Thursday, September 21, 2023
9/21/2023
(PLEASE KEEP IN WORD, DO NOT PDF) Ureteral stents placed after ureteroscopy to remove kidney stones cause significant morbidity, with most patients with an indwelling stent reporting impaired quality of life, pain, and urinary symptoms affecting their everyday life. A critical barrier to developing new treatments to improve symptoms caused by ureteral stents is a lack of understanding of how molecules in the urine contribute to mechanisms and patient experiences after ureteroscopy. Here, we build on our recent discoveries that stent-induced ureteral smooth muscle dysfunction, cessation of peristalsis, and resultant hydronephrosis are driven by stretch-induced inflammation of the ureter. We will leverage our analytical pipeline that identified prostaglandin E2 (PGE2) and 1-methylnicotinamide (1-MNA) as biomarkers for stent-induced ureteral inflammatory changes and dysfunction in pigs. We have an interdisciplinary team that is uniquely poised to discover and validate urinary biomarkers of stent symptoms by combining expertise in using analytic chemistry, ureteral physiology, and clinical epidemiology. The proposed research tests the central hypothesis that that indwelling ureteral stents trigger similar mechanisms in humans and that at least PGE2 and 1-MNA are urinary biomarkers for stent-associated ureteral dysfunction and symptoms in humans. In doing so, the proposed studies will identify pathways that could be targets for novel therapeutics to prevent stent symptoms. In this proposal, we generate key preliminary data using data and urine samples from 50 of the 484 adolescent and adult participants who underwent ureteroscopy with ureteral stent placement and enrolled in the Study to Enhance Understanding of sTent-associated Symptoms (STENTS) conducted by the NIDDK-supported Urinary Stone Disease Research Network. In Aim 1, we determine the association between PGE2 and 1-MNA and stent symptoms. We will evaluate the association between these putative biomarkers in pre-operative urine, and the course of patient-reported pain intensity, pain interference, and urinary symptoms after ureteroscopy with stent placement. In Aim 2, we will expand the list of urine biomarkers using our untargeted analytical approach to quantify and identify unknown biomarkers for ureteral obstruction and stent-associated symptoms. The proposed work provides key preliminary data validating known and new urinary biomarkers for stent-associated ureteral inflammatory changes and dysfunction in humans. Once validated in a smaller cohort, their association with stent-associated pain and discomfort can be further validated in a larger patient cohort and incorporated into existing predictive models for stent-complications to identify patients more likely to develop severe symptoms. This will form the basis of a subsequent R01 application.
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