Associations Between Sodium-Glucose Co-transporter 2 Inhibitors and Urologic Diseases: Implications for Lower Urinary Tract Symptoms From a Multi-State Health System Analysis.

OBJECTIVE: To analyze the frequency of new urologic visits and urologic diagnoses in patients prescribed sodium-glucose co-transporter-2 inhibitors (SGLT-2is). MATERIAL AND METHODS: Records from a multi-state health system between 2014 and 2022 were reviewed to identify patients referred for outpatient urology evaluation within 2 years of diabetes medication prescription. Patients were stratified by the prescription of SGLT-2is or another diabetes medication. Frequency of urology visits within 1-year, urologic diagnoses, and prescriptions to treat lower urinary tract symptoms (LUTS) were compared. Patients were stratified by whether they had achieved HbA1c goal (≥7% or <7%) following treatment as well as by sex. Multivariable logistic regression was performed to determine if SGLT-2 use independently predicted outcomes of interest. RESULTS: 163,827 patients met inclusion criteria. Use of SGLT-2is was associated with a higher frequency of early urologic referral, balanitis/balanoposthitis, overactive bladder, urinary frequency, urgency, and need for LUTS medications in males with HbA1c ≥7%. Females on SGLT-2is with HbA1c ≥7% also had higher rates of urinary incontinence. In those with HbA1c <7%, only balanitis/balanoposthitis and urinary incontinence were higher in the SGLT-2i cohorts for males and females, respectively. Multivariable analysis found SGLT-2i use as predictive of early urology referral, balanitis/balanoposthitis, urinary urgency, frequency, overactive bladder, and need for LUTS medications in males. Multivariable analysis of females demonstrated similar results. CONCLUSION: SGLT-2is may lead to worse urologic outcomes and increased utilization of urologic care relative to other diabetic medications. Future studies are necessary to identify which patients are at highest risk of adverse urologic outcomes.

An exploratory study investigating the impact of the bladder tumor microbiome on Bacillus Calmette Guerin (BCG) response in non-muscle invasive bladder cancer.

PURPOSE: Intravesical Bacillus Calmette-Guerin (BCG) is standard of care for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). The effect of the bladder microbiome on response to BCG is unclear. We sought to characterize the microbiome of bladder tumors in BCG-responders and non-responders and identify potential mechanisms that drive treatment response. MATERIALS AND METHODS: Patients with archival pre-treatment biopsy samples (2012-2018) were identified retrospectively. Prospectively, urine and fresh tumor samples were collected from individuals with high-risk NMIBC (2020-2023). BCG response was defined as tumor-free 2 years from induction therapy. Extracted DNA was sequenced for 16S rRNA and shotgun metagenomics. Primary outcomes were species richness (α-diversity) and microbial composition (ß-diversity). Paired t-tests were performed for α-diversity (Observed species/Margalef). Statistical analysis for ß-diversity (weighted and unweighted UniFrac distances, weighted Bray-Curtis dissimilarity) were conducted through Permanova, with 999 permutations. RESULTS: Microbial species richness (P < 0.001) and composition (P = 0.001) differed between BCG responders and non-responders. Lactobacillus spp. were significantly enriched in BCG-responders. Shotgun metagenomics identified possible mechanistic pathways such as assimilatory sulfate reduction. CONCLUSION: A compositional difference exists in the tumor microbiome of BCG responders and non-responders with Lactobacillus having increased abundance in BCG responders.

Metabolic syndrome and the urinary microbiome of patients undergoing percutaneous nephrolithotomy.

Objective: To identify possible stone-promoting microbes, we compared the profiles of microbes grown from stones of patients with and without metabolic syndrome (MetS). The association between MetS and urinary stone disease is well established, but the exact pathophysiologic relationship remains unknown. Recent evidence suggests urinary tract dysbiosis may lead to increased nephrolithiasis risk. Methods: At the time of percutaneous nephrolithotomy, bladder urine and stone fragments were collected from patients with and without MetS. Both sample types were subjected to expanded quantitative urine culture (EQUC) and 16 S ribosomal RNA gene sequencing. Results: Fifty-seven patients included 12 controls (21.1%) and 45 MetS patients (78.9%). Both cohorts were similar with respect to demographics and non-MetS comorbidities. No controls had uric acid stone composition. By EQUC, bacteria were detected more frequently in MetS stones (42.2%) compared to controls (8.3%) (p=0.041). Bacteria also were more abundant in stones of MetS patients compared to controls. To validate our EQUC results, we performed 16 S ribosomal RNA gene sequencing. In 12/16 (75.0%) sequence-positive stones, EQUC reliably isolated at least one species of the sequenced genera. Bacteria were detected in both "infectious" and "non-infectious" stone compositions. Conclusion: Bacteria are more common and more abundant in MetS stones than control stones. Our findings support a role for bacteria in urinary stone disease for patients with MetS regardless of stone composition.

The natural history of benign prostatic hyperplasia-related voiding symptoms following penile prosthesis implantation.

Background: There is a rising prevalence of benign prostatic hyperplasia (BPH)-related urinary symptoms along with erectile dysfunction in the aging male population. Therefore, assessment of lower urinary tract symptoms (LUTS) is advised before penile prosthesis surgery with some men requiring preoperative transurethral surgical management to reduce the risk of post-procedure complications. However, less is known about the natural history of men with uncomplicated LUTS who do not require surgical management for BPH before penile prosthesis. Objective: We sought to assess the natural history of BPH-related uncomplicated LUTS in men following penile prosthesis surgery. Design: Single institution retrospective review. Methods: Following institutional review board approval, we performed a retrospective review of all adult males with a preoperative diagnosis of LUTS undergoing penile prosthesis surgery at our institution from January 2017 to November 2022. The primary outcome was progression to transurethral surgery. Results: From 2017 to 2022, 211 patients with preexisting LUTS underwent penile prosthesis surgery and met all criteria for inclusion including no history of transurethral surgery. The median (interquartile range, IQR) AUA symptom score (AUA-SS) was 12 (12). Post-void residual was below 200 cc in 96.2% of patients preoperatively and 99.1% of patients after surgery. At a median (IQR) follow-up duration of 9 (23) months after surgery, 5.7% (12/211) of patients had progressed to bladder outlet surgery and 35.5% of patients endorsed LUTS bother with a median (IQR) AUA-SS of 14.5 (11.8). Conclusion: The majority of patients with uncomplicated LUTS did not require bladder outlet surgery following penile prosthesis implantation and could be managed with conservative or pharmacologic measures alone. Prostate gland size was significantly larger in patients who progressed to bladder outlet surgery. While the results are overall reassuring, further study is needed to identify specific factors associated with pursuing bladder outlet surgery in this small subset of patients.

A Review of Combined Phosphodiesterase-5-Inhibitors and α-Blockers versus Phosphodiesterase-5-Inhibitors Alone for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia.

Guidelines from the American Urological Association (AUA) and the European Association of Urology (EAU) present conflicting recommendations regarding combination therapy of phosphodiesterase 5 inhibitors (PDE5is) with α-blockers to treat benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS). Use of PDE5is is widespread in the population of patients with LUTS/BPH. In this scoping review, we examine the evidence regarding the safety and efficacy of combined PDE5is and α-blockers compared to PDE5i medications alone. A search was conducted using PubMed, Cochrane, and Web of Science to identify manuscripts discussing the safety of PDE5i and α-blockers in combination or comparing this combination to PDE5is alone in the treatment of LUTS/BPH. Study designs, data, and conclusions were qualitatively analyzed. Combination therapy was found to be safe across all studies; importantly, no evidence documents increased risk of hypotension. Most studies reported added improvement in symptom and quality of life scores compared to PDE5i alone, with additional International Prostate Symptom Score (IPSS) change ranging from -1.30 to -8.50 and IPSS quality of life score change ranging from -0.15 to -1.50. Objective metrics such as postvoid residual volumes and maximum flow rate were inconsistently reported. Taken together, the current body of data suggests that combining PDE5i α-blocker therapy is safe and that there are opportunities for additional symptomatic improvement, though it should be utilized for select patients. Situations with particular utility could include patients with comorbid erectile dysfunction or without sufficient improvement on monotherapy.

KEY POINTS combination therapy with PDE5i and α-blockers is more effective than PDE5i medications alone for lowering IPSScombination therapy with PDE5i and α-blockers is not associated with a significantly greater number of adverse events than PDE5i medications alonethe improvements seen in IPSS with combination therapy compared to PDE5i alone may or may not reach the threshold of clinical significancePDE5i and α-blocker combination therapy should be considered a safe regimen that can be used in appropriate clinical situations, like for patients with comorbid ED and those who do not achieve sufficient control of symptoms with a daily PDE5i alone.

Long-term outcomes after plaque excision grafting for Peyronie's disease and subanalysis of patients who undergo the procedure despite preoperative counseling against it.

BACKGROUND: Plaque excision and grafting (PEG) has been recommended for patients with Peyronie's disease (PD) with >60° curvature and/or hinge effect and strong preoperative erections, while placement of an inflatable penile prosthesis (IPP) is recommended when rigidity is suboptimal. Nevertheless, many patients counseled to undergo an IPP decline and insist on proceeding with PEG due to personal preference or desire to avoid an implant. AIM: We aim to review long-term outcomes in patients who underwent PEG for PD at our institution and investigate whether there is any difference in long-term outcomes in patients who undergo PEG despite a recommendation to undergo IPP. METHODS: We conducted a retrospective chart review from 2007 to 2021 on PEG surgery performed at a single tertiary care institution in patients ≥18 years old who had >3 months of follow-up. OUTCOMES: Postoperative information was gathered from the electronic medical record, including postoperative erectile function, patient satisfaction, and the ability to engage in penetrative sexual intercourse. RESULTS: An overall 251 patients underwent PEG with a median follow-up of 12 months (IQR, 6-54). Among these, 54 (22%) were initially advised to undergo IPP but elected for PEG. Patients who underwent PEG despite counseling to undergo IPP reported lower postoperative ability to engage in intercourse (51% vs 76%). Seven (13%) patients initially advised to undergo IPP eventually received an IPP, relative to 7 (4%) initially advised to undergo PEG. CLINICAL IMPLICATIONS: Thorough preoperative assessment of erectile function and penile deformity can guide clinician counseling and manage patient expectations during decision making between PEG surgery and IPP implantation for PD. STRENGTHS AND LIMITATIONS: Limitations of this study include its retrospective nature, high attrition to follow-up, and risk of recall and selection bias. This is a large study with a median follow-up of 12 months, with a high-volume single surgeon who treats patients in a specialized population of complex cases. CONCLUSION: Patients who were initially counseled to undergo IPP due to suboptimal erectile rigidity but elected for PEG had worse postoperative ability to engage in penetrative intercourse, and a higher proportion of these patients eventually received an IPP.

Penile prostheses harbor biofilms driven by individual variability and manufacturer even in the absence of clinical infection.

BACKGROUND: Culture-based studies have shown that penile prostheses harbor biofilms in the presence and absence of infection, but these findings have not been adequately validated using contemporary microbiome analytic techniques. AIM: The study sought to characterize microbial biofilms of indwelling penile prosthesis devices according to patient factors, device components, manufacturer, and infection status. METHODS: Upon penile prostheses surgical explantation, device biofilms were extracted, sonicated, and characterized using shotgun metagenomics and culture-based approaches. Device components were also analyzed using scanning electron microscopy. OUTCOMES: Outcomes included the presence or absence of biofilms, alpha and beta diversity, specific microbes identified and the presence of biofilm, and antibiotic resistance genes on each prosthesis component. RESULTS: The average age of participants from whom devices were explanted was 61 ± 11 years, and 9 (45%) of 20 had a diagnosis of diabetes mellitus. Seventeen devices were noninfected, and 3 were associated with clinical infection. Mean device indwelling time prior to explant was 5.1 ± 5.1 years. All analyzed components from 20 devices had detectable microbial biofilms, both in the presence and absence of infection. Scanning electron microscopy corroborated the presence of biofilms across device components. Significant differences between viruses, prokaryotes, and metabolic pathways were identified between individual patients, device manufacturers, and infection status. Mobiluncus curtisii was enriched in manufacturer A device biofilms relative to manufacturer B device biofilms. Bordetella bronchialis, Methylomicrobium alcaliphilum, Pseudoxanthomonas suwonensis, and Porphyrobacter sp. were enriched in manufacturer B devices relative to manufacturer A devices. The most abundant bacterial phyla were the Proteobacteria, Actinobacteria, and Firmicutes. Glycogenesis, the process of glycogen synthesis, was among the predominant metabolic pathways detected across device components. Beta diversity of bacteria, viruses, protozoa, and pathways did not differ among device components. CLINICAL IMPLICATIONS: All components of all penile prostheses removed from infected and noninfected patients have biofilms. The significance of biofilms on noninfected devices remains unknown and merits further investigation. STRENGTHS AND LIMITATIONS: Strengths include the multipronged approach to characterize biofilms and being the first study to include all components of penile prostheses in tandem. Limitations include the relatively few number of infected devices in the series, a relatively small subset of devices included in shotgun metagenomics analysis, and the lack of anaerobic and other expanded conditions for culture. CONCLUSION: Penile prosthesis biofilms are apparent in the presence and absence of infection, and the composition of biofilms was driven primarily by device manufacturer, individual variability, and infection, while being less impacted by device component.

Microbe-metabolite interaction networks, antibiotic resistance, and in vitro reconstitution of the penile prosthesis biofilm support a paradigm shift from infection to colonization.

To understand differences between asymptomatic colonized and infected states of indwelling medical devices, we sought to determine penile prosthesis biofilm composition, microbe-metabolite interaction networks, and association with clinical factors. Patients scheduled for penile prosthesis removal/revision were included. Samples from swabbed devices and controls underwent next-generation sequencing, metabolomics, and culture-based assessments. Biofilm formation from device isolates was reconstituted in a continuous-flow stir tank bioreactor. 93% of 27 analyzed devices harbored demonstrable biofilm. Seven genera including Faecalibaculum and Jeotgalicoccus were more abundant in infected than uninfected device biofilms (p < 0.001). Smokers and those with diabetes mellitus or cardiac disease had lower total normalized microbial counts than those without the conditions (p < 0.001). We identified microbe-metabolite interaction networks enriched in devices explanted for infection and pain. Biofilm formation was recapitulated on medical device materials including silicone, PTFE, polyurethane, and titanium in vitro to facilitate further mechanistic studies. Nearly all penile prosthesis devices harbor biofilms. Staphylococcus and Escherichia, the most common causative organisms of prosthesis infection, had similar abundance irrespective of infection status. A series of other uncommon genera and metabolites were differentially abundant, suggesting a complex microbe-metabolite pattern-rather than a single organism-is responsible for the transition from asymptomatic to infected or painful states.

Expanded Utilization of Intralesional Therapies for Treatment of Peyronie's Disease.

Purpose: In this narrative review we explore additional indications for which intralesional collagenase Clostridium histolyticum (CCH) injection therapy may be used, in addition to those utilized in the IMPRESS trials. The goal is to provide updated assessment of available intralesional therapies and justify whether to expand clinical indications based on advancements over the last decade. Results: Patients receiving CCH in the acute phase of PD have shown significant improvement in penile curvature - which may be even more significant than reported due to progressive curvature over the longitudinal course of injection therapy. Across studies, patients with ventral plaques achieved the greatest curvature improvement (~30°) compared to PD patients with dorsal or lateral plaques. Patients with curvature > 90° have been minimally documented. However, the concept of patients with higher degree of curvature achieving more significant degrees of improvement prevails across studies. Studies including PD patients with volume loss deformities or indentation(s) focus on curvature improvement and do not gauge improvement in these girth loss or indentation features specifically. PD patients with calcification may benefit from CCH, however, critical analysis of included study designs and results compared to placebo do not lend for strong support of CCH in PD at this time. Conclusion: Based on the most recent research, the use of CCH in the acute phase of PD and patients with ventral penile plaques may be effective and safe. The limited available research on the efficacy of CCH on calcified plaque(s) and curvature greater than 90° is promising, however, more research is needed to ensure safety and success in this patient cohort. Finally, the current literature continues to show the use of CCH is not effective in PD patients with volume loss, indentation, or hourglass deformity. When expanding the use of CCH to patients not originally included in the IMPRESS trials, providers must prioritize minimizing chances of potential injury to urethral tissue. Finally, further investigation is required to determine whether CCH has utility for curvature greater than 90° or calcified plaques, although the limited available literature is promising.

Impact of intravesical Bacillus Calmette-Guérin and chemotherapy on the bladder microbiome in patients with non-muscle invasive bladder cancer.

Introduction: Intravesical therapy (IVT), including Bacillus Calmette-Guérin (BCG), is the standard of care for high grade (HG) non-muscle invasive bladder cancer (NMIBC). Despite the use of IVT, many patients recur after treatment. The bladder microbiome and its role in disease processes has recently risen to prominence. We aim to characterize changes that occur in the bladder microbiome over the course of intravesical therapy and assess whether these changes correlate with outcomes in patients with NMIBC. Methods: Patients with NMIBC undergoing induction BCG or intravesical therapy were prospectively enrolled from January 2019 to March 2020. Patients with clinical T2 or greater pathology or active urinary tract infection at enrollment were excluded. Twenty-nine patients had catheterized (bladder) urine samples collected prior to induction intravesical therapy and prior to each IVT instillation. Twenty-seven received BCG while 2 received intravesical gemcitabine. Bacteria were identified using 16S ribosomal RNA gene sequencing. Bladder microbiome changes were evaluated and differences between patients who recurred and patients who did not recur after IVT were investigated. Results: Across the 29 patients analyzed, bacterial richness decreased significantly following intravesical therapy (Richness, P=0.01). Evenness and overall diversity did not change significantly (Pielou, P=0.62; Shannon, P=0.13). Patients who experienced recurrence had a higher relative abundance of Aerococcus in their urine (P<0.01), while those who did not recur had significantly more Ureaplasma (P=0.01) and Escherichia/Shigella species (P=0.05). Patients with decreased levels of alpha diversity were more likely to fall within the non-recurrence cohort. Conclusion: IVT for NMIBC appears to change the urinary microbiome by decreasing richness while not altering evenness or overall diversity. The presence of Aerococcus species may be predictive of a poor cancer response to IVT, while the presence of Ureaplasma and Escherichia/Shigella may predict a favorable response to IVT. Further studies are warranted to elucidate and confirm the significance of changes in the bladder microbiome.