Can urinary nerve growth factor and bladder wall thickness correlation in children have a potential role to predict the outcome of non-monosymptomatic nocturnal enuresis?

INTRODUCTION: Measurement of bladder wall thickness (BWTh) by ultrasound has been introduced as a new and promising technique to assess bladder dysfunction, and increased levels of nerve growth factor have also been reported in the bladder tissue and urine of patients with sensory urgency and detrusor overactivity (DO).

OBJECTIVE: In this study we aimed to generate a clinically useful tool with urinary nerve growth factor levels and ultrasonographic BWTh to find possible pathogenetic clues and prognostic indicators as guides for the choice of therapy of non-monosymptomatic nocturnal enuresis.

METHODS: A total of 110 children, aged 6-16 years old, were involved in this prospective study. Group 1 consisted of children with non-monosymptomatic nocturnal enuresis (n = 40), Group 2 of children with monosymptomatic nocturnal enuresis (n = 40) and Group 3 of children with healthy normal controls (n = 30). Children were evaluated with detailed history and physical examination, including neurologic examination; they were asked to complete a self-reported questionnaire and a 3-day bladder diary with the aid of their parents. The number of wet nights, the number of voids per night, the presence of daytime voiding symptoms (urgency, urge incontinence, incontinence, holding maneuvers, frequency), fluid intake, and any history of urinary tract infections (UTIs) were recorded. Monosymptomatic nocturnal enuresis and non-monosymptomatic nocturnal enuresis diagnosis was made using the International Children's Continence Society definition. Urinary nerve growth factor levels were measured by enzyme-linked immunosorbent assay and BWTh was measured transabdominally by a uroradiologist who specialized in pediatric ultrasonography. Urinary nerve growth factor levels were normalized by urinary creatinine levels and compared in all subgroups.

RESULTS: The mean age of the study group was 9.6 (range 6-16) years. The mean BWTh was significantly increased in Group 1 compared with Group 2 (4.33 ± 1.12 mm, 2.33 ± 1.03 mm; p < 0.001) and healthy controls (4.33 ± 1.12 mm, 1.86 ± 0.57 mm; p < 0.001, respectively). Urinary levels of nerve growth factor corrected to urine creatinine (NGF/Cr) significantly increased in Group 1 with to Group 2 (2.75 ± 1.15 vs. 0.58 ± 0.15; p < 0.001) and controls (2.75 ± 1.15 vs.0.28 ± 0.10; p < 0.001, respectively). In receiver operating characteristic analysis, BWTh was found to have sensitivity of 95% and specificity of 85.7% (3.00 area under the curve [AUC] 0.937; 95%) and NGF/Cr had sensitivity of 97.5% and specificity of 98.6% (0.885; AUC, 999; 95%) in predicting lower urinary tract symptoms (LUTS) for non-monosymptomatic nocturnal enuresis (NMNE) (Figure).

DISCUSSION: In our study we have investigated that BWTh together with urinary NGF levels normalized to the concentration of urinary creatinine (NGF/Cr) may predict daytime voiding problems in children with primary nocturnal enuresis (PNE). The main basis of this study is previous findings which demonstrated that ultrasonography (US)-based measurement of BWTh is a useful diagnostic parameter for LUTS in children, and that increased levels of NGF in bladder tissue and urine such as sensory urgency, DO, and overactive bladder (OAB) was indicated by clinical and experimental studies. The present study demonstrated that urinary NGF/Cr levels and BWTh measurements were significantly increased in patients with NMNE with daytime urinary symptoms (urgency, urge-incontinence, incontinence, frequency) showing symptoms of an OAB than controls and MNE.

CONCLUSION: BWTh measurements and NGF/Cr values, as non-invasive tools, may guide therapy and improve outcomes in the treatment of children with NMNE. Further studies including a larger number of patients would be of great interest.