Proteasuria: extending an existing term into a framework for concentration-based and catalytic protease diagnostics...

Proteases are central to cancer pathobiology and attractive targets for noninvasive diagnosis. Diagnostic use of urinary proteases has developed along two methodologically distinct streams: measurement of protein abundance by immunoassay and increasingly by mass spectrometry, and direct measurement of enzymatic activity using peptide substrates. However, no common terminology unifies these approaches. This narrative review synthesizes evidence published between 2016 and 2026, concentrating on urine and, for the transferability of the methodology, on fecal water and serum. Saliva and seminal fluid are surveyed only to show that protease biomarkers there are measured by abundance alone. It adopts, from its existing use in nephrology, the term proteasuria as a unifying construct for the urinary protease diagnostic field, proposing a wider scope than the pathophysiological sense in which it was introduced. Two operational subtypes are defined: concentration-based and catalytic proteasuria. The distinction rests on the parameter measured rather than on the detection chemistry. Within the catalytic subtype single-enzyme detection using a selective substrate is distinguished from disease profiling using a multi-substrate panel. Evidence was identified by a PubMed search supplemented by citation and semantic search and screened by a single reviewer without protocol registration or formal risk-of-bias assessment. Concentration-based proteasuria is the clinically established stream, yet no urinary analyte has displaced cystoscopy, and approved assays remain insufficient as stand-alone rule-out or triage tests. The catalytic stream rests mainly on small single-center case-control studies reporting activity qualitatively; only one reports formal diagnostic performance, with a single elastase-specific substrate in 12 cases and 24 controls, and no head-to-head comparison with concentration-based assays has been published. Analytical validity is partial: substrate selectivity is established by combinatorial screening and confirmed with inhibitor and orthogonal controls, but precision, limits of quantification in urine and inter-laboratory reproducibility are not systematically reported, and no reference material or external quality-assessment scheme exists for this assay class. A largely independent exogenous stream of synthetic urinary biomarkers and activity-based nanosensors reports high accuracy, but all published diagnostic-accuracy data derive from animal models. On a translational-readiness scale the urinary catalytic stream is proof-of-concept, research-grade work, and any realistic target is therefore not cystoscopy but the margin at which established assays fail, principally low-grade noninvasive disease. The same reasoning identifies the detection of advanced adenoma, for which the fecal immunochemical test performs poorly, as the concrete benchmark for extending the framework to fecal protease profiling in colorectal cancer.