Transition from acute kidney injury to chronic kidney disease: molecular mechanisms and therapeutic interventions

Abstract

Acute kidney injury (AKI) is now more frequently recognized as a crucial driver of chronic kidney disease (CKD) rather than merely a curable clinical event. The progression from AKI to CKD (AKI-CKD) mainly results from inadequate adaptive repair mechanisms, which cause ongoing structural damage and a gradual deterioration in kidney function. Here, we systematically dissect the pathological mechanisms underlying this process, with particular emphasis on persistent cell cycle arrest, cellular senescence, chronic infiltration of immune cells, and capillary rarefaction. Leveraging recent advancements in single-cell and spatial omics, we highlight how distinct tubular epithelial cell (TEC) states and aberrant cell–cell interactions orchestrate a profibrotic niche marked by prolonged fibroblast activation and excessive accumulation of extracellular matrix (ECM). Central to these processes is the improper activation of crucial signaling pathways, such as transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic homolog (Smad), Wnt/β-catenin, and Hedgehog signaling, accompanied by profound metabolic reprogramming and epigenetic remodeling. We also summarize emerging biomarkers, and strategies enabled by imaging and omics technologies for early diagnosis and risk stratification. Finally, we discuss therapeutic interventions targeting maladaptive signaling networks, inflammatory circuits, and fibrotic pathways to promote adaptive regeneration and prevent CKD progression. We aim to provide insights into improving long-term renal prognosis with a comprehensive examination of the pathological mechanism, diagnostic approaches and targeted interventions associated with the AKI-CKD transition.