Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Feb;27(2):371-9.
doi: 10.1681/ASN.2015030261. Epub 2015 Nov 11.

Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps

Hamid Rabb  1 , Matthew D Griffin  2 , Dianne B McKay  3 , Sundararaman Swaminathan  4 , Peter Pickkers  5 , Mitchell H Rosner  4 , John A Kellum  6 , Claudio Ronco  7 ; Acute Dialysis Quality Initiative Consensus XIII Work Group
Collaborators, Affiliations
Review

Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps

Hamid Rabb et al. J Am Soc Nephrol. 2016 Feb.

Abstract

Inflammation is a complex biologic response that is essential for eliminating microbial pathogens and repairing tissue after injury. AKI associates with intrarenal and systemic inflammation; thus, improved understanding of the cellular and molecular mechanisms underlying the inflammatory response has high potential for identifying effective therapies to prevent or ameliorate AKI. In the past decade, much knowledge has been generated about the fundamental mechanisms of inflammation. Experimental work in small animal models has revealed many details of the inflammatory response that occurs within the kidney after typical causes of AKI, including insights into the molecular signals released by dying cells, the role of pattern recognition receptors, the diverse subtypes of resident and recruited immune cells, and the phased transition from destructive to reparative inflammation. Although this expansion of the basic knowledge base has increased the number of mechanistically relevant targets of intervention, progress in developing therapies that improve AKI outcomes by modulation of inflammation remains slow. In this article, we summarize the most important recent developments in understanding the inflammatory mechanisms of AKI, highlight key limitations of the commonly used animal models and clinical trial designs that may prevent successful clinical application, and suggest priority approaches for research toward clinical translation in this area.

Keywords: acute renal failure; clinical nephrology; immunology; pathophysiology of; renal disease and progression.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Interactions between injury, inflammatory mediators and outcome during AKI. (Upper panel) Varying types of insult instigate activation of the innate and adaptive immune system within the kidney. Renal dysfunction during AKI may result from the initial receptor–mediated triggers as well the subsequent cellular responses and various secondary sequelae. (Lower panel) In the clinical setting, the nature and outcome of the inflammatory response in AKI are dictated by not only an archetypal genome–encoded response program but also, primary and secondary modifiers (including therapeutic interventions), which have received less attention in experimental studies and must be taken into consideration in the design of clinical trials of inflammation-modifying therapies. DAMP, damage–associated molecular pattern; PAMP, pathogen–associated molecular pattern; PRRs, pattern recognition receptors.
Figure 2.
Figure 2.
Types of inflammatory responses during AKI. An idealized schematic is shown of the phases of inflammation that occur within the healthy kidney after acute insults on the basis of current understanding from preclinical (mostly rodent) models. Initial cell damage and death trigger, over minutes to hours, a primary acute inflammatory response involving resident and infiltrating leukocytes. This phase, if appropriately regulated, evolves over several days into a phase of active repair and regeneration, which is dependent on regulatory and reprogrammed leukocyte subsets. As indicated in the lower panel, molecular and cellular details of the early and later phases of the inflammatory process provide specific therapeutic target opportunities, but strategies that involve blocking/inhibiting elements of the acute inflammatory response may, paradoxically, introduce a risk of disrupting the natural transition to the repair phase if improperly timed.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Okusa MD, Rosner MH, Kellum JA, Ronco C: Acute Dialysis Quality Initiative XIII Workgroup: Therapeutic Targets of Human AKI: Harmonizing Human and Animal AKI. J Am Soc Nephrol 27: 371–379, 2016 - PMC - PubMed
    1. Medzhitov R: Inflammation 2010: New adventures of an old flame. Cell 140: 771–776, 2010 - PubMed
    1. Linfert D, Chowdhry T, Rabb H: Lymphocytes and ischemia-reperfusion injury. Transplant Rev (Orlando) 23: 1–10, 2009 - PMC - PubMed
    1. Ratliff BB, Rabadi MM, Vasko R, Yasuda K, Goligorsky MS: Messengers without borders: Mediators of systemic inflammatory response in AKI. J Am Soc Nephrol 24: 529–536, 2013 - PubMed
    1. Chen GY, Nuñez G: Sterile inflammation: Sensing and reacting to damage. Nat Rev Immunol 10: 826–837, 2010 - PMC - PubMed