Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders.

Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. SIGNIFICANCE STATEMENT: Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.

Recurrent and complicated urinary tract infections in women: Utility of advanced testing to enhance care.

BACKGROUND: The United States currently faces a public health crisis with regarding to antibiotic-resistant bacteria, and new urinary tract infection (UTI) diagnostics are needed. Women with recurrent UTI (rUTI) and complicated UTI (cUTI) are at particular risk given their complexity and the paucity of adequate testing modalities. The standard urine culture (SUC) is the cornerstone for diagnosis, but it has many shortcomings. These pitfalls lead to dissatisfaction and frustration among women afflicted with rUTI and cUTI, as well as overuse of antibiotics. One innovation is PCR UTI testing, which has been shown to outperform SUC among symptomatic women. AIMS: This article discusses UTI PCR testing, as well as a possible role in clinical practice. MATERIALS AND METHODS: Published literature was reviewed and summarized. RESULTS: Management of rUTI and cUTI is complex, and providers should have all diagnostics available to facilitate providing optimal care. Urine PCR testing faces reimbursement issues despite fulfilling clinical indication parameters as described by insurance companies. DISCUSSION: The role of UTI PCR testing remains unclear. Reimbursement issues have led to underuse and limited real-world outcomes reinforcing benefit. CONCLUSION: This study proposes an algorithm for PCR testing among women with rUTI and cUTI.

Prevalence of Sleep CALM nocturia factors in a male veteran population.

INTRODUCTION: Nocturia is a complex and multifactorial condition, associated with several genitourinary abnormalities as well as a host of conditions beyond the urinary tract, and thus often poses a significant diagnostic challenge in real-world practice. Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications, the so-called "Sleep C.A.L.M." factors, are five common causes of nocturia requiring judicious evaluation according to current consensus guidelines. This study aims to assess the prevalence of the Sleep C.A.L.M. factors in a nocturia clinical population. METHODS: Retrospective analysis of frequency-volume charts from men with ≥2 nocturnal voids as well as concurrent demographic, clinical, and medical history data to identify patients with each of the Sleep C.A.L.M. FACTORS: Comorbidities and medications were classified as a single group. RESULTS: A total of 213 subjects met the criteria for inclusion (median age 68.0 [63.5-75.5] years). The prevalence of 1) sleep disorders, 2) comorbidities and/or medication use, 3) actions (i.e., modifiable behaviors/lifestyle factors), and 4) lower urinary tract dysfunction was 31%, 31%, 19%, and 41%, respectively. Among included participants, 73% were found to have at least 1 Sleep C.A.L.M. factor, and 33% had multiple Sleep C.A.L.M. FACTORS: Results were similar upon stratification by age and nocturnal polyuria status. CONCLUSIONS: The Sleep C.A.L.M. factors are highly common among nocturia patients in the clinical urology setting. Although many of these factors are strongly associated with advanced age in community-based nocturia study samples, they appear common even among younger men in a nocturia patient population; the differential effect of age and individual Sleep C.A.L.M. factors on nocturia pathophysiology requires further investigation.

Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications ("Sleep C.A.L.M.") in the evaluation and management of nocturia: A simple approach to a complex diagnosis.

INTRODUCTION: Nocturia arises from a fundamental mismatch between nocturnal urine production, storage capacity, and sleep architecture, which may be driven by abnormalities of the genitourinary tract, but also by sleep disorders, medical diseases, patient actions/lifestyle factors, or medications. This article introduces a novel system for organizing the complex differential diagnosis for nocturia, as proposed by an international collective of practicing urologists, physician specialists, and sleep experts: "Sleep CALM"-Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications. METHODS: Narrative review of current evidence regarding the relevance of each "Sleep CALM" factor to nocturia pathogenesis, evaluation, and management. RESULTS: Nocturia and sleep disorders are highly intertwined and often bidirectional, such that nocturnal awakenings for reasons other than a sensation of bladder fullness should not be used as grounds for exclusion from nocturia treatment, but rather leveraged to broaden therapeutic options for nocturia. Nocturia is an important potential harbinger of several serious medical conditions beyond the genitourinary tract. Urologists should have a low threshold for primary care and medical specialty referral for medical optimization, which carries the potential to significantly improve nocturnal voiding frequency in addition to overall health status. Adverse patient actions/lifestyle factors, lower urinary tract dysfunction, and medication use commonly coexist with disordered sleep and comorbid medical conditions, and may be the primary mediators of nocturia severity and treatment response, or further exacerbate nocturia severity and complicate treatment. CONCLUSION: "Sleep CALM" provides a memorable and clinically relevant means by which to structure the initial patient history, physical exam, and clinical testing in accordance with current best-practice guidelines for nocturia. Although not intended as an all-encompassing diagnostic tool, the "Sleep CALM" schema may also be useful in guiding individualized ancillary testing, identifying the need for specialty referral and multidisciplinary care, and uncovering first-line treatment targets.

A uro-protective agent with restorative actions on urethral and striated muscle morphology.

PURPOSE: Aging increases oxidative stress, which can have delirious effects on smooth and striated muscle resulting in bladder dysfunction. Consequently, in women aged over 60 years, urinary incontinence (UI) is a prevalent health problem. Despite the prevalence and consequences, UI continues to be undertreated simply because there are few therapeutic options. METHODS: Here we investigated whether 8-aminoguanine (8-AG), a purine nucleoside phosphorylase (PNPase inhibitor), would restore urethra and external sphincter (EUS) muscle morphology in the aged rat. Aged (> 25 months) female Fischer 344 rats were randomized to oral treatment with 8-AG (6 weeks) or placebo, and the urethra and EUS were evaluated by electron microscopy and protein expression (western immunoblotting). RESULTS: Aging was associated with mitochondrial degeneration in smooth and striated muscle cells as compared to young rats. We also observed a significant increase in biomarkers such as PARP, a downstream activator of oxidative/nitrosative stress. Treatment of aged rats with 8-AG normalized all abnormalities to that of a younger state. CONCLUSIONS: 8-AG, a potent inhibitor of PNPase, reverses age-related lower urinary tract morphological and biochemical changes. Our observations support the concept that 8-AG will reverse age-induced lower urinary tract disorders such as UI. These initial findings could have therapeutic implications for the prevention and treatment of age-related UI.

Patient preference elicitation instrument, OABCare, to facilitate shared decision-making in the care of overactive bladder.

AIMS: To describe the development and feasibility of a preference elicitation instrument, OABCare, using choice-based adaptive conjoint analysis (ACA) among patients with overactive bladder (OAB). METHODS: This was a two-phase study. In Phase 1, an extensive literature review along with patient and provider focus groups yielded the attributes and levels for our OABCare instrument. The hierarchical Bayesian random-effects model generated utilities and mean relative importance scores of treatment attributes. Phase 2 consisted of a cohort study to assess the association between OAB treatment uptake and treatment attributes elicited from OABCare, using generalized linear models. RESULTS: Literature review and provider and patient focus groups in Phase 1 yielded themes related to OAB management that were used to develop 11 attributes for the ACA instrument. For Phase 2 of the study, 108 patients were recruited who completed the OABCare instrument. Results showed that the top five attributes with the highest mean utility values were caregiver burden, impaired bladder function, social interaction constraints, treatment side effects, and use of pads. In addition, impaired bladder function (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.1, 2.1), disturbed sleep (OR = 1.24, 95% CI = 1.04, 1.47), social interaction constraints (OR = 1.12, 95% CI = 1.05, 1.32), and out-of-pocket costs (OR = 0.79, 95 % CI = 0.61, 0.94) were associated with OAB treatment uptake. CONCLUSIONS: Our ACA-based instrument, OABCare, is a feasible and acceptable tool for assessing preferences in OAB patients. Preference assessment can facilitate shared decision-making and may enhance the quality of OAB care. Future work will evaluate the OABCare instrument in different subgroups based on sociodemographic, clinical, and treatment characteristics, and its integration into clinical care settings.

First voided volume: A novel approach to characterize nocturia.

AIMS: Nocturnal polyuria syndrome (NPS) denotes nocturnal polyuria (NP) in the absence of identifiable contributory factors. The trajectory of nocturnal urine production (NUP; typically expressed as ml/hour) may be useful in delineating between NP patients with versus without NPS, but changes in absolute urine volume, the directly measured substrate for behavioral and pharmacologic interventions targeting nocturnal urine production, have not been well characterized. This study compares the ratio of the first nocturnal voided volume (FNVV) to the nocturnal average voided volume (NAVV) in patients with versus without NPS. METHODS: Secondary analysis of 24-h voiding diaries from male patients greater than or equal to 18 years of age with two or more nocturnal voids and NP using two different criteria for NP: NUP greater than or equal to 90 ml/h and nocturnal polyuria index (NPi) greater than or equal to 0.33. Patients with diabetes insipidus and CPAP-adherent obstructive sleep apnea (OSA) were excluded. Patients were divided into 2 groups: secondary NP (OSA, congestive heart failure, and chronic kidney disease) and NPS (absence of edema, diuretic use, and the aforementioned comorbidities). FNVV was defined as the volume of urine accompanying the first nocturic episode. NAVV was defined as nocturnal urine volume/(number of nocturnal voids + 1). The nocturnal urine trajectory ratio (NUTR) was defined as FNVV/NAVV. RESULTS: At NUP greater than or equal to 90 ml/h, NUTR was significantly greater in patients with (n = 73) versus without (n = 28) NPS (1.10 [0.89-1.33] vs. 0.91 [0.55-1.15], p = .012). At NPi greater than or equal to 0.33, NUTR was likewise significantly greater in patients with (n = 92) versus without (n = 32) NPS (1.09 [0.90-1.33] vs. 0.91 [0.57-1.17], p = .010). CONCLUSIONS: The volume of urine produced in the early hours of sleep is central to identification of NPS in patients with nocturia.

Nocturia and electrocardiographic abnormalities among patients at an inner-city cardiology clinic.

AIMS: Nocturia has been increasingly recognized as a potential manifestation of cardiovascular disease. However, the relationship between nocturia and electrocardiographic (ECG) abnormalities has not been studied. This study aims to characterize the diagnostic utility of nocturia in identifying left ventricular hypertrophy (LVH), left atrial enlargement (LAE), and prolonged QTc on ECG. METHODS: Retrospective analysis of nocturnal voiding frequency and contemporaneous ECG data from consecutive patients evaluated at a university-based outpatient cardiology clinic. Three sets of three incremental binary multiple logistic regression models controlling for (1) age, (2) sex and race, and (3) body mass index, hypertension, diabetes mellitus, and diuretic utilization were performed to determine whether nocturia was predictive of LVH, LAE, and prolonged QTc. RESULTS: Included patients (n = 143, 77.6% nocturia) were predominantly African-American (89.5%), female (74.1%), and obese (61.5%), of whom 44.1%, 41.3%, and 27.3% had LVH, LAE, and prolonged QTc, respectively. Older age, African-American race, obesity, hypertension, diuretic use, LVH, and LAE were significantly associated with nocturia on univariate analysis. No significant differences were observed in the strength of associations between nocturia and LVH, LAE, or QTc prolongation based on age. Nocturia independently predicted LVH in Models I-III (odds ratios [ORs], 2.99-3.20; relative risks [RRs], 1.18 for all, p ≤ .046) and LAE in Models I-III (ORs, 4.24-4.72; RRs, 1.21 for all, p ≤ .015). No significant associations were observed between nocturia and prolonged QTc. CONCLUSIONS: Nocturia may be a risk marker for underlying structural cardiac abnormalities.

Nocturia is Associated with High Atherosclerotic Cardiovascular Disease Risk in Women: Results from the National Health and Nutrition Examination Survey.

Growing evidence has identified nocturia as a potential manifestation of several cardiovascular disease states. We aimed to determine whether a relationship exists between nocturia and global atherosclerotic cardiovascular disease (ASCVD) risk, defined by the American College of Cardiology/American Heart Association (ACC/AHA) ASCVD risk calculator, using a large nationally-representative study sample from the United States. We explored potential associations between nocturia and ASCVD risk in adults aged 40-79 years with no prior history of overt/known atherosclerotic disease from 7 consecutive cycles of the National Health and Nutrition Examination Survey. Subjects were classified by whether they met the ASCVD high-risk threshold following current ACC/AHA consensus guidelines (10-year major adverse cardiovascular event risk ≥ 20%). Logistic regression analyses were used to explore associations between nocturia (defined as ≥ 2 nocturnal voids) and ASCVD risk. The prevalence of nocturia and high ASCVD risk were 27.0% and 10.9%, respectively. Nocturia, older age, increased body mass index, and diuretic use were associated with high ASCVD risk on univariate logistic regression. After adjusting for age, body mass index, and diuretic use, nocturia remained associated with significantly greater odds of high ASCVD risk in females but not in males. Elicitation of nocturia on clinical history taking may serve to identify high cardiovascular risk in females. Future studies are needed to elucidate mechanisms underlying this association.

Blinding in Clinical Trials: Seeing the Big Picture.

Blinding mitigates several sources of bias which, if left unchecked, can quantitively affect study outcomes. Blinding remains under-utilized, particularly in non-pharmaceutical clinical trials, but is often highly feasible through simple measures. Although blinding is generally viewed as an effective method by which to eliminate bias, blinding does also pose some inherent limitations, and it behooves clinicians and researchers to be aware of such caveats. This article will review general principles for blinding in clinical trials, including examples of useful blinding techniques for both pharmaceutical and non-pharmaceutical trials, while also highlighting the limitations and potential consequences of blinding. Appropriate reporting on blinding in trial protocols and manuscripts, as well as future directions for blinding research, will also be discussed.

Foundational Statistical Principles in Medical Research: Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value.

Sensitivity, which denotes the proportion of subjects correctly given a positive assignment out of all subjects who are actually positive for the outcome, indicates how well a test can classify subjects who truly have the outcome of interest. Specificity, which denotes the proportion of subjects correctly given a negative assignment out of all subjects who are actually negative for the outcome, indicates how well a test can classify subjects who truly do not have the outcome of interest. Positive predictive value reflects the proportion of subjects with a positive test result who truly have the outcome of interest. Negative predictive value reflects the proportion of subjects with a negative test result who truly do not have the outcome of interest. Sensitivity and specificity are inversely related, wherein one increases as the other decreases, but are generally considered stable for a given test, whereas positive and negative predictive values do inherently vary with pre-test probability (e.g., changes in population disease prevalence). This article will further detail the concepts of sensitivity, specificity, and predictive values using a recent real-world example from the medical literature.

Can we harness the placebo effect to improve care in lower urinary tract dysfunction? ICI-RS 2019.

The proposal "Can we harness the placebo effect to improve care in lower urinary tract dysfunction?" was discussed at the International Consultation on Incontinence-Research Society (ICI-RS) 2019 meeting. The placebo effect can change the treatment outcome whether the treatment is an active treatment or placebo. The total active treatment outcome is a combination of the placebo and the active treatment effect which is seen in placebo-controlled trials. The placebo effect plays an important role in the treatment of lower urinary tract dysfunction in overactive bladder, bladder pain syndrome, and stress urinary incontinence. In clinical practice, a number of factors can be employed to use the placebo effect to maximize its effect on patients receiving an active treatment, such as having the same environment for review such as the same appointment time, same room, and same clinician. Clinicians should also be aware of the nocebo effect which is increased with an overemphasis on side effects or negative outcomes.

Are oxidative stress and ischemia significant causes of bladder damage leading to lower urinary tract dysfunction? Report from the ICI-RS 2019.

Several studies indicate that pelvic ischemia and oxidative stress may play a significant role in lower urinary tract dysfunction (LUTD), including detrusor overactivity (DO)/overactive bladder (OAB) and detrusor underactivity (DU)/underactive bladder (UAB). The present article addresses proposal 1: "Are oxidative stress and ischemia significant causes of bladder damage leading to LUTD?" from the 2019 International Consultation on Incontinence-Research Society (ICI-RS) meeting. Bladder ischemia in animals and humans is briefly described, along with the proposed progression from ischemia to LUTD. Bladder ischemia is compared with ischemia of other organs, and the ongoing development of pelvic ischemia animal models is discussed. In addition, the distribution of blood within the bladder during filling and voiding and the challenges of quantification of blood flow in vivo are described. Furthermore, oxidative stress, including potential biomarkers and treatments, and challenges regarding antioxidant therapy for the treatment of LUTD are discussed. Finally, seven critical research questions and proposed studies to answer those questions were identified as priorities that would lead to major advances in the understanding and treatment of lower urinary tract symptoms (LUTS)/LUTD associated with pelvic ischemia and oxidative stress.

Association between urinary symptom severity and white matter plaque distribution in women with multiple sclerosis.

AIMS: Multiple sclerosis (MS) is characterized by demyelinated white matter plaque throughout the central nervous system. Plaque involvement in regions that regulate micturition may be associated with urinary symptom severity in patients with MS. The aim of this prospective study is to investigate the relationship between cerebral plaque volume (PV), location, and urinary symptoms in women with MS. METHODS: We conducted a case-control pilot study of women with MS undergoing routine yearly brain MRI. Women were administered the American Urologic Association-Symptom Index (AUA-SI) and divided into two groups: severe urinary symptoms (AUA-SI ≥20) and mild symptoms (AUA-SI ≤7). PV and location in the brain were determined using a validated automated white matter lesion segmentation algorithm. RESULTS: This study of 36 women found that the median total PV did not differ between groups. Women with severe urinary symptoms had larger median PV in the left frontal lobe (LFL) and right limbic lobe (RLL) compared with women with mild urinary symptoms. Within the RLL, women with severe symptoms had a larger median PV in the right cingulate gyrus (RCG). There was a moderate correlation between LFL lesion volume and RLL lesion volume with the AUA emptying subscore; however, these regions did not correlate with the storage subscore. CONCLUSIONS: This preliminary study found urinary symptom severity in women with MS is associated with PV in the RCG and LFL, and not total cerebral PV. These findings may explain why disease burden alone is not a predictor of severity or type of voiding dysfunction in patients with MS.

Time of peak nocturnal diuresis rate between men with secondary nocturnal polyuria versus nocturnal polyuria syndrome.

AIM: Compare the circadian trajectory of diuresis between nocturnal polyuria (NP) patients with versus without identifiable contributory comorbidities. METHODS: Retrospective analysis of frequency-volume charts from male patients with clinically-significant nocturia (≥2 nocturnal voids) and NP (defined by nocturnal urine production [NUP] ≥90 mL/hour or nocturnal polyuria index [NPi] ≥0.33). Patients with NP and chronic kidney disease, congestive heart failure, and/or undertreated obstructive sleep apnea (OSA) were deemed to have secondary NP. Nocturnal polyuria syndrome (NPS) was defined as NP without edema, loop diuretic use, or the aforementioned conditions. Patients with diabetes insipidus or OSA with appropriate continuous positive airway pressure utilization were excluded. The timing and volumes of nocturnal voids were used to derive "early" and "late" nocturnal diuresis rates (mL/hour of urine produced before and after the first nocturnal awakening, respectively). The likelihood of an early peak nocturnal diuresis rate (ie, early >late nocturnal diuresis rate) was compared between patients with NPS versus secondary NP using both a crude and adjusted odds ratio. RESULTS: The likelihood of an early peak nocturnal diuresis rate in patients with NPS compared with secondary NP was 2.58 (1.05-6.31) at NUP ≥ 90 mL/hour and 1.96 (0.87-4.42) at NPi ≥ 0.33 on crude analysis, and 2.44 (0.96-6.24) and 1.93 (0.83-4.48) after adjustment, respectively. CONCLUSIONS: A peak early nocturnal diuresis rate was significantly more likely in patients with NPS at NUP ≥ 90 mL/hour, with similar odds ratios at NPi ≥ 0.33 and following adjustment. Delineating nocturic patients by NP subgroup may facilitate more individualized management. PATIENT SUMMARY: Many people have to wake up to urinate because they produce too much urine at night-a condition known as "nocturnal polyuria." Nocturnal polyuria might be caused by drinking too much fluid, other behavioral factors, or conditions that make your body hold on to too much fluid, like heart disease, kidney disease, and sleep apnea. In cases of nocturnal polyuria where no clear cause can be identified, it is thought that patients may suffer from a deficiency in nighttime vasopressin, a hormone that plays a key role in how much urine you produce. In this study, we compared the pattern of nighttime urine production in patients with different causes of nocturnal polyuria, which may lead to more personalized treatment options for patients with this condition.

Impact of food and drinks on urine production: A systematic review.

CONTEXT: The impact of food and drinks on body fluid metabolism is of direct clinical relevance but current evidence remains fragmented. AIM: Synthesise current evidence on the role of food and drinks in urine production. METHODS: Systematic review as per PRISMA guidelines using MEDLINE and EMBASE databases (completed October 2019). Studies reporting on the effect of food, food constituents, and drinks on urine production were included. Two authors performed an independent extraction of relevant articles using predetermined data sets and completed quality-of-study indicators. RESULTS: A total of 49 studies were included, of which 21 enroled human subjects, and 28 were clinically relevant animal studies (all of which utilised rodent models). The included studies were determined to be of variable quality. High dietary sodium, as well as wine, spirits, high-caffeine coffee, and caffeinated energy drinks, increased urine production in human studies. Decreased urine production was associated with low dietary sodium and consumption of milk, orange juice, and high-salt/high-sugar drinks. In animal models, a variety of fruits, vegetables, herbs, spices, and honey were associated with increased urine production. CONCLUSION: Current evidence suggests that although several types of food and drinks may impact body fluid metabolism, the quality of the data is variable. Urine production appears to be influenced by multiple factors including composition (ie, moisture, macronutrients, and electrolytes), metabolite load, and the presence of specific diuresis-promoting substances (eg, caffeine, alcohol) and other bioactive phytochemicals. Future research is needed to support current evidence and the physiologic mechanisms underlying these findings.

Aging increases the expression of vasopressin receptors in both the kidney and urinary bladder.

AIMS: The goal of this study was to determine whether aging effects the expression of V1a and V2 vasopressin receptors in the urinary bladder mucosa (UBM) and kidney. METHODS: UBM and kidneys were obtained from young (3 months-of-age) and old (25-30 months-of-age) female Fisher 344 rats. Tissue samples were analyzed by western blotting for V1a and V2 receptor expression, and rat plasma levels of vasopressin levels were measured by ELISA. RESULTS: V1a and V2 receptors were detected in both the UBM and kidneys. Aging significantly (P < 0.05) increased the expression of V2 receptors by 2.80 ± 0.52 and 6.52 ± 1.24-fold in the UBM and kidneys, respectively. Aging also increased V1a receptor expression in the kidneys (5.52 ± 1.05 fold; P < 0.05), but not in the UBM. To the best of our knowledge, because this is the first detection of V2 receptors in the mammalian bladder mucosa, we also probed human UBM for V2 receptors and observed high expression in human UBM. Unlike V1a and V2 receptors, aging had only a minor effect on plasma vasopressin levels (8% increase). CONCLUSIONS: V2 receptors are substantially increased in the aging UBM. The role of these receptors in UBM is as yet undefined, but given their presence and action in the kidneys, the possible effect of these receptors in free water regulation should be considered. The large age-related increase in the expression of V2 receptors in both the UBM and kidney may contribute to the effectiveness of desmopressin in age-related nocturia.