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Keywords:

  • bladder outlet obstruction;
  • diagnosis;
  • obstructive uropathy;
  • transforming growth factor-β1;
  • urinary obstruction;
  • urodynamics

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Abstract Background: Urinary transforming growth factor-β1 (TGF-β1) levels have been shown to correlate with elevated intrapelvic pressure associated with ureteropelvic junction obstruction. Other studies have evaluated urinary TGF-β1 levels in prostate cancer. This study tests the hypothesis that urinary TGF-β1 levels might correlate with objective measures of bladder outlet obstruction (BOO).

Methods: Twenty-three men (age: 46–85 years) with lower urinary tract symptoms underwent urodynamic studies consisting of non-invasive uroflowmetry, cystometrogram and voiding pressure flow studies. Patients were classified as obstructed (n = 17) or not obstructed (n = 6) based on Abrams-Griffith nomograms. Urinary TGF-β1 was extracted from an aliquot of urine obtained at the time of bladder catheterization for urodynamic studies. Urinary TGF-β1 levels were then determined by enzyme-linked immunosorbent assay (ELISA).

Results: There was a strong correlation between urinary TGF-β1 levels and the presence of obstruction by Abrams-Griffith nomogram criteria (P = 0.025). Urinary TGF-β1 levels were significantly higher in men with obstruction (0.039 ± 0.011 pg/mL) than in men without obstruction (0.029 ± 0.009 pg/mL; P = 0.036).

Conclusion: Urinary TGF-β1 levels correlate with objective measures of BOO. Further study is needed to test the utility of urinary TGF-β1 as a non-invasive diagnostic tool for BOO.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Transforming growth factor-β1 (TGF-β1) is a multifunctional polypeptide growth factor. Its function varies depending on cell type and growth conditions. It is a member of a family of regulatory proteins including activins, inhibins and bone morphogenetic proteins (BMP).

Transforming growth factor-β1 is known to be upregulated after injury that alters the collagen balance in the extracellular matrix. It is usually an inhibitor of proliferation, but may pathologically increase net proliferation by increasing collagen production, decreasing collagenolysis and increasing binding of matrix proteins.

In the kidney, TGF-β1 is elicited primarily at the level of the tubules and to a lesser extent at the glomerular level. There has been growing interest in the possible role of TGF-β1 in pathological conditions of the urinary tract, namely, obstructive uropathy. A non-invasive marker for bladder outlet obstruction (BOO) would have important clinical applications in assisting with diagnosis, stratification of interventions and monitoring of therapeutic response. We attempted to correlate the urinary concentration of TGF-β1 with the presence of BOO in the hope of identifying a non-invasive clinical marker.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Following Institutional Review Board approval and informed consent, 23 men with lower urinary tract symptoms underwent urodynamic studies consisting of non-invasive uroflowmetry, cystometrogram and voiding pressure flow studies. An aliquot of urine obtained at the time of bladder catheterization for urodynamic studies was collected to measure urinary TGF-β1 levels. Samples were stored at –80 C before reconstitution and assay.

Voiding pressure flow studies were performed using the Dantec Minuet system (Dantec Medical Inc., Allendale, NJ, USA). A 9-Fr transurethral dual-lumen urodynamic catheter (Lifetech Inc., Stafford, TX, USA) was used and bladder filling performed with saline at a rate of 30 mL/min. Patients were classified as either obstructed (high-pressure, low-flow on invasive urodynamic studies) or not obstructed based on the Abrams-Griffith nomogram. Patient characteristics are summarized in Table 1. Patients with equivocal findings on the Abrams-Griffith nomogram were excluded from this study.

Table 1.  Patient characteristics
No. patients23
Age (years)
Mean63.3
Range46.0–85.0
AUA symptom score
Mean22.1
Range15.0–32.0
Maximal flow rate (Qmax: cm3/s)
Mean10.9
Range 6.5–19.3
Maximal detrusor pressure (cm H2O)
Mean65.2
Range49.0–117.0

Urinary TGF-β1 was extracted with the Sepralyte kit (Analytichem International, Harbor City, CA, USA).1 Urinary TGF-β1 levels were then evaluated with the Predicta® ELISA TGF-β1 kit (Genzyme Corporation, Cambridge, MA, USA). The TGF-β1 immunoassay samples were activated and tested according to tissue culture instructions. Reagents and standards were prepared according to kit instructions. Optical density was determined at 450 nm.

Statistical analyses were performed using the InStat statistics program (GraphPAD software, San Diego, CA, USA) to compare the data obtained from two different patient populations by Student’s t-test and correlation coefficient. P-values < 0.05 were considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

A statistically significant correlation was found between BOO and TGF-β1 concentrations in urine (P = 0.025; Fig. 1). Six patients were classified as non-obstructed using the Abrams-Griffith nomogram, while 17 patients were obstructed. Urinary TGF-β1 levels were significantly higher in men with obstruction (0.039 ± 0.011 pg/mL) than in those who were unobstructed (0.029 ± 0.009 pg/mL; Fig. 2; P = 0.036).

image

Figure 1. Correlation between degree of obstruction (maximum detrusor pressure/maximum urinary flow rate) and levels of TGF-β1 (pg/mL; P = 0.025).

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image

Figure 2. Urinary TGF-β1 levels are significantly higher in obstructed patients (▪, n = 17) compared to non-obstructed patients (□, n = 6; P = 0.036).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Transforming growth factor-β1 is associated with pathological obstruction of the upper urinary tract. In animal models, up-regulation of TGF-β1 mRNA was seen to be associated with fibrinogenesis and apoptosis of normal cells after experimental obstruction was induced.2,3

Seremitis et al.4 showed that TGF-β1 is upregulated at the transcription level in the renal pelvis of children with ureteropelvic junction (UPJ) obstruction. Palmer et al.5 also demonstrated high concentrations of urinary TGF-β1 in the renal pelvis of children with UPJ obstruction. One weakness of our study is that upper tract imaging was not performed to exclude an upper tract obstruction as a source of urinary TGF-β1. However, upper tract imaging is not routinely obtained for men with lower urinary tract symptoms and all the men studied had normal serum creatinine levels and no flank pain.

Transforming growth factor-β1 has also been implicated in diseases of the prostate. Retrovirally induced TGF-β1 was found to cause benign growth abnormalities in mouse prostatic cells.6 It has also been shown in the extracellular matrix of adenocarcinoma of the prostate. Finally, Perry et al.7 showed that urinary TGF-β1 levels were increased in patients with prostate cancer. However, they did not correlate levels with obstructive symptomatology.

We hypothesized that if renal obstruction has been shown to correlate with increased levels of TGF-β1 and if TGF-β1 has been shown to induce benign prostatic hyperplasia in an animal model, then TGF-β1 may be useful as a non-invasive marker for BOO. Results from a recent study by Dell et al.8 showed increased excretion of urinary TGF-β1 in children with posterior urethral valves relative to healthy controls. We have identified a close correlation between TGF-β1 levels in the urine and objective measures of obstruction involving invasive urodynamic studies. Future prospective studies with larger sample sizes will be needed to determine whether urinary TGF-β1 levels will be sufficiently accurate to discriminate between obstructed and non-obstructed patients without the need for invasive urodynamics. Further studies should also include men with equivocal findings on urodynamic studies.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References

Urinary TGF-β1 levels correlate with objective measurements of BOO. Further studies with larger sample sizes are needed to confirm the utility of TGF-β1 as a non-invasive marker for outlet obstruction.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. References
  • 1
    Ranganathan G, Lyons R, Jiang NS, Moses H. Transforming growth factor type b in normal human urine. Biochem. Biophys. Res. Commun. 1987; 148 (3): 150312.
  • 2
    Walton G, Buttyan R, Garcia-Montes E, Olsson CA, Hensle TW, Sawczuk IS. Renal growth factor expression during the early phase of experimental hydronephrosis. J. Urol. 1992; 148 (2 Part 2): 5104.
  • 3
    Kanet H, Morrissey J, Klahr S. Increased expression of TGF-beta1 mRNA in the obstructed kidney of rats with unilateral ureteral ligation. Kidney Internat. 1993; 44: 31321.
  • 4
    Seremitis GM & Maizels M. TGF-beta mRNA expression in the renal pelvis after experimental and clinical ureteropelvic junction obstruction. J. Urol. 1996; 156: 2616.
  • 5
    Palmer LS, Maizels M, Kaplan WE, Firlit CF, Cheng EY. Urine levels of transforming growth factor-beta 1 in children with ureteropelvic junction obstruction. Urology 1997; 50: 76973.
  • 6
    Timme TL, Yang G, Rogers E et al. Retroviral transduction of transforming growth factor-β1 induces pleiotropic benign prostatic growth abnormalities in mouse prostate reconstitutions. Lab. Invest. 1996; 74: 74760.
  • 7
    Perry KT, Anthony CT, Case T, Steiner MS. Transforming growth factor beta as a clinical biomarker for prostate cancer. Urology 1997; 49: 1515.
  • 8
    Dell KM, Hoffman BB, Leonard MB, Ziyadeh FN, Schulman SL. Increased urinary transforming growth factor-beta1 excretion in children with posterior urethral valves. Urology 2000; 56: 3114.