Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy
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Published on: February 15, 2022
Eric D Morrell1, John A Kellum2,3,4,5, Núria M Pastor-Soler6,7,8
1Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA. morrelled@upmc.edu.
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.
Insights
Sepsis causes acute kidney injury (AKI) through complex inflammation and apoptosis, not just low blood flow. Identifying patient immune status is key to developing effective treatments for septic AKI.
Area of Science:
- Nephrology
- Immunology
- Critical Care Medicine
Background:
- Sepsis is a leading cause of acute kidney injury (AKI) in hospitalized patients.
- The precise molecular mechanisms underlying septic AKI remain incompletely understood.
- Septic AKI pathogenesis differs significantly from ischemic AKI, often occurring independently of hypoperfusion.
Purpose of the Study:
- To elucidate the molecular pathways and mechanisms mediating septic AKI.
- To investigate the role of inflammatory states, Toll-like receptors (TLRs), and apoptosis in septic AKI.
- To address the failure of current targeted therapies and propose a future research direction.
Main Methods:
- Review of experimental data from the past 20 years on septic AKI pathogenesis.
- Analysis of the roles of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
- Examination of inflammatory signaling, TLR activation, and apoptotic pathways in the kidney.
Main Results:
- Septic AKI involves a complex interplay of pro- and anti-inflammatory responses.
- Toll-like receptors (TLRs) in the kidney recognize PAMPs and DAMPs, activating downstream inflammatory cascades.
- Apoptosis is implicated in septic AKI, but targeted therapies have shown limited clinical success.
Conclusions:
- The heterogeneity of septic AKI, presenting across an immunologic spectrum, explains the failure of one-size-fits-all therapies.
- Future research must focus on stratifying patients based on their position on the immunologic spectrum.
- Personalized therapeutic strategies targeting specific points in the inflammatory cascade, TLR pathways, or apoptosis are needed for effective septic AKI treatment.
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