Kidney disease progression in pediatric and adult posterior urethral valves (PUV) patients.

BACKGROUND: Posterior urethral valves (PUV) is the most common cause of obstructive uropathy in boys; approximately 15% develop kidney failure by early adulthood. However, rates of kidney function decline are poorly defined in PUV children and adults, as is the impact of potentially modifiable chronic kidney disease (CKD) progression risk factors. METHODS: We conducted a retrospective review of all PUV patients followed at our institution from 1995 to 2018. Inclusion criteria were estimated glomerular filtration rate (eGFR) > 20 ml/min/1.73 m2 after 1 year of age, no dialysis or kidney transplant history, and ≥ 2 yearly serum creatinine values after age 1 year. eGFRs were calculated using creatinine-based estimating formulas for children (CKID U25) or adults (CKD-EPI). The primary outcome was annualized change in eGFR, assessed with linear mixed effects models. We also examined the association of acute kidney injury (AKI), proteinuria, hypertension (HTN), and recurrent febrile urinary tract infections (UTIs) with eGFR decline. RESULTS: Fifty-two PUV patients met the inclusion criteria. Median (interquartile range) eGFR decline was 2.6 (2.1, 3.1) ml/min/1.73 m2/year. Children (n = 35) and adults (n = 17) demonstrated progressive decline. Proteinuria and recurrent UTIs were significantly associated with faster progression; AKI and HTN were also associated but did not reach significance. CONCLUSION: PUV patients show progressive loss of kidney function well into adulthood. Proteinuria and recurrent UTIs are associated with faster progression, suggesting potential modifiable risk factors. This is the first study to report annualized eGFR decline rates in PUV patients, which could help inform the design of clinical trials of CKD therapies.

Survey of the infant male urobiome and genomic analysis of Actinotignum spp.

The urinary bladder harbors a community of microbes termed the urobiome, which remains understudied. In this study, we present the urobiome of healthy infant males from samples collected by transurethral catheterization. Using a combination of enhanced culture and amplicon sequencing, we identify several common bacterial genera that can be further investigated for their effects on urinary health across the lifespan. Many genera were shared between all samples suggesting a consistent urobiome composition among this cohort. We note that, for this cohort, early life exposures including mode of birth (vaginal vs. Cesarean section), or prior antibiotic exposure did not influence urobiome composition. In addition, we report the isolation of culturable bacteria from the bladders of these infant males, including Actinotignum spp., a bacterial genus that has been associated with urinary tract infections in older male adults. Herein, we isolate and sequence 9 distinct strains of Actinotignum spp. enhancing the genomic knowledge surrounding this genus and opening avenues for delineating the microbiology of this urobiome constituent. Furthermore, we present a framework for using the combination of culture-dependent and sequencing methodologies for uncovering mechanisms in the urobiome.

The Role of Mobile Genetic Elements in Virulence Factor Carriage from Symptomatic and Asymptomatic Cases of Escherichia coli Bacteriuria.

Uropathogenic Escherichia coli (UPEC) is extremely diverse genotypically and phenotypically. Individual strains can variably carry diverse virulence factors, making it challenging to define a molecular signature for this pathotype. For many bacterial pathogens, mobile genetic elements (MGEs) constitute a major mechanism of virulence factor acquisition. For urinary E. coli, the total distribution of MGEs and their role in the acquisition of virulence factors is not well defined, including in the context of symptomatic infection versus asymptomatic bacteriuria (ASB). In this work, we characterized 151 isolates of E. coli, derived from patients with either urinary tract infection (UTI) or ASB. For both sets of E. coli, we catalogued the presence of plasmids, prophage, and transposons. We analyzed MGE sequences for the presence of virulence factors and antimicrobial resistance genes. These MGEs were associated with only ~4% of total virulence associated genes, while plasmids contributed to ~15% of antimicrobial resistance genes under consideration. Our analyses suggests that, across strains of E. coli, MGEs are not a prominent driver of urinary tract pathogenesis and symptomatic infection. IMPORTANCE Escherichia coli is the most common etiological agent of urinary tract infections (UTIs), with UTI-associated strains designated "uropathogenic" E. coli or UPEC. Across urinary strains of E. coli, the global landscape of MGEs and its relationship to virulence factor carriage and clinical symptomatology require greater clarity. Here, we demonstrate that many of the putative virulence factors of UPEC are not associated with acquisition due to MGEs. The current work enhances our understanding of the strain-to-strain variability and pathogenic potential of urine-associated E. coli and points toward more subtle genomic differences distinguishing ASB from UTI isolates.

Defining the Infant Male Urobiome and Moving Towards Mechanisms in Urobiome Research.

The urinary bladder harbors a community of microbes termed the urobiome, which remains understudied. In this study, we present the urobiome of healthy infant males from samples collected by transurethral catheterization. Using a combination of extended culture and amplicon sequencing, we identify several common bacterial genera that can be further investigated for their effects on urinary health across the lifespan. Many genera were shared between all samples suggesting a consistent urobiome composition among this cohort. We note that, for this cohort, early life exposures including mode of birth (vaginal vs. Caesarean section), or prior antibiotic exposure did not influence urobiome composition. In addition, we report the isolation of culturable bacteria from the bladders of these infant males, including Actinotignum schaalii, a bacterial species that has been associated with urinary tract infection in older male adults. Herein, we isolate and sequence 9 distinct strains of A. schaalii enhancing the genomic knowledge surrounding this species and opening avenues for delineating the microbiology of this urobiome constituent. Furthermore, we present a framework for using the combination of culture-dependent and sequencing methodologies for uncovering mechanisms in the urobiome.

Urinary tract infections in cystic fibrosis patients.

Improved understanding of non-respiratory infections in cystic fibrosis (CF) patients will be vital to sustaining the increased life span of these patients. To date, there has not been a published report of urinary tract infections (UTIs) in CF patients. We performed a retrospective chart review at a major academic medical center during 2010-2020 to determine the features of UTIs in 826 CF patients. We identified 108 UTI episodes during this period. Diabetes, distal intestinal obstruction syndrome (DIOS), and nephrolithiasis were correlated with increased risk of UTIs. UTIs in CF patients were less likely to be caused by Gram-negative rods compared to non-CF patients and more likely to be caused by Enterococcus faecalis. The unique features of UTIs in CF patients highlight the importance of investigating non-respiratory infections to ensure appropriate treatment.

Ambulatory urodynamic monitoring: state of the art and future directions.

Urodynamic studies are a key component of the clinical evaluation of lower urinary tract dysfunction and include filling cystometry, pressure-flow studies, uroflowmetry, urethral function tests and electromyography. However, pitfalls of traditional urodynamics include physical and emotional discomfort, artificial test conditions with catheters and rapid retrograde filling of the bladder, which result in variable diagnostic accuracy. Ambulatory urodynamic monitoring (AUM) uses physiological anterograde filling and, therefore, offers a longer and more physiologically relevant evaluation. However, AUM methods rely on traditional catheters and pressure transducers and do not measure volume continuously, which is required to provide context for pressure changes. Novel telemetric AUM (TAUM) methods that use wireless, catheter-free, battery-powered devices to monitor bladder pressure and volume while patients carry out their daily activities are currently being investigated. TAUM devices under current development are innovating in the areas of remote monitoring, rechargeable energy sources, device deployment and retrieval and materials engineering to provide increased diagnostic accuracy and improved comfort for patients with incontinence or voiding dysfunction. These devices hold promise for improving the diagnosis and management of patients with lower urinary tract disorders.

Harnessing the mesenchymal stem cell secretome for regenerative urology.

The extensive arsenal of bioactive molecules secreted by mesenchymal stem cells (MSCs), known as the secretome, has demonstrated considerable therapeutic benefit in regenerative medicine. Investigation into the therapeutic potential of the secretome has enabled researchers to replicate the anti-inflammatory, pro-angiogenic and trophic effects of stem cells without the need for the cells themselves. Furthermore, treatment with the MSC secretome could circumvent hurdles associated with cellular therapy, including oncogenic transformation, immunoreactivity and cost. Thus, a clear rationale exists for investigating the therapeutic potential of the MSC secretome in regenerative urology. Indeed, preclinical studies have demonstrated the therapeutic benefits of the MSC secretome in models of stress urinary incontinence, renal disease, bladder dysfunction and erectile dysfunction. However, the specific mechanisms underpinning therapeutic activity are unclear and require further research before clinical translation. Improvements in current proteomic methods used to characterize the secretome will be necessary to provide further insight into stem cells and their secretome in regenerative urology.

Perioperative Troponin is a Predictor of Both Short- and Intermediate-term Mortality Among Patients Undergoing Major Urologic Surgery.

OBJECTIVE: To determine whether a positive troponin is a predictor of intermediate- and long-term mortality in patients undergoing major urologic surgeries at our institution. METHODS: This is a retrospective analysis of patients undergoing major urologic surgery at the Cleveland Clinic from 2010-2015. Patients were stratified by the presence and maximum value of troponin blood-draw, if performed within 30 days of surgery. Survival analysis was performed using Kaplan-Meier function (univariate) and Cox regression analysis (continuous) to assess mortality risk. RESULTS: Within 30 days of surgery, 1305 (15.5%) patients a troponin drawn, and 304 (3.6%) of them had an abnormal troponin level (>0.01 ng/mL). Patients with positive troponin drawn for cause within 30 days of surgery had a significantly decreased overall survival at 5 years of 70.6% (95% CI 62.6, 77.2) when compared to patients with negative troponin (81.7% [95% CI 77.4, 85.3]) and no troponin drawn (90.4% [95% CI 89.0, 91.6]). CONCLUSION: For cause serum troponin blood draw and peak levels demonstrated a positive correlation with all-cause mortality in patients undergoing major urologic surgeries Prospective studies are needed to better understand the utility of postoperative troponin as predictive marker of mortality.

Sex differences in lower urinary tract biology and physiology.

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.

Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress.

OBJECTIVE: Endothelial cell (EC) migration is essential for healing of arterial injuries caused by angioplasty, but a high cholesterol diet inhibits endothelial repair. In vivo studies suggest that apolipoprotein A-I (apoA-I), the major protein constituent of HDL, is essential for normal healing of arterial injuries. ApoA-I mimetics, including 4F, have been designed to mimic the amphipathic portion of the apoA-I molecule. This study was undertaken to determine if 4F improves endothelial migration and healing. METHODS: A razor scrape assay was used to analyze the effect of 4F on EC migration in vitro. Endothelial healing in vivo was assessed following electrical injury of carotid arteries in mice. Markers of oxidative stress were also examined. RESULTS: Lipid oxidation products inhibited EC migration in vitro, but preincubation with L-4F preserved EC migration. Endothelial healing of carotid arterial injuries in mice on a high cholesterol diet was delayed compared with mice on a chow diet with 27.8% vs. 48.2% healing, respectively, at 5 days. Administration of D-4F improved endothelial healing in mice on a high cholesterol diet to 43.4%. D-4F administration had no effect on lipid levels but decreased markers of oxidation. In vivo, there was a significant inverse correlation between endothelial healing and plasma markers of oxidative stress. CONCLUSION: These studies suggested that an apoA-I mimetic can improve endothelial healing of arterial injuries by decreasing oxidative stress.

Outcomes after photoselective vaporization of the prostate and transurethral resection of the prostate in patients who develop prostatic obstruction after radiation therapy.

OBJECTIVE: To compare the need for repeat treatment or urinary diversion in patients undergoing transurethral resection of the prostate (TURP) compared with photoselective vaporization of the prostate (PVP) after brachytherapy or external beam radiation therapy (EBRT). METHODS: The prostate cancer database of Cleveland Clinic includes 3600 patients who have undergone prostate brachytherapy and 2500 patients who have undergone EBRT. We cross-referenced these patients with the electronic medical record to identify patients who required PVP or TURP after radiation. The primary outcome was the need for any further intervention after PVP or TURP, including bladder neck incision, repeat TURP, or permanent supravesicular diversion. RESULTS: Sixty of the 3600 patients (1.7%) required prostate reduction surgery after brachytherapy. Of these 60 patients, 19 of 40 (47.5%) who underwent TURP required further intervention, and 10 of 20 patients (50%) who underwent PVP required subsequent intervention. Twenty-eight of the 2500 patients (1.1%) required prostate reduction surgery after EBRT. Of these 28 patients, 5 of 18 patients (27.8%) who underwent TURP required further intervention, and 5 of 10 patients (50%) who underwent PVP required subsequent intervention. Following either type of radiation there was not a significant difference in the need for further treatment based on the type of surgery (P >.999 for brachytherapy; P = .412 for EBRT). The median time between radiation and prostate reduction surgery is 20.2 months (range, 14.6-27.6) after brachytherapy and 53.3 months (range, 27.5-53.3) after EBRT (P = .0005). CONCLUSION: This study suggests that PVP and TURP are comparable in treating prostatic obstruction after brachytherapy or EBRT. However, obstruction after brachytherapy occurs earlier compared with after EBRT.

Declines in erythrocyte sedimentation rates in patients with rheumatoid arthritis over the second half of the 20th century.

OBJECTIVE: To analyze baseline erythrocyte sedimentation rates (ESR) in cohorts of patients with rheumatoid arthritis (RA), which had been included in a review concerning longterm mortality, in reports published between 1973 and 2008, with baseline observations between 1954 and 2000. METHODS: A computer search and complementary review of the literature had identified 84 unique cohorts with RA for which mortality over 5-40 years was reported. Baseline ESR data were available for 23 of the 84 cohorts. Mean and median ESR, age, disease duration, and rheumatoid factor (RF) status were compiled and analyzed in tertiles according to first year of patient recruitment. RESULTS: Among 7 cohorts recruited initially between 1954 and 1980, median ESR at baseline was 47 mm/h (mean 50 mm/h, range 43-66), compared to median 38 mm/h (mean 41 mm/h, range 34-64) among 8 cohorts recruited between 1981 and 1984, and median 36 mm/h (mean 35 mm/h, range 28-42) among 8 cohorts recruited between 1985 and 1996. The lowest mean ESR among 7 cohorts with baseline in 1980 or earlier was 43 mm/h, and the highest reported mean ESR among 8 cohorts recruited after 1985 was 42 mm/h. In 3 cohorts recruited after 1985 from Sweden, Finland, and Spain, mean baseline ESR was < 30 mm/h. CONCLUSION: Mean ESR fell by 30% in cohorts of patients with RA recruited before 1981 compared to cohorts recruited after 1984. This decline may reflect changes in both the natural history and approaches to therapy of RA.