Neurourology and Urodynamics

Department of Urology, Maastricht University Medical Centre, Maastricht, The Netherlands Department of Neurourology, University Hospital Bonn, Bonn, Germany Department of Urology, Moinhos de Vento Hospital, Porto Alegre, Brazil Department of Surgery, Case Western Reserve University, Cleveland, Ohio Department of Urology, Uniklinik Aachen, Aachen, Germany Department of Urogynaecology, King’s College Hospital, London, UK

650 million (about 13% of the world's adult population) were obese (BMI, ≥30 kg/m 2 ; 11% of men and 15% of women). 1 Obesity directly contributes to more than 300 000 deaths per year in the United States, is associated with medical co-morbidities such as heart disease, hypertension, diabetes, cancer and depression, and adversely affects the quality of life. 2 Epidemiological studies document obesity as a strong independent risk factor for urinary incontinence (UI). 3 Therefore, it is important to elaborate the relationship between obesity and UI because it can have an impact on the diagnosis and management of UI in daily practice. This is a consensus report of the proceedings of a Research Proposal from the annual International Consultation on Incontinence-Research Society (ICI-RS), 14 June to 16 June 2018 (Bristol, UK): "What are the relationships between obesity and UI, and the effects of successful bariatric surgery? Following the group discussion, we decided to elaborate the following questions: 1. What is the relationship between obesity and UI?
What evidence can be extracted from translational and clinical studies? 2. Does obesity affect the outcome of treatment for stress urinary incontinence (SUI) and urge urinary incontinence (UUI)? 3. Is weight reduction (both conservative approaches and bariatric surgery) associated with improvement of UI?

TRANSLATIONAL VIEW
Obesity predisposes individuals to a plethora of chronic diseases 4 including insulin resistance and diabetes, cardiovascular complications, 5 and lower urinary tract symptoms (LUTS). Systemic inflammation and oxidative stress are strongly associated with the development of these pathological events. 6 Risk factors depend not on excess body weight per se, but rather on the regional distribution of excess body fat. Visceral adipose tissue (VAT) found around organs in the thoracic and, to a greater extent, in the abdominal cavity, has morphological and functional differences from subcutaneous adipose tissue. 7 In the overweight and obese state, VAT (an endocrine organ) undergoes dysregulation of secreted factors, collectively termed adipokines, resulting in increased secretion of proinflammatory factors including the pleiotropic hormone leptin and cytokines such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-8, and C-reactive protein. Leptin is best known for its regulation of body weight by signaling the nutritional status to the hypothalamus and other organs. 8 The proinflammatory actions of leptin emerge when leptin satiety signaling goes awry in obesity resulting in chronic hyperleptinemia. In addition, leptin activates NADPH oxidases and induces the production of reactive intermediates such as H 2 O 2 contributing to oxidative stress in obesity. 6 Secretion of the pleiotropic hormone adiponectin with anti-inflammatory actions, 9 positive input in insulin sensitivity and involvement in the repair of damaged vasculature is decreased in obesity. Obesity is also associated with an increase in plasma free fatty acids, which can also have wide-ranged pathophysiological impacts inclusive of oxidative stress. 10 Obesity is a common risk factor for LUTS including UI. 11 Weight loss magnitude is shown to be an independent predictor of incontinence improvement for women and men. 12 While this may be as a result of decreased pressure on the bladder and pelvic floor, positive outcomes are attributed to corrective metabolic effects of reduced central adiposity leading to reduced systemic inflammation and oxidative stress among others. In animal studies, the anti-inflammatory agent, etanercept (interferes with TNF-α signaling at its receptor) 13 and in addition, resveratrol (via antioxidant activity) 14 had positive effects on LUTS in obese mice.
In translational studies of obesity-associated disease, which mainly use rodents, the prerequisite of making the animals overweight or obese is not a simple matter. Animal models of obesity are either (a) genetic, such as spontaneous mutants (eg, Zucker fatty [fa/fa] rats) and transgenic lines (db/db and ob/ob mice), these models use a deficiency in leptin signaling to cause a rapid and reliable onset of obesity or (b) diet-induced obesity (DIO) (eg, using high-fat chow), with a wide range of reported success rates. DIO is the product of the same geneenvironment interactions that underlie the majority of human obesity cases, with slower progression and increased leptin production. 15 With the recognition of the importance of hyperleptinemia in obesity-associated disease, it would, therefore, be important not to eliminate it in the animal model. Newcomers to obesity research face a daunting task of finding a consensus between methodological approaches in the scientific literature inclusive of animal models, assessment of disease parameters such as adiposity (BMI, an unreliable proxy for the measure of adiposity is commonly used due to the prohibitive costs of magnetic resonance imaging), sexes and ages of the animals used and time points of the studies. The future path of this research would perhaps benefit from a more standardised approach in basic methodologies, which lie at the core of obesity-associated disease research.
3 | OBESITY AND UI: CLINICAL VIEW BMI correlates with intra-abdominal pressure, which increases intravesical pressure and exerts increased force on the pelvic floor, hence increasing the risk for SUI. Furthermore, increased intra-abdominal pressure can lead to the weakening of the pelvic floor innervation and musculature. 16,17 According to a recent study of Brucker et al 18 SUI is significantly more prevalent in the patients with obese (mean BMI, 45 kg/m 2 ) than UUI (25% vs 15%). In a subgroup of younger patients <50 years), the difference was even clearer (27% vs 11%). In a prospective study of 30 982 middle-aged women, increasingly higher BMI over time was related to increasing odds of developing UI, which is similar for all incontinence types. 19 Yet, a BMI ≥40 kg/m 2 (morbid obesity) increased the incidence of SUI three-fold, and UUI six-fold. Functional disability and mobility problems often accompany gross obesity and are further risk factors for UI. 20 Waetjen et al 21 noted that a BMI increase of 5 kg/m 2 increased SUI by 30% and UUI by 15%. Also in elderly women, obesity is reported as an incontinence predictor and BMI had a specific effect on mixed urinary incontinence prediction. 22 Chronically increased BMI is also associated with an elevated risk of UI in later life. Symptom severity also appears to worsen with the duration of increased BMI status, again confirming the detrimental effect of obesity on continence.
Interestingly, the relationship between adiposity and overactive bladder (OAB) symptoms varies by sex according to the results from the Boston Area Community Health Survey. 23 In women, an increase in adiposity is generally associated with a nearly linear increase in OAB prevalence. This is in contrast to men, in whom as adiposity increases, the prevalence of OAB decreases to a certain point (BMI, 27.5 kg/m 2 ), after which as adiposity increases, the OAB prevalence increases again. In women, this relationship has been attributed to biomechanical (and neuroendocrine) factors, whereas men, who have greater pelvic floor strength, may be less susceptible to these forces with fewest symptoms in the overweight range. Recent data from Japan suggest that excess abdominal visceral fat volume (central obesity) as calculated on computed tomography scans, rather than BMI, is an important risk factor of OAB in men. 24 4 | TREATMENT OF SUI-DOES OBESITY AFFECT OUTCOME?
In midurethral sling surgery for SUI, the majority of studies with short-term follow-up (<2 years) found no significant differences in the surgical outcomes according to BMI. The cure rates of the available studies are summarized in Table 1, indicating a trend towards favorable results in normal-weight patients, but without reaching statistical significance. Also, the satisfaction rates were mostly better in patients with a lower BMI, but again this difference was not significant and not consistent across all studies. Considering the chronic influence of obesity on the pelvic floor, longer follow-up may be required to evaluate the association of obesity with outcomes of mid-urethral sling surgery in women. Only a small number of studies have followed their subjects for >5 years after surgery to evaluate the influence of obesity. 25 when they analyzed the baseline characteristics of subjects in the stress incontinence surgical treatment efficacy trial SISTEr (n = 655) and the trial of midurethral slings TOMUS (n = 597) trials. Moreover, as BMI weight categories increased, subjective and objective UI severity seemed to increase. In a study by Heinonen et al 28 139 patients underwent TOT with a mean follow-up of 6.5 years. The objective and subjective cure rates were 89% and 83%, respectively. In their evaluated cohort, mean BMI was 28 (range, . Patients with BMI higher 30 had significantly higher scores on condition-specific questionnaires and significantly lower scores on quality of life questionnaires, indicating the lower general quality of life and health than in those with BMI less or equal 30.

| TREATMENT OF OAB AND
UUI-DOES OBESITY AFFECT OUTCOME?

| Pharmacological treatment
Cardozo et al 36 conducted a pooled data analysis of seven randomized placebo-controlled trials to evaluate the relationship between BMI and the efficacy or tolerability of solifenacin 5 and 10 mg. The baseline incidence of UUI increased with increasing BMI and age; relatively more women than men were incontinent. Meta-analysis showed that this drug was more efficacious than placebo for all OAB symptoms across all BMI categories, and between sexes. In a multicenter, double-blinded, randomized controlled trial with 645 women, there was no change in effect associated with BMI on treatment success with the oral anticholinergic drug fesoterodine. 37 In addition, a doubleblind, placebo-controlled trial in 575 patients with OAB showed that BMI was not associated with dose escalation from fesoterodine 4 to 8 mg. 38 One study evaluated the effect of BMI on the efficacy of mirabegron 50 mg in 169 women with OAB. The authors found no evidence in support of the hypothesis that the BMI would influence treatment outcome of mirabegron. 39

| Sacral neuromodulation
Only a few studies have explored predictors of treatment outcome with sacral neuromodulation (SNM). White et al 40 evaluated the predictors of outcome in SNM. Increased baseline BMI was found to decrease the chance of achieving ≥50% UUI episodes reduction. The study model estimated that a woman with a BMI of 25 would have a roughly 50% greater chance of achieving ≥50% improvement in UUI compared with a BMI of 35. In a prospective longitudinal study, investigators found that among other factors, decreased BMI, had a higher risk of reoperation. 41 In another study, the results suggested that lower BMI might predict reoperation, however, BMI was not significant when adjusted for other covariates. 42 A more recent retrospective review also failed to find any associations between obesity and reoperation. 43 Furthermore, a study in children showed that there is no association between age, sex, or BMI and postoperative complications in this large cohort of pediatric SNM. 44

| Onabotulinum toxin A (BoNT-A)
For BoNTA, we found only one study that evaluated BMI as a predictive factor for treatment outcome. Owen et al 45 evaluated patient factors associated with treatment outcome in a cohort of women with idiopathic detrusor overactivity. They found that besides smoking, higher BMI was associated with an increased risk of treatment failure.

REDUCTION PROGRAMS AND BARIATRIC SURGERY
In 2015 a Cochrane review was published, which included all available trials of lifestyle modification interventions for UI. 46 This review included 11 trials, with a total of 5974 patients. Four studies (n = 4701) compared specific weight loss strategies with control interventions. [47][48][49][50] One trial suggested that more women following weight loss programs reported improvement in UI at 6 months 76% vs 54%, risk ratio 1.40, and this effect was sustained at 18 months.
According to the 6th International Consultation on incontinence, weight loss of 5% of initial body weight has an impact on the reduction of UI symptoms and the odds of developing UI at 1 year can be reduced by 3% for every kilogram lost by overweight and obese women (Level of Evidence 1). Weight loss as a nonsurgical intervention should be recommended to obese and overweight women with UI (Grade of Recommendation A).
Several studies have evaluated the role of bariatric surgery in reducing UI episodes among patients with obese. Subak et al 50 performed an observational cohort study to examine the change in UI before and after bariatric surgery and to identify factors associated with improvement and remission among women and men in the first 3 years after bariatric surgery. The frequency and type of UI episodes in the past 3 months were assessed using a validated questionnaire. Prevalent UI was defined as at least weekly UI episodes, and remission was defined as a change from prevalent UI at baseline to less than weekly UI episodes at follow-up. Of 2458 participants, 1987 (80.8%) completed baseline and follow-up assessments. At baseline, the median age was 47 years, the median BMI was 46 kg/m 2 , and 78.8% were women. UI was more prevalent among women (49.3%) than men (21.8%). The 3-year prevalence was higher than the 1-year prevalence for both sexes but was substantially lower than the baseline (24.8% among women and 12.2% among men).
Lian et al 51 conducted a systematic review and meta-analysis evaluating the effect of bariatric surgery on various pelvic floor disorders in obese women. Eleven cohort studies were included in the analysis. Pooled results revealed that bariatric surgery was associated with a significant improvement in pelvic floor dysfunctions as a whole. In a subanalysis, there was a significant improvement in UI and pelvic organ prolapse. No significant improvement was found in fecal incontinence or sexual function.

| RELATIONSHIP BETWEEN THE DEGREE OF WEIGHT REDUCTION AND IMPROVEMENT OF INCONTINENCE
According to Subak et al 50 weight loss was independently related to UI remission (relative risk, 1.08; 95% confidence interval [95%CI], 1.06-1.10 in women and 1.07; 95% CI, 1.02-1.13 in men) per 5% weight loss, as were younger age and the absence of a severe walking limitation.
Burgio et al 52 carried out a prospective cohort study to assess changes in the prevalence and severity of UI and fecal incontinence in morbidly obese women undergoing laparoscopic Roux-en-Y gastric bypass. One hundred one women (aged 20-55 years) with a BMI of 40 or more were followed to 12 months. Mean BMI decreased from 48.9 (baseline) to 30.2 at 12 months postoperatively. Prevalence of UI decreased from 66.7% to 37.0% at 12 months (P < .001). The magnitude of weight loss was associated with a reduction in UI prevalence (P = .01). Among incontinent women who lost 18 or more BMI points, 71% regained urinary continence at 12 months.

| SHOULD WE ADVOCATE BARIATRIC SURGERY IN ALL (MORBIDLY) THE PATIENTS WITH OBESE WHO SEEK TREATMENT FOR UI?
Because both SUI and UUI can be a consequence of obesity, it is questionable whether anti-incontinence surgery should be offered to all the patients as a first treatment. From a general health perspective, successful reduction of (severe) obesity is most beneficial to the patient, because many other co-morbidities such as diabetes, hypertension, and arthritis are expected to diminish. However, the risks of bariatric surgery should not be underestimated because the likelihood of major complications from weight-loss surgery is approximately • What are the exact effects of obesity on lower urinary tract function? Are these effects sex-and/or agespecific? • Which patients with obesity and UI benefit most from weight reduction programs or bariatric surgery?

Translational
• Can we identify biomarkers that are associated with metabolic effects (oxidative stress and inflammation) responsible for bladder dysfunction? • What is the effect of anti-inflammatory agents (eg, etanercept and resveratrol) on LUTS in patients with obesity? • What is the role of leptin in obese patients with LUTS?

Clinical
• Is the volume of visceral adipose tissue a better predictor for the outcome of incontinence treatment than BMI? How can we (noninvasively) measure this in clinical trials? • What is the effect of weight reduction on urodynamic parameters (eg, bladder capacity, detrusor activity, and sphincteric function)? • What is the effect of weight reduction on voiding parameters (eg, urgency, frequency, and nocturia)?
• Which patients will present de novo storage symptoms after bariatric surgery? What are the effects of weight gain postoperatively?
Research challenges • What are the long-term benefits of bariatric surgery on co-morbidities (metabolic syndrome, diabetes, and hypertension) and their relationship with lower urinary tract function? • Is it possible to build a statistical model to predict preoperatively, which patients with UI will be cured after bariatric surgery? Is there a BMI cut-off which could be used as a prognostic factor? • Should we consider bariatric surgery as a primary treatment for UI in patients with severe obesity? Is it ethical to perform anti-incontinence surgery in these patients?

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4%. 53 Also, chronic metabolic issues including osteopenia and nutritional derangements can occur due to malabsorption. For now, it does not seem realistic to exclude patients with obese from the perspective of immediate improvement with surgery. The ethics behind this decision and socio-demographical aspects with regard to the alarming increase in obesity are debatable. Nonetheless, with advances in weight reduction strategies and bariatric surgery in the future, the treatment approach to UI in patients with obese might change. (Table 2) 9 | CONCLUSIONS Obesity is strongly associated with an increased prevalence of both SUI and UUI. In the pathophysiology, both mechanical and metabolic factors play an important role. The treatment outcome of UI does not seem to be highly dependent on BMI. Weight reduction is positively correlated with improvement of incontinence symptoms and therefore should be advocated in the treatment.