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Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists

Nature Clinical Practice Nephrology volume 2, pages 432–444 (2006)Cite this article

Abstract

Acute kidney injury (AKI) is associated with a high degree of morbidity and mortality and its incidence is increasing. These factors, together with a lack of successful clinical trials, necessitate a comprehensive evaluation of the pathogenesis of AKI and trial design. The progress that has been made in elucidating the pathogenesis of AKI has defined inflammation as an early event and therefore a potential target for therapeutic intervention. This Review summarizes recent advances in our understanding of the role of inflammation in AKI as well as our approach to limiting inflammation using compounds that stimulate adenosine 2A receptors (A2ARs). A2ARs are members of a family of guanine nucleotide-binding proteins that have become a focus of interest primarily because of their ability to broadly inactivate the inflammatory cascade. An A2A agonist—ATL146 ester (ATL146e)—is currently being tested in a phase III clinical trial as a pharmacological stress agent in cardiac perfusion imaging studies. This study, together with extensively published preclinical data, will facilitate testing of ATL146e in human trials of AKI.

Key Points

  • Components of the immune system—including neutrophils, lymphocytes, macrophages and dendritic cells—participate in ischemia–reperfusion-related kidney damage

  • During ischemia, concentrations of endogenous adenosine (which regulates renal circulation) increase, probably contributing to termination of the damaging immune response

  • Adenosine receptors of the A2A subtype are expressed in renal and nonrenal tissues, including hematopoietic precursors of immune cells

  • Activation of A2A receptors by administration of agonists abrogates ischemia–reperfusion-related inflammation

  • The A2A receptor agonist ATL146 ester is currently being tested in a phase III trial of cardiac perfusion imaging

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Figure 1: Clinical stages of acute renal failure.
Figure 2: Immune response in renal ischemia–reperfusion injury.
Figure 3: Macrophage activation.
Figure 4: Adenosine 2A agonist structure and binding affinities.
Figure 5: Adenosine 2A receptor agonists attenuate renal ischemia–reperfusion injury.

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Acknowledgements

The authors are grateful to Drs Diane Rosin (Department of Pharmacology, University of Virginia), Alaa S Awad and Sang-Kyung Jo (Korea University) for careful reading of the manuscript and helpful discussions, and to Ms Liping Huang and Hong Ye (Department of Medicine) for expert technical assistance. Much of the data on A2A agonists has resulted from fruitful collaborative research projects with Drs Joel Linden (Department of Medicine, University of Virginia), Yuan Ji Day (Department of Anesthesiology, Chang Gung Memorial Hospital, Taipei, Taiwan) and Timothy Macdonald (Department of Chemistry, University of Virginia). This work was supported in part by funds from NIH RO1DK56223, RO1DK62324 and RO1DK065957.

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    Li Li & Mark D Okusa

  2. John C Buchanan Distinguished Professor of Internal Medicine in the Department of Medicine, Carter Immunology Center and the Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA

    Li Li & Mark D Okusa

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Correspondence to Mark D Okusa.

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Mark D Okusa is a scientific advisor for Adenosine Therapeutics, LLC, Charlottesville, VA. Adenosine Therapeutics, LLC, provided ATL146 ester for studies reported in this manuscript. L Li declared no competing interests.

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Li, L., Okusa, M. Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists. Nat Rev Nephrol 2, 432–444 (2006). https://doi.org/10.1038/ncpneph0238

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