Urinary ATP may be a dynamic biomarker of detrusor overactivity in women with overactive bladder syndrome

Miguel Silva-Ramos, Isabel Silva, Olga Oliveira, Sónia Ferreira, Maria Júlia Reis, José Carlos Oliveira, Paulo Correia-de-Sá, Miguel Silva-Ramos, Isabel Silva, Olga Oliveira, Sónia Ferreira, Maria Júlia Reis, José Carlos Oliveira, Paulo Correia-de-Sá

Abstract

Background: Nowadays, there is a considerable bulk of evidence showing that ATP has a prominent role in the regulation of human urinary bladder function and in the pathophysiology of detrusor overactivity. ATP mediates nonadrenergic-noncholinergic detrusor contractions in overactive bladders. In vitro studies have demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladder samples (OAB) release more ATP than controls. Here, we compared the urinary ATP concentration in samples collected non-invasively from OAB women with detrusor overactivity and age-matched controls.

Methods: Patients with neurologic diseases, history of malignancy, urinary tract infections or renal impairment (creatinine clearance <70 ml/min) were excluded. All patients completed a 3-day voiding diary, a 24 h urine collection and blood sampling to evaluate creatinine clearance. Urine samples collected during voluntary voids were immediately freeze-preserved for ATP determination by the luciferin-luciferase bioluminescence assay; for comparison purposes, samples were also tested for urinary nerve growth factor (NGF) by ELISA.

Results: The urinary content of ATP, but not of NGF, normalized to patients' urine creatinine levels (ATP/Cr) or urinary volume (ATP.Vol) were significantly (P<0.05) higher in OAB women with detrusor overactivity (n = 34) than in healthy controls (n = 30). Significant differences between the two groups were still observed by boosting urinary ATP/Cr content after water intake, but these were not detected for NGF/Cr. In OAB patients, urinary ATP/Cr levels correlated inversely with mean voided volumes determined in a 3-day voiding diary.

Conclusion: A high area under the receiver operator characteristics (ROC) curve (0.741; 95% CI 0.62-0.86; P<0.001) is consistent with urinary ATP/Cr being a highly sensitive dynamic biomarker for assessing detrusor overactivity in women with OAB syndrome.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow diagram of patients’ selection.
Figure 1. Flow diagram of patients’ selection.
Figure 2. Urinary ATP and NGF levels…
Figure 2. Urinary ATP and NGF levels determined before (A: ATP, nM and B: NGF, pg/ml) and after normalization to urine creatinine content (C: ATP/Cr, pmol/mg and D: NGF, pg/mg) in women with OAB (n = 34) and age-matched controls (n = 36).
Columns are mean values ± standard deviation (SD). *P<0.05 (unpaired Student’s t-test with Welch’s correction) represent significant differences from controls. In E and F, represented are the receiver-operator characteristics (ROC) curves of urinary ATP/Cr and urinary NGF/Cr in OAB patients, respectively. Please note that, for this cohort, ATP/Cr has a better area under de curve (AUC = 0.7407; 95% confidence interval (CI) = 0.62–0.86; P<0.001) than NGF/Cr (AUC = 0.5391; 95% CI = 0.39–0.69; P<0.001).
Figure 3. Analysis of ATP/Cr (pmol/mg) and…
Figure 3. Analysis of ATP/Cr (pmol/mg) and NGF/Cr (pg/mg) content in paired urine samples collected from control women (A and B) and OAB patients (C and D) at arrival to the consultation (1st void) and after water intake (2nd void).
See Table 2, for correlation between variables (Spearman test).
Figure 4. Relationship between urinary (A) ATP/Cr…
Figure 4. Relationship between urinary (A) ATP/Cr (pmol/mg) and (B) NGF/Cr (pg/mg) content and the mean voided volume determined in a 3-day voiding diary for women with OAB and age-matched controls.
Columns are mean values ± standard deviation (SD) from n number of individuals (shown in parenthesis). *P<0.05 (unpaired Student’s t-test with Welch’s correction) represent significant differences from controls.
Figure 5. Urinary (A) ATP/Cr (pmol/mg) and…
Figure 5. Urinary (A) ATP/Cr (pmol/mg) and (B) NGF/Cr (pg/mg) content in women with detrusor overactivity complaining only of urgency (OAB dry, n = 7) and of urgency associated with urge urinary incontinence (OAB wet, n = 21) as compared to age-matched controls (n = 36).
Columns are mean values ± standard deviation (SD). *,**P<0.05 (one-way ANOVA with Dunn’s multiple comparison test) represent significant differences from controls and between OAB dry and OAB wet subgroups, respectively.

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