REVIEW URRENT C OPINION
Biomarkers in lower urinary tract symptoms/ overactive bladder: a critical overview Tiago Antunes-Lopes a,b, Ce´lia D. Cruz a,c, Francisco Cruz a,b, and Karl D. Sievert d
Purpose of review Biomarkers constitute objectively measurable characteristics that can be evaluated as indicators of physiological and pathogenic processes and might be used as diagnostic, prognostic or predictive tools in clinical care. This review examines the availability of biomarkers to treat the dynamic and complex symptoms of overactive bladder (OAB). Recent findings OAB biomarkers may contribute to reveal the origin of storage symptoms in otherwise healthy individuals. The research encompassing the changes that occur in the bladder or in the peripheral (and central) nervous system might be determined through blood or urinary molecules (neurotrophins, ATP, prostaglandins, C-reactive protein and cytokines) or the measurement of events occurring in the bladder wall (bladder wall or detrusor wall thickness, oxyhemoglobin and deoxyhemoglobin concentration). These biomarkers might contribute to a better understanding of the pathophysiologic mechanisms underlying OAB. Summary The word biomarker to name all the parameters described above, from bladder wall thickness to urinary molecules, has been introduced to call the attention to a field wherein objective noninvasive parameters were nonexistent. OAB treatment based on a biomarker, in comparison to the treatment based on a diagnosis made from a careful history and exclusion of urinary tract infection, is not supported by current literature. Keywords biomarker, bladder wall thickness, cytokines, lower urinary tract symptom, neurotrophins, overactive bladder
INTRODUCTION Biomarkers are objectively measurable characteristics that may be used to define the presence of a condition (diagnostic biomarker), its severity and progression (prognostic biomarker) or the response to a particular treatment (predictive biomarker) [1]. In overactive bladder (OAB), reported biomarkers have included quantifiable products in urine or blood, genetic assays and urodynamic and imaging tests able to detect detrusor overactivity [2,3]. Validated questionnaires, although sharing some of the aforementioned biomarker features, differ by the fundamental fact that they are subjective and, for that reason, they will not be further addressed. Gene expression and biomarkers for interstitial cystitis are also outside the scope of this review. Although the Trp (64)Arg polymorphism of the b3-adrenoceptor gene may be associated with OAB syndrome in some populations, there is no evidence that it influences the response to receptor agonists [4]. www.co-urology.com
Despite the already extensive research on this topic, it is still unclear if OAB management will benefit from the routine use of biomarkers. OAB is not a disease, but rather a complex set of storage symptoms. It is not equivalent to detrusor overactivity, which is characterized by the urodynamic observation of involuntary detrusor contractions during bladder filling [5]. Therefore, the advantage
a Translational NeuroUrology, IBMC – Institute for Molecular and Cell Biology, University of Porto, bDepartment of Urology, Hospital de S. Joa˜o, c Department of Experimental Biology, Faculty of Medicine of Porto, University of Porto, Porto, Portugal and dDepartment of Urology, Eberhard-Karls University, Tubingen, Germany
Correspondence to Professor Karl D. Sievert, MD, PhD, FACS, FRCS, Eberhard-Karls University, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany. Tel: +49 7071 298 6611; fax: +49 7071 29 5092; e-mail: [email protected] Curr Opin Urol 2014, 24:352–357 DOI:10.1097/MOU.0000000000000064 Volume 24 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lower urinary tract symptoms Antunes-Lopes et al.
KEY POINTS Biomarkers are objectively measurable characteristics that may be used to define the presence of a condition (diagnostic biomarker), its severity and progression (prognostic biomarker) or the response to a particular treatment (predictive biomarker). Several molecular biomarkers have been recently identified in the urine and/or in the blood of OAB patients. Other biomarkers related to physiological parameters include bladder wall or detrusor wall thickness and the concentration of oxyhemoglobin and deoxyhemoglobin in the bladder wall. A hypothesis can be made that variations of biomarkers are attributed to the origin of storage symptoms. The true value of these molecules and physiological parameters in OAB is debatable and actively discussed in the urological community.
of an objective biomarker to confirm the presence of OAB symptoms might be of reduced value in clinical practice as both patients and caregivers have difficulties to define urgency in relation to urge. The routine use of biomarkers also contradicts with the fact that approved drugs for OAB treatment are only intended to control symptoms and improve health-related quality of life. Furthermore, none of the approved therapies, including antimuscarinics, the b3- adrenoceptor agonist mirabegron, onabotulinum toxin type A or neuromodulation, have been specifically designed for a particular OAB subpopulation. Similarly, the initiation or reintroduction of OAB medication in asymptomatic patients based on a positive test suggests that they have no proven benefit. Nevertheless, biomarkers may have a purpose in contributing in determining the origin of OAB in otherwise healthy individuals. In fact, the pathophysiology of lower urinary tract symptoms (LUTS) is highly complex and multifactorial [6]. Biomarkers that predict, at the time of diagnosis, those patients in whom symptoms will persist or progress may have obvious advantages to guide clinical decisions. Moreover, they may be useful in the management of women with mixed urinary incontinence (MUI), which currently is managed based on the subjective decision of which type of incontinence is more bothersome. Ultimately, OAB biomarkers may also be helpful in establishing the cause of a recurrence of urinary incontinence after a previous successful surgery for stress urinary incontinence (SUI). The authors recommend that the reader follow this overview, while keeping in mind the limitations
and advantages of OAB biomarkers. The potential problems of accessing putative biomarkers will be addressed in this critical review.
NONINVASIVE METHODS TO DETECT DETRUSOR OVERACTIVITY Detrusor overactivity, the urodynamic indication of OAB, requires an invasive and expensive test. Thus, several methods to detect detrusor overactivity by noninvasive methods are currently under investigation.
Near-infrared spectroscopy Near-infrared spectroscopy detects oxygen-dependent hemodynamic changes in the bladder detrusor. This technology uses light in the near-infrared area, which is able to penetrate the skin, to measure changes in the concentration of oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb) in the bladder, reflecting detrusor oxygen consumption. In a study of 41 individuals with OAB symptoms, nearinfrared spectroscopy showed an average sensitivity of 92% and specificity of 72% in the detection of detrusor overactivity [area under the curve (AUC): 0.80–0.82, P
Biomarkers in lower urinary tract symptoms/ overactive bladder: a critical overview Tiago Antunes-Lopes a,b, Ce´lia D. Cruz a,c, Francisco Cruz a,b, and Karl D. Sievert d
Purpose of review Biomarkers constitute objectively measurable characteristics that can be evaluated as indicators of physiological and pathogenic processes and might be used as diagnostic, prognostic or predictive tools in clinical care. This review examines the availability of biomarkers to treat the dynamic and complex symptoms of overactive bladder (OAB). Recent findings OAB biomarkers may contribute to reveal the origin of storage symptoms in otherwise healthy individuals. The research encompassing the changes that occur in the bladder or in the peripheral (and central) nervous system might be determined through blood or urinary molecules (neurotrophins, ATP, prostaglandins, C-reactive protein and cytokines) or the measurement of events occurring in the bladder wall (bladder wall or detrusor wall thickness, oxyhemoglobin and deoxyhemoglobin concentration). These biomarkers might contribute to a better understanding of the pathophysiologic mechanisms underlying OAB. Summary The word biomarker to name all the parameters described above, from bladder wall thickness to urinary molecules, has been introduced to call the attention to a field wherein objective noninvasive parameters were nonexistent. OAB treatment based on a biomarker, in comparison to the treatment based on a diagnosis made from a careful history and exclusion of urinary tract infection, is not supported by current literature. Keywords biomarker, bladder wall thickness, cytokines, lower urinary tract symptom, neurotrophins, overactive bladder
INTRODUCTION Biomarkers are objectively measurable characteristics that may be used to define the presence of a condition (diagnostic biomarker), its severity and progression (prognostic biomarker) or the response to a particular treatment (predictive biomarker) [1]. In overactive bladder (OAB), reported biomarkers have included quantifiable products in urine or blood, genetic assays and urodynamic and imaging tests able to detect detrusor overactivity [2,3]. Validated questionnaires, although sharing some of the aforementioned biomarker features, differ by the fundamental fact that they are subjective and, for that reason, they will not be further addressed. Gene expression and biomarkers for interstitial cystitis are also outside the scope of this review. Although the Trp (64)Arg polymorphism of the b3-adrenoceptor gene may be associated with OAB syndrome in some populations, there is no evidence that it influences the response to receptor agonists [4]. www.co-urology.com
Despite the already extensive research on this topic, it is still unclear if OAB management will benefit from the routine use of biomarkers. OAB is not a disease, but rather a complex set of storage symptoms. It is not equivalent to detrusor overactivity, which is characterized by the urodynamic observation of involuntary detrusor contractions during bladder filling [5]. Therefore, the advantage
a Translational NeuroUrology, IBMC – Institute for Molecular and Cell Biology, University of Porto, bDepartment of Urology, Hospital de S. Joa˜o, c Department of Experimental Biology, Faculty of Medicine of Porto, University of Porto, Porto, Portugal and dDepartment of Urology, Eberhard-Karls University, Tubingen, Germany
Correspondence to Professor Karl D. Sievert, MD, PhD, FACS, FRCS, Eberhard-Karls University, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany. Tel: +49 7071 298 6611; fax: +49 7071 29 5092; e-mail: [email protected] Curr Opin Urol 2014, 24:352–357 DOI:10.1097/MOU.0000000000000064 Volume 24 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lower urinary tract symptoms Antunes-Lopes et al.
KEY POINTS Biomarkers are objectively measurable characteristics that may be used to define the presence of a condition (diagnostic biomarker), its severity and progression (prognostic biomarker) or the response to a particular treatment (predictive biomarker). Several molecular biomarkers have been recently identified in the urine and/or in the blood of OAB patients. Other biomarkers related to physiological parameters include bladder wall or detrusor wall thickness and the concentration of oxyhemoglobin and deoxyhemoglobin in the bladder wall. A hypothesis can be made that variations of biomarkers are attributed to the origin of storage symptoms. The true value of these molecules and physiological parameters in OAB is debatable and actively discussed in the urological community.
of an objective biomarker to confirm the presence of OAB symptoms might be of reduced value in clinical practice as both patients and caregivers have difficulties to define urgency in relation to urge. The routine use of biomarkers also contradicts with the fact that approved drugs for OAB treatment are only intended to control symptoms and improve health-related quality of life. Furthermore, none of the approved therapies, including antimuscarinics, the b3- adrenoceptor agonist mirabegron, onabotulinum toxin type A or neuromodulation, have been specifically designed for a particular OAB subpopulation. Similarly, the initiation or reintroduction of OAB medication in asymptomatic patients based on a positive test suggests that they have no proven benefit. Nevertheless, biomarkers may have a purpose in contributing in determining the origin of OAB in otherwise healthy individuals. In fact, the pathophysiology of lower urinary tract symptoms (LUTS) is highly complex and multifactorial [6]. Biomarkers that predict, at the time of diagnosis, those patients in whom symptoms will persist or progress may have obvious advantages to guide clinical decisions. Moreover, they may be useful in the management of women with mixed urinary incontinence (MUI), which currently is managed based on the subjective decision of which type of incontinence is more bothersome. Ultimately, OAB biomarkers may also be helpful in establishing the cause of a recurrence of urinary incontinence after a previous successful surgery for stress urinary incontinence (SUI). The authors recommend that the reader follow this overview, while keeping in mind the limitations
and advantages of OAB biomarkers. The potential problems of accessing putative biomarkers will be addressed in this critical review.
NONINVASIVE METHODS TO DETECT DETRUSOR OVERACTIVITY Detrusor overactivity, the urodynamic indication of OAB, requires an invasive and expensive test. Thus, several methods to detect detrusor overactivity by noninvasive methods are currently under investigation.
Near-infrared spectroscopy Near-infrared spectroscopy detects oxygen-dependent hemodynamic changes in the bladder detrusor. This technology uses light in the near-infrared area, which is able to penetrate the skin, to measure changes in the concentration of oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb) in the bladder, reflecting detrusor oxygen consumption. In a study of 41 individuals with OAB symptoms, nearinfrared spectroscopy showed an average sensitivity of 92% and specificity of 72% in the detection of detrusor overactivity [area under the curve (AUC): 0.80–0.82, P
