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Urine Biomarkers and Bladder Pain Syndrome

  • Pierre Bouchelouche
  • Kirsten Bouchelouche
Chapter

Abstract

There is currently no specific diagnostic test for bladder pain syndrome (BPS). Potential diagnostic biomarkers with varying sensitivity and specificity for BPS have been described in urine, serum, and bladder tissue. However, the specificity of these tests for BPS has been questioned. Ideally, biomarkers should enable a definitive diagnosis of BPS in the face of competing potential etiologies, provide information about treatment impact, and play a central role in the development of novel therapeutic agents.

The search for noninvasive techniques for diagnosis of BPS has led to the study of urine biomarkers.

This article describes the current state of the art with regard to urine biomarkers of BPS, and describes the areas that need continuing research.

References

  1. 1.
    Dimitrakov J. A road map to biomarker discovery and validation in urological chronic pelvic pain syndrome. J Urol. 2008;179:1660–1.PubMedCrossRefGoogle Scholar
  2. 2.
    Biomarkes Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.CrossRefGoogle Scholar
  3. 3.
    Hewitt SM, Dear J, Star RA. Discovery of protein biomarkers for renal diseases. J Am Soc Nephrol. 2004;15:1677–89.PubMedCrossRefGoogle Scholar
  4. 4.
    Holliday EG, Scott RJ, Attia J. Evidence-based medicine in the era of biomarkers: teaching a new dog old tricks? Clin Pharmacol Ther. 2010;88:740–2.PubMedCrossRefGoogle Scholar
  5. 5.
    Erickson DR. Urine markers of interstitial cystitis. Urology. 2001;57:15–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Keay S, Takeda M, Tamaki M, Hanno P. Current and future directions in diagnostic markers in interstitial cystitis. Int J Urol. 2003;10(Suppl):S27–30.PubMedCrossRefGoogle Scholar
  7. 7.
    Clemmensen OJ, Lose G, Holm-Bentzen M, Colstrup H. Skin reactions to urine in patients with interstitial cystitis. Urology. 1988;32:17–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Parsons CL, Stein P. Role of toxic urine in interstitial cystitis. J Urol. 1990;143:373A.Google Scholar
  9. 9.
    Parsons CL, Bautista SL, Stein PC, Zupkas P. Cyto-injury factors in urine: a possible mechanism for the development of interstitial cystitis. J Urol. 2000;164:1381–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Keay S, Zhang CO, Trifillis AL, Hise MK, Hebel JR, Jacobs SC, Warren JW. Decreased 3H-thymidine incorporation by human bladder epithelial cells following exposure to urine from interstitial cystitis patients. J Urol. 1996;156:2073–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Keay S, Zhang CO, Chai T, Warren J, Koch K, Grkovic D, Colville H, Alexander R. Antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor in men with interstitial cystitis versus chronic pelvic pain syndrome. Urology. 2004;63:22–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Keay SK, Szekely Z, Conrads TP, Veenstra TD, Barchi Jr JJ, Zhang CO, Koch KR, Michejda CJ. An antiproliferative factor from interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide. Proc Natl Acad Sci U S A. 2004;101:11803–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Freeman MR, Yoo JJ, Raab G, Soker S, Adam RM, Schneck FX, Renshaw AA, Klagsbrun M, Atala A. Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder. J Clin Invest. 1997;99:1028–36.PubMedCrossRefGoogle Scholar
  14. 14.
    Keay S, Zhang CO, Kagen DI, Hise MK, Jacobs SC, Hebel JR, Gordon D, Whitmore K, Bodison S, Warren JW. Concentrations of specific epithelial growth factors in the urine of interstitial cystitis patients and controls. J Urol. 1997;158:1983–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Keay S, Kleinberg M, Zhang CO, Hise MK, Warren JW. Bladder epithelial cells from patients with interstitial cystitis produce an inhibitor of heparin-binding epidermal growth factor-like growth factor production. J Urol. 2000;164:2112–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang CO, Li ZL, Kong CZ. APF, HB-EGF, and EGF biomarkers in patients with ulcerative vs. non-ulcerative interstitial cystitis. BMC Urol. 2005;5:7.PubMedCrossRefGoogle Scholar
  17. 17.
    Erickson DR, Xie SX, Bhavanandan VP, Wheeler MA, Hurst RE, Demers LM, Kushner L, Keay SK. A comparison of multiple urine markers for interstitial cystitis. J Urol. 2002;167:2461–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Erickson DR, Tomaszewski JE, Kunselman AR, Bentley CM, Peters KM, Rovner ES, Demers LM, Wheeler MA, Keay SK. Do the National Institute of Diabetes and Digestive and Kidney Diseases cystoscopic criteria associate with other clinical and objective features of interstitial cystitis? J Urol. 2005;173:93–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Erickson DR, Tomaszewski JE, Kunselman AR, Stetter CM, Peters KM, Rovner ES, Demers LM, Wheeler MA, Keay SK. Urine markers do not predict biopsy findings or presence of bladder ulcers in interstitial cystitis/painful bladder syndrome. J Urol. 2008;179:1850–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Moskowitz MO, Byrne DS, Callahan HJ, Parsons CL, Valderrama E, Moldwin RM. Decreased expression of a glycoprotein component of bladder surface mucin (GP1) in interstitial cystitis. J Urol. 1994;151:343–5.PubMedGoogle Scholar
  21. 21.
    Byrne DS, Sedor JF, Estojak J, Fitzpatrick KJ, Chiura AN, Mulholland SG. The urinary glycoprotein GP51 as a clinical marker for interstitial cystitis. J Urol. 1999;161:1786–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Akcay T, Konukoglu D. Glycosaminoglycans excretion in interstitial cystitis. Int Urol Nephrol. 1999;31:431–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Hurst RE, Parsons CL, Roy JB, Young JL. Urinary glycosaminoglycan excretion as a laboratory marker in the diagnosis of interstitial cystitis. J Urol. 1993;149:31–5.PubMedGoogle Scholar
  24. 24.
    Wei DC, Politano VA, Selzer MG, Lokeshwar VB. The association of elevated urinary total to sulfated glycosaminoglycan ratio and high molecular mass hyaluronic acid with interstitial cystitis. J Urol. 2000;163:1577–83.PubMedCrossRefGoogle Scholar
  25. 25.
    Erickson DR, Mast S, Ordille S, Bhavanandan VP. Urinary epitectin (MUC-1 glycoprotein) in the menstrual cycle and interstitial cystitis. J Urol. 1996;156:938–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Erickson DR, Sheykhnazari M, Ordille S, Bhavanandan VP. Increased urinary hyaluronic acid and interstitial cystitis. J Urol. 1998;160:1282–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Sant GR, Kempuraj D, Marchand JE, Theoharides TC. The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology. 2007;69:34–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology. 2001;57:47–55.PubMedCrossRefGoogle Scholar
  29. 29.
    Simmons JL, Bunce PL. On the use of an antihistamine in the treatment of interstitial cystitis. Am Surg. 1958;24:664–7.PubMedGoogle Scholar
  30. 30.
    Theoharides TC, Sant GR, El Mansoury M, Letourneau R, Ucci Jr AA, Meares Jr EM. Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. J Urol. 1995;153:629–36.PubMedCrossRefGoogle Scholar
  31. 31.
    Enerback L, Fall M, Aldenborg F. Histamine and mucosal mast cells in interstitial cystitis. Agents Actions. 1989;27:113–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Kastrup J, Hald T, Larsen S, Nielsen VG. Histamine content and mast cell count of detrusor muscle in patients with interstitial cystitis and other types of chronic cystitis. Br J Urol. 1983;55:495–500.PubMedCrossRefGoogle Scholar
  33. 33.
    Lynes WL, Flynn SD, Shortliffe LD, Lemmers M, Zipser R, Roberts LJ, Stamey TA. Mast cell involvement in interstitial cystitis. J Urol. 1987;138:746–52.PubMedGoogle Scholar
  34. 34.
    Holm-Bentzen M, Sondergaard I, Hald T. Urinary excretion of a metabolite of histamine (1,4-methyl-imidazole-acetic-acid) in painful bladder disease. Br J Urol. 1987;59:230–3.PubMedCrossRefGoogle Scholar
  35. 35.
    Boucher W, El Mansoury M, Pang X, Sant GR, Theoharides TC. Elevated mast cell tryptase in the urine of patients with interstitial cystitis. Br J Urol. 1995;76:94–100.PubMedCrossRefGoogle Scholar
  36. 36.
    Okragly AJ, Niles AL, Saban R, Schmidt D, Hoffman RL, Warner TF, Moon TD, Uehling DT, Haak-Frendscho M. Elevated tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor levels in the urine of interstitial cystitis and bladder cancer patients. J Urol. 1999;161:438–41.PubMedCrossRefGoogle Scholar
  37. 37.
    El Mansoury M, Boucher W, Sant GR, Theoharides TC. Increased urine histamine and methylhistamine in interstitial cystitis. J Urol. 1994;152:350–3.PubMedGoogle Scholar
  38. 38.
    Yun SK, Laub DJ, Weese DL, Lad PM, Leach GE, Zimmern PE. Stimulated release of urine histamine in interstitial cystitis. J Urol. 1992;148:1145–8.PubMedGoogle Scholar
  39. 39.
    Erickson DR, Kunselman AR, Bentley CM, Peters KM, Rovner ES, Demers LM, Tomaszewski JE. Is urine methylhistamine a useful marker for interstitial cystitis? J Urol. 2004;172:2256–60.PubMedCrossRefGoogle Scholar
  40. 40.
    Johansson SL, Fall M. Clinical features and spectrum of light microscopic changes in interstitial cystitis. J Urol. 1990;143:1118–24.PubMedGoogle Scholar
  41. 41.
    Spada CS, Krauss AH, Nieves AL, Woodward DF. Effects of leukotrienes B4 (LTB4) and D4 (LTD4) on motility of isolated normodense human eosinophils and neutrophils. Adv Exp Med Biol. 1997;400B:699–706.PubMedGoogle Scholar
  42. 42.
    Venge P. The human eosinophil in inflammation. Agents Actions. 1990;29:122–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Desreumaux P, Nutten S, Colombel JF. Activated eosinophils in inflammatory bowel disease: do they matter? Am J Gastroenterol. 1999;94:3396–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Keppler D, Muller M, Klunemann C, Guhlmann A, Krauss K, Muller J, Berger U, Leier I, Mayatepek E. Transport and in vivo elimination of cysteinyl leukotrienes. Adv Enzyme Regul. 1992;32:107–16.PubMedCrossRefGoogle Scholar
  45. 45.
    Lose G, Frandsen B, Holm-Bentzen M, Larsen S, Jacobsen F. Urine eosinophil cationic protein in painful bladder disease. Br J Urol. 1987;60:39–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Bouchelouche K, Kristensen B, Nordling J, Horn T, Bouchelouche P. Increased urinary leukotriene E4 and eosinophil protein X excretion in patients with interstitial cystitis. J Urol. 2001;166:2121–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Felsen D, Frye S, Trimble LA, Bavendam TG, Parsons CL, Sim Y, Vaughan Jr ED. Inflammatory mediator profile in urine and bladder wash fluid of patients with interstitial cystitis. J Urol. 1994;152:355–61.PubMedGoogle Scholar
  48. 48.
    Lotz M, Villiger P, Hugli T, Koziol J, Zuraw BL. Interleukin-6 and interstitial cystitis. J Urol. 1994;152:869–73.PubMedGoogle Scholar
  49. 49.
    Peters KM, Diokno AC, Steinert BW. Preliminary study on urinary cytokine levels in interstitial cystitis: does intravesical bacille Calmette-Guerin treat interstitial cystitis by altering the immune profile in the bladder? Urology. 1999;54:450–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Martins SM, Darlin DJ, Lad PM, Zimmern PE. Interleukin-1B: a clinically relevant urinary marker. J Urol. 1994;151:1198–201.PubMedGoogle Scholar
  51. 51.
    Lamale LM, Lutgendorf SK, Zimmerman MB, Kreder KJ. Interleukin-6, histamine, and methylhistamine as diagnostic markers for interstitial cystitis. Urology. 2006;68:702–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Ehren I, Hosseini A, Lundberg JO, Wiklund NP. Nitric oxide: a useful gas in the detection of lower urinary tract inflammation. J Urol. 1999;162:327–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Lundberg JO, Ehren I, Jansson O, Adolfsson J, Lundberg JM, Weitzberg E, Alving K, Wiklund NP. Elevated nitric oxide in the urinary bladder in infectious and noninfectious cystitis. Urology. 1996;48:700–2.PubMedCrossRefGoogle Scholar
  54. 54.
    Logadottir YR, Ehren I, Fall M, Wiklund NP, Peeker R, Hanno PM. Intravesical nitric oxide production discriminates between classic and nonulcer interstitial cystitis. J Urol. 2004;171:1148–50.PubMedCrossRefGoogle Scholar
  55. 55.
    Wheeler MA, Smith SD, Saito N, Foster Jr HE, Weiss RM. Effect of long-term oral l-arginine on the nitric oxide synthase pathway in the urine from patients with interstitial cystitis. J Urol. 1997;158:2045–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Smith SD, Wheeler MA, Foster Jr HE, Weiss RM. Urinary nitric oxide synthase activity and cyclic GMP levels are decreased with interstitial cystitis and increased with urinary tract infections. J Urol. 1996;155:1432–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Koskela LR, Thiel T, Ehren I, De Verdier PJ, Wiklund NP. Localization and expression of inducible nitric oxide synthase in biopsies from patients with interstitial cystitis. J Urol. 2008;180:737–41.PubMedCrossRefGoogle Scholar
  58. 58.
    Sant GR. Etiology, pathogenesis, and diagnosis of interstitial cystitis. Rev Urol. 2002;4 Suppl 1:S9–S15.PubMedGoogle Scholar
  59. 59.
    Theoharides TC, Pang X, Letourneau R, Sant GR. Interstitial cystitis: a neuroimmunoendocrine disorder. Ann N Y Acad Sci. 1998;840:619–34.PubMedCrossRefGoogle Scholar
  60. 60.
    Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther. 2002;302:839–45.PubMedCrossRefGoogle Scholar
  61. 61.
    Pang X, Marchand J, Sant GR, Kream RM, Theoharides TC. Increased number of substance P positive nerve fibres in interstitial cystitis. Br J Urol. 1995;75:744–50.PubMedCrossRefGoogle Scholar
  62. 62.
    Marchand JE, Sant GR, Kream RM. Increased expression of substance P receptor-encoding mRNA in bladder biopsies from patients with interstitial cystitis. Br J Urol. 1998;81:224–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Burkman RT. Chronic pelvic pain of bladder origin: epidemiology, pathogenesis and quality of life. J Reprod Med. 2004;49:225–9.PubMedGoogle Scholar
  64. 64.
    Chen Y, Varghese R, Lehrer J, Tillem S, Moldwin R, Kusner L. Urinary substance P is elevated in women with interstitial cystitis. J Urol. 1999;161(4):26.CrossRefGoogle Scholar
  65. 65.
    Kushner L, Chiu PY, Brettschneider N, Lipstein A, Eisenberg E, Rofeim O, Moldwin R. Urinary substance P concentration correlates with urinary frequency and urgency in interstitial cystitis patients treated with intravesical dimethyl sulfoxide and not intravesical anesthetic cocktail. Urology. 2001;57:129.PubMedCrossRefGoogle Scholar
  66. 66.
    Campbell DJ, Tenis N, Rosamilia A, Clements JA, Dwyer PL. Urinary levels of substance P and its metabolites are not increased in interstitial cystitis. BJU Int. 2001;87:35–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Hohenfellner M, Nunes L, Schmidt RA, Lampel A, Thuroff JW, Tanagho EA. Interstitial cystitis: increased sympathetic innervation and related neuropeptide synthesis. J Urol. 1992;147:587–91.PubMedGoogle Scholar
  68. 68.
    Kuo HC, Liu HT, Chancellor MB. Can urinary nerve growth factor be a biomarker for overactive bladder? Rev Urol. 2010;12:e69–77.PubMedGoogle Scholar
  69. 69.
    Jacobs BL, Smaldone MC, Tyagi V, Philips BJ, Jackman SV, Leng WW, Tyagi P. Increased nerve growth factor in neurogenic overactive bladder and interstitial cystitis patients. Can J Urol. 2010;17:4989–94.PubMedGoogle Scholar
  70. 70.
    Liu HT, Tyagi P, Chancellor MB, Kuo HC. Urinary nerve growth factor level is increased in patients with interstitial cystitis/bladder pain syndrome and decreased in responders to treatment. BJU Int. 2009;104:1476–81.PubMedCrossRefGoogle Scholar
  71. 71.
    Liu HT, Tyagi P, Chancellor MB, Kuo HC. Urinary nerve growth factor but not prostaglandin E2 increases in patients with interstitial cystitis/bladder pain syndrome and detrusor overactivity. BJU Int. 2010;106:1681–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997;79:572–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Schnegelsberg B, Sun TT, Cain G, Bhattacharya A, Nunn PA, Ford AP, Vizzard MA, Cockayne DA. Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol. 2010;298:R534–R47.PubMedCrossRefGoogle Scholar
  74. 74.
    Tamm I, Horsefall Jr FL. A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses. J Exp Med. 1952;95:71–97.PubMedCrossRefGoogle Scholar
  75. 75.
    Raffi HS, Bates Jr JM, Laszik Z, Kumar S. Tamm–Horsfall protein acts as a general host-defense factor against bacterial cystitis. Am J Nephrol. 2005;25:570–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Raffi HS, Bates Jr JM, Laszik Z, Kumar S. Tamm–horsfall protein protects against urinary tract infection by proteus mirabilis. J Urol. 2009;181:2332–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Bade JJ, Marrink J, Karrenbeld A, van der WL, Mensink HJ. Increased urinary levels of Tamm–Horsfall glycoprotein suggest a systemic etiology of interstitial cystitis. J Urol. 1996;156:943–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Parsons CL, Stein P, Zupkas P, Chenoweth M, Argade SP, Proctor JG, Datta A, Trotter RN. Defective Tamm–Horsfall protein in patients with interstitial cystitis. J Urol. 2007;178:2665–70.PubMedCrossRefGoogle Scholar
  79. 79.
    Argade SP, Vanichsarn C, Chenoweth M, Parsons CL. Abnormal glycosylation of Tamm–Horsfall protein in patients with interstitial cystitis. BJU Int. 2009;103:1085–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Shingleton WB, Fleischmann J. Urinary interleukin-2 inhibitor and the voiding symptoms in women patients with interstitial cystitis. Semin Urol. 1991;9:120–3.PubMedGoogle Scholar
  81. 81.
    Zuraw BL, Sugimoto S, Parsons CL, Hugli T, Lotz M, Koziol J. Activation of urinary kallikrein in patients with interstitial cystitis. J Urol. 1994;152:874–8.PubMedGoogle Scholar
  82. 82.
    Lutgendorf SK, Kreder KJ, Rothrock NE, Hoffman A, Kirschbaum C, Sternberg EM, Zimmerman MB, Ratliff TL. Diurnal cortisol variations and symptoms in patients with interstitial cystitis. J Urol. 2002;167:1338–43.PubMedCrossRefGoogle Scholar
  83. 83.
    Keay S, Zhang CO, Trifillis AL, Hebel JR, Jacobs SC, Warren JW. Urine autoantibodies in interstitial cystitis. J Urol. 1997;157:1083–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Stein PC, Torri A, Parsons CL. Elevated urinary norepinephrine in interstitial cystitis. Urology. 1999;53:1140–3.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Smooth Muscle Research Center, Department of Clinical Biochemistry, Koege HospitalUniversity of CopenhagenCopenhagenDenmark

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