Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury
Megan L. Baker, Lloyd G. Cantley
Megan L. Baker, Lloyd G. Cantley
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Review

Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury

Abstract

Acute kidney injury (AKI) encompasses pathophysiology ranging from glomerular hypofiltration to tubular cell injury and outflow obstruction. This Review will focus on the tubulointerstitial processes that underlie most cases of AKI. Tubular epithelial cell (TEC) injury can occur via distinct insults, including ischemia, nephrotoxins, sepsis, and primary immune-mediated processes. Following these initial insults, tubular cells can activate survival and repair responses or they can develop mitochondrial dysfunction and metabolic reprogramming, cell-cycle arrest, and programmed cell death. Developing evidence suggests that the fate of individual tubular cells to survive and proliferate or undergo cell death or senescence is frequently determined by a biphasic immune response with initial proinflammatory macrophage, neutrophil, and lymphocyte infiltration exacerbating injury and activating programmed cell death, while alternatively activated macrophages and specific lymphocyte subsets subsequently modulate inflammation and promote repair. Functional recovery requires that this reparative phase supports proteolytic degradation of tubular casts, proliferation of surviving TECs, and restoration of TEC differentiation. Incomplete resolution or persistence of inflammation can lead to failed tubular repair, fibrosis, and chronic kidney disease. Despite extensive research in animal models, translating preclinical findings to therapies remains challenging, emphasizing the need for integrated multiomic approaches to advance AKI understanding and treatment.

Authors

Megan L. Baker, Lloyd G. Cantley

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Figure 2

Surviving epithelial cell responses to distinct injury stimuli.

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Surviving epithelial cell responses to distinct injury stimuli. (A) The ...
(A) The repertoire of injury responses by tubular cells that survive the initial insult is limited and is at least in part determined by both the type and severity of injury. Primary responses such as metabolic reprogramming, inflammasome activation, and cast formation often predominate in specific types of initial injury. (B) However, many of the secondary immune responses are shared and can lead to cell-cycle arrest, PCD pathways, and recruitment of secondary immune cells.