International Urogynecology Journal

, Volume 24, Issue 7, pp 1065–1072 | Cite as

Biomarkers in overactive bladder

  • Alka A. Bhide
  • Rufus Cartwright
  • Vik Khullar
  • G. Alessandro Digesu
Review Article

Abstract

A biomarker is an indicator of a particular disease. It is generally used to define the presence (diagnostic biomarker), severity, progression (prognostic biomarker) of a condition and/or its response to a specific treatment (predictive biomarker). Biomarkers can be specific cells, enzymes, hormones, genes or gene products, which can be detected and measured in parts of the body such as blood, urine or tissue. Therefore, biomarkers have been suggested to play an important role in both the clinical assessment and the management of patients, as well as in the research setting. Recently, interest has gathered in urinary biomarkers as a tool to assess overactive bladder (OAB), potentially playing a role in the diagnosis, disease progression and monitoring response to treatment. Urinary biomarkers identified so far include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), prostaglandins, cytokines and C-reactive protein. The aim of this review was to review the published literature on biomarkers in OAB. A literature review using Pub Med, clinicaltrials.gov and the controlled trials online registries was performed from 1970 up to June 2012. The search keywords were: the International Continence Society (ICS) definition of "OAB", “nerve growth fac- tor” (NGF), “brain derived growth factor” (BDNF), “prostaglandins,” “cytokines,” “genetic biomarkers” and “C reactive protein”.

The results were limited for fully published English-language articles. The search was then subsequently expanded to include urinary biomarkers in interstitial cystitis and bladder pain where relevant. Each of the studies/articles was reviewed, interpreted and discussed to consider the role of urinary biomarkers in OAB. Using the search criteria, a total of 20 studies (animal and human) that investigated the role of urinary biomarkers in OAB were identified. Full text versions of these articles were obtained and reviewed. Studies on NGF suggested that urinary levels were higher in OAB patients and decreased with antimuscarinic and botulinum toxin treatment. BDNF studies have demonstrated raised levels in OAB and also increased levels in situations of acute bladder inflammation. The role of urinary prostaglandins, cytokines and CRP does not appear to be specific to the OAB disease process according to the current available evidence. Based on the evidence so far NGF and BDNF appear to be the most promising biomarkers in OAB. Although still in their infancy these neurotrophic factors could potentially diagnose OAB, replacing urodynamics and aiding in monitoring disease progression and response to treatment in addition to clinical symptoms.

Keywords

Overactive bladder Urinary biomarkers Nerve growth factor Brain derived growth factor Prostaglandins Cytokines CRP 

Notes

Conflicts of interest

None.

References

  1. 1.
    Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J et al (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J Pelvic Floor Dysfunct 21(1):5–26. doi: 10.1007/s00192-009-0976-9
  2. 2.
    Cartwright R, Afshan I, Derpapas A, Vijaya G, Khullar V (2011) Novel biomarkers for overactive bladder. Nat Rev Urol Mar 8(3):139–145CrossRefGoogle Scholar
  3. 3.
    Chu FM, Dmochowski R (2006) Pathophysiology of overactive bladder. Am J Med 119 [3 Suppl 1]:3–8PubMedCrossRefGoogle Scholar
  4. 4.
    Steers WD (2002) Pathophysiology of overactive bladder and urge urinary incontinence. Rev Urol 4 [Suppl 4]:S7–S18PubMedGoogle Scholar
  5. 5.
    Tanner R, Chambers P, Khadra MH, Gillespie JI (2000) The production of nerve growth factor by human bladder smooth muscle cells in vivo and in vitro. BJU Int 85(9):1115–1119PubMedCrossRefGoogle Scholar
  6. 6.
    Vizzard MA (2000) Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction. Exp Neurol 161(1):273–284PubMedCrossRefGoogle Scholar
  7. 7.
    Moore KH, Simons A, Mukerjee C, Lynch W (2000) The relative incidence of detrusor instability and bacterial cystitis detected on the urodynamic-test day. BJU Int 85(7):786–792PubMedCrossRefGoogle Scholar
  8. 8.
    Hessdoerfer E, Jundt K, Peschers U (2011) Is a dipstick test sufficient to exclude urinary tract infection in women with overactive bladder? Int Urogynecol J 22(2):229–232PubMedCrossRefGoogle Scholar
  9. 9.
    Walsh CA, Siddins A, Parkin K, Mukerjee C, Moore KH (2011) Prevalence of “low-count” bacteriuria in female urinary incontinence versus continent female controls: a cross-sectional study. Int Urogynecol J 22(10):1267–1272PubMedCrossRefGoogle Scholar
  10. 10.
    Oddiah D, Anand P, McMahon SB, Rattray M (1998) Rapid increase of NGF, BDNF and NT-3 mRNAs in inflamed bladder. Neuroreport 9(7):1455–1458PubMedCrossRefGoogle Scholar
  11. 11.
    Qiao LY, Vizzard MA (2002) Cystitis-induced upregulation of tyrosine kinase (TrkA, TrkB) receptor expression and phosphorylation in rat micturition pathways. J Comp Neurol 454(2):200–211PubMedCrossRefGoogle Scholar
  12. 12.
    Kim JC, Park EY, Seo SI, Park YH, Hwang TK (2006) Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J Urol 175(5):1773–1776PubMedCrossRefGoogle Scholar
  13. 13.
    Liu HT, Chancellor MB, Kuo HC (2009) Decrease of urinary nerve growth factor levels after antimuscarinic therapy in patients with overactive bladder. BJU Int 103(12):1668–1672PubMedCrossRefGoogle Scholar
  14. 14.
    Liu HT, Lin H, Kuo HC (2011) Increased serum nerve growth factor levels in patients with overactive bladder syndrome refractory to antimuscarinic therapy. Neurourol Urodyn 30(8):1525–1529PubMedCrossRefGoogle Scholar
  15. 15.
    Liu HT, Chancellor MB, Kuo HC (2009) Urinary nerve growth factor levels are elevated in patients with detrusor overactivity and decreased in responders to detrusor botulinum toxin-A injection. Eur Urol 56(4):700–706PubMedCrossRefGoogle Scholar
  16. 16.
    Kuo HC, Liu HT, Tyagi P, Chancellor MB (2010) Urinary nerve growth factor levels in urinary tract diseases with or without frequency urgency syndrome. LUTS 2:88–94Google Scholar
  17. 17.
    Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C et al (2008) BDNF as a pain modulator. Prog Neurobiol 85(3):297–317PubMedCrossRefGoogle Scholar
  18. 18.
    Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, Yan Q et al (1997) Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J Neurosci 17(21):8476–8490PubMedGoogle Scholar
  19. 19.
    Pezet S, Malcangio M, McMahon SB (2002) BDNF: a neuromodulator in nociceptive pathways? Brain Res Brain Res Rev 40(1–3):240–249PubMedCrossRefGoogle Scholar
  20. 20.
    Pinto R, Frias B, Allen S, Dawbarn D, McMahon SB, Cruz F et al (2010) Sequestration of brain derived nerve factor by intravenous delivery of TrkB-Ig2 reduces bladder overactivity and noxious input in animals with chronic cystitis. Neuroscience 166(3):907–916PubMedCrossRefGoogle Scholar
  21. 21.
    Pinto R, Lopes T, Frias B, Silva A, Silva JA, Silva CM et al (2010) Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol Sep 58(3):360–365CrossRefGoogle Scholar
  22. 22.
    Antunes-Lopes T, Pinto R, Carvalho-Barros S, Diniz P, Martins-Silva C et al (2012) Urinary levels of brain derived neurotrophic factor (BDNF) in women with overactive bladder (OAB) syndrome correlate with the severity of symptoms. Eur Urol Suppl 10(2):277–278CrossRefGoogle Scholar
  23. 23.
    Bultitude MI, Hills NH, Shuttleworth KE (1976) Clinical and experimental studies on the action of prostaglandins and their synthesis inhibitors on detrusor muscle in vitro and in vivo. Br J Urol 48(7):631–637PubMedCrossRefGoogle Scholar
  24. 24.
    Ishizuka O, Mattiasson A, Andersson KE (1995) Prostaglandin E2-induced bladder hyperactivity in normal, conscious rats: involvement of tachykinins. J Urol 153(6):2034–2038PubMedCrossRefGoogle Scholar
  25. 25.
    Schussler B (1990) Comparison of the mode of action of prostaglandin E2 (PGE2) and sulprostone, a PGE2-derivative, on the lower urinary tract in healthy women. A urodynamic study. Urol Res 18:349–352PubMedCrossRefGoogle Scholar
  26. 26.
    Liu HT, Tyagi P, Chancellor MB, Kuo HC (2010) Urinary nerve growth factor but not prostaglandin E2 increases in patients with interstitial cystitis/bladder pain syndrome and detrusor overactivity. BJU Int 106(11):1681–1685PubMedCrossRefGoogle Scholar
  27. 27.
    Tyagi P, Barclay D, Zamora R, Yoshimura N, Peters K, Vodovotz Y et al (2010) Urine cytokines suggest an inflammatory response in the overactive bladder: a pilot study. Int Urol Nephrol 42(3):629–635PubMedCrossRefGoogle Scholar
  28. 28.
    Ghoniem G, Faruqui N, Elmissiry M, Mahdy A, Abdelwahab H, Oommen M et al (2011) Differential profile analysis of urinary cytokines in patients with overactive bladder. Int Urogynecol J 22(8):953–961PubMedCrossRefGoogle Scholar
  29. 29.
    Kushner I (1982) The phenomenon of the acute phase response. Ann N Y Acad Sci 389:39–48PubMedCrossRefGoogle Scholar
  30. 30.
    Pepys MB, Hirschfield GM (2003) C-reactive protein: a critical update. J Clin Invest 111(12):1805–1812PubMedGoogle Scholar
  31. 31.
    Hsiao SM, Lin HH, Kuo HC (2012) The role of serum C-reactive protein in women with lower urinary tract symptoms. Int Urogynecol J 23(7):935-940 doi: 10.1007/s00192-012-1715-1 PubMedCrossRefGoogle Scholar
  32. 32.
    Chuang YC, Tyagi V, Liu RT, Chancellor MB, Tyagi P (2010) Urine and serum C-reactive protein levels as potential biomarkers of lower urinary tract symptoms. Urol Sci 21(3):132–136CrossRefGoogle Scholar
  33. 33.
    Chung SD, Liu HT, Lin H, Kuo HC (2011) Elevation of serum c-reactive protein in patients with OAB and IC/BPS implies chronic inflammation in the urinary bladder. Neurourol Urodyn 30(3):417–420PubMedCrossRefGoogle Scholar
  34. 34.
    Kupelian V, McVary KT, Barry MJ, Link CL, Rosen RC, Aiyer LP et al (2009) Association of C-reactive protein and lower urinary tract symptoms in men and women: results from Boston Area Community Health survey. Urology 73(5):950–957PubMedCrossRefGoogle Scholar
  35. 35.
    Van der Hel OL, van der Luijt RB, Bueno de Mesquita HB, van Noord PA, Slothouber B, Roest M et al (2002) Quality and quantity of DNA isolated from frozen urine in population-based research. Anal Biochem 304(2):206–211Google Scholar
  36. 36.
    Wennberg A-L, Altman D, Lundholm C, Klint A, Iliadou A, Peeker R et al (2011) Genetic influences are important for most but not all lower urinary tract symptoms: a population-based survey in a cohort of adult Swedish twins. Eur Urol 59(6):1032–1038PubMedCrossRefGoogle Scholar
  37. 37.
    Rohr G, Kragstrup J, Gaist D, Christensen K (2004) Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand 83(10):978–982PubMedGoogle Scholar
  38. 38.
    Ferreira CE, Fonseca AM, Silva ID, Girão MJ, Sartori MG, Castro RA (2011) The relationship between the Trp 64 Arg polymorphism of the beta 3-adrenoceptor gene and idiopathic overactive bladder. Am J Obstet Gynecol 205(1):82.e10–4CrossRefGoogle Scholar

Copyright information

© The International Urogynecological Association 2013

Authors and Affiliations

  • Alka A. Bhide
    • 1
  • Rufus Cartwright
    • 1
  • Vik Khullar
    • 1
  • G. Alessandro Digesu
    • 1
  1. 1.Department of UrogynaecologySt. Mary’s HospitalLondonUK

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