Use of Urinary Nerve Growth Factor as A Biomarker to Determine Complete Resolution of Bladder Inflammation After Acute Bacterial Cystitis in Women

Recurrent UTI is a very bothersome and a popular problem in the urogynecology clinical practice. According to the International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction, recurrent UTI is defined as at least three symptomatic and medically diagnosed UTI in the previous 12 months. The previous UTI(s) should have resolved prior to a further UTI being diagnosed. Recurrent UTI is one of the most common diagnoses for female pelvic floor dysfunction.

Patients with recurrent UTI might also have bladder irritative symptoms. Previous studies have revealed that patients with recurrent UTI have elevated urinary NGF, suggesting chronic inflammation is present in the bladder of these patients after resolution of UTI. The investigators preliminary results showed that chronic inflammation, urothelial cell apoptosis and impairment of barrier function of urothelial cells could be the underlying pathophysiology of recurrent UTI in women. Chronic inflammation might reside in the bladder wall after resolution of UTI, which might also cause urothelial dysfunction and defective barrier function and UTI will be easy to recur in these patients. This evidence provides a new focus for clinical management and future research of recurrent urinary tract infection.

Based on these knowledge, the investigators hypothesized that chronic inflammation might reside in the bladder wall, which might also cause urothelial dysfunction and defective barrier function. UTI might be easy to recur in these patients with residual chronic bladder inflammation. If the investigators can determine complete resolution of the chronic inflammation after acute cystitis episode, it is possible to inhibit recurrent cystitis through treating the inflammation with anti-inflammatory agents.

Nerve growth factor (NGF) is a small secreted protein which induces the differentiation and survival of particular target neurons. NGF has been implicated as a chemical mediator of pathology-induced changes in C-fiber afferent nerve excitability and reflex bladder activity. The levels of neurotrophic factors including NGF increase in the bladder after spinal cord injury (SCI) and increased levels of NGF have been detected in the lumbosacral spinal cord and dorsal root ganglion of rats after SCI. Chronic administration of NGF into the bladder of rats induces bladder hyperactivity and increases the firing frequency of dissociated bladder afferent neurons. Increased levels of urinary NGF have also been detected in BOO patients exhibiting overactive bladder (OAB) symptoms. Increased bladder tissue NGF was noted in patients with interstitial cystitis/painful bladder syndrome (IC/PBS). Recent research has focused on the urinary NGF levels in detecting OAB and IC/PBS in lower urinary tract dysfunction (LUTD). Evidences have shown that urinary proteins such as NGF and prostaglandin E2 levels increase in patients with OAB, sensory urgency and detrusor overactivity (DO). Patients with OAB-dry and OAB-wet have significantly higher urinary NGF levels compared to the control group and patients with increased bladder sensation. The urinary NGF levels increase physiologically with small scale in the normal subjects at urge to void but increase pathologically with large scale in OAB patients at small bladder volume and at urgency sensation. The urinary NGF levels decrease after antimuscarinic therapy and further decrease after detrusor botulinum toxin injections in refractory OAB. Put together, the urinary NGF levels seem to be a potential biomarker for diagnosis of OAB and the underlying chronic inflammation.

Several urological diseases including bacterial cystitis, lower ureteral stone and urothelial cell carcinoma may develop storage symptoms mimicking OAB or IC/PBS. The urinary NGF levels are also elevated in these disorders. In the previous study the investigators found that UTI may increase NGF production in urine associated with urinary tract stones. Patients with resolution of UTI but also with persistent OAB may have high urinary NGF levels. These results provide evidence that urinary NGF is a product of inflammation in the urinary tract. Therefore, urinary NGF may be considered as a second-line product following urothelial damage or changes of urothelial environment that initiate the sensory nerve excitation and cause bladder hypersensitivity or DO. Measuring urinary NGF is a non-invasive tool to assess chronic inflammatory status and for longitudinal comparison of the treatment.