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  • Review Article
  • Published:

Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD

Nature Reviews Nephrology volume 11, pages 264–276 (2015)Cite this article

Subjects

Key Points

  • Acute injury to the kidney is often associated with maladaptive repair and incomplete resolution, leading to residual abnormalities in kidney structure and function

  • Increasing age, and chronic low-grade insults to the tubular epithelium increase epithelial cell sensitivity to episodes of acute kidney injury, leading to maladaptive repair and progression of chronic kidney disease

  • Maladaptive repair is characterized by fibrosis, vascular rarefaction, tubular loss, glomerulosclerosis and the presence of a chronic inflammatory infiltrate within the kidney

  • Injured renal tubular epithelial cells become arrested at G2/M and adopt a profibrotic phenotype, which affects other epithelial cells, pericytes and the immune system

  • Myofibroblasts that likely arise from renal pericytes proliferate and contribute to the deposition of extracellular matrix and resulting fibrosis within the injured kidney

  • Maladaptive repair after acute kidney insults shares many common features with kidney ageing and can be thought of as a state of accelerated kidney ageing

Abstract

Acute kidney injury is an increasingly common complication of hospital admission and is associated with high levels of morbidity and mortality. A hypotensive, septic, or toxic insult can initiate a cascade of events, resulting in impaired microcirculation, activation of inflammatory pathways and tubular cell injury or death. These processes ultimately result in acutely impaired kidney function and initiation of a repair response. This Review explores the various mechanisms responsible for the initiation and propagation of acute kidney injury, the prototypic mechanisms by which a substantially damaged kidney can regenerate its normal architecture, and how the adaptive processes of repair can become maladaptive. These mechanisms, which include G2/M cell-cycle arrest, cell senescence, profibrogenic cytokine production, and activation of pericytes and interstitial myofibroblasts, contribute to the development of progressive fibrotic kidney disease. The end result is a state that mimics accelerated kidney ageing. These mechanisms present important opportunities for the design of targeted therapeutic strategies to promote adaptive renal recovery and minimize progressive fibrosis and chronic kidney disease after acute insults.

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Figure 1: A summary of some of the mechanisms involved in initial tissue injury and subsequent repair of the kidney after acute kidney injury.
Figure 2: The evolution of tissue injury, death and subsequent adaptive repair after AKI.
Figure 3: Maladaptive repair of AKI leads to CKD.
Figure 4: Common mechanisms in kidney ageing and progressive kidney injury.
Figure 5: Replicative and stress-induced premature senescence in kidney injury.
Figure 6: Eukaryotic cell-cycle checkpoints.

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Authors and Affiliations

  1. Renal Division and Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, 02115, MA, USA

    David A. Ferenbach & Joseph V. Bonventre

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The authors contributed equally to researching data for the article, discussion of its content, writing and reviewing and/or editing of the manuscript before submission.

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J.V.B is co-inventor on KIM-1 patents that are assigned to Partners HealthCare and licensed to Johnson & Johnson, Sekisui, Novartis, Biogen Idec., R & D, and Astute. He is a consultant for Astellas, Novartis, Roche and Sekisui regarding the safety and efficacy of therapeutics or diagnostics for acute kidney injury. He holds equity in MediBeacon, Sentien and Thrasos, and has grant support from Novo Nordisk and Roche. D.A.F declares no competing interests.

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Ferenbach, D., Bonventre, J. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol 11, 264–276 (2015). https://doi.org/10.1038/nrneph.2015.3

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