Lower urinary tract dysfunctions (LUTDs) are difficult to diagnose based on symptoms. Previous studies have revealed that certain inflammatory proteins and biomarkers in urine are elevated in women with detrusor overactivity (DO), interstitial cystitis / bladder pain syndrome (IC/BPS), and bladder outlet obstruction. In this study, we aimed to measure urinary biomarkers including inflammatory cytokines, neurogenic proteins, and oxidative stress biomarkers, compare the urine levels of a cluster of these biomarkers between LUTDs caused by a bladder pathology and non-bladder pathology, and identify specific bladder diseases based on the elevated levels of urine biomarkers.

In total, 253 women with video urodynamics (VUDS)- and cystoscopy-confirmed DO, IC/BPS, dysfunctional voiding (DV), and hypersensitive bladder (HSB) and normal controls were included. Before diagnosis and treatment, urine samples were collected at a full bladder, and inflammatory proteins (interleukin (IL)-1β, IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor [VEGF]), neurogenic proteins (nerve growth factor [NGF], brain derived neurotrophic factor [BDNF], and prostaglandin E2 [PGE2]), and oxidative stress biomarkers (8-hydroxydeoxyguanosine [8-OHdG], 8-isoprostane, and total antioxidant capacity [TAC]) were measured. The urine levels of biomarkers were compared between groups with bladder dysfunctions and controls, and the cutoff value was determined. Several urine biomarkers, which had a sensitivity of >60%, were combined to test the sensitivity of these combined biomarkers in identifying total pathological bladder diseases and specific bladder disease.

After VUDS and urological examinations, bladder dysfunctions were classified into DO (n = 31), IC/BPS (n = 114), DV (n = 45), HSB (n = 29), and control (n = 34) groups. Significantly higher urinary levels of 8-isoprostane and TAC were noted in patients with DO and IC/BPS. The other urine biomarkers increased or decreased variably among different LUTD (Table 1). By using a cystomeric bladder capacity of ≤ 350 mL, 186/219 (84.9%) of the patients with DO, IC/BPS, DV, and HSB can be discriminated from the controls. Among these urine biomarkers, oxidative stress biomarkers (8-isoprostane, 8-OHdG, or TAC) are useful for identifying pathological bladder dysfunction (DO, IC/BPS, and DV) and HSB. With an elevated IL-1β and lower IL-2 and elevated TNF-α levels, most patients with DV can be identified. The levels of 8-OHdG were significantly higher in patients with IC/BPS and DV but not in those with DO. Between DO and IC/BPS, a higher NGF level can identify 58.3% of IC/BPS cases, whereas a lower NGF level can identify 75.0% of DO cases (Figure 1).

According to these data, because most of women with bladder dysfunctions had a smaller CBC than controls, we could use a small CBC (<350 mL) as the first biomarker to exclude most of the women with normal bladder, leaving patients with DO, IC/BPS, DV, and HSB. In addition, because oxidative stress biomarkers 8-isoprostane and TAC were significantly increased in women with DO and IC/BPS and 8-OHdG level was significantly elevated in women with IC/BPS and DV, the elevation of either one of these three oxidative stress biomarkers could identify 87.6% of women with DV, whereas the use of a lower urine level of TAC could identify 84.0% of women with HSB. The remaining 141 women with DO, IC/BPS, and DV could be further discriminated by an elevated urine VEGF level for 80.7% of women with DO and IC/BPS or an elevated IL-1β level or TNF-α for 77.8% of women with DV. Finally, a lower urine NGF level could be used to separate DO and a higher NGF level for IC/BPS. Although not all women with bladder dysfunction could be identified, by using this diagnostic algorithm by CBC and different urine biomarker levels, we still could discriminate different bladder dysfunctions in women with frequency and urgency syndrome. The use of a cluster of urine biomarkers allows us to identify patients with DO, IC/BPS, and DV based on elevated urine levels of oxidative stress biomarkers 8-isoprostane, TAC, or 8-OHdG and identify HSB with a low TAC. By an elevated level of IL-1β or TNF-α, DV can be separated from these bladder disorders. An increased VEGF level is associated with DO and IC/BPS, whereas increased NGF level might further identify IC/BPS. These urine biomarkers are useful parameters for urologists to identify LUTDs in women with frequency and urgency symptoms.

The results of this study revealed that bladder dysfunction in women with LUTS can be discriminated using clusters of urinary levels of inflammatory proteins, neurogenic proteins, and oxidative stress biomarkers. Among these urine biomarkers, oxidative stress biomarkers 8-isoprostane, 8-OhdG, and TAC are useful for identifying pathological bladder dysfunctions (DO, IC/BPS, and DV) and HSB. Increased levels of IL-1β and TNF-α can be used to identify DV, whereas an increased NGF level can be used to distinguish IC/BPS and DO.