and lack of longitudinal post-treatment data. Future multi-center studies with larger cohorts are warranted to validate diagnostic thresholds across diverse populations. Additionally, incorporating male participants and patients with neurological or metabolic comorbidities will enhance generalizability.
Conclusion
Urinary NGF/Cr and BDNF/Cr levels are significantly elevated in untreated female OAB patients and correlate strongly with symptom severity, particularly urgency and UUI. NGF/Cr demonstrates superior diagnostic accuracy, with a cutoff of 26.32 pg/mg offering high sensitivity for OAB detection. These biomarkers represent objective tools to complement subjective assessments, advancing personalized diagnosis and therapeutic monitoring.
doi.org/10.1097/CM9.0000000000000214
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