Urine biomarkers in ESSIC type 2 interstitial cystitis/bladder pain syndrome and overactive bladder with developing a novel diagnostic algorithm

Abstract

This study aimed to investigate the diagnostic values of urine cytokines in interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder (OAB) patients, and to develop a novel diagnostic algorithm. Urine samples were collected from 40 IC/BPS, 40 OAB patients, and 30 controls. Commercially available multiplex immunoassays were used to analyze 31 targeted cytokines. Urine cytokine profiles were significantly different among study groups and controls. MIP-1β showed the highest sensitivity (92.2%) for identifying diseased study patients from controls. The cytokines with high diagnostic values for distinguishing between IC and OAB included IL-10, RANTES, eotaxin, CXCL10, IL-12p70, NGF, IL-6, IL-17A, MCP-1, and IL-1RA. The diagnostic algorithm was subsequently developed according to the diagnostic values obtained. MIP-1β was selected for the initial screening test to diagnose diseased patients and controls with diagnostic rates of 81.6% and 68.4%, respectively. As confirmation tests for IC/BPS, the diagnostic rates of eotaxin, CXCL10, and RANTES were 73.3%, 72.7%, and 69.7%, respectively. As the confirmation test for OAB, the diagnostic rate of IL-10 was 60%. Urine cytokine profiles of IC/BPS and OAB patients differed from those of controls and might be useful as biomarkers for diagnosis. A novel pilot diagnostic algorithm was developed based on these profiles.

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

“…It is well established that mast cells are implicated in other disorders characterized by afferent hypersensitivity and neurogenic inflammation that frequently overlap those of IC/BPS without Hunner lesions [67][68][69][70]. In this context, previous reports of elevated NGF levels in patients with IC/BPS are unsurprising [22,27,71,72]. Liu et al reported that both urinary and serum levels of NGF were significantly elevated in patients with IC/BPS compared with those of healthy subjects; however, these did not correlate with clinical characteristics [71].…”

“…A tailored approach that targets characteristic immunological inflammatory processes and epithelial denudation for IC/BPS with Hunner lesions, or the sensitized/altered nervous system, urothelial malfunction, associations with other FSSs, and psychosocial problems for IC/BPS without Hunner lesions, may lead to better outcomes in future investigations of potential biomarkers of IC/BPS. NGF NHL Increased levels of NGF in serum [71,72], urine [27,71], and bladder [22] of NHL [22,27,71,72] NO HL Up-regulation of mRNA and protein levels of NO products in the HL bladder [30,44,45] PD-ECGF NHL Increased urinary levels of PD-ECGF and high association with bladder glomerulations [48] [47,48] TLR4 Unspecified Increased response to TLR4 stimulation in PBMC of IC/BPS patients and significant association with symptom changes and spread [39,42] TLR7 HL Overexpression of mRNA and protein of TLR7 in the HL bladder [40] TNFα Unspecified Increased levels of TNFα in the serum [72] and urine [73] of IC/BPS patients [72,73] VEGF HL Overexpression of VEGF in the HL bladder [8] and significant association between urinary levels of VEGF and clinical symptoms in UCPPS [36] [8,36,43] † HL: Hunner lesion subtype (IC/BPS with Hunner lesions), NHL: non-Hunner lesion subtype (IC/BPS without Hunner lesions).…”

“…Another candidate chemokine as a biomarker of IC/BPS is C-C motif chemokine ligand 2 (CCL2), also known as monocyte chemotactic protein-1 (MCP-1). Previous studies have reported increased levels of urinary CCL2 in patients with IC/BPS [ 25 , 27 , 28 ]. In 16 women with IC/BPS, Peters et al reported a positive correlation between urinary levels of CCL2 and daily urinary frequency and treatment responsive changes.…”

Nutritional Supplements for the Treatment of Neuropathic Pain

“…This finding is important because NGF is a major contributor to the peripheral sensory hypersensitivity observed in neuropathic pain [43,44]. Furthermore, NGF has been demonstrated to be an inducer of substance P in experimental models [44][45][46][47]. CSF levels of substance P are increased in fibromyalgia patients, the prototypical neuropathic pain disease model, while serum substance P levels are normal or low in these patients [48].…”

A Systematic Review of Therapeutic Approaches Used in Experimental Models of Interstitial Cystitis/Bladder Pain Syndrome

“…The compromised urothelial barrier results in the leakage of urine solutes, such as potassium and urea into the lamina propria, leading to the activation of inflammatory response with increased urothelial release of signaling molecules (e.g., acetylcholine (ACh), adenosine triphosphate (ATP), nitric oxide (NO)) and proinflammatory mediators, such as interleukins (IL)1, IL6, and IL8, tumor necrosis factor alpha (TNFα), and nerve growth factor (NGF), as well as increased nerve fiber density and inflammatory (mast cell) infiltrates, which ultimately contribute to urgency and pain [ 15 , 18 , 19 ]. Proinflammatory mediators sensitize afferent nerve terminals by activating transient receptor potential (TRP) channels resulting in the release of neuropeptides (e.g., calcitonin gene-related peptide (CGRP) and substance P) that induce mast cell degranulation and further stimulate the release of proinflammatory mediators, leading to a perpetual cycle of inflammation and pain [ 20 , 21 , 22 , 23 ].…”