Therapeutic potential of tubular serine protease inhibitors in proteinuria

Proteinuria is both a predictor and mediator of chronic kidney disease (CKD) progression, but treatment options targeting its underlying mechanisms are limited. Emerging evidence suggests that aberrantly filtered serine proteases contribute to the pathogenesis of proteinuria and progressive kidney injury through multiple pathways, including podocyte injury, inappropriate activation of the epithelial sodium channel (ENaC), and tubular complement activation. Serine protease inhibitors, such as aprotinin, camostat mesylate, and nafamostat mesylate, as well as off-target effects of amiloride, have shown promise in preclinical and early clinical studies by mitigating these pathological processes. These drugs reduce proteinuria, sodium retention, oxidative stress, inflammation, and fibrosis. However, clinical translation is hindered by limited data from controlled trials, varying pharmacokinetics, and concerns about systemic adverse effects and long-term safety. Endogenous serine protease inhibitors help maintain proteolytic balance in the kidneys, but their capacity may be overwhelmed in proteinuria. Although complete inhibition could disrupt essential functions, pharmacologic modulation of tubular serine protease activity may be a more effective strategy by preserving beneficial activity while limiting pathological effects. This review synthesizes current knowledge on the pathophysiological role of tubular serine proteases and evaluates the therapeutic potential of their inhibition as a potential target in proteinuric diseases. We identify key knowledge gaps, including the need for mechanistic pharmacodynamic trials, biomarker-guided patient selection using urinary serine protease activity, and long-term efficacy and safety studies. Serine protease inhibitors are a promising, underexplored therapeutic strategy in proteinuric conditions that may complement existing treatments by targeting specific pathogenic mechanisms involved in disease progression.