Abstract
Sepsis‐induced acute kidney injury (SI‐AKI) is common and associated with high mortality. Survivors are at increased risk of chronic kidney disease. The precise mechanism underlying SI‐AKI is unknown, and no curative treatment exists. Toll‐like receptor 4 (TLR4) activates the innate immune system in response to exogenous microbial products. The result is an inflammatory reaction aimed at clearing a potential infection. However, the consequence may also be organ dysfunction as the immune response can cause collateral damage to host tissue. The purpose of this review is to describe the basis for how ligand binding to TLR4 has the potential to cause renal dysfunction and the mechanisms by which this may take place in gram‐negative sepsis. In addition, we highlight areas for future research that can further our knowledge of the pathogenesis of SI‐AKI in relation to TLR4 activation. TLR4 is expressed in the kidney. Activation of TLR4 causes cytokine and chemokine release as well as renal leucocyte infiltration. It also results in endothelial and tubular dysfunction in addition to altered renal metabolism and circulation. From a physiological standpoint, inhibiting TLR4 in large animal experimental SI‐AKI significantly improves renal function. Thus, current evidence indicates that TLR4 has the ability to mediate SI‐AKI by a number of mechanisms. The strong experimental evidence supporting a role of TLR4 in the pathogenesis of SI‐AKI in combination with the availability of pharmacological tools to target TLR4 warrants future human studies.
Highlights
Sepsis and acute kidney injury (AKI)More than 5% of hospitalized patients suffer from AKI and have an increased risk of dying or
We explore how one specific Toll-like receptors (TLRs), Toll-like receptor 4 (TLR4), may cause acute kidney injury (AKI) in sepsis
This has led to the hypothesis that local renal and/or systemic inflammation contributes to Sepsis-induced acute kidney injury (SI-AKI) and that the kidney failure often seen in association with sepsis not necessarily has to involve inadequate global renal perfusion (Lipcsey & Bellomo 2011)
Summary
More than 5% of hospitalized patients suffer from AKI and have an increased risk of dying or. Compared to other aetiologies of AKI, sepsis is associated with significantly higher mortality rates This can be attributed to the fact that septic patients often suffer from various comorbidities and generally are severely ill. In large animal models of septic shock, it has been shown that AKI develops even though renal blood flow is increased or unchanged (Langenberg et al 2006, Frithiof et al 2011) This has led to the hypothesis that local renal and/or systemic inflammation contributes to SI-AKI and that the kidney failure often seen in association with sepsis not necessarily has to involve inadequate global renal perfusion (Lipcsey & Bellomo 2011). The recent shift in focus from SI-AKI being a cardiovascular problem to becoming an inflammatory
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