The overactive bladder (OAB) syndrome is a condition of urinary urgency with or without urgency incontinence and is usually accompanied by frequency and nocturia [1]. Urgency-frequency symptoms can be due to psychological factors, increased urine production, uninhibited urge to void due to central nervous system (CNS) lesions, or having detrusor overactivity (DO) [2]. Multiple treatment modalities have been developed to treat OAB, but none can achieve complete relief of this syndrome [3]. Recent studies have postulated that urothelial dysfunction, abnormal expression of sensory receptors, increased excitability of the detrusor muscles, and CNS sensitization may contribute to the development of OAB [4]. Down-regulation of both BK and SK2 and upregulation of Cx26 in the bladder mucosa in patients with mixed urinary incontinence have been found to contribute to urothelial instability and are correlated with the severity of OAB symptoms in these patients [5]. Although urodynamic study is a well-established method for diagnosing the presence of DO, not all patients with OAB are found to have DO [6]. A better way to diagnose OAB and to assess therapeutic outcome in patients with OAB seems mandatory.

Nerve growth factor (NGF) is a small secreted protein that induces the differentiation and survival of particular target neurons (nerve cells). NGF has been implicated as a chemical mediator of pathology-induced changes in C-fiber afferent nerve excitability and reflex bladder activity [7,8]. The levels of neurotrophic factors including NGF increase in the bladder after spinal cord injury (SCI) [7,9], and increased levels of NGF have been detected in the lumbosacral spinal cord and dorsal root ganglia of rats after SCI [10]. Endogenous NGF contributes to lower urinary tract dysfunction after SCI. Intrathecal application of NGF antibodies suppresses detrusor hyperreflexia and detrusor-sphincter-dyssynergia in rats with SCI [10,11]. Intrathecal administration of NGF antibodies also blocks autonomic dysreflexia induced by bladder or distal bowel distension in rats with SCI [12].

NGF is also considered to be a link between inflammation and altered pain signaling. In patients with interstitial cystitis/painful bladder syndrome (IC/PBS), neurotrophins, including NGF, neurotrophin-3, and glial cell line-derived neurotrophic factor, have been detected in the urine [13]. Increased expression of NGF is also present in bladder biopsies from women with IC/PBS [14]. Patients with IC/PBS who responded to intravesical botulinum toxin (BoNT-A) injection have been found to have reduced bladder tissue NGF expression [15].

Increased levels of NGF have also been reported in the bladder tissue and urine of patients with sensory urgency and DO [16,17]. Previous studies on NGF in OAB or DO usually measured the bladder tissue level. Evidence has shown that visceral epithelia are a major source of NGF production and that NGF may regulate the function of adult visceral sensory and motor neurons [18]. The level of NGF in urine could increase bladder sensation or cause DO through some undetermined pathways [19]. Kim et al found that urinary NGF levels are increased in both men and women with OAB syndrome [20]. Yokoyama et al and associates evaluated urinary NGF in OAB patients and found that urinary NGF levels were elevated in neurogenic DO, spinal disease, and sensory urgency; however, urinary NGF was not found to be elevated in idiopathic DO [21]. It is rational to hypothesize that NGF produced in the urothelium and suburothelium can be secreted into the bladder lumen. Stretching of the urothelium might induce production of NGF in the bladder tissue and secretion into the urine. Measurement of NGF in the urine is likely to be a more relevant and sensitive biomarker for OAB than bladder tissue NGF levels.

Measurement of urinary NGF levels in patients with OAB and different conditions has provided insight to the underlying pathophysiology of this sensory disorder. Any inflammation in the urinary tract can cause an elevation of the urinary NGF level. Therefore, it can be suggested that OAB could be an inflammatory disorder of the bladder. The results of recent investigations suggest that the urinary NGF level is a promising biomarker for the diagnosis of OAB. Measurement of urinary NGF levels may serve as a useful objective test to evaluate treatment outcome of OAB. However, the high percentage of patients having low NGF levels limits the wide application of the urinary NGF level as a biomarker for diagnosis of OAB or DO. Therefore, it is rational to hypothesize that NGF might be a downstream protein produced as a result of several bladder dysfunction or systemic disorders. Nevertheless, in patients with OAB who are treated with antimuscarinics or botulinum toxin injection, urinary NGF levels have been shown to decrease significantly in association with reduction of urgency severity. Thus, it may be possible to use urinary NGF levels as a biomarker for assessment of therapeutic outcome in patients with OAB.