Hypothesis / aims of study
Urothelial dysfunction and suburothelial inflammation were important pathognomonic bladder features in both interstitial cystitis (IC) and overactive bladder (OAB). Inflammatory cytokines and chemokines play crucial roles in their pathogenesis. This study is aimed to investigate the diagnostic values of urine cytokines and chemokines in IC and OAB, and to find the potential biomarkers.
Study design, materials and methods
Urine samples were prospectively and consecutively collected from 90 IC patients (ESSIC type 2 with glomerulations), 30 OAB patients (proven detrusor overactivity in video-urodynamic studies), and 28 controls (genuine stress urinary incontinence women without other lower urinary tract dysfunction). Commercially available multiplex immunoassays (MILLIPLEX®map kit) were used to analyse 32 targets including inflammatory cytokines, chemokine, and neurotrophins. Urine cytokines levels were compared among groups. The diagnostic values of each target were calculated, and the diagnostic flow-chart was developed to discriminate IC from OAB and controls according to the diagnostic values
Among groups, urine cytokines profiles were significantly different (Table 1). The cytokines with high diagnostic values (AUC > 0.7) to discriminate the diseased status (including IC and OAB) from controls included MCP-1, MIP-1β, IL-12p40, and IL-7. Among these cytokines, MIP-1β was the cytokine with high diagnostic value (AUC 0.722), the highest sensitivity (86.3%) and the acceptable specificity (50.0%). MIP-1β was selected as the screening test to distinguish IC and OAB from controls by the optimal cut-off value 1.57pg/mL, with the diagnostic rate of 87.7% (Fig 1). Furthermore, the cytokines with high diagnostic values (AUC > 0.7) to distinguish IC and OAB, included IL-10, Eotaxin, IL-1RA, RANTES, IP-10, BDNF, and IL-2. The diagnostic rates of IC by Eotaxin, RANTES, and IP-10 were more than 75%.
Interpretation of results
Up to present, this study was the clinical research with the largest case number of IC and OAB patients, and with the most targets of urine biomarkers investigated in the same subjects. In compared with controls, the majority of urine cytokines levels were significantly higher in both IC and OAB patients. In addition, IC and OAB patients had different urine cytokines profiles, which might reflect their different pathological bladder conditions. Currently, there is no ideal single biomarker to discriminate IC or OAB from controls, especially in urine, which was more easily affected by the individual conditions. The combination of multiple targets for the clinical diagnosis is the more rational strategy. By the examinations of multiple targets in urine, MIP-1β was the cytokine with the highest sensitivity. MIP-1β is produced by monocytes, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells. It functions as the chemoattractant for NK cells, monocytes and a variety of other immune cells. It was selected as the marker to screen the diseased status (including IC and OAB) from controls due to its high sensitivity. This indicated that MIP-1β was the important common inflammatory protein in IC and OAB. In the past, cytokines including Eotaxin, RANTES, and IP-10 were all reported important urinary biomarkers of IC in compared with controls. In this study, these cytokines were also proven to be of high diagnostic values to distinguish IC and OAB. These non-invasive examinations of urinary cytokines could provide important diagnostic information of the pathologic bladder in IC and OAB.
In compared with controls, both IC/BPS and OAB patients had different urine cytokines profiles, which might reflect their different pathologic conditions inside the bladder. By the combination of multiple targets in urine, we could use MIP-1β to serve as screening test of diseased status and use Eotaxin, RANTES, and IP-10 to serve as confirmation tests of IC. Urinary cytokines, serving as non-invasive biomarkers, might have diagnostic roles in IC and OAB.