Frontiers in noninvasive diagnosis of kidney transplant rejection: from molecular messengers to functional imaging

Abstract

Kidney transplantation remains the optimal treatment for end-stage renal disease, but long-term allograft survival is threatened by immune-mediated rejection, particularly subclinical forms. Traditional monitoring relying on serum creatinine and invasive biopsy is limited by delayed sensitivity, procedural risks, and sampling error. This review synthesizes recent advances in noninvasive diagnostics, focusing on two complementary pathways: liquid biopsy and functional imaging. Liquid biopsy, utilizing biomarkers such as do-nor-derived cell-free DNA and urinary chemokines CXCL9/CXCL10, enables real-time, sensitive detection of graft injury and immune activation prior to overt structural damage. Functional imaging techniques, including ultrasound elastography and multiparametric magnetic resonance imaging, provide macroscopic quantification of tissue properties such as stiffness, perfusion, and oxygenation. Furthermore, the emerging paradigm of multimodal integration, powered by artificial intelligence, combines molecular and imaging data to enable precise risk stratification, digital pathology, and virtual biopsy models. Although challenges in cost-effectiveness and standardization persist, the development of a tiered, noninvasive diagnostic framework promises to minimize reliance on invasive procedures. This approach facilitates early detection and precise management of rejection, ultimately improving long-term graft outcomes.