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.

Figure 1. Patterns of epithelial cell injury in response to distinct injury stimuli.

Defined classes of tubular insults can induce distinct initial mechanisms and distributions of cellular injury. From left to right, macrocirculatory insufficiency in ischemic injury results in mitochondrial dysfunction and cellular metabolic and energy disturbances. In toxin-mediated AKI, the cellular mechanisms of injury are dependent on toxin characteristics and toxin handling within the tubule (i.e., secretion or filtration and accumulation within tubular space or TEC absorption and intracellular accumulation). Septic AKI is characterized by endothelial injury and activation along with TEC injury resulting from both pattern recognition receptor activation on TECs as well as cellular energy and metabolic derangements from macro-and microcirculatory insufficiency. In immune-mediated injury such as AIN, antigens elicit a cell-mediated T cell hypersensitivity immune response either directly or after hydrolysis and processing by tubular cells to form a hapten bridge. PCT, proximal convoluted tubule; PST, proximal straight tubule.

Figure 2. Surviving epithelial cell responses to distinct injury stimuli.

(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.

Figure 3. Resolution of AKI.

Immediately following injury, dying cells form casts in the tubular lumen in association with Tamm-Horsfall protein while surviving TECs recruit proinflammatory macrophages and lymphocytes to the tubulointerstitium. (Left) With successful repair and recovery after AKI, casts are cleared and proinflammatory macrophages shift to a proreparative phenotype that promotes TEC proliferation and dampens the immune response, allowing TECs to redifferentiate and restore tubule architecture and function. A small subset of Pax2⁺ tubular progenitors also contribute to regeneration of necrotic epithelial regions (199). (Right) If injury to a particular tubule or region is severe or sustained, the local immune response is amplified with enhanced recruitment of proinflammatory T cells and B cells into the interstitium and persistence of proinflammatory macrophage populations. This can lead to tubular cell G2/M arrest and adoption of a senescence-associated secretory phenotype with release of inflammatory cytokines, growth factors, proteases, and immune modulators that recruit additional proinflammatory macrophages and lymphocytes that sustain the local inflammatory response and can lead to secondary injury to adjacent tubules. This persistent inflammatory milieu promotes prolymphangiogenic signaling, ongoing TEC injury, profibrotic signaling, and progressive impairment of GFR.