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Although effective repair can result in the complete recovery of kidney function, this process is frequently incomplete. In instances where repair is unsuccessful, the kidney experiences maladaptive alterations that may progressively result in chronic kidney disease (CKD), a phenomenon referred to as failed repair. This condition is precipitated by hypotensive, septic, or toxic insults, which initiate a series of pathophysiological processes, including microcirculatory dysfunction, the activation of inflammatory responses, and the death of tubular epithelial cells. These events collectively compromise renal function and trigger a complex repair response. This review provides a comprehensive examination of the multifactorial mechanisms underlying the initiation and progression of AKI, the regenerative pathways facilitating structural recovery in severely damaged kidneys, and the critical transition from adaptive repair to maladaptive remodeling. Central to this transition are mechanisms such as epigenetic reprogramming, G2\/M cell-cycle arrest, cellular senescence, mitochondrial dysfunction, metabolism reprogramming, and cell death, which collectively drive the progression of CKD. These mechanistic insights offer a robust foundation for the development of targeted therapeutic strategies aimed at enhancing adaptive renal repair.<\/jats:p>","DOI":"10.3390\/biom15060794","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T09:47:34Z","timestamp":1748512054000},"page":"794","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Mechanisms of Acute Kidney Injury\u2013Chronic Kidney Disease Transition: Unraveling Maladaptive Repair and Therapeutic Opportunities"],"prefix":"10.3390","volume":"15","author":[{"given":"Dongxue","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Clinical Research Center of Hubei Critical Care Medicine, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Clinical Research Center of Hubei Critical Care Medicine, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0236-9840","authenticated-orcid":false,"given":"Yiming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Clinical Research Center of Hubei Critical Care Medicine, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5861-398X","authenticated-orcid":false,"given":"Zhiyong","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Clinical Research Center of Hubei Critical Care Medicine, Wuhan 430071, China"},{"name":"Intensive Care Unit, The Second Affiliated Hospital of Hainan Medical College, Haikou 570100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1038\/s42255-021-00450-3","article-title":"Heritable shifts in redox metabolites during mitochondrial quiescence reprogramme progeny metabolism","volume":"3","author":"Hocaoglu","year":"2021","journal-title":"Nat. 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