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Pathophysiology of ischemic acute kidney injury

Nature Reviews Nephrology volume 7, pages 189–200 (2011)Cite this article

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Abstract

Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event leading to unacceptably high morbidity and mortality, development of chronic kidney disease (CKD), and transition from pre-existing CKD to end-stage renal disease. Data indicate a close interaction between the many cell types involved in the pathophysiology of ischemic AKI, which has critical implications for the treatment of this condition. Inflammation seems to be the common factor that links the various cell types involved in this process. In this Review, we describe the interactions between these cells and their response to injury following ischemia. We relate these events to patients who are at high risk of AKI, and highlight the characteristics that might predispose these patients to injury. We also discuss how therapy targeting specific cell types can minimize the initial and subsequent injury following ischemia, thereby limiting the extent of acute changes and, hopefully, long-term structural and functional alterations to the kidney.

Key Points

  • During ischemic acute kidney injury (AKI), ATP depletion results in cytoskeletal changes in epithelial and endothelial cells, causing disruption of function, and a decrease in glomerular filtration rate

  • Apoptosis and necrosis are major mechanisms of cell death that have important roles in ischemia, with the contribution of each pathway depending on the extent of the injury

  • Under physiological conditions, endothelial cells regulate permeability, vascular tone, coagulation, and inflammation; endothelial cells that are dysfunctional substantially contribute to the extension phase of AKI

  • Inflammation and its mediators orchestrate the extension phase of ischemic AKI, and limit injury to tubular epithelial cells and vascular endothelial cells, thereby promoting repair

  • Complex interactions between epithelial cells, endothelial cells, inflammatory mediators, and cytokines can result in persistent injury during acute tubular necrosis

  • Stem cells, mesenchymal cells, and endothelial progenitor cells contribute to the repair and regeneration of tubular cells and endothelial cells following injury, and could provide attractive targets for therapeutic intervention

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Figure 1: Pathogenesis of ischemic AKI.
Figure 2: Effects of sub-lethal injury to tubular cells and their recovery.
Figure 3: Events in endothelial cell activation, injury, and reduced microvascular flow.

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Indiana University School of Medicine, 950 West Walnut Street, R2–202, Indianapolis, 46202, IN, USA

    Asif A. Sharfuddin & Bruce A. Molitoris

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A. A. Sharfuddin and B. A. Molitoris contributed equally to researching data for the article, discussion of the content, writing and reviewing/editing of the manuscript before submission.

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Correspondence to Bruce A. Molitoris.

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Competing interests

B. A. Molitoris has worked as a consultant for and received grant/research support from Eli Lilly and Quark Pharmaceuticals. He is also a patent holder/applicant with Eli Lilly. A. A. Sharfuddin declares no competing interests.

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Sharfuddin, A., Molitoris, B. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 7, 189–200 (2011). https://doi.org/10.1038/nrneph.2011.16

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