Deep Phenotyping the Anterior Urethral Stricture: Characterizing the Relationship Between Inflammation, Fibrosis, Patient History and Disease Pathophysiology

No AccessJournal of UrologyTranslational Research Article9 Apr 2024Deep Phenotyping the Anterior Urethral Stricture: Characterizing the Relationship Between Inflammation, Fibrosis, Patient History and Disease Pathophysiology Wade R. Gutierrez, Yi Luo, Laila Dahmoush, Jacob J. Oleson, Charles H. Schlaepfer, Benjamin N. Breyer, Sean P. Elliott, Jeremy B. Myers, Alex J. Vanni, Denise Juhr, Katherine N. Christel, and Bradley A. Erickson Wade R. GutierrezWade R. Gutierrez , Yi LuoYi Luo , Laila DahmoushLaila Dahmoush , Jacob J. OlesonJacob J. Oleson https://orcid.org/0000-0001-6343-3274 , Charles H. SchlaepferCharles H. Schlaepfer , Benjamin N. BreyerBenjamin N. Breyer , Sean P. ElliottSean P. Elliott , Jeremy B. MyersJeremy B. Myers , Alex J. VanniAlex J. Vanni , Denise JuhrDenise Juhr , Katherine N. ChristelKatherine N. Christel , and Bradley A. EricksonBradley A. Erickson Corresponding Author: Bradley A. Erickson, Professor of Urology, Carver College of Medicine, University of Iowa, 3233 RCP, Iowa City, IA 52246 ( ([email protected]) ). https://orcid.org/0000-0001-5237-3464 View All Author Informationhttps://doi.org/10.1097/JU.0000000000003962AboutPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookLinked InTwitterEmail Abstract Introduction: Anterior urethral stricture disease (aUSD) is a complex, heterogeneous condition which is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally consider etiology. However, as we transition towards personalized, minimally invasive treatments for aUSD and begin to consider aUSD prevention strategies, disease pathophysiology will become increasingly important. The purpose of this study was to perform a deep phenotype of men undergoing anterior urethroplasty for aUSD. We hypothesized that unique biologic signatures and potential targets for intervention would emerge based on stricture presence/absence, stricture etiology, and the presence/absence of stricture inflammation. Materials/Methods: Men with aUSD undergoing urethroplasty were recruited from one of five participating centers. Enrollees provided urethral stricture tissue and blood/serum on the day of surgery and completed patient reported outcome measure questionnaires both pre and post-operatively. The initial study had three aims: (1) to determine pediatric and adult subacute and repeated perineal trauma (SRPT) exposures using a study-specific SRPT questionnaire (2) to determine the degree of inflammation and fibrosis in aUSD and peri-aUSD (normal urethra) tissue and (3) to determine levels of systemic inflammatory and fibrotic cytokines. Two controls groups provided serum (normal vasectomy patients) and urethral tissue (autopsy patients). Cohorts were based on the presence/absence of stricture, by presumed stricture etiology (idiopathic, traumatic/iatrogenic, lichen sclerosus [LS]), and by the presence/absence of stricture inflammation. Results: Of 138 enrolled men (120 tissue/serum; 18 stricture tissue only), 78 had idiopathic strictures, 33 had trauma-related strictures, and 27 had LS-related strictures. BMI, stricture length, and stricture location significantly differed between cohorts (P < .001 for each). The highest BMIs and the longest strictures were observed in the LS cohort. SRPT exposures did not significantly differ between etiology cohorts, with > 60% of each reporting low/mild risk. Stricture inflammation significantly differed between cohorts, with mild to severe inflammation present in 27% of trauma-related strictures, 54% of idiopathic strictures, and 48% of LS strictures (P = 0.036). Stricture fibrosis did not significantly differ between cohorts (P = .7). Three serum cytokines were significantly higher in patients with strictures compared to stricture-free controls: IL-9 (P = .001), PDGF-BB (P = 0.004), and CCL5 (P = .01). No differences were observed in the levels of these cytokines based on stricture etiology. However, IL-9 levels were significantly higher in patients with inflamed strictures than in patients with strictures lacking inflammation (P = .019). Degree of stricture inflammation positively correlated with serum levels of IL-9 (Spearman's rho 0.224, P = .014). Conclusion: The most common aUSD etiology is idiopathic. Though convention has implicated SRPT as causative for idiopathic strictures, here we found that patients with idiopathic strictures had low SRPT rates that were similar to rates in patients with a known stricture etiology. Stricture and stricture-adjacent inflammation in idiopathic stricture were similar to LS strictures, suggesting shared pathophysiologic mechanisms. IL-9, PDGF-BB and CCL5, which were elevated patients with strictures, have been implicated in fibrotic conditions elsewhere in the body. Further work will be required to determine if this shared biologic signature represents a potential mechanism for an aUSD predisposition. © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Supplementary Materials Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Keywordsurethral stricturepathophysiologyinflammationfibrosisphenotypingMetrics Author Information Wade R. Gutierrez More articles by this author Yi Luo More articles by this author Laila Dahmoush More articles by this author Jacob J. Oleson More articles by this author Charles H. Schlaepfer More articles by this author Benjamin N. Breyer More articles by this author Sean P. Elliott More articles by this author Jeremy B. Myers More articles by this author Alex J. Vanni More articles by this author Denise Juhr More articles by this author Katherine N. Christel More articles by this author Bradley A. Erickson Corresponding Author: Bradley A. Erickson, Professor of Urology, Carver College of Medicine, University of Iowa, 3233 RCP, Iowa City, IA 52246 ( ([email protected]) ). More articles by this author Expand All Advertisement PDF downloadLoading ...