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 β2-microglobulin (uBMG) and α1-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®), 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.

The authors have declared no competing interest.

Kandai Nozu receives the Grants-in-Aid for Scientific Research (KAKENHI, 23K07698), Childhood-onset, rare and intractable kidney diseases in Japan, Research on rare and intractable diseases, Health, Labour and Welfare Sciences Research Grants (23FC1047), the Japan Agency for Medical Research and Development (AMED) (Grant Number 24015773 and 22810094 and 23ek0109617s1702)

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This study was approved by the Institutional Review Board of Kobe University Graduate School of Medicine (IRB No. 301, B230224) and adhered to the ethical guidelines of the Japanese Ministry of Health, Labor and Welfare, and the Declaration of Helsinki.

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All data supporting the findings of this study are available from the corresponding author upon reasonable request. SomaScan proteomic data, processed urinary myoglobin measurements, and associated clinical metadata will be shared in a de-identified form for non-commercial academic purposes.