Up Front MattersMessengers without Borders Mediators of Systemic Inflammatory Response in AKIRatliff, Brian B.; Rabadi, May M.; Vasko, Radovan; Yasuda, Kaoru; Goligorsky, Michael S. Author Information Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York Correspondence: Dr. Michael S. Goligorsky or Dr. Brian B. Ratliff, Departments of Medicine, Pharma-cology, and Physiology, Renal Research Institute, New York Medical College, 15 Dana Road, BSB C-06, Valhalla, NY 10595. Email: [email protected] or [email protected] Journal of the American Society of Nephrology 24(4):p 529-536, April 2013. | DOI: 10.1681/ASN.2012060633 Buy Metrics Abstract The list of signals sent by an injured organ to systemic circulation, so-called danger signals, is growing to include multiple metabolites and secreted moieties, thus revealing a highly complex and integrated network of interlinked systemic proinflammatory and proregenerative messages. Emerging new data indicate that, apart from the well established local inflammatory response to AKI, danger signaling unleashes a cascade of precisely timed, interdependent, and intensity-gradated mediators responsible for development of the systemic inflammatory response. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation is at the core of this brief overview. It has a potential to explain the additive effects of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual degree of acute kidney damage. Although therapies for ameliorating AKI per se remain limited, a potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic inflammatory response, while preserving its intrinsic proregenerative stimuli. Copyright © 2013 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.