The association of urinary BDNF, ATP, and MMP-2 with bladder compliance in children with myelodysplasia.

AIM: The purpose of our study was to evaluate the relationship of urinary brain-derived neurotrophic factor (BDNF), adenosine triphosphate (ATP), matrix metallopreteinase-2 (MMP-2) with urodynamic findings and upper urinary tract deterioration (UUTD) in children with myelodysplasia. MATERIALS AND METHODS: Children with myelodysplasia evaluated in outpatient clinic between 2022 and 2023 were included. All patients underwent urinary ultrasonography, voiding cystourethrography, urodynamics, and DMSA scintigraphy. Urine samples were collected before urodynamics. Control urine was collected from 10 healthy children. Urinary biomarker values of patients and controls were compared, and subgroup analysis was performed. RESULTS: The median age of 40 children (26 girls) included in the study was 108 (8-216) months, and the control group (six girls) was 120 (60-154) (p = 0.981). Urinary BDNF, MMP-2, and ATP were found to be significantly higher in children with myelodysplasia compared to the control (p = 0.007, p = 0.027, p = 0.014, respectively). The three biomarker values were similar in children with bladder compliance below or above 10 cmH2O/mL (p = 0.750, p = 0.844, p = 0.575). No difference was found in terms of UUTD in all three biomarkers (p = 0.387, p = 0.892, p = 0.705). A negative correlation was found between urinary ATP and compliance (p < 0.05). CONCLUSION: In this study, all three biomarkers were found to be higher in children with myelodysplasia than in controls. There was a negative correlation between urinary ATP and compliance. Urinary biomarkers may contribute the follow-up of children with neurogenic lower urinary tract deterioration in future with their noninvasive features. However, the lack of standardization and the inability to reliably predict risky groups are important shortcomings of urinary biomarkers.

Urinary brain-derived neurotrophic factor and nerve growth factor as noninvasive biomarkers of overactive bladder in children.

Introduction: Overactive bladder (OAB) is the most common urinary disorder and the leading cause of functional daytime intermittent urinary incontinence in children. The aim of this study was to determine whether urinary brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) concentrations, normalized to urine creatinine, could be used as biomarkers for diagnosis and treatment monitoring of OAB in children. Materials and methods: Urine samples of 48 pediatric patients with OAB were collected at the start of anticholinergic therapy (baseline), at follow-up visits (3 and 6 months), and from 48 healthy controls. Urinary BDNF and NGF concentrations were determined by ELISA method (Merck, Darmstadt, Germany) and Luminex method (Thermo Fisher Scientific, Waltham, USA). Differences of frequency between quantifiable analyte concentrations between subject groups were determined using Fisher's exact test. Results: There was no statistically significant difference between quantifiable analyte concentrations between patients at baseline and the control group for BDNF and NGF by either the ELISA or Luminex method (P = 1.000, P = 0.170, P = 1.000, and P = N/A, respectively). There was a statistically significant difference between quantifiable BDNF by the ELISA method between patients at baseline and complete success follow-up (P = 0.027), while BDNF by Luminex method and NGF by both methods were not statistically significant (P = 0.078, P = 0.519, and P = N/A, respectively). Conclusions: This study did not demonstrate that urinary BDNF and NGF concentrations, can be used as biomarkers for diagnosis and therapy monitoring of OAB in children.

Relationship of Bladder Pain With Clinical and Urinary Markers of Neuroinflammation in Women With Urinary Urgency Without Urinary Incontinence.

PURPOSE: The pathogenesis of bladder pain is poorly understood. Our hypothesis is that in women with urinary urgency without incontinence, bladder pain is associated with the presence of neurogenic inflammation in the bladder wall and neuroinflammatory biomarkers in the urine. METHODS: We conducted a prospective cross-sectional study of women with urinary urgency without incontinence. Urinary symptoms were measured using Female Genitourinary Pain Index. Neuropathic pain, a clinical biomarker of neuroinflammation, was measured using the PainDETECT questionnaire. Inflammatory neuropeptides measured in the urine included nerve growth factor (NGF), brain-derived neurotrophic factor, vascular endothelial growth factor, and osteopontin. Neuropathic pain scores and urinary neuropeptide levels were compared between patients with and without bladder pain using univariable and multivariable analyses. RESULTS: In 101 women with urinary urgency without incontinence, 62 (61%) were in the bladder pain group (visual analog scale score, ≤ 3), whereas 39 (39%) were in the no bladder pain group. Urinary symptom scores (5.0 ± 3.1 versus 3.5 ± 2.4, P < 0.001) and neuropathic pain scores (13.3 ± 8.6 vs 5.1 ± 4.8, P < 0.001) were significantly higher for the bladder pain group than for the no bladder pain group. On multivariable analysis after controlling for age, body mass index, and severity of urinary urgency, bladder pain score was significantly associated with elevated urinary levels of vascular endothelial growth factor (P = 0.04) and osteopontin (P = 0.02), whereas the neuropathic pain score was significantly associated with an increased NGF level (P = 0.03). CONCLUSIONS: In women with urinary urgency without incontinence, bladder pain is associated with the presence of clinical and urinary biomarkers of neuroinflammation.

Urinary Nerve Growth Factor in full-term, preterm and intra uterine growth restriction neonates: Association with brain growth at 30-40 days of postnatal period and with neuro-development outcome at two years. A pilot study.

Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) are crucial for the peripheral and central nervous system development, respectively, and differential brain and blood levels in Intra Uterine Growth Restriction (IUGR) and prematurity have been found. As reduced growth of brain regions, measured at 30-40 days of postnatal period, has been demonstrated in preterm and IUGR neonates who showed impaired neuro-development at two years of age, in this study, the levels of NGF and BDNF were evaluated in the urine samples of 30-40 day-old subjects who were full-term, preterm and IUGR and showed a normal or an abnormal neuro-development at follow up after two years. Neurotrophins were measured concurrently with volumes of whole brain, thalamus, frontal cortex and cerebellum. Values were then correlated with later neuro-developmental outcome. Biochemical parameters and cerebral volumes were assessed using colorimetric ELISA kits and three-dimensional ultra-sonography (3DUS), respectively. Neuro-development was estimated using the Griffiths-II test. Urinary NGF and brain volumes significantly correlated and were lower in preterm and IUGR subjects characterized by poor neuro-development. No differences were seen in the case of BDNF. The present investigation demonstrates, for the first time, the strong and direct association of NGF with brain growth at the initial phase of the postnatal period and with neuro-developmental outcome in later life. Remarkably, urinary NGF may be suggested as an early prognostic indicator of high long-term risk of motor and cognitive impairment in IUGR and preterm neonates.

The profile of urinary biomarkers in overactive bladder.

AIMS: In overactive bladder (OAB) research, different biomarkers have been proposed as diagnostic tools and may be used to create individual patient profiles. Assessing the diagnostic performance of biomarkers would better outline their utility. Therefore, our aim was to investigate the diagnostic value of four urinary biomarkers: human brain derived neurotrophic factor (hBDNF), malondialdehyde (MDA), h nerve growth factor (hNGF) and h 8-hydroxydeoxyguanosine in women with OAB. These are neurotrophins/oxidative stress markers that have been linked to lower urinary tract symptoms. METHODS: A total of 105 women were included in the study and distributed in two groups: a group with OAB (n = 53) and a control group (n = 50). The levels of the biomarkers were determined using enzyme-linked immunosorbent assay technique and they were compared between the groups. If the Mann-Whitney test demonstrated a statistically significant difference, receiver operating curves (ROC) analysis was undertaken. RESULTS: When normalized to urinary creatinine, hBDNF, MDA, and hNGF showed significantly increased values in women with OAB as compared to controls, whereas 8-OHdG showed no significant difference. The diagnostic performance of these biomarkers was analyzed based on the area under the ROC curve (AUC). MDA had the highest AUC (0.75), followed by hNGF (0.69) and hBDNF (0.67). CONCLUSIONS: Our findings suggest that MDA, a relatively novel biomarker in OAB research, has a fair performance as a diagnostic tool for OAB. Moreover, urinary neurotrophins (NGF and BDNF) as biomarkers may have a role in the diagnostic pathways of women with OAB symptoms.

Serum and urinary levels of brain-derived neurotrophic factor (BDNF) in enuresis. / Niveles séricos de factor neurotrófico derivado de cerebro en la enuresis.

OBJECTIVES: Enuresis is one of the most frequently seen psycho-social problems in childhood, which causes anxiety and stress in the child, thus affecting his/her self-respect and quality of life. The aim of the study was to determine the role of bladder function or psychologic factors or both as factors causing enuresis. METHODS: This study on pediatric patients with primary enuresis included 30 patients with monosymptomatic nocturnal enuresis (MonoNE), 30 patients with polysymptomatic nocturnal enuresis (PolyNE), and 30 healthy controls, making a total of 90 subjects with an age range of 8-18. In all subjects, the levels of serum and urinary Brain-Derived Neurotrophic Factor (BDNF) were measured, in addition to urinary creatinine levels and calculated as BDNF/Cr ng/mg creatinine (BDNF/ Cr). RESULTS: The serum BDNF results of the PolyNE group (0.949±0.587) were significantly lower than those of the control group (1.158±0.587) (p=0.014). The urinary BDNF results of the PolyNE group (1.107±0.360) were significantly higher than those of both the MonoNE (0.657±0.272) and the control (0.670±0.271) groups (p<0.0001). The BDNF/Cr results of the PolyNE group (1.472±0.714) were significantly higher than those of the MonoNE group (0.956±1.017) and the control group (0.931±0.618) (p=0.044 and p=0.032, respectively). CONCLUSIONS: In addition to bladder-specific problems, it is possible for anxiety and psychological stress-induced problems to occur in PolyNE. Therefore, in addition to the increasing number of studies on the bladder in enuresis, further studies on the neurogenic and psychogenic aspects of enuresis should be carried out.

OBJETIVOS: La enuresis es uno de los problemas psicosociales más frecuentes en la infancia, que causa ansiedad y estrés a los niños, afectando a su autoestima y calidad de vida. El objetivo de este estudio es la determinación del papel de la función vesical, los factores psicológicos o ambos como factores causales de la enuresis.MÉTODOS: Este estudio en pacientes pediátricos con enuresis incluyó 30 pacientes con enuresis nocturna monosintomática (ENmono), 30 pacientes con enuresis nocturna polisintomática (ENpoli) y 30 controles sanos, sumando un total de 90 individuos con un rango de edad entre 8-18 años. En todos los casos se midieron los niveles séricos y urinarios de factor neurotrófico derivado del cerebro (FNDC), además de los niveles de creatinina urinaria y se hizo el cálculo de FNDC/Cr ng/mg creatinina. RESULTADOS: Los resultados de FNDC sérico en el grupo ENpoli (0,949±0,587) fueron significativamente menores que los del grupo control (1,158±0,587) (p=0,014). Los resultados de FNDC urinario en el grupo de ENpoli (1,107±0,360) fueron significativamente mayores que los de los grupos ENmono (0,657±0,272) y control (0,670±0,271) (p<0,0001). Los resultados de FNDC/Cr el grupo ENpoli (1,472±0,714) eran significativamente mayores que los de los grupos ENMono (0,956±1,017) y control (0,931±0,618) (p=0,044 y p=0,032, respectivamente). CONCLUSIONES: Además de problemas específicos vesicales, es posible que los problemas de ansiedad e inducidos por estrés psicológico ocurran en la ENPoli. Por lo tanto, además del creciente número de estudios sobre la vejiga en enuresis, es necesario desarrollar más estudios sobre los aspectos neurogénicos y psicogénicos de la enuresis.

Serum and urinary levels of brain-derived neurotrophic factor (bdnf) in enuresis / Niveles séricos de factor neurotrófico derivado de cerebro en la enuresis

OBJECTIVES: Enuresis is one of the most frequently seen psycho-social problems in childhood, which causes anxiety and stress in the child, thus affecting his/her self-respect and quality of life. The aim of the study was to determine the role of bladder function or psychologic factors or both as factors causing enuresis. METHODS: This study on pediatric patients with primary enuresis included 30 patients with monosymptomatic nocturnal enuresis (MonoNE), 30 patients with polysymptomatic nocturnal enuresis (PolyNE), and 30 healthy controls, making a total of 90 subjects with an age range of 8-18. In all subjects, the levels of serum and urinary Brain-Derived Neurotrophic Factor (BDNF) were measured, in addition to urinary creatinine levels and calculated as BDNF/Cr ng/mg creatinine (BDNF/ Cr). RESULTS: The serum BDNF results of the PolyNE group (0.949 ± 0.587) were significantly lower than those of the control group (1.158 ± 0.587) (p = 0.014). The urinary BDNF results of the PolyNE group (1.107 ± 0.360) were significantly higher than those of both the MonoNE (0.657 ± 0.272) and the control (0.670 ± 0.271) groups (p < 0.0001). The BDNF/Cr results of the PolyNE group (1.472 ± 0.714) were significantly higher than those of the MonoNE group (0.956 ± 1.017) and the control group (0.931 ± 0.618) (p = 0.044 and p = 0.032, respectively). CONCLUSIONS: In addition to bladder-specific problems, it is possible for anxiety and psychological stress-induced problems to occur in PolyNE. Therefore, in addition to the increasing number of studies on the bladder in enuresis, further studies on the neurogenic and psychogenic aspects of enuresis should be carried out

OBJETIVOS: La enuresis es uno de los problemas psicosociales más frecuentes en la infancia, que causa ansiedad y estrés a los niños, afectando a su autoestima y calidad de vida. El objetivo de este estudio es la determinación del papel de la función vesical, los factores psicológicos o ambos como factores causales de la enuresis. MÉTODOS: Este estudio en pacientes pediátricos con enuresis incluyó 30 pacientes con enuresis nocturna monosintomática (ENmono), 30 pacientes con enuresis nocturna polisintomática (ENpoli) y 30 controles sanos, sumando un total de 90 individuos con un rango de edad entre 8-18 años. En todos los casos se midieron los niveles séricos y urinarios de factor neurotrófico derivado del cerebro (FNDC), además de los niveles de creatinina urinaria y se hizo el cálculo de FNDC/Cr ng/mg creatinina. RESULTADOS: Los resultados de FNDC sérico en el grupo ENpoli (0,949 ± 0,587) fueron significativamente menores que los del grupo control (1,158 ± 0,587) (p = 0,014). Los resultados de FNDC urinario en el grupo de ENpoli (1,107 ± 0,360) fueron significativamente mayores que los de los grupos ENmono (0,657 ± 0,272) y control (0,670 ± 0,271) (p < 0,0001). Los resultados de FNDC/Cr el grupo ENpoli (1,472 ± 0,714) eran significativamente mayores que los de los grupos ENMono (0,956 ± 1,017) y control (0,931 ± 0,618) (p = 0,044 y p = 0,032, respectivamente). CONCLUSIONES: Además de problemas específicos vesicales, es posible que los problemas de ansiedad e inducidos por estrés psicológico ocurran en la ENPoli. Por lo tanto, además del creciente número de estudios sobre la vejiga en enuresis, es necesario desarrollar más estudios sobre los aspectos neurogénicos y psicogénicos de la enuresis

Urinary TIMP-2 and MMP-2 are significantly associated with poor bladder compliance in adult patients with spina bifida.

AIMS: To assess the predictive values of six urinary markers (nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], matrix metalloproteinase 2 [MMP-2], tissue inhibitor metalloproteinase 2 [TIMP-2], transformation growth factor ß-1 [TGF-B1], and prostaglandin 2 [PGE2]) for adverse urodynamic features and for upper urinary tract damage in adult patients with spina bifida. MATERIALS AND METHODS: A single-center prospective trial was conducted from March 2015 to March 2017 including all consecutive adult patients with spina bifida seen for urodynamic testing. The urine was collected and stored at -80°C. A urodynamic and an upper urinary tract were systematically performed. At the end of the inclusion period, urines were defrosted and urinary nerve growth factor, BDNF, TIMP-2, and TGF-B1 were assessed using validated ELISA kits. The urinary markers levels were adjusted on the urinary creatinine level. Urinary MMP-2 levels were assessed by zymography. RESULTS: Fourty patients were included. Only TIMP-2 and MMP-2 were significantly associated with poor bladder compliance (P = .043 and P = .039, respectively). TIMP-2 was also the only urinary marker significantly associated with upper urinary tract damage on imaging (OR = 19.81; P = .02). Of all urodynamic parameters, bladder compliance and maximum detrusor pressure were the only ones associated with upper urinary tract damage on imaging (P = .01 and P = .02), The diagnostic performances of urinary TIMP-2 for upper urinary tract damage were slightly superior to PdetMax and bladder compliance with an area under the curve of 0.72. CONCLUSION: Urinary TIMP-2 and MMP-2 were significantly associated with poor bladder compliance and urinary TIMP-2 was significantly associated with upper urinary tract damage. These findings support a pathophysiological role of extracellular matrix remodeling in poor bladder compliance of adult patients with spina bifida.

Urinary nerve growth factor can predict therapeutic efficacy in children with monosymptomatic nocturnal enuresis.

AIM: To determine the urinary levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in children with monosymptomatic nocturnal enuresis (MNE) and evaluate whether these factors can be used as biomarkers for the treatment outcome. METHODS: NGF and BDNF levels were measured and compared in 38 children (28 boys and 10 girls) with MNE and 25 children (18 boys and 7 girls) with no urinary symptoms were assessed. The mean ages in the patient and control groups were 9 and 10 years, respectively (P = .49). The patients were treated with either alarm or desmopressin therapy. RESULTS: The urinary NGF/creatinine and BDNF/creatinine ratios were significantly higher in the patient group than in the control group (P = .0003 and P = .0095, respectively). NGF and BDNF levels showed a significant positive correlation (P = .0020, r = 0.40). With respect to the degree of response, 19 patients (50%) showed complete response (CR) or partial response (PR), and 19 patients (50%) showed nonresponse (NR). The urinary NGF/creatinine and BDNF/creatinine ratios were significantly higher in the NR group than in the CR and PR groups (P = .0003 and P = .0003, respectively). CONCLUSIONS: Urinary NGF/creatinine and BDNF/creatinine ratios were significantly higher in children with MNE than in healthy controls. Urinary NGF/creatinine can be predictive factors of a poor treatment outcome in children with MNE.

BDNF and NGF gene polymorphisms and urine BDNF-NGF levels in children with primary monosymptomatic nocturnal enuresis.

INTRODUCTION: The pathophysiology and genetic influences in nocturnal enuresis have not been fully elucidated. Delayed neuronal maturation has been suggested as a pathogenetic mechanism in primary monosymptomatic nocturnal enuresis (PMNE). Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neurotrophins affecting maturation of the nervous system. OBJECTIVE: The aim of this preliminary study was to investigate BDNF and NGF gene polymorphisms and urine levels of BDNF and NGF in children with PMNE as a first time. STUDY DESIGN: The single-nucleotide polymorphisms of BDNF (rs6265:G > A:Val66Met; rs8192466:C > T:Thr2Ile) and NGF (rs6330:C > T:Ala35Val, rs11466112:C > T:Arg221Trp) were investigated by comparing 104 children with PMNE and 140 healthy control subjects. Children with non-PMNE were excluded. DNA isolation and detection of polymorphisms were performed by real-time polymerase chain reaction. In addition, urine BDNF and NGF levels of 47 PMNE and 29 healthy children were measured by enzyme-linked immunosorbent assay method and normalized to urine creatinine (Cr) concentration for comparisons. RESULTS: There were no differences in genotype and allele frequencies of BDNF rs6265 and NGF rs6330 polymorphisms between patients with PMNE and the control group (P > 0.05). No mutant alleles were found in BDNF rs8192466 and NGF rs11466112 polymorphisms in either group. Children with PMNE had higher urine BDNF/Cr (0.020 ± 0.010 vs 0.010 ± 0.002; P = 0.008) and NGF/Cr ratio (3.01 ± 1.87 pg/mg vs 1.77 ± 0.26 pg/mg; P = 0.002) compared with the control subjects. However, no significant differences were found in BDNF/Cr and NGF/Cr values between GG, GA, and AA genotypes of BDNF rs6265 polymorphism and CC and CT genotypes of NGF rs6330 polymorphism (P > 0.05). DISCUSSION: In this study, no association of BDNF and NGF gene polymorphisms with PMNE was found, and urine neurotrophin concentrations were not directly influenced by investigated polymorphisms. Although, previously increased urine neurotrophin secretion has been found in detrusor overactivity, bladder inflammation, and dysfunctional voiding, this preliminary results also showed an increase in neurotrophins in PMNE. Higher urine neurotrophin levels may be related to delayed and continued neuronal maturation or increased production of neurotrophins in the bladder. The increased urine neurotrophins in PMNE may be an indicator of increased sensory nerve excitability of the bladder, contributing to the development of enuresis. CONCLUSION: This study showed that investigated neurotrophin gene polymorphisms did not make a significant contribution to the development of PMNE, but urine levels of neurotrophin gene products were higher in PMNE. Owing to the complexity and heterogeneity of genotype-phenotype relationships in enuresis, further studies are needed in PMNE.

Value of Urinary Brain-Derived Neurotrophic Factor Levels on the Assessment of Botulinum Toxin Type A Treatment for Neurogenic Detrusor Overactivity in Children with Myelodysplasia.

PURPOSE: Urinary cytokines are proposed to predict urodynamic findings and outcome of intradetrusor botulinum neurotoxin type A injection in children with myelodysplasia. The relationship between urinary brain-derived neurotrophic factor and neurogenic and nonneurogenic detrusor overactivity has been shown as well. We prospectively investigated the effect of intradetrusor botulinum neurotoxin type A injection on urine brain-derived neurotrophic factor levels in children with nonneurogenic detrusor overactivity due to myelodysplasia. MATERIALS AND METHODS: Urine samples of 23 children with nonneurogenic detrusor overactivity due to myelodysplasia were collected and analyzed before and 1 and 3 months after intradetrusor botulinum neurotoxin type A injection, and urodynamics were performed before and 6 weeks after injection. Brain-derived neurotrophic factor levels and urodynamic findings were analyzed and statistical comparisons were done. RESULTS: Mean ± SD age was 100.0 ± 34.5 months. Ratio of girls to boys was 2.8. Brain-derived neurotrophic factor levels significantly decreased (p <0.006), and maximum cystometric capacity and maximum detrusor pressure improved significantly following intradetrusor botulinum neurotoxin type A injection compared to preoperatively (p <0.001). No statistical correlations were determined between brain-derived neurotrophic factor levels and urodynamics. Of all analyses only bladder compliance 5 ml/cm H2O or less vs greater than 5 ml/cm H2O at postoperative urodynamics was associated with statistically increased urine brain-derived neurotrophic factor levels, suggesting that increased urine brain-derived neurotrophic factor predicts treatment failure. CONCLUSIONS: The present study does not suggest that urine brain-derived neurotrophic factor is a reliable followup marker in children with nonneurogenic detrusor overactivity due to myelodysplasia. However, this factor may have a role in treatment planning, which needs to be established in future large prospective studies.

BDNF: mRNA expression in urine cells of patients with chronic kidney disease and its role in kidney function.

Podocyte loss and changes to the complex morphology are major causes of chronic kidney disease (CKD). As the incidence is continuously increasing over the last decades without sufficient treatment, it is important to find predicting biomarkers. Therefore, we measured urinary mRNA levels of podocyte genes NPHS1, NPHS2, PODXL and BDNF, KIM-1, CTSL by qRT-PCR of 120 CKD patients. We showed a strong correlation between BDNF and the kidney injury marker KIM-1, which were also correlated with NPHS1, suggesting podocytes as a contributing source. In human biopsies, BDNF was localized in the cell body and major processes of podocytes. In glomeruli of diabetic nephropathy patients, we found a strong BDNF signal in the remaining podocytes. An inhibition of the BDNF receptor TrkB resulted in enhanced podocyte dedifferentiation. The knockdown of the orthologue resulted in pericardial oedema formation and lowered viability of zebrafish larvae. We found an enlarged Bowman's space, dilated glomerular capillaries, podocyte loss and an impaired glomerular filtration. We demonstrated that BDNF is essential for glomerular development, morphology and function and the expression of BDNF and KIM-1 is highly correlated in urine cells of CKD patients. Therefore, BDNF mRNA in urine cells could serve as a potential CKD biomarker.

[Sensitivity and specificity of urinary and serum neurotrophins in the diagnosis of neurogenic detrusor overactivity in multiple sclerosis].

Lower urinary tract dysfunction is common among neurological patients. Traditionally, the basic method of diagnosis is a complex urodynamic study. In recent years, many studies have focused on the search for new non-invasive diagnostic modalities. In particular, neurotrophins are considered as potential biological markers of a neurogenic bladder. AIM: To estimate the sensitivity and specificity of the serum and urinary nerve growth factor (NGF) and brain neurotrophic factor (BDNF) in MS patients as markers of detrusor overactivity. MATERIALS AND METHODS: The study comprised 20 patients with multiple sclerosis, who complained of voiding problems. The control group consisted of 20 people without neurological diseases, lower urinary tract symptoms and detrusor overactivity estimated by filling cystometry. Apart from standard laboratory tests, diagnostic evaluation included a complex urodynamic study, ultrasound of the urinary tract, cystoscopy, testing serum and urinary NGF and BDNF using the enzyme immunoassay. The diagnostic significance of neurotrophins was evaluated using ROC analysis. RESULTS: According to the ROC analysis, the diagnostic sensitivity and specificity of serum NGF as a marker of detrusor hyperactivity was 57% and 93%, respectively (for serum NGF more or equal 26 pg/ml). The quality of the test according to the expert scale of AUC values was "very good" (AUC=0.806). Detecting NGF in patients urine was less effective. The sensitivity and specificity were 52% and 40%, respectively (for NGF more or equal 6 pg/ml). The quality of the test according to the expert scale of AUC values was "average" (AUC=0.64). The serum BDNF demonstrated high sensitivity (90%) and low specificity (23%), AUC=0.56. The urinary BDNF was more informative, (AUC=0.65). The combination of all four markers provides a sensitivity of 85.7% and a specificity of 66.7% (AUC=0.824). CONCLUSIONS: Testing serum and urinary neurotrophins in patients with multiple sclerosis can be used to diagnose detrusor overactivity. The NGF is a highly specific biomarker, while the BDNF is highly sensitive. Combined testing for serum NGF and BDNF is most informative.

Novel biomarkers of overactive bladder syndrome.

The social aspect of overactive bladder syndrome (OAB) and the lack of objective diagnostic methods for this syndrome have spurred research into its potential biomarkers which can constitute useful diagnostic tools, while also allowing the evaluation of the intensity of clinical symptoms and the efficacy of implemented pharmacotherapy in OAB patients. Due to the complex etiopathogenesis of this syndrome, the researchers are seeking biomarkers connected with inflammation or nerve growth. The aim of this review was to analyse the latest literature data regarding potential biomarkers in OAB. The most promising opportunities are connected with the diagnostic use of the nerve growth factor (NGF), the brain derived neurotrophic factor (BDNF), C-reactive protein (CRP), prostaglandins and cytokines. Despite the most promising results to date having been obtained with regards to neurotrophic factors, it seems that, at the moment, none of these meets the criteria for becoming an isolated OAB marker. It is also suggested that the combined use of several biomarkers will facilitate obtaining the appropriate level of specificity and selectivity to allow their use in clinical practice.

Urinary biomarkers in patients with detrusor underactivity with and without bladder function recovery.

PURPOSE: Detrusor underactivity (DU) is frequently encountered in elderly patients. Part of patients with DU might have bladder function recovery after treatment. This study investigated urinary proteins in these DU patients with and without bladder function recovery. METHODS: A total of 37 patients with chronic urinary retention and urodynamically proven DU were enrolled. After treatment, 24 DU patients had bladder function recovery whereas 13 had not, after 1-year follow-up. Urine collection at baseline was performed, and the urinary protein including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and prostaglandin E2 (PGE2) were measured by ELISA. Twenty urodynamically normal, 34 detrusor overactivity (DO) and 15 detrusor hyperactivity and inadequate contractility (DHIC) patients served as comparative groups. RESULTS: Urinary NGF levels were significantly higher than normal in patients with DU (9.2 ± 20.3 vs 1.85 ± 2.9 pg/ml, p = 0.037). Urinary BDNF level was only significantly higher in patients with DU than that of the control group (153 ± 199 vs 77.4 ± 47.7 pg/ml, p = 0.033) but not in patients with DHIC or DO. Compared with the control group, the urinary BDNF level was significantly higher in DU patients with bladder function recovery (190 ± 239 pg/ml, p = 0.033) but not in patients without recovery (85.8 ± 43.7 pg/ml, p = 0.612). The PGE2 level was significantly higher than the control group in DU patients with bladder function recovery (1290 ± 836 pg/ml, p < 0.0001) but not in patients without recovery (383 ± 237 pg/ml, p = 0.130). CONCLUSION: Patients with DU and higher urinary PGE2 and BDNF levels might have a chance to recover bladder function than those with a lower protein level.

Association of increased urine brain derived neurotrophic factor with lower urinary tract symptoms in men with benign prostatic hyperplasia.

Urinary brain-derived neurotrophic factor (BDNF), an ubiquitous neurotrophin, was found to rise in patients with benign prostatic hyperplasia (BPH). We hypothesized that the urinary level of BDNF could be a potential biomarker for lower urinary tract symptoms (LUTS) in patients with BPH. Totally, 76 patients with BPH-caused LUTS and 32 male control subjects without BPH were enrolled. International Prostate Symptom Score (IPSS) was applied to assess the symptom severity of LUTS. Urodynamic tests were performed for the diagnosis of underlying detrusor overactivity (DO) in the patients with BPH. Urine samples were collected from all subjects. Urinary BDNF levels were measured using enzyme-linked immunosorbent assays and normalized by urinary creatinine (Cr) levels. Seventy-six BPH patients were divided into moderate LUTS group (n=51, 720) according to the IPSS. Of the 76 BPH patients, DO was present in 34 (44.7%) according to the urodynamic test. The urinary BDNF/Cr levels were significantly higher in BPH patients with moderate LUTS (8.29±3.635, P<0.0001) and severe LUTS (11.8±6.44, P<0.0001) than normal controls (1.71±0.555). Patients with severe LUTS tended to have higher urinary BDNF/Cr levels than patients with moderate LUTS (11.8±6.44 vs. 8.29±3.635, P=0.000). The conditions of BPH with LUTS correlated with elevated urinary BDNF levels, and urinary BDNF levels were even higher in BPH-DO patients. The results of this study have provided evidence to suggest that urinary BDNF level test could evaluate the severity of LUTS in BPH patients, and BDNF level can be used as a biomarker for the diagnosis of DO in BPH patients.

The use of biomarkers in the diagnosis and treatment of overactive bladder: Can we predict the patients who will be resistant to treatment?

AIMS: The main objective of this study was to define urinary biomarkers that can predict the severity of overactive bladder and detect patients who would benefit most from treatment. METHODS: Patients with an OAB diagnosis and healthy controls were included in the study. A bladder diary and a validated OAB questionnaire were given to all patients. In the OAB group, solifenacin 5 mg daily was given for 1 month. Urine samples were taken before the treatment and after the first month of the treatment in both groups and urinary BDNF, NGF, GAG, and MCP-1 levels were measured. RESULTS: A total of 45 OAB patients and 45 healthy age-matched controls were included. BDNF/Cre, NGF/Cre, MCP-1/Cre, and GAG/Cre levels were significantly higher in the OAB group. The levels of these biomarkers significantly decreased after 1 month of solifenacin treatment. After treatment, 66.7% of patients OAB symptoms were relieved and 33.3% did not respond to the treatment. Although basal biomarker levels did not differ between responder and non-responder groups, the ratio of decrease in biomarker levels was significantly higher in treatment-sensitive patients. Postmenopausal women were more resistant to treatment when compared with the premenopausal group. CONCLUSIONS: Urinary biomarkers have a role in the pathophysiology of OAB however they did not predict the patients who would benefit from the treatment and in whom antimuscarinics would be useless. Future studies with higher numbers of patients and different OAB subgroups are needed to investigate the exact role of these (and other) biomarkers. Neurourol. Urodynam. 36:390-393, 2017. © 2015 Wiley Periodicals, Inc.

Urinary neurotrophic peptides in postmenopausal women with and without overactive bladder.

AIMS: The aim of this study was to compare the expression of urinary nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), substance P (SP), and calcitonin-gene related peptide (CGRP) in women with and without overactive bladder (OAB). We sought to determine factors associated with higher expression of these neuropeptides. METHODS: Participants with OAB and age-matched controls were enrolled. Symptom severity was assessed with validated questionnaires. Urinary neurotrophin levels, symptom scores, and clinical data were compared between the groups. Multivariate analysis determined independent factors associated with urinary neurotrophin levels. RESULTS: Sixty-seven women (38 OAB, 29 controls) were included. Women with OAB and controls were similar in age, race, body mass index, parity, and smoking status. Women with OAB were more likely to report a history of pelvic pain and pelvic surgery. Neurotrophic factor levels normalized to urinary creatinine did not differ between the groups. Increasing age was associated with greater urinary levels of BDNF and NGF (ß = 0.23, 95%CI 0.11-0.34 and 0.75, 95%CI 0.17-1.33, respectively, P < 0.02). Higher urinary NGF was associated with increasing BMI (ß = 0.81, 95%CI 0.05-1.57, P = 0.04) while pain was associated with elevated urinary SP (ß = 0.21, 95%CI 0.09-0.33, P = 0.001). CONCLUSIONS: Our data does not support a relationship between urinary neurotrophin levels and OAB in age-matched postmenopausal women. Further research is necessary to elucidate the role of urinary neurotrophins in the diagnosis and management of OAB. Neurourol. Urodynam. 36:740-744, 2017. © 2016 Wiley Periodicals, Inc.

Effect of Training Exercise on Urinary Brain-derived Neurotrophic Factor Levels and Cognitive Performances in Overweight and Obese Subjects.

Exercise-mediated, brain-derived neurotrophic factor induction benefits health and cognitive functions. The multifaceted interplay between physical activity, urinary brain-derived neurotrophic factor levels and cognitive functioning has been largely neglected in previous literature. In this pilot study, two bouts of training exercise (65% and 70% of heart rate reserve) influenced urinary brain-derived neurotrophic factor levels and cognitive performances in 12 overweight and obese participants. Percent heart rate reserve, expenditure energy, brain-derived neurotrophic factor urinary levels and cognitive performances were measured before and after the exercise. No significant variations in energy expenditure were observed, while differences of heart rate reserve between two groups were maintained. Both bouts of training exercise induced a similar reduction in urinary brain-derived neurotrophic factor levels. Only visuo-spatial working memory capacity at 65% of heart rate reserve showed a significant increase. These findings indicate a consistent effect of training exercise on urinary brain-derived neurotrophic factor levels and cognitive factors in overweight and obese participants.

Urinary Neurotrophin Levels Increase in Women With Stress Urinary Incontinence After a Midurethral Sling Procedure.

OBJECTIVE: To investigate the association between urinary neurotrophin levels, maximum flow rate (Qmax) variation, and the appearance of urgency in women with stress urinary incontinence (SUI) after a midurethral sling (MUS) procedure. MATERIALS AND METHODS: Thirty-one women with SUI were treated with a MUS. One year later, the outcome of surgery and the onset of urgency were assessed. At baseline and 1-year follow-up, urine was collected to measure nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) concentration, and Qmax variation was calculated. Urine samples from healthy women (n = 20) without lower urinary tract symptoms and overactive bladder (OAB) wet patients (n = 32) were used as controls. Urinary neurotrophin levels were measured by enzyme-linked immunosorbent assay and normalized to creatinine concentration. RESULTS: At baseline, urinary levels of NGF and BDNF were similar between SUI and healthy women (NGF: 2.10 ± 0.68 vs 1.99 ± 1.05; BDNF: 1.99 ± 0.71 vs 1.81 ± 0.90), and significantly inferior to OAB wet patients (NGF: 2.10 ± 0.68 vs 2.50 ± 0.54, P < .05; BDNF: 1.99 ± 0.71 vs 2.71 ± 0.45, P < .05). After surgery, there was a significant increase of both neurotrophins (vs baseline, P < .05) to the values of OAB wet patients. Moreover, there was a significantly higher percentage increase of NGF in women with de novo urgency than in those without lower urinary tract symptoms (P = .019). A trend for a higher mean Qmax reduction in women with de novo urgency was also found (P = .085). CONCLUSION: These findings suggest that increased bladder outlet resistance after a MUS may play a key role in the rise of urinary neurotrophins, promoting sensitization of bladder primary afferents and causing de novo urgency in susceptible patients.