Validation of the diagnostic utility of urinary midkine for the detection of bladder cancer

As it has been demonstrated previously that midkine (also known as neurite growth-promoting factor 2) protein levels in urine of bladder cancer (BCa) patients are increased compared to healthy controls, the present study validated the diagnostic utility of midkine in an independent patient cohort and compared the observed values with voided urine cytology (VUC), which is the current reference standard for non-invasive diagnosis of BCa. Voided urine samples were prospectively collected from 92 BCa patients and 70 control subjects. Protein levels of midkine were assessed using a commercially available enzyme-linked immunosorbent assay and normalized to urinary creatinine. The diagnostic performance of urinary midkine was evaluated by receiver operating characteristic curves. The best combinations of sensitivities and specificities were determined by Youden's Index. Midkine concentrations were significantly elevated in urine samples from BCa patients compared to controls (P<0.001; Mann-Whitney U Test). The level of midkine was associated with disease progression, with the highest concentrations in urine specimens of patients with pT1 and ≥pT2a, as well as high-grade tumors (P<0.001; Mann-Whitney U test). Sensitivities of urinary midkine and VUC were 69.7 and 87.6%, respectively. The corresponding specificities for midkine and VUC were 77.9 and 87.7%, respectively. The combined use of VUC and midkine improved the sensitivity to 93.3%, but reduced the specificity to 66.2%. Despite its reduced discriminatory power for low-grade and low-stage BCa, urinary midkine can be utilized for the identification of high-grade pT1 and ≥pT2a tumors. This means that midkine may potentially be suitable for the identification of patients with high risk BCa.