Recurrent urinary tract infection (RUTI) in postmenopausal women has become an important and challenging clinical problem with limited therapeutic options. Cystoscopy with fulguration of trigonitis (CFT) is a treatment option for women for whom antibiotic therapy is no longer effective or well-tolerated. CFT effectively resolves trigonitis and prevents recurrent episodes in approximately 70% of cases, but the scientific basis for this is poorly understood [1]. One hypothesis explaining the efficacy of this treatment is that the fulgurated areas of the bladder no longer express the surface proteins, such as uroplakin-3, that pathogens use to attach to and invade the urothelium [2]. The goal of this study was to test this hypothesis by evaluating the expression of uroplakin-3a along the luminal surface of umbrella cells in biopsies from both naïve and previously fulgurated bladder regions.

Following IRB approval, cold cup bladder biopsies of both regions of visible cystitis (infected) and no visible cystitis (control) were obtained from women with antibiotic refractory, uncomplicated RUTI undergoing CFT under anesthesia. In patients with a prior CFT procedure, the “control” biopsy was taken in the previously fulgurated region as cystitis was never visible in these areas. Control and infected biopsies from 5 patients, 2 with a prior CFT procedure and 3 naïve, were analyzed by immunofluorescence (IF) confocal microscopy using antibodies against uroplakin-3a (Novus, rabbit). Ten representative images were taken of the urothelial region of each section and scored using the criteria described in the table legend.

The uroplakin-3a scoring results are presented in the table along with relevant clinical data. In healthy tissue, uroplakin-3 staining is normally observed as a contiguous line on the luminal surface of umbrella cells. Contiguous urothelial staining of uroplakin-3a was only observed in the control regions of patients without a prior CFT procedure (N=3). No uroplakin-3a staining was detected in the previously fulgurated control regions of patients with a prior CFT (N=2). The infected regions of all patients, all of which had not been previously fulgurated, showed varying degrees of uroplakin-3a staining, but always less than or equal to the matched control region.

One hypothesis explaining the effectiveness of fulguration is protection against UTI recurrence by hindering attachment of bacteria to surface proteins, such as uroplakin-3a. The most common pathogen causing UTI is Uropathogenic Escherichia coli (UPEC) which has been studied in mice. UPEC attaches via type 1 pili to the bladder epithelial surface lined with umbrella cells that express uroplakin-3a. This initial infection starts an interactive cycle of infection and inflammation. The host inflammatory response that follows includes severe cystitis, urothelial exfoliation, and urothelial remodeling in mice models. In the mice studies, urothelial cells were smaller in size, had weakened intercellular junctions, and lacked terminal differentiation [3]. This remodeled urothelium is “sensitized” and more susceptible to infection.

However, the architecture of human bladder urothelium in women with antibiotic refractory RUTI is unknown. The urothelial response to fulguration procedure is also unknown. With bladder biopsies of RUTI patients undergoing fulguration, we are able to visualize for the first time urothelial surface proteins like uroplakin-3a and study host inflammation. If these RUTI women have sensitized, remodeled urothelium that makes them susceptible to recurrence, treatment aimed at changing the architecture of the urothelium, such as fulguration, could counteract the sensitization process. Fulguration decreasing uroplakin-3a on the umbrella cells of the bladder epithelium would hinder the bacterial attachment step in the interactive cycle of infection and inflammation.

In this preliminary study, no uroplakin-3a expression was observed in the urothelium sections from biopsies of visually uninfected regions of the bladder that had been previously fulgurated. These results suggest that the presumptive umbrella cells of the healed urothelium post-CFT no longer express uroplakin-3a.

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