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76 reviewsCONTEXT AND SIGNIFICANCE Liquid biopsy has emerged as a promising approach for non-invasive diagnostics. In theory, urinary cell-free DNA (ucfDNA) can be used as a completely non-invasive liquid biopsyfor many diseases. UcfDNA comprises transrenal ucfDNA from the bloodstream and those locally shedfrom the urinary tract (i.e., urinary-tract ucfDNA). However, whether these two types of ucfDNA have differentcharacteristics remains to be explored. Ma et al. have demonstrated that transrenal clearance of plasma DNAis preferentially enhanced in open chromatin regions. Furthermore, distinct fragmentation patterns exist between the transrenal and urinary-tract ucfDNA. Capitalizing on such different characteristics of ucfDNA hasallowed the development of a new approach for detecting or monitoring disorders with renal manifestations,including chronic renal diseases, preeclampsia, and urological cancers.