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Review
, 27 (2), 371-9

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

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Review

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

Hamid Rabb et al. J Am Soc Nephrol.

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.

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.

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