Hunner Type Interstitial Cystitis Research Articles

A genome-wide cross-trait analysis identifying shared genetic basis and causal relationships between Hunner-type interstitial cystitis and autoimmune diseases in East Asian populations

PurposeEpidemiological studies have demonstrated the clinical link between Hunner interstitial cystitis (HIC) and autoimmune diseases (ADs), suggesting potential shared genetic bases for their comorbidity. We aimed to investigate the shared genetic architecture and causal relationships between HIC and ADs.MethodsWe conducted a genome-wide cross-trait study with ~170000 individuals of East Asian ancestry to investigate the shared architecture between HIC and ADs. Bidirectional Mendelian randomization (MR) was used to assess potential causal relationships and a multi-trait analysis of GWAS (MTAG) was conducted to identify their associated pleiotropic loci. Fine-mapping analysis narrowed candidate gene susceptibility loci and colocalization analysis was performed to identify shared variants at specific locus. Lastly, transcriptome-wide association (TWAS) and functional analysis were utilized to explore potential shared gene-tissue associations.ResultsThrough bidirectional MR analysis, we observed a positive causal effect of AIH(ORIVW=1.09, PIVW=1.00×10-3) and RA (ORIVW=1.47, PIVW<1.00×10-4) on HIC and a negative causal effect of UC on HIC (ORIVW=0.89, PIVW< 1.00×10-4). Furthermore, we unveiled a robust positive causal effect of HIC on T1D(ORConMix=1.05, PConMix=1.77×10-3). Cross-trait meta-analysis identified a total of 64 independent SNPs associated with HIC and ADs. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to the autoimmune system.ConclusionsOur findings might offer insights into the shared underlying etiology of HIC and ADs.

APRIL/BAFF upregulation is associated with clonal B-cell expansion in Hunner-type interstitial cystitis.

Hunner-type interstitial cystitis (HIC) is a chronic inflammatory disease of the urinary bladder with an unknown etiology. We conducted comprehensive immunogenomic profiling of bladder specimens obtained by biopsy and cystectomy from 37 patients with HIC. Next-generation RNA sequencing demonstrated abundant plasma cell infiltration with frequent light chain restriction in HIC-affected bladder tissue. Subsequent analysis of the B-cell receptor repertoire revealed spatial and temporal expansion of B-cell clones. The extent of B-cell clonal expansion was significantly correlated with the gene expression levels of TNFSF13 and TNFSF13B, which encode APRIL and BAFF, respectively. These findings indicate that APRIL and BAFF are the key regulators of clonal B-cell expansion in HIC and might serve as therapeutic targets in this debilitating disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Potential Role of Macrophage Polarization in the Progression of Hunner-Type Interstitial Cystitis.

Hunner-type interstitial cystitis (HIC) is a chronic inflammatory condition of the bladder. However, it remains unclear whether there is a causal relationship between the presence of Hunner lesions and seemingly normal-appearing areas in the bladder (non-Hunner lesions). This study aimed to investigate the fundamental aspects of HIC by examining potential genetic differences between Hunner and non-Hunner lesions and elucidate their role as potential markers in the progression and suppression of the disease. This cross-sectional study enrolled patients with HIC (n = 10) who underwent supratrigonal cystectomy along with augmentation cystoplasty. Full-thickness bladder tissue was collected from Hunner and non-Hunner lesions in the same patient. Normal bladder tissue biopsies were also obtained as controls. Whole transcriptome analysis was performed to analyze the gene expression patterns and immune cell populations. The mucosal layers of patients exhibited similar pathway dysregulation across Hunner and non-Hunner lesions, with immunerelated pathways being prominently affected. In the mucosal layer, genes related to anti-inflammatory and immune suppression were downregulated in Hunner lesions compared to non-Hunner lesions. Moreover, in Hunner lesions, genes related to macrophage differentiation and polarization, such as VSIG4, CD68, MAFB, and LIRB4, were downregulated. The cell fraction of M2 macrophages was found to decrease in Hunner lesions. Immunohistochemical staining revealed an elevated fraction of M1 macrophages and a reduced fraction of M2 macrophages in Hunner lesions compared to those in non-Hunner lesions. In the muscular layer, transcriptomic evidence of muscle thickness was observed in both Hunner and non-Hunner lesions; however, the difference was not significant. Hunner lesions showed a reduced expression of anti-inflammatory and immunosuppressive factors compared to non-Hunner lesions, along with alterations in immune cell populations. This study suggests the possibility that macrophage polarization is related to the progression from non-Hunner lesions to Hunner lesions, suggesting its relevance to the characteristics of autoimmune diseases.

Neutrophil-to-lymphocyte ratio as a promising non-invasive biomarker for symptom assessment and diagnosis of interstitial cystitis/bladder pain syndrome

BackgroundOur study aims to investigate the association between the serum neutrophil-to-lymphocyte ratio (NLR) and interstitial cystitis (IC), as well as to explore whether NLR can serve as a diagnostic marker to distinguish IC from overactive bladder (OAB). We postulate that elevated NLR levels are intricately linked to the onset and clinical presentation of IC, and that the NLR profiles in OAB patients exhibit discernible disparities from those of IC patients.MethodsIn a retrospective analysis, we scrutinized the medical records of 70 women diagnosed with IC/BPS, 20 women diagnosed with OAB, and a randomly selected cohort of 150 healthy women who underwent physical examinations during the same temporal frame. A comprehensive panel of blood tests was administered to all participants, and NLR was determined through the calculation of the neutrophil-to-lymphocyte proportion. Additionally, symptom assessment questionnaires and urination diaries were collected from IC/BPS patients.ResultsNLR levels exhibited significant distinctions among the IC/BPS, Normal, and OAB groups (P < 0.001). Within the IC/BPS group, Hunner type interstitial cystitis (HIC) demonstrated notably divergent NLR levels in comparison to non-Hunner type interstitial cystitis (NHIC) (p = 0.001). Additionally, we observed positive correlations between NLR and Nighttime voids (r = 0.268, p = 0.029), ICPI (r = 0.327, p = 0.007), ICSI (r = 0.369, p = 0.002), PUF Symptom Scale (r = 0.263, p = 0.032), and PUF (r = 0.297, p = 0.015). The receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.765 for NLR in distinguishing IC/BPS from the Normal group, and an AUC of 0.707 in discerning IC from OAB. Furthermore, the AUC of NLR was 0.723 for identifying HIC and NHIC patients.ConclusionsOur study unveils the prospective utility of serum NLR as a promising biomarker for both diagnostic and symptom evaluation purposes in IC/BPS patients. It effectively demarcates this condition from OAB, which presents with similar clinical features. Consequently, NLR demonstrates potential as a non-invasive diagnostic instrument to distinguish between the subtypes of IC, particularly HIC and NHIC, which manifest similar symptoms within the IC/BPS spectrum.

Recurrence after postoperative intravesical instillation therapy in Hunner type interstitial cystitis

We performed a prospective, single-arm study comparing outcomes between transurethral ablation plus postoperative instillation of hyaluronic acid and chondroitin sulfate (HACS group) and transurethral ablation only in patients with Hunner type interstitial cystitis (historical control group). A total of 78 patients were enrolled, and 51 were included in the per-protocol analysis set. The 2-year recurrence rate was 47.1% (95% CI, 32.9–61.5) in the HACS group, which was significantly lower than that in the control group (86.2%; 95% CI, 74.6–93.9, P < 0.001). After instillation therapy, the hazard ratio for recurrence was 0.38 (95% CI, 0.23–0.65, P < 0.001). The HACS group had an increased recurrence-free survival with the median interval not being reached, while it was 11.4 months in the control group (95% CI, 8.8–13.8, P < 0.001). Regardless of the instillation treatment, there were significant improvements in all symptom questionnaire scores and pain compared to the baseline. However, in the instillation group, improvement was stable even after 12 months. In patients with Hunner type interstitial cystitis, intravesical instillation of hyaluronic acid and chondroitin sulfate after transurethral ablation significantly reduced the recurrence rate and maintained symptom improvement for more than 1 year.

Th1/17 polarization and potential treatment by an anti-interferon-γ DNA aptamer in Hunner-type interstitial cystitis

Hunner-type interstitial cystitis (HIC) is a rare, enigmatic inflammatory disease of the urinary bladder with no curative treatments. In this study, we aimed to characterize the unique cellular and immunological factors specifically involved in HIC by comparing with cystitis induced by Mycobacterium bovis bacillus Calmette-Guérin, which presents similar clinicopathological features to HIC. Here, we show that T helper 1/17+polarized immune responses accompanied by prominent overexpression of interferon (IFN)-γ, enhanced cGAS-STING cytosolic DNA sensing pathway, and increased plasma cell infiltration are the characteristic inflammatory features in HIC bladder. Further, we developed a mouse anti-IFN-γ DNA aptamer and observed that the intravesical instillation of the aptamer significantly ameliorated bladder inflammation, pelvic pain and voiding dysfunction in a recently developed murine HIC model with little migration into the blood. Our study provides the plausible basis for the clinical translation of the anti-IFN-γ DNA aptamer in the treatment of human HIC.

Efficacy and Safety of Low-dose Oral Prednisolone for Patients with Refractory Hunner-type Interstitial Cystitis.

Hunner-type interstitial cystitis (HIC) is an immunological, chronic inflammatory disease. The efficacy of corticosteroid as a treatment for HIC is unclear. To assess the efficacy and safety of low-dose oral prednisolone (PSL) treatment for patients with refractory HIC. This retrospective observational study reviewed the clinical outcomes of 31 patients with refractory HIC who received oral PSL daily (initial dose, 5.0 or 7.5 mg) for at least 12 mo between 2016 and 2023. The dose was tapered to the minimum that maintained symptom relief during follow-up. Treatment outcomes were evaluated using a seven-graded global response assessment (scores ≥+2, moderately or markedly improved, were defined as treatment response), O'Leary and Sant symptom and problem indices (OSSI/OSPI), overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, a quality of life (QOL) score, and frequency-volume chart variables. Related complications were also documented. The mean follow-up period was 20.1±14.6 mo. The overall response rates at 1, 3, 6, 9, and 12 mo at doses of 6.7, 6.7, 5.2, 4.0, and 3.0 mg were 38.7%, 48.4%, 54.8%, 61.3%, and 64.5%, respectively. Compared with baseline, OSSI/OSPI and pain intensity improved significantly from 1 mo after PSL induction. The OABSS, QOL score, urinary frequency, and voided volume improved significantly from 9 mo after PSL induction. No patients discontinued treatment due to adverse events, although hypertension and glucose intolerance occurred in two patients, but these were resolved by temporal medications. This study showed that low-dose oral PSL significantly improves bladder pain, urinary symptoms, and QOL in patients with HIC, without serious adverse events. Further prospective evaluation is warranted to verify the potential efficacy and safety of low-dose PSL for HIC. This retrospective observational study reviewed the clinical outcomes of 31 patients suffering from refractory Hunner-type interstitial cystitis treated with low-dose oral prednisolone. Low-dose prednisolone improved bladder pain, urinary symptoms, and quality of life significantly, without serious adverse events. The response rate of 64.5% at 12 mo was comparable with the rates reported in previous studies that used higher doses of prednisolone. This study provides a rationale for further prospective evaluation of low-dose prednisolone for this intractable disease.

Optimal endoscopic treatment and partial cystectomy with or without bladder augmentation for Hunner-type interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) presents a significant challenge for urologists in terms of management, owing to its chronic nature and adverse impact on patient quality of life. Given the potential distinction between two disease entities within IC/BPS, namely Hunner-type IC and BPS without Hunner lesion, there is a need for an optimal therapeutic approach that focuses on the bladder lesions in Hunner-type IC. In cases where Hunner lesions are observed, complete transurethral ablation of these lesions should be prioritized as the initial intervention, as it has demonstrated effectiveness in symptom control. However, recurrence remains a limitation of this intervention. The techniques of resection and coagulation are equally effective in terms of symptom relief and recurrence prevention. Reconstructive surgery becomes necessary in cases of end-stage IC/BPS where various therapeutic approaches have failed. Patient selection is crucial in reconstructive surgery, particularly for patients with clear Hunner lesions and small bladder capacity who have not responded to previous treatments. Furthermore, it is vital to consider the patients' expectations and preferences adequately. Based on a comprehensive review of the literature and our own clinical experiences, subtotal cystectomy followed by bladder augmentation is considered a safe and effective surgical option. This stepwise and tailored therapeutic approach aims to optimize patients' quality of life by specifically targeting Hunner-type IC.

Serum anandamide and lipids associated with linoleic acid can distinguish interstitial cystitis/bladder pain syndrome from overactive bladder: An exploratory study.

Diagnosing interstitial cystitis/bladder pain syndrome presents a major challenge because it relies on subjective symptoms and empirical cystoscopic findings. A practical biomarker should discriminate diseases that cause increased urinary frequency, particularly overactive bladder. Therefore, we aimed to identify blood biomarkers that can discriminate between interstitial cystitis/bladder pain syndrome and overactive bladder. We enrolled patients with Hunner-type interstitial cystitis (n = 20), bladder pain syndrome (n = 20), and overactive bladder (n = 20) and without lower urinary tract symptoms (controls, n = 15) at Ueda Clinic and Nara Medical University Hospital from February 2020 to August 2021. The degree of interstitial cystitis/bladder pain syndrome symptoms was evaluated using the interstitial cystitis symptom and problem indices. Metabolomics analysis was performed on 323 serum metabolites using liquid chromatography time-of-flight mass spectrometry. In the Hunner-type interstitial cystitis or bladder pain syndrome group, we observed smaller relative areas, including anandamide, acylcarnitine (18:2), linoleoyl ethanolamide, and arachidonic acid, compared to those in the overactive bladder or control group. Notably, the differences in the relative areas of anandamide were statistically significant (median: 3.950e-005 and 4.150e-005 vs. 8.300e-005 and 9.800e-005), with an area under the curve of 0.9321, demonstrating its ability to discriminate interstitial cystitis/bladder pain syndrome. Serum anandamide may be a feasible diagnostic biomarker for interstitial cystitis/bladder pain syndrome. Reduced serum anandamide levels may be associated with pain and inflammation initiation, reflecting the pathology of interstitial cystitis/bladder pain syndrome. Furthermore, our findings suggest that abnormal linoleic acid metabolism may be involved in the pathogenesis of interstitial cystitis/bladder pain syndrome.

Genome-wide association study identifies risk loci within the major histocompatibility complex region for Hunner-type interstitial cystitis

Hunner-type interstitial cystitis (HIC) is a rare, chronic inflammatory disease of the urinary bladder with unknown etiology and genetic background. Here, we conduct a genome-wide association study of 144 patients with HIC and 41,516 controls of Japanese ancestry. The genetic variant, rs1794275, in the major histocompatibility complex (MHC) region (chromosome 6p21.3) is associated with HIC risk (odds ratio [OR]= 2.32; p= 3.4×10-9). The association is confirmed in a replication set of 26 cases and 1,026 controls (p=0.014). Fine mapping demonstrates the contribution to the disease risk of a completely linked haplotype of three human leukocyte antigen HLA-DQβ1 amino acid positions, 71, 74, and 75 (OR= 1.94; p= 5×10-8) and of HLA-DPβ1 amino acid position 178, which tags HLA-DPB1∗04:02 (OR= 2.35; p= 7.5×10-8). The three HLA-DQβ1 amino acid positions are located together at the peptide binding groove, suggesting their functional importance in antigen presentation. Our study reveals genetic contributions to HIC risk that may be associated with class II MHC molecule antigen presentation.

Deep Learning Models for Cystoscopic Recognition of Hunner Lesion in Interstitial Cystitis

BackgroundAccurate cystoscopic recognition of Hunner lesions (HLs) is indispensable for better treatment prognosis in managing patients with Hunner-type interstitial cystitis (HIC), but frequently challenging due to its varying appearance. ObjectiveTo develop a deep learning (DL) system for cystoscopic recognition of a HL using artificial intelligence (AI). Design, setting, and participantsA total of 626 cystoscopic images collected from January 8, 2019 to December 24, 2020, consisting of 360 images of HLs from 41 patients with HIC and 266 images of flat reddish mucosal lesions resembling HLs from 41 control patients including those with bladder cancer and other chronic cystitis, were used to create a dataset with an 8:2 ratio of training images and test images for transfer learning and external validation, respectively. AI-based five DL models were constructed, using a pretrained convolutional neural network model that was retrained to output 1 for a HL and 0 for control. A five-fold cross-validation method was applied for internal validation. Outcome measurements and statistical analysisTrue- and false-positive rates were plotted as a receiver operating curve when the threshold changed from 0 to 1. Accuracy, sensitivity, and specificity were evaluated at a threshold of 0.5. Diagnostic performance of the models was compared with that of urologists as a reader study. Results and limitationsThe mean area under the curve of the models reached 0.919, with mean sensitivity of 81.9% and specificity of 85.2% in the test dataset. In the reader study, the mean accuracy, sensitivity, and specificity were, respectively, 83.0%, 80.4%, and 85.6% for the models, and 62.4%, 79.6%, and 45.2% for expert urologists. Limitations include the diagnostic nature of a HL as warranted assertibility. ConclusionsWe constructed the first DL system that recognizes HLs with accuracy exceeding that of humans. This AI-driven system assists physicians with proper cystoscopic recognition of a HL. Patient summaryIn this diagnostic study, we developed a deep learning system for cystoscopic recognition of Hunner lesions in patients with interstitial cystitis. The mean area under the curve of the constructed system reached 0.919 with mean sensitivity of 81.9% and specificity of 85.2%, demonstrating diagnostic accuracy exceeding that of human expert urologists in detecting Hunner lesions. This deep learning system assists physicians with proper diagnosis of a Hunner lesion.

EARLY EXPERIENCE OF INTRAVESICAL INSTILLATION OF DIMETHYL SULFOXIDE 50% SOLUTION FOR HUNNER TYPE INTERSTITIAL CYSTITIS IN A CLINIC

(Objectives) To analyze the early observations in intravesical instillation of dimethyl sulfoxide (DMSO) 50% solution for Hunner-type interstitial cystitis (HIC) in our clinic and discuss possible factors affecting outcomes and future tasks. (Materials and methods) Seven patients who received DMSO therapy upon HIC relapse after transurethral resection of Hunner lesions with hydrodistension were enrolled for this study. For DMSO, 50 mL of 50% intravesical solution was administered six times every two weeks. Treatment evaluation was conducted using O'Leary & Sant Interstitial Cystitis Symptom and Problem Indexes (ICSI and ICPI), numerical rating scale (NRS) for bladder pain (0-10 points), and the post-treatment variations for which the pre-treatment values of the 24-hour urinary frequency, the average voided volume, and the maximum voided volume were used. The patient satisfaction survey was conducted with a questionnaire, and cystoscopy was conducted for all cases before and after treatment. (Results) All the patients were females with an average age of 58.3 years old. According to the Society of Interstitial cystitis of Japan Severity Criteria, 5 of the 7 cases showed a moderate level. No severe side effects were observed, and all the patients achieved six times administration. Changes in the points from the pre-treatment baseline values to the post-treatment values were -6.1, -9.1, and -10.0 for Pain NRS, ICSI, and ICPI, respectively. In addition, the 24-hour urinary frequency decreased by 5.34 times, while the average voided volume and the maximum voided volume increased to 60.3 mL and 75.7 mL, respectively. Subjective symptoms of all the patients improved, and cystoscopy revealed the disappearance or remission of Hunner lesions. (Conclusions) If Hunner lesions can be diagnosed, DMSO therapy could be used effectively and safely for HIC. The therapy is also promising for use as a future initial therapy. Therefore, the accurate diagnosis of Hunner lesions will be more important in the future.

The Japanese Herbal Medicine Yokukansan Exerted Antioxidant and Analgesic Effects in an Experimental Rat Model of Hunner-Type Interstitial Cystitis

Background and Objectives: The Japanese herbal medicine Yokukansan (YKS) has analgesic properties and is used for various pain disorders. The purpose of the present study was to investigate the effects of YKS in Hunner-type interstitial cystitis (HIC) using an experimental rat model of HIC and to explore its antioxidant activity and role as the underlying mechanism of action. Materials and Methods: The antioxidant capacity of YKS was evaluated by determining its hydroxyl radical (·OH) scavenging capacity using electron spin resonance (ESR). Next, the effects of YKS administration were explored using a toll-like receptor-7 agonist-induced rat model of HIC. The von Frey test was performed to assess bladder pain. Three days after HIC induction, the bladder was removed, and the expression of oxidative stress parameters in the bladder wall was investigated (reactive oxygen metabolites (ROMs), ·OH, and 8-hydroxy-2′-deoxyguanosine (8-OhdG)). Results: YKS had a ·OH scavenging capacity according to the ESR study. In the von Frey test, a significant decrease in the withdrawal threshold was observed in the HIC group compared with the control group; however, the decrease was ameliorated by the administration of YKS. Oxidative stress parameters showed increasing tendencies (ROMs test and 8-OHdG) or a significant increase (·OH) in the HIC group compared with the control group; however, the increase was significantly suppressed by the administration of YKS. Conclusions: These findings suggest that YKS is effective against HIC and that its antioxidant activity is involved in the mechanism of action.

Reduction of Bladder Capacity Under Anesthesia Following Multiple Recurrences and Repeated Surgeries of Hunner Lesions in Patients With Interstitial Cystitis

PurposeTo investigate the influence of multiple recurrences and repeated surgeries of Hunner lesions on bladder capacity under general anesthesia in patients with interstitial cystitis (IC).MethodsWe retrospectively reviewed the clinical records of Hunner-type IC (HIC) patients who underwent transurethral fulguration or resection of Hunner lesions combined with hydrodistension by a single surgeon between 2011 and 2020. Recurrence was defined as reappearance of uncontrolled urinary symptoms in association with new Hunner lesions identified by cystoscopy. Recurrent Hunner lesions were then treated by transurethral surgeries. The recurrence-free rate, potential predictive factors of recurrence, and changes in bladder capacity under anesthesia were examined at each surgical procedure.ResultsA total of 92 surgeries were performed in 47 HIC patients, 23 (49%) of whom required multiple procedures (range, 1–5 times). The mean recurrence-free time after the first surgery was 21.7 months. The recurrence-free rate was 53% at 24 months, and decreased to 32% at 48 months. There were no significant differences in age, sex, bladder capacity under anesthesia at the first surgery, duration from symptom onset to the first surgery, O’Leary-Sant questionnaire including symptom and problem indexes, visual analogue scale pain score, and the number of comorbidities between the cases with or without recurrence. Bladder capacity under anesthesia was gradually decreased as the number of surgeries was increased, and bladder capacity at the fourth procedure was significantly decreased to 80% of the capacity at the first surgery.ConclusionsThese results suggest that multiple recurrences and repeated surgeries of Hunner lesions result in a reduction of bladder capacity under anesthesia in HIC patients although no predictive factors for recurrence of Hunner lesions were detected.

Effects of human Muse cells on bladder inflammation, overactivity, and nociception in a chemically induced Hunner-type interstitial cystitis-like rat model.

We investigated the effects of locally administered human multilineage-differentiating stress enduring (Muse) cells, nontumorigenic pluripotent-like endogenous stem cells, on bladder tissues, function, and nociceptive behavior in a chemically induced Hunner-type interstitial cystitis (HIC)-like rat model without immunosuppressant. Chemical cystitis was induced by intravesical instillation of 0.2 N hydrochloride (HCl) for 15 min in female F344 rats. SSEA-3+ Muse cells, SSEA-3- non-Muse cells or Hanks' balanced salt solution (HBSS; vehicle) were injected into the anterior and posterior bladder wall at each 1×104 cells/10 μl 6 h after HCl application. The sham group received HBSS without HCl instillation. Urinary frequency was assessed using metabolic cages, cystometrograms, nociceptive behavior, and histological analysis of the bladder and L6 spinal cord. Increases in urinary frequency and decreases in bladder capacity compared with the sham group were observed in the vehicle and non-Muse groups, but not in the Muse group, at 1 week. Significant increases in nociceptive behavior compared with the sham group and the expression of TNFα in the bladder and c-Fos in the bilateral dorsal horns of L6 spinal cord were also observed in the vehicle and non-Muse groups, whereas these changes were not seen in the Muse group at 1 week. Histological analysis exhibited a higher proportion of injected Muse cells remaining in the urothelial basal layer and lamina propria of the bladder than non-Muse cells until 4 weeks. Muse cell therapy could be a promising modality for treating HIC.

Identification of diagnostic serum biomarkers for Hunner-type interstitial cystitis.

Diagnosis of Hunner-type interstitial cystitis (HIC) relies on the ability to identify Hunner lesions endoscopically, which can lead to storage symptom misdiagnosis. Here, we examined serum biomarkers for HIC and verified their utility. Based on the previous definition of the Japanese guidelines, which did not distinguish HIC and non-HIC diseases, we searched for serum biomarkers in 25 patients with interstitial cystitis (IC) and 25 control participants using metabolomics during 2013-2014. In 2019, we conducted a validation study in HIC and control groups. Serum samples were analyzed using liquid chromatography-tandem mass spectrometry, and candidate biomarker concentrations were compared between the groups using Mann-Whitney test. Metabolomics targeted 678 metabolites and revealed that the levels of 14 lysolipids, seven γ-glutamyl amino acids, and two monoacylglycerols were significantly different between the IC and control groups. The following metabolites were selected from each metabolite category as candidates: 1-linoleoylglycerophosphocholine (1-linoleloyl-GPC [18:2]), γ-glutamylisoleucine (γ-Glu-Ile), and 1-arachidonylglycerol (1-AG). The serum concentrations of 1-linoleoyl-GPC (18:2) in the HIC and control groups were 27 920 ± 6261 and 40 360 ± 1514 ng/mL (P=0.0003), respectively. The serum concentrations of γ-Glu-Ile and 1-AG were not significantly different between the groups. When the cut-off value of 1-linoleoyl-GPC (18:2) was set at 28 400 ng/mL, the sensitivity and specificity were 68% and 84%, respectively. Serum 1-linoleoyl-GPC (18:2) is a candidate diagnostic biomarker for HIC. Additional studies on whether this biomarker can distinguish HIC from other diseases with high urination frequency are required for its clinical use.

Supervised machine learning algorithm identified KRT20, BATF and TP63 as biologically relevant biomarkers for bladder biopsy specimens from interstitial cystitis/bladder pain syndrome patients.

This study was carried out to identify biomarkers that distinguish Hunner-type interstitial cystitis from non-Hunner-type interstitial cystitis patients. Total ribonucleic acid was purified from 212 punch biopsy specimens of 89 individuals who were diagnosed as interstitial cystitis/bladder pain syndrome. To examine the expression profile of patients' bladder specimens, 68 urothelial master transcription factors and nine known markers (E-cadherin, cytokeratins, uroplakins and sonic hedgehog) were selected. To classify the biopsy samples, principal component analysis was carried out. A decision tree algorithm was adopted to identify critical determinants, in which 102 and 116 bladder specimens were used for learning and validation, respectively. Principal component analysis segregated tissues from Hunner-type and non-Hunner-type interstitial cystitis specimens in principal component axes 2 and 4. Principal components 2 and 4 contained urothelial stem/progenitor transcription factors and cytokeratins, respectively. A decision tree identified KRT20, BATF and TP63 to classify non-Hunner-type and Hunner-type interstitial cystitis specimens. KRT20 was lower in tissues from Hunner-type compared with non-Hunner-type interstitial cystitis specimens (P < 0.001). TP63 was lower in Hunner's lesions compared with adjacent mucosa from Hunner-type interstitial cystitis patients (P < 0.001). Blinded validation using additional biopsy specimens verified that the decision tree showed fairly precise concordance with cystoscopic diagnosis. KRT20, BATF and TP63 were identified as biologically relevant biomarkers to classify tissues from interstitial cystitis/bladder pain syndrome specimens. The biologically explainable determinants could contribute to defining the elusive interstitial cystitis/bladder pain syndrome pathogenesis.

β-Defensin 2, an Antimicrobial Peptide, as a Novel Biomarker for Ulcerative Interstitial Cystitis; Can β-Defensin 2 Suspect the Dysbiosis of Urine Microbiota?

As urine is not sterile, inflammatory reactions caused by dysbiosis of the urinary microbiota may induce interstitial cystitis. A study was conducted to determine whether β-defensin 2 (BD-2), a specific antimicrobial peptide in the bladder, could be used as a novel diagnostic marker for ulcerative interstitial cystitis (IC). Urine samples from three female groups were examined: healthy controls (n = 34, Control group), non-Hunner type IC (n = 40, NHIC group), and Hunner type IC (n = 68, HIC group). Urine samples were collected via a transurethral catheter and assayed for BD-2 levels using enzyme linked immunosorbent assay. Under general or regional anesthesia, cystoscopy with diagnostic and therapeutic hydrodistension was performed in NHIC and HIC groups patients. These patients underwent a biopsy of the bladders. Based on the urinary specimens from 142 patients, BD-2 expression was found to be 18-fold higher in patients with Hunner type IC than in patients with non-Hunner type IC. The enhanced secretion of BD-2 exhibited a strong correlation with increased mast cell counts associated with bladder IC pathology. Enhanced urinary secretion of the antimicrobial peptide BD-2 from Hunner type IC patients associated with clinical phenotypes and demonstrated relatively robust levels to be used as a potential biomarker. Moreover, the increased urinary level of BD-2 may suggest a new possibility of biomarkers caused by dysbiosis of the urinary microbiota in ulcerative IC.

Cystectomy for patients with Hunner-type interstitial cystitis at a tertiary referral center in Japan.

To evaluate the outcomes of partial and total cystectomy in patients with refractory Hunner-type interstitial cystitis (HIC). Patients with end-stage HIC who underwent supratrigonal partial cystectomy with augmentation ileocystoplasty (PC-CP) or total cystectomy with ileal conduit (TC-IC) were identified retrospectively. Changes in the 11-point numerical rating scale of bladder pain and in 7-grade quality of life (QOL) scores were evaluated. Changes in the O'Leary and Sant's Symptom Index (OSSI) and O'Leary and Sant's Problem Index (OSPI) were analyzed in patients with PC-CP. Peri- and postoperative complications and patient satisfaction with overall outcomes were examined. Four patients (one female) underwent PC-CP and 13 (nine females) underwent TC-IC. Bladder pain persisted in three PC-CP patients, but resolved completely in all TC-IC patients. Pain scale and QOL scores improved significantly in patients with TC-IC (P < .01), but not in those with PC-CP. OSSI/OSPI scores did not improve significantly in patients with PC-CP. Three PC-CP patients required clean intermittent catheterization due to voiding dysfunction or persistent pain. Two TC-IC patients developed stricture of the ureteroileal anastomosis, resulting in permanent placement of a ureteral stent in one case and nephrostomy in the other. Satisfaction rate was higher in the TC-IC than in the PC-CP group (76.9% vs 25.0%, P < .05). TC-IC provided reliable pain relief and improved QOL in patients with end-stage HIC, but the small case number and limited methodology restrict interpretation of the results. Further studies are needed to identify appropriate candidates and optimal surgical procedures.

Overexpression of HIF1α in Hunner Lesions of Interstitial Cystitis: Pathophysiological Implications.

The aim of our study was to elucidate biological changes in Hunner lesions, which underlie the pathophysiology of Hunner-type interstitial cystitis, by characterizing their whole transcriptome and immunopathological profiles. Paired bladder mucosal biopsies, 1 sample each from the Hunner lesion and nonlesion area, were obtained from 25 patients with Hunner-type interstitial cystitis. The samples were subjected to whole-transcriptome profiling; immunohistochemical quantification of CD3, CD4, CD8, CD20, CD138, mast cell tryptase, cytokeratin and HIF1α; and quantitative polymerase chain reaction for IFN-α, IFN-β, IFN-γ, TNF, TGF-β1, HIF1α, IL-2, IL-4, IL-6, IL-10 and IL-12A. The results were compared between the lesion and nonlesion areas. RNA sequencing identified 109 differentially expressed genes and 30 significantly enriched biological pathways in Hunner lesions. Up-regulated pathways (24) included HIF1α signaling pathway, PI3K-Akt signaling pathway, RAS signaling pathway and MAPK signaling pathway. By contrast, down-regulated pathways (6) included basal cell carcinoma and protein digestion and absorption. The mRNA levels of HIF1α, IFN-γ and IL-2, and the HIF1α protein level were significantly higher in lesion areas. Otherwise, there were no significant differences between the lesion and nonlesion samples in terms of mRNA levels of inflammatory cytokines or histological features such as lymphoplasmacytic and mast cell infiltration, epithelial denudation and CD4/CD8 T-lymphocyte ratio. Our findings demonstrate significant overexpression of HIF1α and up-regulation of its related biological pathways in Hunner lesions. The results indicate that ischemia, in conjunction with inflammation, plays a pathophysiological role in this subtype of interstitial cystitis/bladder pain syndrome, particularly in Hunner lesions.