From AKI to CKD mechanisms of maladaptive repair and disease progression.

Acute kidney injury (AKI) and chronic kidney disease (CKD) were traditionally regarded as distinct clinical entities, largely defined by the reversibility or irreversibility of renal dysfunction. However, growing clinical and experimental evidence now supports a continuum model in which AKI serves as a major initiating event for subsequent CKD development and progression. Even when conventional indices suggest functional recovery, persistent subclinical injury may drive long-term structural, metabolic, and transcriptional alterations that predispose the kidney to chronic damage. In this review, we synthesize current clinical, epidemiological, and mechanistic evidence linking AKI to CKD, with particular emphasis on maladaptive repair. We propose that maladaptive tubular epithelial repair represents the central coordinating event in this transition. Failed redifferentiation, sustained cell cycle arrest, partial epithelial reprogramming, and metabolic inflexibility convert injured tubular cells from targets of injury into active drivers of chronic remodeling. Persistent inflammation and immune dysregulation amplify tissue injury. Meanwhile, microvascular rarefaction and endothelial dysfunction reduce oxygen delivery and promote chronic hypoxia. Moreover, mitochondrial dysfunction, lipid accumulation, defective organelle quality control, and sustained cellular stress signaling reinforce tubular vulnerability and limit regenerative capacity. Emerging evidence also indicates that epigenetic and transcriptional memory may stabilize maladaptive cellular states, thereby lowering the threshold for re-injury and accelerating CKD progression. By integrating these interconnected pathways, we present a unified framework for the AKI-to-CKD continuum and discuss key translational opportunities, including time-sensitive intervention, mechanistic stratification, and biomarker-guided risk prediction. A more precise understanding of post-AKI remodeling may enable early and individualized strategies to prevent CKD progression.