The Addition of Urinary Urokinase-Type Plasminogen Activator to Urinary Nuclear Matrix Protein 22 and Cytology Improves the Detection of Bladder Cancer

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Abstract
We have previously reported that urinary urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are elevated in patients with bladder cancer. In the current study we tested the hypothesis that urinary uPA and uPAR would add to the predictive ability of urinary nuclear matrix protein 22 (NMP22) and cytology for the diagnosis of bladder cancer. Urinary uPA, uPAR and NMP22 were measured in voided specimens obtained before cystoscopy in 229 consecutive subjects at risk for transitional cell carcinoma (TCC), of whom 122 (53%) were found to have bladder TCC. Bladder washout samples for cytology were also collected in 191 subjects. Associations with TCC were tested by logistic regression. Nonparametric ROC curves were generated and AUCs were compared. Urinary uPA, uPAR and NMP22 were higher in patients with TCC than in controls (p <0.001, 0.016 and <0.001, respectively), while uPA (test for trend p = 0.018) was associated with the risk of TCC after adjusting for NMP22 (p = 0.028), urinary cytology (p <0.001), age (p = 0.107) and uPAR (test for trend p = 0.756). The overall AUC for determining TCC was not different between uPA and NMP22 (0.746 and 0.714, p = 0.092). However, in the high sensitivity region of the ROC curve the AUC of uPA was larger than that of NMP22. Adding uPA to NMP22 and cytology improves their ability to predict bladder TCC by a statistically and prognostically substantial margin. An approach using multiple biomarkers may improve the diagnostic accuracy of voided urinary diagnostic tests.