Abstract / Summary
Acute kidney injury (AKI) is a consistent precursor of incident and progressive chronic kidney disease (CKD). The transition reflects failed tubular repair followed by tubular atrophy, peritubular capillary rarefaction, and progressive interstitial fibrosis. Maladaptive cellular senescence is driven by persistent DNA-damage response signalling, mitochondrial dysfunction, mechanistic target of rapamycin complex 1 activation, and durable G2/M arrest. Senescent tubular cells develop a senescence-associated secretory phenotype enriched in transforming growth factor beta, interleukin-6, and plasminogen activator inhibitor-1, thereby propagating fibrogenesis through paracrine signalling. Epigenetic reprogramming encodes maladaptation through promoter hypermethylation of nephroprotective loci, repressive histone H3 lysine 27 trimethylation deposited by enhancer of zeste homolog 2 -polycomb repressive complex 2, and dysregulation of pro-fibrotic non-coding RNAs. These processes are mechanistically interlocked through nuclear factor kappa B and bromodomain-containing protein 4 activity, as well as metabolic -epigenetic coupling involving acetyl-CoA, alpha-ketoglutarate, and S-adenosylmethionine. Urinary kidney injury molecule-1, tissue inhibitor of metalloproteinases-2•insulin-like growth factor-binding protein 7, residual albuminuria, circulating growth differentiation factor-15, and selected senescence-associated secretory phenotype factors may improve risk stratification beyond serum creatinine, although most remain investigational in the post-AKI setting. Senolytics, senomorphics, epigenetic modifiers, and clustered regularly interspaced short palindromic repeats-based epigenome editors remain at preclinical or early-clinical stages, and no AKI-specific phase 3 trial has been completed. Translation therefore requires validated molecular biomarkers, protocolised post-AKI surveillance, and globally inclusive trials with measurable milestones.