The AKI-CKD Continuum: Mechanisms and Therapeutic Interventions

Abstract

Acute kidney injury (AKI) affects 10-15% of hospitalized patients, and nearly one-quarter progress to chronic kidney disease (CKD), reflecting a failure to recognize the temporally dynamic continuum linking these conditions. This review synthesizes emerging evidence demonstrating that AKI-to-CKD continuum unfolds through four mechanistically distinct phases: (1) hyperacute injury (0–24 h), defined by bioenergetic collapse, mitochondrial permeability transition, oxidative stress, and early inflammatory priming; (2) acute response - persistent AKI (1–7 days), dominated by coordinated pyroptotic-apoptotic-necroptotic cell death (PANoptosis) and lipid peroxidation-driven ferroptosis, impaired mitophagy, aberrant G2/M arrest, and amplified cytokine release; (3) acute kidney disease (AKD) (2–8 weeks) characterized by maladaptive repair mechanisms, encompassing persistent TGF-β/SMAD signaling, metabolic reprogramming toward glycolysis, mechanotransductive YAP/TAZ activation, endothelial rarefaction, and stabilization of pro-fibrotic non-coding RNA networks; and (4) CKD (>12 weeks), where irreversible extracellular matrix deposition, chronic hypoxia, immune dysregulation, and established myofibroblast phenotypes perpetuate fibrosis. Three universal processes integrate these stages: (1) epigenetic injury memory through chromatin remodeling at pro-fibrotic loci, (2) metabolic reprogramming and epigenetic crosstalk, involving substrates such as S-adenosylmethionine and α-ketoglutarate, reinforcing self-perpetuating renal fibrosis and (3) renal functional reserve. However, substrate availability and cellular contexts are temporally variable, rendering phase-agnostic, single-target approaches ineffective because they fail to align with the evolving molecular environments. A temporally informed, multi-phase strategy that targets these universal mechanisms at optimal time-windows is crucial for preventing or attenuating this irreversible AKI-to-CKD continuum.