The AKI-CKD Continuum: Mechanisms and Therapeutic Interventions

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ID: 324343
2026
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Abstract
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.
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openalex_W7201994569 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Hrushikesh Kulkarni, Shrikant R. Mulay, Anil Bhanudas Gaikwad
Journal nephrology dialysis transplantation
Year 2026
DOI
10.1093/ndt/gfag180
URL
https://doi.org/10.1093/ndt/gfag180
Keywords Keywords not found

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