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Review
. 2011 Nov;121(11):4210-21.
doi: 10.1172/JCI45161. Epub 2011 Nov 1.

Cellular pathophysiology of ischemic acute kidney injury

Joseph V Bonventre  1 , Li Yang
Affiliations
Review

Cellular pathophysiology of ischemic acute kidney injury

Joseph V Bonventre et al. J Clin Invest. 2011 Nov.

Abstract

Ischemic kidney injury often occurs in the context of multiple organ failure and sepsis. Here, we review the major components of this dynamic process, which involves hemodynamic alterations, inflammation, and endothelial and epithelial cell injury, followed by repair that can be adaptive and restore epithelial integrity or maladaptive, leading to chronic kidney disease. Better understanding of the cellular pathophysiological processes underlying kidney injury and repair will hopefully result in the design of more targeted therapies to prevent the injury, hasten repair, and minimize chronic progressive kidney disease.

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Figures

Figure 1
Figure 1. Causes of reduction in generalized or regional renal blood flow (RBF).
Various pathophysiological states and medications can contribute to reduction of RBF, causing generalized or localized ischemia to the kidney leading to AKI. This figure represents a partial list and points to ischemia as being a common pathway in a variety of clinical states affecting the kidney.
Figure 2
Figure 2. Normal nephron, corticomedullary oxygen gradient, and outer medullary microvascular anatomy.
(A) Anatomy of nephron with regions identified. Outer medulla vasculature is shown with capillaries in red and venous system in blue. (B) The vasa recta with countercurrent exchange of oxygen resulting in a gradient of decreasing oxygen tension.
Figure 3
Figure 3. Endothelial injury in ischemia/reperfusion AKI.
(A) Normal epithelium and endothelium separated by a small interstitial compartment. A glycocalyx coats the endothelium. (B) Ischemia/reperfusion causes swelling of endothelial cells; disruptions of the glycocalyx and endothelial monolayer; and upregulation of adhesion molecules such as ICAMs, VCAMs, and selectins, resulting in enhanced leukocyte-endothelium interactions. There is formation of microthrombi, and some leukocytes migrate through the endothelial cells into the interstitial compartment. The interstitial compartment is expanded with enhanced numbers of inflammatory cells and interstitial edema forms. (C) Transmission electron microscopy of normal human peritubular capillary (Cap). (D–F) Acute tubular necrosis. The peritubular capillaries (PT) show vacuolar degeneration of the endothelial cell (arrow in D), thickening and multilayer basement membrane formation (arrows in E), and attachment and penetration of monocyte-like cells (arrows in F) in the interstitial region. Scale bars: 2 μm (C and F); 1 μm (D and E).
Figure 4
Figure 4. Immune response in ischemic AKI.
The injured tubular epithelium releases proinflammatory cytokines and chemokines, which aid in recruiting immune cells. Epithelial cells also express adhesion molecules, TLRs, and T cell costimulatory molecules, which activate the immune cells and amplify the inflammatory responses. Neutrophils, macrophages, and natural killer T (NKT) cells cause direct injury to tubular epithelial cells. DCs are involved in both the innate and adaptive immune responses through secretion of inflammatory cytokines and presentation of antigens to T lymphocytes.
Figure 5
Figure 5. Pathology after ischemia in humans.
(A) Outer medulla in human ischemic AKI. The proximal tubules (PT) lose brush border, and cells are released into the lumen (thin arrows). Inflammatory cells are seen in the interstitial compartment (thick arrow). Light microscopy: original magnification, ×400; scale bar: 50 μm. (B) Electron microscopy sections through normal human proximal tubules. (C–E) Human AKI. (C) In ischemic AKI, lymphocytes are seen infiltrating into the tubule wall (arrow). (D and E) Loss of brush border and contraction of the cell (arrow in D and dashed arrow in E) with necrosis (D and E) of proximal tubules are shown. Cellular debris is apparent in the lumen (solid arrows in E). Scale bars: 2 μm (B–E). TBM, tubular basement membrane.
Figure 6
Figure 6. Normal repair in ischemic AKI.
(A) The current understanding of tubular injury and repair after ischemic AKI. With IRI, the normally highly polar epithelial cell loses its polarity and brush border with proteins mislocated on the cell membrane. With increasing time/severity of ischemia, there is cell death by either necrosis or apoptosis. Some of the necrotic debris is released into the lumen. Viable epithelial cells migrate and cover denuded areas of the basement membrane. These cells undergo division and replace lost cells. Ultimately, the cells go on to differentiate and reestablish the normal polarity of the epithelium. (B) The photomicrograph shows a vigorous repair process after ischemic injury in the mouse. Cells that have entered the cell cycle are stained with Ki-67. Cells specifically in the S phase of the cell cycle have taken up BrdU, which had been injected into the animal. Arrows point to some of the cross sections of tubules that are filled with cellular debris. Scale bar: 50 μm. Image in B reproduced with permission from Nature Medicine (128).
Figure 7
Figure 7. Abnormal repair in ischemic AKI.
Repair after AKI can result in incomplete repair and fibrotic lesions, which may result in progressive renal dysfunction. Factors including long-term hypoxia and hypertension result from chronic loss of peritubular microvessels. Sustained production of profibrotic cytokines such as IL-13, arginase, and TGF-β1 from the chronically activated macrophages (MΦ) contribute to postischemic fibrosis. Renal tubular epithelial cells also play a critical role in the development of fibrosis through fundamental changes in their proliferation processes, including cell cycle arrest in the G2/M phase. This results in a secretory phenotype that facilitates the production by the epithelial cells of profibrotic growth factors (including TGF-β1 and CTGF). Fibrogenesis is stimulated, and progression to chronic renal failure is accelerated.
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