Chronic low grade inflammation, in the absence of infection, is believed to be an underlying precipitant of many conditions associated with aging [1]. Detrusor overactivity (DO) is well known to increase with age. While the aetiology of DO remains unknown, infection and inflammation have been hypothesised as potential contributors. In patients with refractory DO (RDO), without any cystitis, the role of aging and inflammatory changes remains unclear. This study aimed to observe any differences in the concentrations of relevant cytokines in the urine of RDO patients (without acute UTI) in relation to age, versus age-matched controls.

Midstream urine samples were collected with careful labial toilet from postmenopausal women (>50 years). Prolapse or urodynamic stress incontinence patients with sterile urine (No growth <106 CFU/mL) were controls. RDO patients had urodynamically proven DO with normal voiding function and sterile urine. The concentration of 27 cytokines were analysed [Human Cytokine 27-plex Assay (Bio-Rad)]. Urinary cytokines were grouped into pro-inflammatory, chemokines and regulatory cytokines based on their known properties; results were compared for each clinical group. Analysis was by linear regression of cytokine concentration with age.

Urine from 45 controls and a consecutive series of 48 RDO women was tested. Ages of controls and RDOs were similar (Table 1). Direct comparison between the groups (without factoring in age), demonstrates four cytokines that are significantly more elevated in RDO women (IL-5, IL-12p70, IL-17A and GM-CSF, data not shown, p<0.05). With the exception of GM-CSF, these cytokines are associated with activity of innate lymphoid cells that play a key role in maintaining the inflammatory balance within the body [2]. In the control group, 4 out of 27 cytokines were observed to have a positive correlation with increasing age (Table 1) with an equal ratio of pro and regulatory (anti-inflammatory) cytokines. In women with RDO, the concentration of 18 of the 27 cytokines increased with age (Table 1). These cytokines were predominantly pro-inflammatory and chemotactic (chemokines) in nature.

A major finding of this study was the breadth of cytokines that are elevated with increasing age in RDO women with sterile urine, versus controls. Some cytokines (i.e. IP-10) that were significantly elevated with age in those with RDO, were known to function as natural killer cell attractants, and are upregulated in recurrent infection [3]. Other cytokines that positively correlated with age (i.e. MIP-1⍺) were more pro-inflammatory in nature and can be activated by any chronic inflammatory state.

Previous studies of cytokine signals in women with urge incontinence have mainly focused on patients with newly diagnosed OAB, whereas we studied 48 women with urodynamically proven refractory DO and 45 age matched controls. To our knowledge, this is the first definitive study of cytokine levels in refractory DO women in relation to age. Our findings support the notion that in these women, even in the absence of an acute infection, increased cytokine signalling associated with aging may enhance the sensitivity of afferent nerves and promote urgency symptoms. Elevation of different cytokines based on their function and relationship to infection suggest that aging and infection may play separate roles in the pathophysiology that contributes to the refractory state.

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Sundac et al., (2016) Protein-based profiling of the immune response to uroprathogenic Escherichia coli in adult patients immediately following hospital admission for acute cystitis. Pathogens and Disease. 74. ftw062.