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Systematic Review

Brain-derived neurotrophic factor, nerve growth factor, and high sensitivity C-reactive protein levels in urine in overactive bladder patients: a meta-analysis

[version 1; peer review: 2 not approved]
Edwin Utomo
https://orcid.org/0000-0003-3614-8122
1, Farhat .
https://orcid.org/0000-0003-1204-5321
2, Melvin Nova Gunawanto Barus3, Mohd. Rhiza Z. Tala
https://orcid.org/0000-0003-0446-9626
4
Edwin Utomo
https://orcid.org/0000-0003-3614-8122
1, Farhat .
https://orcid.org/0000-0003-1204-5321
2, Melvin Nova Gunawanto Barus3, Mohd. Rhiza Z. Tala
https://orcid.org/0000-0003-0446-9626
4
PUBLISHED 04 Aug 2021
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Background: Overactive bladder (OAB) is a clinical syndrome characterized by a combination of symptoms including urgency, frequency, and nocturia, with or without urinary incontinence. Overactive bladder has a high prevalence especially in those of an older age and women, with diagnosis depending on the patient’s symptoms. This study aims to assess brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and high sensitivity C-reactive protein (HSCRP) in urine as biomarkers in OAB.
Methods: Studies were searched from Pubmed, Science Direct, Wiley Online Library, and Google Scholar. All studies assessing BDNF, NGF, and HSCRP in urine in OAB patients were included. The standardized mean difference (SMD) and 95% confidence intervals (CI) were then calculated.
Results: A total of 85 studies were included with a total of 11,483 subjects (6,885 OAB patients and 4,598 controls). Based on data analysis results, urinary NGF/Creatinine (NGF/Cr) and NGF level in OAB patients were significantly higher than control (SMD = 1.00, 95%CI = 0.80-1.20, P<0.00001; and SMD = 1.11, 95%CI = 0.79-1.43, P<0.00001). NGF/Cr level was found higher in OAB with incontinence (OAB wet) compared with OAB without incontinence (OAB dry) (SMD = 0.41, 95%CI = 0.23-0.60, P<0.0001), and decreased after treatment (SMD = 0.76, 95%CI = 0.49-1.03, P<0.00001). Urinary BDNF/Cr level was significantly higher in OAB patients compared with controls (SMD = 1.97, 95%CI = 1.14-2.79, P<0.00001), and also decreased significantly after treatment (SMD = 0.75, 95%CI = 0.42-1.08, P<0.00001). The level of HSCRP was significantly higher in OAB patients when compared with controls (SMD = 0.38, 95%CI = 0.12-0.64, P<0.004).
Conclusions: The level of BDNF/Cr, NGF/Cr, NGF, and HSCRP in urine were found higher in OAB compared with controls, which means they may be used as a biomarkers for OAB.

Keywords

brain-derived neurotrophic factor, nerve growth factor, high sensitivity C-reactive protein, overactive bladder

Corresponding author: Mohd. Rhiza Z. Tala
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright:  © 2021 Utomo E et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Utomo E, . F, Barus MNG and Tala MRZ. Brain-derived neurotrophic factor, nerve growth factor, and high sensitivity C-reactive protein levels in urine in overactive bladder patients: a meta-analysis [version 1; peer review: 2 not approved]. F1000Research 2021, 10:747 (https://doi.org/10.12688/f1000research.52992.1) First published: 04 Aug 2021, 10:747 (https://doi.org/10.12688/f1000research.52992.1) Latest published: 04 Aug 2021, 10:747 (https://doi.org/10.12688/f1000research.52992.1)

Introduction

Overactive bladder (OAB) is defined by the International Continence Society as a syndrome characterized with symptoms such as urgency, frequency, and nocturia, with or without urinary incontinence.1 OAB can affect daily activities and social functions such as work, physical activitiy, and sleep. OAB prevalence was found to be higher in older patients and women.1–3 Chronic low-grade inflammation is related to old age, which is a risk factor for various morbidities and mortality.4 The pro-inflammatory state in aging is believed to cause molecular and structural damage contributing to bladder aging and OAB.5 In women, menopause is associated with increased OAB symptoms due to decreased levels of oestrogen after menopause, which has an important role in lower urinary tract function.6

OAB diagnosis currently depends on the patient’s clinical symptoms rather than molecular identification from samples, such as urine, blood, or other biological samples, which are easy to acquire and analyse. While patient examination includes urodynamic test, symptom questionnaire, and urination diary, which has low objectivity and accuracy.7,8

Brain-derived neurotrophic factor (BDNF), along with nerve growth factor (NGF), is a neurotrophic factor, which is a group of proteins with functions in neuron growth, survival, and differentiation. Neurotrophins are able to bind and activate high-affinity tropomyosin-receptor kinase receptor and low-affinity p75 neurotrophin receptor (p75NTR). Increases of NGF levels have been found in inflammation, while BDNF secretion is induced by NGF in inflamed tissue. NGF also plays a role as a peripheral mediator in inflammation.9,10 High sensitivity C-reactive protein (HSCRP) able to detect CRP levels with sensitivity range of 0.01 to 10 mg/L, and HSCRP levels can help to measure low-grade systemic inflammation.11 We perform meta-analysis to assess NGF, BDNF, and HSCRP levels in OAB patients based on previous studies.

Methods

Eligibility criteria and information sources

This study was a meta-analysis study. Inclusion criteria were as follows: studies with OAB patients; studies which measured BDNF, NGF, and HSCRP levels in urine; studies that had data available for size effect analysis (mean, standard deviation, and sample size); and studies available in Bahasa Indonesia or English. Exclusion criteria were review articles, studies in animals, and studies in children. Studies in children were excluded because OAB prevalence was found higher in older patients.

Literature was searched using Pubmed, Science Direct, Wiley Online Library, and Google Scholar. Keywords used for literature searching were ((BDNF OR NGF) OR HSCRP) AND overactive bladder. Information sources were searched until 31 November 2020.

Data collection

The literature searching and data extraction were performed by at least two reviewers independently.

Data variables that were extracted from study samples were as follows: first author name; year of publication; sample size; and BDNF/Creatinine (BDNF/Cr), NGF/Creatinine (NGF/Cr), and HSCRP levels in urine. BDNF/Cr, NGF/Cr and HSCRP levels were extracted in mean and standard deviation.

Data analysis

Data were analysed using standardized mean difference (SMD) and 95% confidence interval (CI) using Review Manager 5.3 software. A P value of less than 0.05 indicated significant statistical data. Heterogeneity was estimated using I2 and Q test. I2 above 50% and P value less than 0.05 indicated significant heterogeneity between studies. If I2 was more than 50%, a random effects model was used. If I2 was less than 50%, a fixed effects model was used instead.

Publication bias was evaluated using funnel plot.

Results

A total of 85 studies7,12–95 were included, with 11,483 subjects (6,885 OAB and 4,598 without OAB) from 969 studies searched from Pubmed, Science Direct, Wiley Online Library, and Google Scholar. Literature searching results can be seen in Figure 1.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure1.gif

Figure 1. PRISMA flowchart.

Comparison of NGF/Cr levels between OAB patients and controls

Based on data analysis results, NGF/Cr levels in urine was found significantly higher in OAB patients compared to controls (SMD = 1.00, 95% CI = 0.80-1.20, P < 0.00001). The heterogeneity test showed significant heterogeneity (P < 0.00001, I2 = 89%), so a random effects model was used to analyse data. The results of the forest plot can be seen in Figure 2.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure2.gif

Figure 2. Forest plot of NGF/Cr levels comparison between OAB patients and controls.

Comparison of urinary NGF levels between OAB patients and controls

Urinary NGF levels were found significantly higher in OAB patients when compared with controls (SMD = 1.11, 95% CI = 0.79-1.43, P < 0.00001). Heterogeneity was found (P < 0.00001, I2 = 91%); therefore, a random effects model was used to analyse data. The results of the forest plot can be seen in Figure 3.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure3.gif

Figure 3. Forest plot of urinary NGF levels comparison between OAB patients and controls.

Comparison of BDNF/Cr levels between OAB patients and controls

OAB patients have significantly higher levels of BDNF/Cr compared to controls (SMD = 1.97, 95% CI = 1.14-2.79, P < 0.00001). Heterogeneity was found (P < 0.00001, I2 = 97%), and a random effects model was used to analyse data. The results of the forest plot can be seen in Figure 4.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure4.gif

Figure 4. Forest plot of BDNF/Cr levels comparison between OAB patients and controls.

Comparison of HSCRP levels between OAB patients and controls

HSCRP levels were found to be higher in OAB patients compared with controls (SMD = 0.38, 95% CI = 0.12-0.64, P < 0.004). There was significant heterogeneity (P < 0.00001; I2 = 93%), so a random effects model was used in data analysis. The results of the forest plot can be seen in Figure 5.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure5.gif

Figure 5. Forest plot of HSCRP levels comparison between OAB patients and controls.

Comparison of NGF/Cr levels between OAB wet patients and OAB dry patients

Levels of NGF/Cr were found significantly higher in patients with OAB with incontinence (OAB wet) compared with OAB without incontinence (OAB dry) (SMD = 0.41, 95% CI = 0.23-0.60, P < 0.0001). A random effects model was used in data analysis because there was a significant heterogeneity (P < 0.02; I2 = 50%). The results of the forest plot can be seen in Figure 6.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure6.gif

Figure 6. Forest plot of NGF/Cr levels comparison between OAB wet patients and OAB dry patients.

Differences in NGF/Cr levels in OAB patients before and after treatment

NGF/Cr levels in urine in OAB patients were significantly decreased after treatment (SMD = 0.76, 95% CI = 0.49-1.03, P < 0.00001). Heterogeneity was found (P < 0.00001; I2 = 88%), and a random effects model was used to analyse the data. The results of the forest plot can be seen in Figure 7.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure7.gif

Figure 7. Forest plot of NGF/Cr levels in OAB patients before and after treatment.

Differences in BDNF/Cr levels in OAB patients before and after treatment

The levels of BDNF/Cr in OAB patients’ urine were significantly decreased after treatment (SMD = 0.75, 95% CI = 0.42-1.08, P < 0.00001). A random effects model was used in data analysis because significant heterogeneity was found (P < 0.00001; I2 = 80%). The results of the forest plot can be seen in Figure 8.

795256c3-3c02-402e-afe7-4dc0a327bafa_figure8.gif

Figure 8. Forest plot of BDNF/Cr levels in OAB patients before and after treatment.

Subgroup analysis

Subgroup analysis was performed based on subject gender and age. Based on subgroup analysis results, there was a significant difference of NGF/Cr levels in urine in both male (SMD = 0.88, 95% CI = 0.60-1.17, P < 0.00001) and female groups (SMD = 1.06, 95% CI = 0.70-1.11, P < 0.00001) compared with controls. A significant difference of NGF/Cr levels was also found in the >50 year old (SMD = 0.91, 95% CI = 0.71-1.11, P < 0.00001) and the <50 year old groups (SMD = 1.47, 95% CI = 0.77-2.18, P < 0.00001) compared with controls.

There was a significant difference of BDNF/Cr levels in urine in both the male (SMD =1.78, 95% CI = 0.95-2.61, P < 0.0001) and female groups (SMD = 2.11, 95% CI = 0.63-3.59, P = 0.005). A significant difference was also significantly in both the >50 year old (SMD = 2.35, 95% CI = 0.89-3.80, P = 0.002) and the <50 year old groups (SMD = 1.46, 95% CI = 0.95-1.96, P < 0.00001).

There was also a significant difference of HSCRP levels in both the male (SMD = 0.63, 95% CI = 0.12-1.13, P = 0.01) and female groups (SMD = 0.24, 95% CI = 0.14-0.33, P < 0.00001). A significant difference was also found in both the >50 year old (SMD = 0.48, 95% CI = 0.11-0.84, P = 0.01) and <50 year old groups (SMD = 0.24, 95% CI = 0.13-0.35, P < 0.0001). Subgroup analysis results can also be seen in Table 1.

Table 1. Subgroup analysis of NGF/Cr, BDNF, and HSCRP levels between OAB patients and controls.

SubgroupsTotal studiesSample sizeSMD (95% CI)PHeterogeneity
OABControlI2 (%)P
NGF/Cr Levels
Gender
Male2108961.01 ((-0.83)-2.86)0.2895<0.00001
Female2113787431.06 (0.70-1.42)<0.0000192<0.00001
Male and Female33152610500.88 (0.60-1.17)<0.0000189<0.00001
Age
>5047273815740.91 (0.71-1.11)<0.0000186<0.00001
<5093743051,47 (0.77-2.18)<0.000193<0.00001
BDNF/Cr Levels
Gender
Male000NANANANA
Female105782942.11 (0.63-3.59)0.00598<0.00001
Male and Female103113311.78 (0.95-2.61)<0.000195<0.00001
Age
>50125873302.35 (0.89-3.80)0.00298<0.00001
<5083022951.46 (0.95-1.96)<0.0000186<0.00001
HSCRP Levels
Gender
Male211897620.24 (0.14-0.33)<0.0000100.87
Female000NANANANA
Male and Female3144816170.63 (0.12-1.13)0.0196<0.00001
Age
>504160919550.48 (0.11-0.84)0.01095<0.00001
<50110284240.24 (0.13-0.35)<0.000193<0.00001

Publication bias

There was no publication bias by funnel plot (Figure 9).

795256c3-3c02-402e-afe7-4dc0a327bafa_figure9.gif

Figure 9. Funnel plot showing publication bias.

Discussions

Based on our analysis, NGF/Cr and NGF levels in urine were found higher significantly in OAB patients compared with controls. Higher NGF/Cr levels were also found in OAB wet patients compared with OAB dry patients. This result is related to higher detrusor muscle activity in OAB wet patients compared with OAB dry.96,97 NGF/Cr levels were decreased after various treatments, such as lifestyle management and antimuscarinic. This means NGF/Cr levels could be used to assess therapeutic effects of OAB treatment. An increase of NGF levels occurs in inflammatory conditions or organ dysfunction which has a role in regulation of sensory sensitivity. NGF could sensitise C afferent fibres, which cause urgency and hyperactivation of bladder reflex, resulting in frequency and urgency incontinence.98,99 When a cut-off point of 26.32 pg/mg was used, NGF/Cr has a sensitivity and specificity of 93.3% and 64.0%.7

In our study, BDNF/Cr levels in urine was found significantly higher in OAB patients compared with controls. An increase of BDNF levels is induced by increased NGF synthesis in inflamed tissue.9 Our study showed that BDNF/Cr levels decreased after various treatments, so BDNF/Cr levels could be used to assess therapeutic effect of OAB treatment. Previous research by Antunes-Lopes et al in 201318 showed that BDNF/Cr levels were higher in OAB patients compared with controls (628.1 ± 590.5 vs 110.4 ± 159.5; P < 0.001), and the levels decreased after treatment with lifestyle modification (432.5 ± 598.0; P < 0.033) or treatment with antimuscarinic (146.6 ± 264.9; P < 0.001).

Based on our data analysis, HSCRP levels was found significantly higher in OAB patients compared with controls. This result shows a connection between inflammation and OAB. Previous research by Kupelian et al in 2012100 showed an association between increases in CRP levels and OAB in males and females. OAB prevalence was also increased with higher CRP levels in that study. An increase in CRP levels could trigger endothelial dysfunction and atherosclerosis. Ischemia caused by atherosclerosis could lead to bladder dysfunction.101 This inflammation and bladder dysfunction then causes the release of various inflammatory mediators, such as NGF and BDNF, which cause an increase in afferent nerve activities resulting in OAB symptoms.102

The limitation of our study is the significant heterogeneity on our analysis. This could be caused by variations in methods and populations of included studies.

In conclusion, urinary NGF/Cr, BDNF/Cr, and HSCRP may be used as biomarker in OAB diagnosis and to assess therapeutic effects of OAB treatments. However, there are still low number of HSCRP studies. More studies on these biomarkers and HSCRP assessment in OAB should be performed in the future.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Open Science Framework: PRISMA checklist for ‘Brain-derived neurotrophic factor, nerve growth factor, and high sensitivity C-reactive protein levels in urine in overactive bladder patients: a meta-analysis’, https://doi.org/10.17605/OSF.IO/R9XAK.103

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).

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Utomo E, . F, Barus MNG and Tala MRZ. Brain-derived neurotrophic factor, nerve growth factor, and high sensitivity C-reactive protein levels in urine in overactive bladder patients: a meta-analysis [version 1; peer review: 2 not approved]. F1000Research 2021, 10:747 (https://doi.org/10.12688/f1000research.52992.1)
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Reviewer Report 08 Dec 2021
Volkan Sen, Dokuz Eylul University School of Medicine, İzmir, Turkey 
Not Approved
VIEWS 9
https://doi.org/10.5256/f1000research.56332.r98386
The authors evaluated some inflammatory factor levels in urine in overactive bladder patients. I have some concerns about the manuscript;
  • Authors must take a PROSPERO number for meta-analysis before the study.
     
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Sen V. Reviewer Report For: Brain-derived neurotrophic factor, nerve growth factor, and high sensitivity C-reactive protein levels in urine in overactive bladder patients: a meta-analysis [version 1; peer review: 2 not approved]. F1000Research 2021, 10:747 (https://doi.org/10.5256/f1000research.56332.r98386)
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Reviewer Report 24 Aug 2021
Pradeep Tyagi, Department of Urology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA 
Not Approved
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https://doi.org/10.5256/f1000research.56332.r91226
The authors have performed a meta-analysis of reports on urine analysis of NGF, BDNF, and CRP. 

The following concerns were noted:
  • Authors should cite PMID: 281025521 and discuss how their findings reconcile with earlier meta-analyses. 
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Tyagi P. Reviewer Report For: Brain-derived neurotrophic factor, nerve growth factor, and high sensitivity C-reactive protein levels in urine in overactive bladder patients: a meta-analysis [version 1; peer review: 2 not approved]. F1000Research 2021, 10:747 (https://doi.org/10.5256/f1000research.56332.r91226)
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A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
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Fundamental flaws in the paper seriously undermine the findings and conclusions

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  1. Pradeep Tyagi, University of Pittsburgh, Pittsburgh, USA
  2. Volkan Sen, Dokuz Eylul University School of Medicine, İzmir, Turkey

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    Alongside their report, reviewers assign a status to the article:
    Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
    Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
    Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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