Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy

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.

Figure 1

Schematic illustration of the activation of the NF-κB transcription factor pathway by liposaccharide (LPS), TNF-α, high mobility group (HMG)B1, and polymicrobial sepsis. LPS binding to Toll-like receptor-4 (TLR-4) is dependent on its interaction with circulating LPS-binding protein (LBP) and the subsequent interplay of this complex to membrane bound CD14 [90]. This LPS-LBP-CD14-TLR-4 complex is thus anchored to various cells within the kidney (especially within the apical brush border of proximal tubules) [60], where it initiates intracellular signaling cascades. CD14 gene expression is upregulated by LPS [91] in human kidney proximal tubular epithelial cells and by TNF-α [92] in mouse renal interstitial and tubular epithelial cells. Activated TLR-4 via LPS stimulates the MyD88 pathway [47,93,94], and ultimately induces phosphorylation of IκB by IκB-kinase-β (IKKβ; tan-colored) within the IKK complex [65]. Phosphorylated IκB is then released from NF-κB, allowing NF-κB to migrate to the nucleus to modulate transcription of various cytokines as shown. HMGB1 activation of TLR-4 activates NF-κB via an alternative mechanism whereby both IKKα and IKKβ (tan-colored) are implicated [54,55]. In cecal ligation and puncture models of sepsis, MyD88 has been shown to be activated independent of TLR-4 by unknown upstream cell surface receptors [72,75]. IRAK, interleukin receptor-associated kinase; MAPK, p38 mitogen-activated protein kinase; TRAF, TNF receptor associated factor.

Figure 2

Schematic illustration of the molecular processes leading to apoptosis in renal proximal tubular epithelial cells. So-called death receptors such as Fas, TNF receptor-1 (TNFR-1), or the TNF-related apoptosis-inducing ligand (TRAIL) receptors bind with extracellular ligands to activate downstream activator caspases [78]. This process is usually mediated by the FADD (Fas-associated protein with death domain) receptor, and ultimately activates caspase-3 - the effector molecule. Within the cell, the intrinsic pathway is initiated via cellular stresses: reactive oxygen species (ROS), nitric oxide, decreased ATP, or cell-cell/cell-matrix perturbations [95]. In response to those stresses, BAX migrates into the mitochondria via activation from BH3-only proteins within the Bcl-2 family [96]. Once they have entered the mitochondria, BAX and other pro-apoptotic proteins form pores within the mitochondrial wall, allowing for the release of cytochrome c, which triggers caspase-dependent and -independent pathways [95].