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Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS)

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 32648

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Prof. Dr. Jochen Neuhaus

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Department of Urology, Research Laboratory, University of Leipzig, Leipzig, Germany
Interests: improving the diagnosis of prostate cancer, bladder cancer and other urologic diseases by development of biomarkers; proteomics; NMR-metabolomics; understanding of molecular mechanisms of receptor signaling and trafficking; elucidating the role of the tumor microenvironment; improvement of minimal invasive focal therapies and immune response priming in urologic cancers
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Dr. Andreas Gonsior

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Department of Urology, University Hospital Leipzig, Leipzig, Germany
Interests: continence threatment and operations; biomarkers for IC/BPS diagnostic; urodynamics; endoscopic surgery

Dr. Mandy Berndt-Paetz

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Department of Urology, Research Laboratory, University of Leipzig, Leipzig, Germany
Interests: bladder cancer and other urological tumors; photodynamic cancer therapy; tumor microenvironment; immune response in urologic cancers; urologic biomarkers; membrane receptor signaling and interactions; endocytosis and trafficking

Special Issue Information

Dear Colleagues,

Interstitial cystitis/bladder pain syndrome is a poorly understood syndrome of lower urinary tract dysfunction, characterized by multiple symptoms including frequency, urgency, small micturition volume, low bladder capacity and discomfort or bladder pain during micturition. Caused by different combinations and severities of single symptoms, IC/BPS is hard to diagnose, and the definitions of the specific disease grades are still under discussion. The lack of appropriate biomarkers, the divergent definitions of the disease, and the comparatively low prevalence of IC/BPS, ranging from 52 to 500/100,000 in females and 8 to 41/100,000 in males, hamper research into IC/BPS. Several diagnostic biomarkers have been proposed, but to date, none has met the requirements for successful clinical application. A peculiar challenge is the gender ratio reported for IC/BPS, which is up to nine times more prevalent in female than in male patients. In part, this could be due to confusing IC/BPS with chronic prostatitis. Therefore, gender-specific biomarker panels might be necessary for optimal performance. Another problem is the lack of prognostic and predictive biomarkers.

The aim of this Special Issue is to collect recent knowledge on IC/BPS biomarkers for improving diagnostics and to promote emerging, new therapeutic options. We also invite manuscripts elucidating the molecular background of biomarkers, helping to better clarify the etiology and physiology of IC/BPS. Original work, as well as reviews, is welcome.

Prof. Dr. Jochen Neuhaus
Dr. Andreas Gonsior
Dr. Mandy Berndt-Paetz
Guest Editors

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Keywords

urinary bladder
interstitial cystitis/bladder pain syndrome
chronic inflammation
diagnostic biomarkers
prognostic biomarkers
predictive biomarkers
urine
blood
tissue

Published Papers (11 papers)

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Editorial

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4 pages, 178 KiB

Open AccessEditorial

Editorial: Special Issue “Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS)”

by Jochen Neuhaus, Andreas Gonsior and Mandy Berndt-Paetz

Diagnostics 2022, 12(7), 1689; https://doi.org/10.3390/diagnostics12071689 - 11 Jul 2022

Viewed by 1199

Abstract

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a disabling chronic disease of still unknown origin and complex pathophysiology [...] Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

Research

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13 pages, 847 KiB

Open AccessArticle

Can We Use Urinary Cytokine/Chemokine Analysis in Discriminating Ulcer-Type Interstitial Cystitis/Bladder Pain Syndrome?

by Yuan-Hong Jiang, Jia-Fong Jhang and Hann-Chorng Kuo

Diagnostics 2022, 12(5), 1093; https://doi.org/10.3390/diagnostics12051093 - 27 Apr 2022

Cited by 8 | Viewed by 4562

Abstract

Purpose: Interstitial cystitis/bladder pain syndrome (IC/BPS) has ulcer (HIC) and non-ulcer subtypes. Differentiation of these two subtypes could only be based by cystoscopy. This study analyzed the urinary cytokines and chemokines among IC/BPS subtypes and controls for discriminating HIC from non-HIC and controls. Materials and Methods: A total of 309 consecutive patients with clinically diagnosed IC/BPS were enrolled. All patients received cystoscopic hydrodistention under anesthesia and urine samples were collected prior to the procedure. Enrolled patients were classified into subtypes based on the glomerulation grade, maximal bladder capacity (MBC), and presence of Hunner’s lesion. Inflammation-related cytokines and chemokines in urine samples, including interleukin-8 (IL-8), C-X-C motif chemokine ligand 10 (CXCL10), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), eotaxin-1 (eotaxin), IL-6, macrophage inflammatory protein-1 beta (MIP-1β), regulated upon activation, normally T-expressed, and presumably secreted (RANTES), tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) were assayed using commercially available microspheres with the Milliplex^® Human Cytokine/Chemokine Magnetic Bead-based Panel kit. The clinical data and urine levels of analytes between IC/BPS patients and controls, and among HIC, non-HIC, and controls were analyzed. Results: Among the 10 proteins, MCP-1, eotaxin, MIP-1β, TNF-α, and PGE2 were significantly different between IC/BPS and control, while IL-8, CXCL10, BDNF, IL-6, and RANTES were significantly higher in HIC than non-HIC patients. The receiver operating characteristic curve was used to analyze each urine biomarker in the patients with IC/BPS and controls. Among the 10 urine biomarkers, MIP-1β and TNF-α had an area under curve of >0.70 to predict IC/BPS from controls, however, the predictive values of these urine biomarkers to predict HIC from non-HIC were low. Combined cut-off values of MIP-1β and TNF-α can only have a 50% sensitivity and 39.6% specificity in identifying HIC from non-HIC. Conclusion: The results of this study demonstrate that urine cytokines and chemokines may be useful to discriminate patients with HIC from controls. An elevation of urine levels of IL-8, CXCL 10, BDNF, IL-6, and RANTES in IC/BPS patients should prompt physicians to consider the diagnosis of HIC. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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16 pages, 6564 KiB

Open AccessArticle

Lectins as Biomarkers of IC/BPS Disease: A Comparative Study of Glycosylation Patterns in Human Pathologic Urothelium and IC/BPS Experimental Models

by Dominika Peskar, Tadeja Kuret, Jera Jeruc and Andreja Erman

Diagnostics 2022, 12(5), 1078; https://doi.org/10.3390/diagnostics12051078 - 25 Apr 2022

Cited by 4 | Viewed by 1869

Abstract

Pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) remains poorly understood, as well as its effective diagnosis and therapy. Studying changes in tissue glycosylation patterns under pathological conditions is a promising way of discovering novel biomarkers and therapeutic targets. The glycobiology of IC/BPS is largely understudied, therefore we compared glycosylation patterns of normal human urothelium with the urothelium of IC/BPS patients using a selection of 10 plant-based lectins with different monosaccharide preferences. We also compared lectin binding to human urothelium with the two most cited experimental models of IC/BPS, specifically, TNFα-treated human urothelial cell line RT4 and cyclophosphamide-induced chronic cystitis in C57BL6/J mice. Furthermore, binding of four of the selected lectins (ConA, DSL, Jacalin and WGA) was evaluated qualitatively by means of fluorescence microscopy, and quantitatively by fluorescence intensity (F.I.) measurements. Our results reveal a significant reduction in F.I. of Jacalin, as well as a prominent change in the WGA labeling pattern in the urothelium of IC/BPS patients, suggesting their potential use as promising additional biomarkers for histopathological diagnosis of IC/BPS. We have also shown that urothelial glycosylation patterns between selected experimental models and patients with IC/BPS are similar enough to offer an adequate platform for preclinical study of IC/BPS glycobiology. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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10 pages, 979 KiB

Open AccessArticle

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

by Sang Wook Lee, Si Hyun Kim, Kwang Woo Lee, Woong Bin Kim, Hae Woong Choi, Ji Eun Moon, Ahrim Moon and Young Ho Kim

Diagnostics 2021, 11(11), 2082; https://doi.org/10.3390/diagnostics11112082 - 10 Nov 2021

Cited by 4 | Viewed by 1884

Abstract

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. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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Review

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10 pages, 271 KiB

Open AccessReview

Bladder Microbiome in the Context of Urological Disorders—Is There a Biomarker Potential for Interstitial Cystitis?

by Thomas Bschleipfer and Isabell Karl

Diagnostics 2022, 12(2), 281; https://doi.org/10.3390/diagnostics12020281 - 22 Jan 2022

Cited by 2 | Viewed by 2872

Abstract

Since the development of modern cultivation and sequencing techniques, the human microbiome has increasingly become the focus of scientific attention. Even in the bladder, long considered to be a sterile niche, a highly variable and complex microbial colonization has now been demonstrated. Especially in the context of diseases such as interstitial cystitis, whose etiopathogenesis is largely unknown, and whose diagnosis is based on a process of exclusion of confusable diseases, science hopes to gain far-reaching insights for etiology and diagnosis, including the identification of potential biomarkers. While for functional disorders such as urge urinary incontinence and overactive bladder syndrome, initial associations have been demonstrated between reduced microbial diversity and increased symptomatology, as well as shifts in the abundance of specific microorganisms such as Lactobacillus or Proteus, studies in interstitial cystitis show conflicting results and have failed to identify a putative organism or urotype that clearly distinguishes the urinary microbiome of patients with IC/BPS from that of healthy controls. At the present time, therefore, the new insights into the bladder microbiome and its potential influence on urologic disease cannot yet be used in the context of elucidating possible etiopathogenetic causes, as well as in the use of a biomarker for diagnostic or prognostic purposes. Further studies should focus primarily on uniform procedures and detection methods to achieve better comparability of results and increase the likelihood of detecting hidden patterns. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

28 pages, 1828 KiB

Open AccessReview

Urinary Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome and Its Impact on Therapeutic Outcome

by Hung-Yu Lin, Jian-He Lu, Shu-Mien Chuang, Kuang-Shun Chueh, Tai-Jui Juan, Yi-Chang Liu and Yung-Shun Juan

Diagnostics 2022, 12(1), 75; https://doi.org/10.3390/diagnostics12010075 - 29 Dec 2021

Cited by 19 | Viewed by 6874

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as a chronic bladder disorder with suprapubic pain (pelvic pain) and pressure and/or discomfort related to bladder filling accompanied by lower urinary tract symptoms, such as urinary frequency and urgency without urinary tract infection (UTI) lasting for at least 6 weeks. IC/BPS presents significant bladder pain and frequency urgency symptoms with unknown etiology, and it is without a widely accepted standard in diagnosis. Patients’ pathological features through cystoscopy and histologic features of bladder biopsy determine the presence or absence of Hunner lesions. IC/PBS is categorized into Hunner (ulcerative) type IC/BPS (HIC/BPS) or non-Hunner (nonulcerative) type IC/BPS (NHIC/BPS). The pathophysiology of IC/BPS is composed of multiple possible factors, such as chronic inflammation, autoimmune disorders, neurogenic hyperactivity, urothelial defects, abnormal angiogenesis, oxidative stress, and exogenous urine substances, which play a crucial role in the pathophysiology of IC/BPS. Abnormal expressions of several urine and serum specimens, including growth factor, methylhistamine, glycoprotein, chemokine and cytokines, might be useful as biomarkers for IC/BPS diagnosis. Further studies to identify the key molecules in IC/BPS will help to improve the efficacy of treatment and identify biomarkers of the disease. In this review, we discuss the potential medical therapy and assessment of therapeutic outcome with urinary biomarkers for IC/BPS. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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11 pages, 578 KiB

Open AccessReview

Components of the Endogenous Cannabinoid System as Potential Biomarkers for Interstitial Cystitis/Bladder Pain Syndrome

by Saki Sultana, Geraint Berger and Christian Lehmann

Diagnostics 2022, 12(1), 19; https://doi.org/10.3390/diagnostics12010019 - 23 Dec 2021

Cited by 4 | Viewed by 2707

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition causing bladder pressure and pain. The condition is of unknown etiology and is often accompanied by other symptoms, including chronic pelvic pain, increased urinary urgency, and frequency. There is no definitive diagnosis for IC/BPS, and treatment options are currently limited to physical therapy and medications to help alleviate symptoms. The endogenous cannabinoid system (ECS) is an important regulator of numerous physiological systems, including the urinary system. Modulations of the ECS have been shown to be beneficial for IC/BPS-associated pain and inflammation in rodents. As an attempt to identify potential biomarkers for IC/BPS, we reviewed experimental studies where the components of the ECS have been quantified in experimental models of IC/BPS. Further investigations using well-defined animal models and patients’ data are required to obtain stronger evidence regarding the potential for ECS components to be definitive biomarkers for IC/BPS. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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13 pages, 1600 KiB

Open AccessReview

MRI as a Tool to Assess Interstitial Cystitis Associated Bladder and Brain Pathologies

by Rheal A. Towner, Nataliya Smith, Debra Saunders and Robert E. Hurst

Diagnostics 2021, 11(12), 2298; https://doi.org/10.3390/diagnostics11122298 - 08 Dec 2021

Cited by 2 | Viewed by 2643

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, often incapacitating condition characterized by pain seeming to originate in the bladder in conjunction with lower urinary tract symptoms of frequency and urgency, and consists of a wide range of clinical phenotypes with diverse etiologies. There are currently no diagnostic tests for IC/BPS. Magnetic resonance imaging (MRI) is a relatively new tool to assess IC/BPS. There are several methodologies that can be applied to assess either bladder wall or brain-associated alterations in tissue morphology and/or pain. IC/BPS is commonly associated with bladder wall hyperpermeability (BWH), particularly in severe cases. Our group developed a contrast-enhanced magnetic resonance imaging (CE-MRI) approach to assess BWH in preclinical models for IC/BPS, as well as for a pilot study for IC/BPS patients. We have also used the CE-MRI approach to assess possible therapies to alleviate the BWH in preclinical models for IC/BPS, which will hopefully pave the way for future clinical trials. In addition, we have used molecular-targeted MRI (mt-MRI) to quantitatively assess BWH biomarkers. Biomarkers, such as claudin-2, may be important to assess and determine the severity of BWH, as well as to assess therapeutic efficacy. Others have also used other MRI approaches to assess the bladder wall structural alterations with diffusion-weighted imaging (DWI), by measuring changes in the apparent diffusion coefficient (ADC), diffusion tensor imaging (DTI), as well as using functional MRI (fMRI) to assess pain and morphological MRI or DWI to assess anatomical or structural changes in the brains of patients with IC/BPS. It would be beneficial if MRI-based diagnostic tests could be routinely used for these patients and possibly used to assess potential therapeutics. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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12 pages, 295 KiB

Open AccessReview

Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome with and without Hunner Lesion: A Review and Future Perspectives

by Yoshiyuki Akiyama

Diagnostics 2021, 11(12), 2238; https://doi.org/10.3390/diagnostics11122238 - 30 Nov 2021

Cited by 14 | Viewed by 2744

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating urinary bladder condition that presents with a wide variety of clinical phenotypes. It is commonly characterized by persistent pelvic pain and lower urinary tract symptoms, such as urinary frequency and urgency. Current clinicopathological and genomic evidence has indicated that IC/BPS with Hunner lesions is a clinically relevant distinct subtype with proven bladder pathology of subepithelial chronic inflammatory changes that are characterized by enhanced local immune responses and epithelial denudation. However, other forms of IC/BPS lacking Hunner lesions are a symptom syndrome complex of non-inflammatory conditions with little evidence of bladder etiology, characterized by aberrant neural activity in neurotransmission systems which leads to central nervous sensitization with potential involvement of urothelial malfunction, or clinical presentation of somatic and/or psychological symptoms beyond the bladder. Given such distinct potential pathophysiology between IC/BPS subtypes, disease biomarkers of IC/BPS should be provided separately for subtypes with and without Hunner lesions. Tailored approaches that target characteristic immunological inflammatory processes and epithelial denudation for IC/BPS with Hunner lesions, or the sensitized/altered nervous system, urothelial malfunction, association with other functional somatic syndromes, and psychosocial problems for IC/BPS without Hunner lesions, are essential to identify optimal and reliable disease-specific IC/BPS biomarkers. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

10 pages, 267 KiB

Open AccessReview

Biomarkers in the Light of the Etiopathology of IC/BPS

by Jochen Neuhaus, Mandy Berndt-Paetz and Andreas Gonsior

Diagnostics 2021, 11(12), 2231; https://doi.org/10.3390/diagnostics11122231 - 29 Nov 2021

Cited by 6 | Viewed by 2201

Abstract

In this review, we focused on putatively interesting biomarkers of interstitial cystitis/bladder pain syndrome (IC/BPS) in relation to the etiopathology of this disease. Since its etiopathology is still under discussion, the development of novel biomarkers is critical for the correct classification of the patients in order to open personalized treatment options, on the one hand, and to separate true IC/BPS from the numerous confusable diseases with comparable symptom spectra on the other hand. There is growing evidence supporting the notion that the classical or Hunner-type IC (HIC) and the non-Hunner-type IC (NHIC) are different diseases with different etiopathologies and different pathophysiology at the full-blown state. While genetic alterations indicate close relationship to allergic and autoimmune diseases, at present, the genetic origin of IC/BPS could be identified. Disturbed angiogenesis and impairment of the microvessels could be linked to altered humoral signaling cascades leading to enhanced VEGF levels which in turn could enhance leucocyte and mast cell invasion. Recurrent or chronic urinary tract infection has been speculated to promote IC/BPS. New findings show that occult virus infections occurred in most IC/BPS patients and that the urinary microbiome was altered, supporting the hypothesis of infections as major players in IC/BPS. Environmental and nutritional factors may also influence IC/BPS, at least at a late state (e.g., cigarette smoking can enhance IC/BPS symptoms). The damage of the urothelial barrier could possibly be the result of many different causality chains and mark the final state of IC/BPS, the causes of this development having been introduced years ago. We conclude that the etiopathology of IC/BPS is complex, involving regulatory mechanisms at various levels. However, using novel molecular biologic techniques promise more sophisticated analysis of this pathophysiological network, resulting in a constantly improvement of our understanding of IC/BPS and related diseases. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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Open AccessSystematic Review

The Role of Urinary VEGF in Observational Studies of BPS/IC Patients: A Systematic Review

by Pedro Abreu-Mendes, Aurora Costa, Ana Charrua, Rui Almeida Pinto and Francisco Cruz

Diagnostics 2022, 12(5), 1037; https://doi.org/10.3390/diagnostics12051037 - 20 Apr 2022

Cited by 2 | Viewed by 1453

Abstract

Background: Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic pain condition, often underdiagnosed, with an important impact on patient quality of life. More recently, an association between VEGF and its receptors has been suggested in BPS/IC pathophysiology, due to their role in promoting angiogenesis and inflammation, which can enhance bladder pain. Eventually, VEGF may be used as a biomarker for the diagnosis and prognostication of BPS/IC. To further clarify this issue, this review aims to critically summarize the available information, giving rise to a solid starting point for future studies. Methods: We systematically searched PubMed and Embase, using the queries “urinary VEGF”, “urinary VEGF” AND “pain”, “urinary VEGF” AND “lower urinary tract symptoms” and “urinary VEGF” AND “LUTS” from January 2016 to February 2022. Results: A total of 1026 papers were identified from which 7 articles were included in this study, which assessed 1036 participants. Regarding VEGF levels, overactive bladder (OAB) and healthy patients were used for comparison with BPS/IC patients. VEGF concentration seems to be higher when compared to healthy patients and overactive bladder (OAB) patients. Higher levels of VEGF were associated with pain severity, while a decrease in VEGF concentration was associated with pain and symptom improvement in women. However, these findings were not constant in all studies. Conclusions: There is a trend toward a relevant association between increased VEGF levels and pain or symptom severity in BPS/IC patients. Although there are some discrepancies among the studies and the number of patients included is small, VEGF and its receptors should be considered for future studies regarding its use in BPS/IC pathophysiology, diagnosis and prognostication. Full article

(This article belongs to the Special Issue Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS))

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