Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy
Open Access
- 2 September 2014
- journal article
- review article
- Published by Springer Science and Business Media LLC in Critical Care
- Vol. 18 (5), 1-10
- https://doi.org/10.1186/s13054-014-0501-5
Abstract
The most common cause of acute kidney injury (AKI) in hospitalized patients is sepsis. However, the molecular pathways and mechanisms that mediate septic AKI are not well defined. Experiments performed over the past 20 years suggest that there are profound differences in the pathogenesis between septic and ischemic AKI. Septic AKI often occurs independently of hypoperfusion, and is mediated by a concomitant pro- and anti-inflammatory state that is activated in response to various pathogen-associated molecular patterns, such as endotoxin, as well as damage-associated molecular patterns. These molecular patterns are recognized by Toll-like receptors (TLRs) found in the kidney, and effectuate downstream inflammatory pathways. Additionally, apoptosis has been proposed to play a role in the pathogenesis of septic AKI. However, targeted therapies designed to mitigate the above aspects of the inflammatory state, TLR-related pathways, and apoptosis have failed to show significant clinical benefit. This failure is likely due to the protean nature of septic AKI, whereby different patients present at different points along the immunologic spectrum. While one patient may benefit from targeted therapy at one end of the spectrum, another patient at the other end may be harmed by the same therapy. We propose that a next important step in septic AKI research will be to identify where patients lie on the immunologic spectrum in order to appropriately target therapies at the inflammatory cascade, TLRs, and possibly apoptosis.Keywords
This publication has 95 references indexed in Scilit:
- Genomic responses in mouse models poorly mimic human inflammatory diseasesProceedings of the National Academy of Sciences of the United States of America, 2013
- Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsisKidney International, 2012
- Immunosuppression in Patients Who Die of Sepsis and Multiple Organ FailureJama-Journal Of The American Medical Association, 2011
- Circulating mitochondrial DAMPs cause inflammatory responses to injuryNature, 2010
- Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survivalKidney International, 2010
- Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in miceAmerican Journal of Physiology-Renal Physiology, 2008
- Intensity of Renal Support in Critically Ill Patients with Acute Kidney InjuryNew England Journal of Medicine, 2008
- Effects of hemoadsorption on cytokine removal and short-term survival in septic ratsCritical Care Medicine, 2008
- Toll-like receptor-4: Renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritisKidney International, 2005
- The Pathophysiology and Treatment of SepsisNew England Journal of Medicine, 2003