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

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.

Figure 1

A summary of some of the mechanisms involved in initial tissue injury and subsequent repair of the kidney after acute kidney injury. Maladaptive and incomplete repair leads to the development of fibrosis and, ultimately, chronic kidney disease.

Figure 2

The evolution of tissue injury, death and subsequent adaptive repair after AKI. Following an episode of AKI, the kidney is capable of repair back to normal or near-normal structure and function despite apparently severe damage. Initial injury is characterized by endothelial activation, recruitment of myeloid leucocytes and widespread tubular cell injury and death. In ‘adaptive’ repair, over a period of days, debris is cleared by tubular cells and recruited macrophages, and epithelial dedifferentiation occurs followed by proliferation to restore the integrity of the tubular epithelial cell layer. Macrophages support renal growth and recovery by adopting an M2 phenotype before leaving the kidney. Pericytes remain in contact with the capillary network and do not give rise to new myofibroblasts or if they do, this myofibroblast proliferation is reversible. Abbreviations: AKI, acute kidney injury; NO, nitric oxide.

Figure 3

Maladaptive repair of AKI leads to CKD. Studies have highlighted the importance of G2/M cell-cycle arrest in response to severe, repeated and genotoxic renal insults. In the initial repair phase after injury, cells may become arrested in G2/M phase and release cytokines and growth factors that promote inflammatory cell retention within the kidney and ongoing inflammation. Injury and pro-inflammatory stimuli lead to pericyte dissociation from the endothelium, resulting in microvascular rarefaction and the progressive deposition of collagen I by myofibroblasts arising from activated pericytes. Ageing sensitizes tubular cells to G2/M arrest in response to cell stress and DNA damage, providing a potential explanation for the increased risk of CKD progression after AKI in the elderly. Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease.

Figure 4

Common mechanisms in kidney ageing and progressive kidney injury. Features of kidney ageing include tubular loss, glomerulosclerosis, microvascular rarefaction and deposition of interstitial collagen. The number of senescent and G2/M arrested cells present in the ageing kidney also progressively increases. All the above cellular changes are also seen in progressive renal disease in younger patients following acute renal insults. These shared features suggest that progressive chronic kidney disease is functionally equivalent to accelerated ageing of the kidney. Abbreviation: AKI, acute kidney injury.

Figure 5

Replicative and stress-induced premature senescence in kidney injury. Renal cells become senescent either through ageing and telomere shortening, or via genotoxic insults resulting in stress-induced premature senescence. While in terminal growth arrest, these senescent cells remain metabolically active and secrete a range of factors that contribute to the chronic inflammatory state, the progression of renal fibrosis and increased susceptibility of other cells to subsequent insults and senescence. Modified with permission of American Society of Nephrology, from Yang, H. & Fogo, A. B. J. Am. Soc. Nephrol. 21, 1436–2439 (2010); permission conveyed through Copyright Clearance Center, Inc.

Figure 6

Eukaryotic cell-cycle checkpoints. Four phases of cell-cycle progression are seen in eukaryotic cells. Cellular DNA is replicated in the S phase, and cell mitosis occurs in M phase, separated by two gap phases, G1 and G2. Critical checkpoints exist at G1/S and G2/M, where the actions of cyclins, CDKs and their inhibitors determine whether appropriate cell size, DNA replication and integrity exist to allow the initiation of DNA synthesis or the completion of cell division, respectively. Increased numbers of G2/M-arrested cells have been identified as a common feature in models of progressive chronic kidney disease. Abbreviations: CDK, cyclin-dependent kinase; CTGF, connective tissue growth factor; TGF-β, transforming growth factor β.