Proteomic Discovery of Urinary Myoglobin as a Noninvasive Biomarker for PROCHOB caused by CUBN Variants

Chronic benign proteinuria (PROCHOB), caused by biallelic pathogenic variants in CUBN, presents in childhood as isolated, asymptomatic tubular proteinuria with preserved long-term kidney function. Because its clinical presentation closely mimics early stage glomerular diseases with moderate proteinuria and without increased urinary {beta}2-microglobulin (uBMG) and 1-microglobulin, numerous patients undergo unnecessary kidney biopsies and receive angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers before genetic testing is considered. Using high-throughput aptamer-based urinary proteomics (SomaScan(R)), we identified urinary myoglobin as a disease-specific biomarker for PROCHOB. We developed and confirmed a diagnostic approach in which the urinary myoglobin-to-creatinine (uMB/Cr) ratio robustly distinguishes PROCHOB from other moderate glomerular proteinuric kidney diseases. Although certain cases of Dent disease causing megalin dysfunction exhibit increased urinary myoglobin levels, PROCHOB and Dent disease can be clearly distinguished based on the uBMG-to creatinine ratio. This biomarker reflects impaired proximal tubular protein reabsorption because of cubilin dysfunction and remains normal in healthy individuals or those with typical glomerular diseases with moderate proteinuria. Our findings establish a noninvasive diagnostic tool for PROCHOB that prompts targeted genetic testing for CUBN variants using the uMB/Cr and urinary uBMG-to-creatinine ratios. This strategy has the potential to transform the clinical diagnostic pathway for isolated proteinuria.