'Biologic memory' in response to acute kidney injury: cytoresistance, toll-like receptor hyper-responsiveness and the onset of progressive renal disease

• Published in: Nephrology, dialysis, transplantation Vol. 28; no. 8; pp. 1985 - 1993
• Main Author: Zager, Richard A
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2013
• Subjects: Acute Kidney Injury - complications; Acute Kidney Injury - immunology; Animals; Cytoprotection; Disease Progression; Drug Tolerance; Humans; Hypersensitivity; Immunologic Memory - immunology; Kidney Failure, Chronic - etiology; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - pathology; Review - Basic Science and Translational Nephrology; Toll-Like Receptors - metabolism; ischemic preconditioning; chronic kidney disease; acute kidney injury; sepsis syndrome; epigenetics
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gft101

Following the induction of ischemic or toxin-mediated acute kidney injury (AKI), cellular adaptations occur that 're-program' how the kidney responds to future superimposed insults. This re-programming is not simply a short-lived phenomenon; rather it can persist for many weeks, implying that a state of 'biologic memory' has emerged. These changes can be both adaptive and maladaptive in nature and they can co-exist in time. A beneficial adaptation is the emergence of acquired cytoresistance, whereby a number of physiologic responses develop that serve to protect the kidney against further ischemic or nephrotoxic attack. Conversely, some changes are maladaptive, such as a predisposition to Gram-negative or Gram-positive bacteremia due to a renal tubular up-regulation of toll-like receptor responses. This latter change culminates in exaggerated cytokine production, and with efflux into the systemic circulation, extra-renal tissue injury can result (so-called 'organ cross talk'). Another maladaptive response is a persistent up-regulation of pro-inflammatory, pro-fibrotic and vasoconstrictive genes, culminating in progressive renal injury and ultimately end-stage renal failure. The mechanisms by which this biologic re-programming, or biologic memory, is imparted remain subjects for considerable debate. However, injury-induced, and stable, epigenetic remodeling at pro-inflammatory/pro-fibrotic genes seems likely to be involved. The goal of this editorial is to highlight that the so-called 'maintenance phase' of acute renal failure is not a static one, somewhere between injury induction and the onset of repair. Rather, this period is one in which the induction of 'biologic memory' can ultimately impact renal functional recovery, extra-renal injury and the possible transition of AKI into chronic, progressive renal disease.