Urinary Biomarkers in the Evaluation of Primary Hematuria: A Systematic Review and Meta-Analysis

Abstract

Introduction: Urinary biomarkers are entering the clinical landscape as a non-invasive method to evaluate patients for bladder cancer, however it is currently predominantly used in the surveillance setting. The use of biomarkers in the setting of primary hematuria is not widespread despite initial promising results. This study comprehensively reviews the literature on the diagnostic performance of FDA-approved biomarkers in the evaluation of primary hematuria.Methods: According to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement, MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, HTA database, Google Scholar and Web of Science were searched up to June 2017 for studies assessing the diagnostic accuracy of FDA-approved urinary biomarkers amongst patients presenting with primary hematuria. The quality of included studies was assessed using the QUADAS-2 tool.Results: Fourteen studies met the pre-specified eligibility criteria and were included for analysis. The biomarkers assessed in these studies were AssureMDx, Bladder tumor antigen, CxBladder, NMP22, UroVysion and uCyt+. Across these four biomarkers, the sensitivity ranged from 0.67 to 0.95, and specificity from 0.68 to 0.93, respectively. There was significant heterogeneity between the included studies. Limited head-to-head comparison with urine cytology demonstrated that in general, the biomarkers have superior sensitivity but inferior specificity. Overall, the quality of evidence was graded as moderate primarily because of inadequate blinding.Conclusion: The current diagnostic performance of biomarkers are inadequate to replace cystoscopy in the primary hematuria setting. However, AssureMDx in particular may have a role as a triage test for cystoscopy but further prospective data is required to validate these findings. Given the current evidence, the use of these markers as an adjunct to cystoscopy for the evaluation of hematuria should be considered investigational.

Urinary Biomarkers in Bladder Cancer: Where Do We Stand and Potential Role of Extracellular Vesicles

“…There are two approved versions of this test for BCa follow-up in concurrent use with cystoscopy, the BTA TRAK and the BTA Stat (Polymedco Inc., Cortlandt Manor, New York, USA) [ 63 ]. In different reviews and meta-analysis, the BTA Stat has a sensitivity and specificity of 64% and 77%, respectively, whereas the BTA Trak has 65% and 74%, respectively [ 64 , 65 , 66 ]. The sensitivity was higher in the diagnosis of symptomatic patients rather than in follow-up, but with similar specificity.…”

“…The sensitivity was higher in the diagnosis of symptomatic patients rather than in follow-up, but with similar specificity. Both tests demonstrated higher sensitivity than urinary cytology, despite the decreased specificity in conditions where the complement factor H related protein is present, such as in other genitourinary malignancies and benign conditions with hematuria, including lithiasis, inflammation, instrumentation, and intra-vesical therapies [ 31 , 64 , 65 , 66 , 80 ].…”

“…Sensitivity varies between 83% and 85% and specificity between 75% and 87%. These are higher in primary diagnosis than follow-up [ 28 , 64 , 65 , 70 ]. Mowatt et al [ 28 ] compared uCyt+ ™ with urinary cytology and showed that this test presented higher sensitivity (82% versus 44%) and lower specificity (85% versus 94%), respectively.…”

Comparison of the performances of the ADXBLADDER test and urinary cytology in the follow‐up of non‐muscle‐invasive bladder cancer: a blinded prospective multicentric study

“…Urine cytology in conjunction with cystoscopy is considered to be the 'gold standard' and is recommended in the European Guidelines for high‐risk non‐muscle‐invasive bladder cancer (NMIBC). The excellent specificity of urine cytology is well documented; however, the reported sensitivity has been extremely variable [2]. Whilst, historically, cytology was thought to have good sensitivity for high‐grade disease, with reported sensitivities of between 38% and 84% [3], recently, larger multicentric studies have demonstrated much lower sensitivities, with a prospective study of 1016 patients demonstrating an overall sensitivity of 22%, 13% for low‐grade tumours, 23% for high‐grade tumours and 25% for high‐risk tumours [4,5].…”

Non-invasive diagnosis of urinary bladder cancer

“…UroVysion was developed as an adjunct to cytology and is a fluorescence in-situ hybridisation (FISH) analysis of urine cytology, which detects specific genetic amplifications in urothelial cells. Sensitivity is better than for cytology, but still too low to be used to exclude further investigations, and it still suffers from a high inter-observer variability [4]. Recently, newer mRNAand epigenetic-based assays have been reported and made commercially available.…”