Skip to main content

Advertisement

SpringerLink
Log in

Prospective evaluation of candidate urine and cell markers in patients with interstitial cystitis enrolled in a randomized clinical trial of Bacillus Calmette Guerin (BCG)

  • Original Article
  • Published:
World Journal of Urology Aims and scope Submit manuscript

Abstract

We measured candidate urine biomarkers and bladder cell DNA cytometry in interstitial cystitis (IC) patients randomized to receive intravesical Bacillus Calmette Guerin (BCG) or placebo in a multicenter trial. Participants received 6 weekly instillations and were followed for 34 weeks. Urine was collected at baseline, prior to fourth treatment, and at study end. Antiproliferative factor (APF) activity was determined by 3H-thymidine incorporation assay; heparin-binding epidermal growth factor-like growth factor (HB-EGF) and epidermal growth factor-like growth factor (EGF) levels were determined by ELISA. Cellular DNA content was measured by image analysis to determine the mean hyperdiploid fraction (HDF) of the urine cell pellet. Associations between marker levels, and treatment or symptoms, were examined. Baseline APF positivity rate and mean levels of the other biomarkers were similar to previous smaller studies. During the week 34 follow-up, mean HDF decreased (P = 0.0003) and HB-EGF increased (P < 0.0001); both correlated weakly with decreased urgency. There was no difference in any biomarker between symptom responders and non-responders, but the percentage of responders was low and not significantly different for BCG versus placebo. APF positivity, decreased HB-EGF, increased EGF, and increased HDF were confirmed at baseline in IC patients. Changes in HDF and HB-EGF levels correlated weakly with changes in urgency, but the low BCG response rate prevented identification of additional associations between biomarker changes and treatment or symptoms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Tomaszewski JE, Landis JR, Russack V, Williams TM, Wang LP, Hardy C, Brensinger C, Matthews YL, Abele ST, Kusek JW, Nyberg LM (2001) Interstitial cystitis database study group: biopsy features are associated with primary symptoms in interstitial cystitis: results from the interstitial cystitis database study. Urology 57(6 Suppl 1):67–81

    Article  PubMed  CAS  Google Scholar 

  2. Wilmer A, VanCutsem F, Andrioli A, Tack J, Coremans G, Janssens J (1998) Ambulatory gastrojejunal manometry in severe motility-like dyspepsia: lack of correlation between dysmotility, symptoms, and gastric emptying. Gut 42:235–242

    Article  PubMed  CAS  Google Scholar 

  3. Bosch JL, Hop WC, Kirkels WJ, Schroder FH (1995) The International Prostate Symptom Score in community-based sample of men between 58 and 74 years of age: prevalence and correlation of symptoms with age, prostate volume, flow rate, and residual urine volume. Br J Urol 75:622–630

    PubMed  CAS  Google Scholar 

  4. Nichols KK, Nichols JJ, Mitchell GL (2004) The lack of association between signs and symptoms of dry eye disease. Cornea 23:762–770

    Article  PubMed  Google Scholar 

  5. Nichol G, Llewellyn-Thomas HA, Thiel EC, Naylor CD (1996) The relationship between cardiac functional capacity and patient’s symptom-specific utilities for angina: some findings and methodologic lessons. Med Decis Making 16:78–83

    Article  PubMed  CAS  Google Scholar 

  6. Mayer R, Propert KJ, Peters KM, Mayer R, Propert KJ, Peters KM, Payne CK, Zhang Y, Burks D, Culkin DJ, Diokno A, Hanno P, Landis JR, Madigan R, Messing EM, Nickel JC, Sant GR, Warren J, Wein AJ, Kusek JW, Nyberg LM, Foster HE (2005) Interstitial Cystitis Clinical Trials Group: a randomized controlled trial of intravesical bacillus Calmette Guerin for treatment refractory interstitial cystitis. J Urol 173:1186–1191

    Article  PubMed  Google Scholar 

  7. Keay S, Zhang CO, Trifillis AL, Hise MK, Hebel JR, Jacobs SC, Warren JW (1996) Decreased 3H-thymidine incorporation by human bladder epithelial cells following exposure to urine from interstitial cystitis patients. J Urol 156:2073–2078

    Article  PubMed  CAS  Google Scholar 

  8. Keay S, Zhang CO, Kagen DI, Hise MK, Jacobs SC, Hebel JR, Gordon D, Whitmore K, Bodison S, Warren JW (1997) Concentrations of specific epithelial growth factors in the urine of interstitial cystitis patients and controls. J Urol 158:1983–1988

    Article  PubMed  CAS  Google Scholar 

  9. Keay S, Zhang CO, Hise MK, Hebel JR, Jacobs SC, Gordon D, Whitmore K, Bodison S, Gordon N, Warren JW (1998) A diagnostic in vitro assay for interstitial cystitis. Urology 52(6):974–978

    Article  PubMed  CAS  Google Scholar 

  10. Keay SK, Zhang CO, Shoenfelt J, Erickson DR, Whitmore K, Warren JW, Marvel R, Chai T (2001) Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Urology 57(6 Suppl 1):9–14

    Article  PubMed  CAS  Google Scholar 

  11. Erickson DR, Xie SX, Bhavanandan VP, Wheeler MA, Hurst RE, Demers LM, Kushner L, Keay SK (2002) A comparison of multiple urine markers for interstitial cystitis. J Urol 167:2461–2469

    Article  PubMed  CAS  Google Scholar 

  12. Zhang CO, Li ZL, Kong CZ (2005) APF, HB-EGF, and EGF biomarkers in patients with ulcerative vs. non-ulcerative interstitial cystitis. BioMed Central Urol 5:7

    Google Scholar 

  13. Bushman W, Goolsby C, Grayhack JT, Schaeffer AJ (1994) Abnormal flow cytometry profiles in patients with interstitial cystitis. J Urol 152:2262–2266

    PubMed  CAS  Google Scholar 

  14. Rashid HH, Reeder JE, O’Connell MJ, Zhang CO, Messing EM, Keay SK (2004) Interstitial cystitis antiproliferative factor (APF) as a cell-cycle modulator. BioMed Central Urol 4:3

    Google Scholar 

  15. Gillenwater JY, Wein AJ (1988) Summary of the National Institute of Arthritis, Diabetes,Digestive and Kidney Diseases workshop on interstitial cystitis, NIH, Bethesda, Maryland August 28–29, 1987. J Urol 140:203–206

    PubMed  CAS  Google Scholar 

  16. Leppilahti M, Hellstrom P, Tammela TL (2002) Effect of diagnostic hydrodistension and four intravesical hyaluronic acid instillations on bladder ICAM-1 intensity and association of ICAM-1 intensity with clinical response in patients with interstitial cystitis. Urology 60:46–51

    Article  PubMed  Google Scholar 

  17. Erickson DR, Kunselman AR, Bentley CM, Peters KM, Rovner ES, Demers LM, Tomaszewski JE (2004) Is urine methylhistamine a useful marker for interstitial cystitis? J Urol 172:2256–2260

    Article  PubMed  Google Scholar 

  18. Erickson DR (2001) Urine markers of interstitial cystitis. Urology 57(Suppl 6A):15–21

    Article  PubMed  CAS  Google Scholar 

  19. Wheeler MA, Smith SD, Saito N, Foster HE Jr, Weiss RM (1997) Effect of long-term oral l-arginine on the nitric oxide synthase pathway in the urine from patients with interstitial cystitis. J Urol 158:2045–50

    Article  PubMed  CAS  Google Scholar 

  20. Erickson DR, Kunselman AR, Bentley CM, Peters KM, Rovner ES, Wheeler MA, Demers LM, Keay SK (2003) Changes in urine markers and symptom scores after bladder distention for interstitial cystitis. In: NIDDK/ICA international research symposium: research insights into interstitial cystitis, October 31, 2003 (abstract)

  21. Ehren I, Lundberg JO, Adolfsson J, Wiklund NP (1998) Effects of l-arginine treatment on symptoms and bladder nitric oxide levels in patients with interstitial cystitis. Urology 52:1026–1029

    Article  PubMed  CAS  Google Scholar 

  22. Chai TC, Zhang CO, Shoenfelt JL, Johnson HW Jr, Warren JW, Keay S (2000a) Bladder stretch alters urinary heparin-binding epidermal growth factor and antiproliferative factor in patients with interstitial cystitis. J Urol 163:1440–1444

    Article  PubMed  CAS  Google Scholar 

  23. Chai TC, Zhang C-O, Warren JW, Keay S (2000b) Percutaneous sacral third nerve root neurostimulation improves symptoms and normalizes urinary HB-EGF levels and antiproliferative activity in patients with interstitial cystitis. Urology 55:643–646

    Article  PubMed  CAS  Google Scholar 

  24. Keay S, Kleinberg M, Zhang C-O, Hise MK, Warren JW (2000) Bladder epithelial cells from interstitial cystitis patients produce an inhibitor of HB-EGF production. J Urol 64:2112–2118

    Google Scholar 

  25. Mulholland SG, Hanno P, Parsons CL, Sant GR, Staskin DR (1990) Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology 35:552–558

    Article  PubMed  CAS  Google Scholar 

  26. Sant GR, Propert KJ, Hanno PM, Burks D, Culkin D, Diokno AC, Hardy C, Landis JR, Mayer R, Madigan R, Messing EM, Peters K, Theoharides TC, Warren J, Wein AJ, Steers W, Kusek JW, Nyberg LM (2003) Interstitial Cystitis Clinical Trials Group: a pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol 170:810–815

    Article  PubMed  CAS  Google Scholar 

  27. Gregory H, Holmes JE, Willshire IR (1977) Urogastrone levels in the urine of normal adult humans. J Clin Endocrinol Metab 45:668–672

    Article  PubMed  CAS  Google Scholar 

  28. Fisher DA (1988) Epidermal growth factor in the developing mammal. Mead Johnson Symp Perinatal Dev Med 32:33–40

    Google Scholar 

  29. Perheentupa J, Lakshmanan J, Fisher DA (1985) Urine and kidney epidermal growth factor: ontogeny and sex difference in the mouse. Pediatr Res 19:428–432

    Article  PubMed  CAS  Google Scholar 

  30. Tuomela T, Viinikka L, Perheentupa J (1990) Epidermal growth factor in mice: changes during circadian and female reproductive cycles. Acta Endocrinol (Copenhagen) 123:643–648

    CAS  Google Scholar 

  31. Kurachi H, Oka T (1985) Changes in epidermal growth factor concentrations of submandibular gland, plasma, and urine of normal and sialoadrenectomized female mice during various reproductive stages. J Endocrinol 106:197–202

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the other members of the Interstitial Cystitis Clinical Trials Group for their contribution to patient specimen collections. This study was supported by cooperative agreements U01 DK54108, U01 DK54125, U01 DK54127, U01 DK54133, U01 DK54138, and U01 DK54158 from the National Institute for Diabetes and Digestive and Kidney Diseases, and the University of Maryland General Clinical Research Center Grant M01 RR 16500, General Clinical Research Centers Program, National Center for Research Resources (NCRR), National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Maryland School of Medicine, 10 N. Greene Street, Baltimore, MD, 21201, USA

    Susan Keay, Jay E. Reeder, Kristopher Koch, Chen-Ou Zhang, Daivd Grkovic, Kenneth Peters, Yawei Zhang, John W. Kusek, Lee M. Nyberg, Christopher K. Payne & Kathleen J. Propert

Authors
  1. Susan Keay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jay E. Reeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristopher Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen-Ou Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daivd Grkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenneth Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yawei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John W. Kusek
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lee M. Nyberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher K. Payne
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kathleen J. Propert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan Keay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keay, S., Reeder, J.E., Koch, K. et al. Prospective evaluation of candidate urine and cell markers in patients with interstitial cystitis enrolled in a randomized clinical trial of Bacillus Calmette Guerin (BCG). World J Urol 25, 499–504 (2007). https://doi.org/10.1007/s00345-007-0205-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00345-007-0205-4

Keywords

Search

Navigation