Urinary extracellular vesicle proteins for biomarker discovery in chronic kidney disease

Chronic kidney disease (CKD) is a progressive condition characterized by declining kidney function principally driven by diabetes mellitus, glomerulonephritis, and hypertension. Although renal biopsy is the gold standard for diagnosing CKD, its invasive nature restricts its use for early detection and routine clinical applications. Current noninvasive biomarkers, including the estimated glomerular filtration rate and albumin-to-creatinine ratio, are useful indicators of kidney dysfunction but fall short in specificity and sensitivity required to distinguish between CKD subtypes, including diabetic kidney disease and glomerulonephritis. Recently, urinary extracellular vesicles (uEVs), nano-sized lipid bilayer entities ranging from 30 to 1,000 nm in diameter and secreted by renal cells, have emerged as promising biomarkers for CKD. uEVs encapsulate a diverse array of proteins, nucleic acids, and lipids that mirror kidney pathophysiology, presenting a noninvasive means to assess disease progression, inflammation, fibrosis, and oxidative stress within the urinary system. Furthermore, uEVs offer a molecular fingerprint of kidney health, positioning them as potential tools for precision medicine. This review explores the diagnostic potential of uEVs, underscoring the need for standardization in urine collection, normalization techniques, and uEV isolation methodologies. We also highlight uEV-based biomarkers that distinguish various CKD subtypes and mirror pathological changes within the kidneys and urogenital system. As molecular proxies of their cells of origin, uEVs hold significant promise in enhancing CKD diagnostics to enable early detection, disease classification, and the development of novel therapeutic strategies.