Christopher J. Chermansky

The bladder acellular matrix graft in a rat chemical cystitis model: functional and histologic evaluation.

PURPOSE We investigated the feasibility of augmentation in a diseased bladder with a bladder acellular matrix graft. MATERIALS AND METHODS In 50 female Sprague-Dawley rats chemical cystitis was induced by intravesical instillation of HCl repeated monthly to maintain chronic inflammation. Urodynamic studies were performed in all rats 1 week after the induction of chemical cystitis and repeated at sacrifice. The 29 rats in the experimental group underwent partial cystectomy (50% or greater), followed by bladder acellular matrix graft augmentation, while the 21 controls underwent monthly HCl instillation only. The rats were sacrificed at 2 weeks, 1, 2 and 3 months, respectively. The bladder was removed and examined for histological changes. RESULTS Urodynamic studies showed that bladder capacity and compliance were significantly higher in the grafted than in the control group (p = 0.008 and 0.006, respectively, at 3 months). Histological studies revealed urothelial and smooth muscle regeneration within the bladder acellular matrix graft at 1 month and nerve regeneration at 3. The number of mast cells was significantly lower in the grafted region than in the host bladder of all grafted rats (p <0.001). CONCLUSIONS In this rat chemical cystitis model bladder augmentation with a bladder acellular matrix graft led to functional and histological improvement over diseased host bladder.

Pathophysiology and animal modeling of underactive bladder

AbstractWhile the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB.

THERAPEUTIC EFFECTS OF ENDOTHELIN-A RECEPTOR ANTAGONIST ON BLADDER OVERACTIVITY IN RATS WITH CHRONIC SPINAL CORD INJURY

OBJECTIVES We investigated the effects of suppression of endothelin-A (ET(A)) receptors on bladder function and ET-1 levels in the bladder in rats with chronic spinal cord injury (SCI). METHODS We transected the spinal cord of female Sprague-Dawley rats at the level of Th 8-9. Awake cystometrograms were performed 4 weeks after spinal cord transection. We evaluated cystometric parameters such as mean amplitudes of nonvoiding contractions (NVCs), the number of NVCs, voided volume, voiding efficiency, and micturition pressure before and after intravenous (i.v.) injection of ABT-627, an ET(A) antagonist, or A-19261, an ET(B) antagonist, in SCI animals. Four weeks after spinalization, we also measured the protein and mRNA levels of ET-1 in the bladder using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS ABT-627 (1 mg/kg, i.v.) but not A-192621 (10 mg/kg, i.v.) significantly decreased the amplitude of NVCs and the number of NVCs in SCI rats. There were no significant changes in pressure threshold, maximum voiding pressure, voided volume, or voiding efficiency. ELISA analysis for ET-1 showed significantly elevated protein concentrations in SCI rats compared with spinal cord intact rats. Significant upregulation of the ET-1 mRNA was also noted in SCI bladders. CONCLUSIONS These results suggest that upregulation of ET-1 is involved in the mechanism inducing bladder overactivity in chronic SCI rats, and that an ET(A) receptor antagonist can suppress SCI-induced bladder overactivity as indicated by a reduction in NVCs. Thus, ET(A) receptor inhibition could be an effective treatment for neurogenic bladder overactivity in pathological conditions such as SCI.

Electrical stimulation of somatic afferent nerves in the foot increases bladder capacity in healthy human subjects.

PURPOSE We determined whether electrical stimulation of somatic afferent nerves in the foot could delay bladder filling sensations and increase bladder capacity in healthy humans without overactive bladder. MATERIALS AND METHODS Eight subjects underwent 90-minute foot stimulation using skin surface electrodes connected to a transcutaneous electrical nerve stimulator. The electrodes were attached to the bottom of the foot. Subjects completed a 3-day voiding diary, during which foot stimulation was applied on day 2. Stimulation parameters were pulse frequency 5 Hz, rectangular waveform pulse width 0.2 milliseconds and intensity 2 to 6 times the minimal stimulation current necessary to induce toe twitch. Stimulation intensity was set by each subject to a maximal level without causing discomfort. Subjects were provided with 500 to 1,000 ml of water to drink during stimulation. RESULTS Average ± SE volume per void was 350 ± 22 ml during the 24 hours before foot stimulation. This voided volume increased to a mean of 547 ± 52 ml for up to 5 hours after stimulation (p <0.01). Average voided volume returned to 363 ± 21 ml within 36 hours after stimulation. There were no adverse events. CONCLUSIONS Foot stimulation can delay bladder filling sensations and significantly increase bladder capacity in healthy humans without overactive bladder. Although the study group was small, our results support moving forward with clinical trials of foot neuromodulation in patients with overactive bladder.

Brain-derived neurotrophic factor in urinary continence and incontinence

Urinary incontinence adversely affects quality of life and results in an increased financial burden for the elderly. Accumulating evidence suggests a connection between neurotrophins, such as brain-derived neurotrophic factor (BDNF), and lower urinary tract function, particularly with regard to normal physiological function and the pathophysiological mechanisms of stress urinary incontinence (SUI) and bladder pain syndrome/interstitial cystitis (BPS/IC). The interaction between BDNF and glutamate receptors affects both bladder and external urethral sphincter function during micturition. Clinical findings indicate reduced BDNF levels in antepartum and postpartum women, potentially correlating with postpartum SUI. Experiments with animal models demonstrate that BDNF is decreased after simulated childbirth injury, thereby impeding the recovery of injured nerves and the restoration of continence. Treatment with exogenous BDNF facilitates neural recovery and the restoration of continence. Serotonin and noradrenaline reuptake inhibitors, used to treat both depression and SUI, result in enhanced BDNF levels. Understanding the neurophysiological roles of BDNF in maintaining normal urinary function and in the pathogenesis of SUI and BPS/IC could lead to future therapies based on these mechanisms.

Past, Present and Future of Chemodenervation with Botulinum Toxin in the Treatment of Overactive Bladder

Purpose: We systematically reviewed preclinical and clinical studies on bladder chemodenervation with onabotulinumtoxin A to highlight current limitations and future drug delivery approaches. Materials and Methods: We identified peer reviewed basic and clinical research studies of onabotulinumtoxin A in the treatment of neurogenic bladder and refractory idiopathic overactive bladder published between March 2000 and March 2016. Paired investigators independently screened 125 English language articles to identify controlled studies on onabotulinumtoxin A administration in the MEDLINE® database and abstracts presented at annual American Urological Association meetings. The review yielded an evidence base of more than 50 articles relevant to the approach of injection‐free onabotulinumtoxin A chemodenervation. Results: The efficacy and safety of intradetrusor injection of onabotulinumtoxin A for the treatment of overactive bladder are sensitive to injection volume and depth, and this issue has motivated researchers to study injection‐free modes of drug delivery into the bladder. Urothelial denudation with protamine sulfate or dimethyl sulfoxide, liposome encapsulated onabotulinumtoxin A and other physical approaches are being studied to increase toxin permeability and avoid intradetrusor injections. Liposome encapsulated onabotulinumtoxin A enhances toxin activity while reducing its toxin degradation. The safety and efficacy of liposome encapsulated onabotulinumtoxin A were tested in a multicenter, placebo controlled study. Although this treatment successfully reduced urinary frequency and urgency, it did not significantly reduce urgency urinary incontinence episodes. Conclusions: Intradetrusor injection of onabotulinumtoxin A is a safe and effective treatment as reported in several large multicenter, randomized controlled trials. Injection of the toxin into the bladder wall impairs afferent and efferent nerves, but injection‐free drug delivery approaches only impair the bladder afferent nerves. Further studies are needed to develop better drug delivery platforms that overcome the drawbacks of intradetrusor injection, increase patient acceptance and reduce treatment costs.

Advanced therapeutic directions to treat the underactive bladder

Muscarinic agonists are the most commonly used agents for treating the underactive bladder (UAB). However, because of the absence of pharmacologic specificity for bladder-only effects and possibly as a result of degenerative and other post-synaptic changes involving detrusor smooth muscle cells, they are simply not effective and side effects are common. If safe and effective therapy for UAB is made available, then most experts agree that the potential market would exceed industry expectations, just as antimuscarinic agents for overactive bladder did in the late 1990s. The pharmaceutical and biotechnology industries that have a pipeline to urology and women’s health should consider UAB as a potential target condition. A rational approach to treating the pathology of UAB is presented with a discussion of potential targets that may allow the development of safe and effective agents for the treatment of UAB.

Characteristics Associated with Treatment Response and Satisfaction in Women Undergoing OnabotulinumtoxinA and Sacral Neuromodulation for Refractory Urgency Urinary Incontinence

Purpose: We sought to identify clinical and demographic characteristics associated with treatment response and satisfaction in women undergoing onabotulinumtoxinA and sacral neuromodulation therapies. Materials and Methods: We analyzed data from the ROSETTA (Refractory Overactive Bladder: Sacral NEuromodulation versus BoTulinum Toxin Assessment) trial. Baseline participant characteristics and clinical variables were associated with 2 definitions of treatment response, including 1) a reduction in mean daily urgency incontinence episodes during 6 months and 2) a 50% or greater decrease in urgency incontinence episodes across 6 months. The OAB‐S (Overactive Bladder‐Satisfaction) questionnaire was used to assess satisfaction. Results: A greater reduction in mean daily urgency incontinence episodes was associated with higher HUI‐3 (Health Utility Index‐3) scores in the onabotulinumtoxinA group and higher baseline incontinence episodes (each p <0.001) in the 2 groups. Increased age was associated with a lesser decrease in incontinence episodes in the 2 groups (p <0.001). Increasing body mass index (adjusted OR 0.82/5 points, 95% CI 0.70–0.96) was associated with reduced achievement of a 50% or greater decrease in incontinence episodes after each treatment. Greater age (adjusted OR 0.44/10 years, 95% CI 0.30–0.65) and a higher functional comorbidity index (adjusted OR 0.84/1 point, 95% CI 0.71–0.99) were associated with reduced achievement of a 50% or greater decrease in urgency incontinence episodes in the onabotulinumtoxinA group only (p <0.001 and 0.041, respectively). In the onabotulinumtoxinA group increased satisfaction was noted with higher HUI‐3 score (p = 0.002) but there was less satisfaction with higher age (p = 0.001). Conclusions: Older women with multiple comorbidities, and decreased functional and health related quality of life had decreased treatment response and satisfaction with onabotulinumtoxinA compared to sacral neuromodulation for refractory urgency incontinence.

Two-Year Outcomes of Sacral Neuromodulation Versus OnabotulinumtoxinA for Refractory Urgency Urinary Incontinence: A Randomized Trial

BACKGROUND Urgency urinary incontinence (UUI) is a chronic condition for which sacral neuromodulation (SNM) (InterStim/Medtronic) and onabotulinumtoxinA (BTX) (BotoxA/Allergan) are utilized. These therapies have not been compared over extended time. OBJECTIVE To compare UUI episodes (UUIE) over 24 mo following SNM or BTX. DESIGN, SETTING, AND PARTICIPANTS Multicenter, open-label, randomized, extension trial (February 2012-July 2016) at nine US medical centers involving 386 women with ≥6 UUIE over 3 d inadequately managed by medications. Participants were clinical responders to treatment: ≥50% reduction in UUIEs after SNM placement or 1 mo post BTX. INTERVENTION SNM (n=194) versus 200 U BTX (n=192). SNM reprogrammings occurred throughout the 24 mo. After 6 mo, two additional BTX injections were allowed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome: change in mean daily UUIE over 24 mo. SECONDARY OUTCOMES no UUIE, ≥75% and ≥50% UUIE reduction; Overactive Bladder Questionnaire Short Form; Urinary Distress Inventory short form; Incontinence Impact Questionnaire; Patient Global Impression of Improvement; Overactive Bladder Satisfaction of Treatment Questionnaire; and adverse events (AEs). Primary analysis used a linear mixed model. RESULTS AND LIMITATIONS Outcome data were available for 260/298 (87%) clinical responders. No difference in decreased mean UUIE was found over 24 mo (-3.88 vs -3.50 episodes/d,95% confidence interval [CI]=-0.14-0.89; p=0.15), with no differences in UUI resolution, ≥75% or ≥50% UUIE reduction. BTX group maintained higher satisfaction (mean difference=-9.14, 95% CI=-14.38--3.90; p<0.001), treatment endorsement (mean difference=-12.16, 95% CI=-17.7--6.63; p<0.001) through 24 mo. Other secondary measures did not differ. Recurrent urinary tract infections (UTIs) were higher after BTX (24% vs 10%; p<0.01), 6% required intermittent catheterization post second injection. SNM revision and removals occurred in 3% and 9% patients, respectively. CONCLUSIONS Both treatments offered sustainable UUI improvement, and higher BTX dosing had low clean intermittent catheterization rates, but with UTI risk. SNM revision/removal rates were low due to standardized lead placement with strict treatment response definitions. PATIENT SUMMARY We compared a large group of US women with severe urgency urinary incontinence (UUI) who received sacral neuromodulation (InterStim) or onabotulinumtoxinA (Botox A) therapy during a 2-yr period. We found that both therapies had similar success in reducing UUI symptoms, and adverse events were low. However, women in the BotoxA group had higher satisfaction and endorsement with their treatment, but with a higher chance of a urinary tract infection. We conclude that both therapies offer sustained reduction in daily incontinence over 2 yr.

Transcutaneous Electrical Nerve Stimulation of the Foot: Results of a Novel At-home, Noninvasive Treatment for Nocturnal Enuresis in Children

OBJECTIVE To evaluate the effect of a novel at-home approach to electrical foot stimulation of peripheral tibial nerve branches on the frequency of nocturnal enuresis episodes in children. MATERIALS AND METHODS Children aged 5 to 18 having 2 or more bedwetting episodes per week for at least 3 consecutive months were eligible. The study was a total of 6 weeks. Participants completed a baseline nighttime voiding diary during the first 2 weeks. This was followed by 2 weeks of foot stimulation for 60 minutes each night. During the stimulation period, and the following 2 weeks poststimulation, participants completed the nighttime voiding diary. RESULTS Twenty-two patients with a mean age of 11.4 years (range 7-16) completed the study. Overall, there was a significant reduction in mean total wet nights from 9.0 ± 4.0 to 6.8 ± 4.8 during the stimulation period (P < .01) and a sustained significant reduction to 7.2 ± 5.0 wet nights during the poststimulation period (P = .02). Sixteen patients (72.7%) showed improvement of at least 1 less wet night during stimulation, demonstrating a significant improvement from a mean of 7.9 ± 3.7 to 4.8 ± 3.5 wet nights during the 2-week stimulation (P < .01) and maintained an improved mean of 5.1 ± 4.0 wet nights during the poststimulation period (P < .01). There were no adverse events experienced by any child. CONCLUSION Transcutaneous foot stimulation is a well-tolerated, noninvasive, at-home treatment that may reduce the number of wet nights in children with nocturnal enuresis.