Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

PLOS ONE, Dec 2019

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.

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Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

et al. (2013) Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome. PLoS ONE 8(5): e64696. doi:10.1371/journal.pone.0064696 Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome Miguel Silva-Ramos 0 Isabel Silva 0 Olga Oliveira 0 So nia Ferreira 0 Maria Ju lia Reis 0 Jose 0 Carlos Oliveira 0 Paulo Correia-de-Sa 0 Rui Medeiros, IPO, Inst Port Oncology, Portugal 0 1 Laborato rio de Farmacologia e Neurobiologia, UMIB, Instituto de Ciencias Biome dicas Abel Salazar (ICBAS) - Universidade do Porto (UP) , Porto , Portugal , 2 Servic o de Urologia - Centro Hospitalar do Porto (CHP) , Porto , Portugal , 3 Servic o de Qu mica Cl nica - Centro Hospitalar do Porto (CHP) , Porto , Portugal 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 nonadrenergicnoncholinergic 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 agematched 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 freezepreserved 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. - Funding: The research was partially supported by Fundacao para a Ciencia e a Tecnologia (FCT projects PTDC/SAU-OSM/104369/2008 and Pest/OE/UI0215/ 2011), Associacao Portuguesa de Urologia and University of Porto/Caixa Geral de Depo sitos (Investigacao Cientfica na Pre-Graduacao). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Overactive bladder (OAB) is a complex clinical syndrome based on self-reported symptoms of urinary urgency associated with incontinence in up to one-third of cases, usually accompanied by daytime frequency and nocturia, in the absence of proven infection or other obvious pathology [1]. It has been reported an overall prevalence of 12,8% in women [2], and a significant impact on patients quality of life [3]. The precise pathogenesis underlying OAB remains to be clarified and might be multifactorial. OAB symptoms are often associated with detrusor overactivity, which is diagnosed by invasive urodynamic testing as involuntary contractions of the detrusor muscle during bladder filling. Regrettably, the relationship between clinical symptoms and urodynamic findings is not reliable [4,5]. In fact, procedure constrains such as saline infusion rate and temperature, patient position, and anxiety, may yield distinct urodynamic results [6], which makes urodynamic confirmation of detrusor overactivity with only limited clinical value regarding the severity or prognosis of idiopathic OAB [7,8]. This renders urodynamic investigation with suboptimal characteristics to evaluate OAB patients and urge the search for new accurate, reliable and non-invasive tests to predict detrusor overactivity and to assess patients therapeutic outcome (reviewed in [9]). Recently, low grade inflammatory mediators, such as cytokines, prostaglandin E2 (PGE2) and nerve growth factor (NGF), gained significant attention as urinary biomarkers of detrusor overactivity. Although they correlate with OAB symptom severity, they have not been shown to have independent prognostic benefit (reviewed in [10]) and they still cannot replace the s (...truncated)


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Miguel Silva-Ramos, Isabel Silva, Olga Oliveira, Sónia Ferreira, Maria Júlia Reis, José Carlos Oliveira, Paulo Correia-de-Sá. Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome, PLOS ONE, 2013, 5, DOI: 10.1371/journal.pone.0064696