Pathways of renal injury in systemic gram‐negative sepsis

Abstract

Acute renal failure is a grave complication of systemic gram-negative sepsis. The pathophysiological mechanisms of sepsis leading to kidney injury result in part from systemic inflammatory and haemodynamic alterations. These are triggered by the interaction of endotoxin with Toll-like receptor 4 (TLR4) on cells of the immune system. Recently, TLR4 and other co-effector molecules were identified on renal tubular and vascular cells. Furthermore, it was demonstrated that systemic endotoxin has direct access to renal sites where these receptors are expressed. Therefore, we review data in support of this novel pathway of renal injury in sepsis, whereby systemic endotoxin causes direct injury through interactions with local epithelial and endothelial TLR4.

Endotoxin Uptake by S1 Proximal Tubular Segment Causes Oxidative Stress in the Downstream S2 Segment

“…10 -12 The reduction in GFR is traditionally ascribed to renal perfusion defects as well as the cytokine-mediated cellular damage to the endothelium and tubules. 13 Historically, interventions that are effective in treating animal models of sepsis-induced AKI have rarely met with success in the clinical arena. This is due in part to nonrepresentative animal models, inadequate clinical trials, and highly heterogeneous and complex patient population.…”

“…Indeed, we have recently shown, in a cecal ligation and puncture (CLP) model of sepsis in the rat, that endotoxin is readily filtered and taken up by proximal tubular cells. 13,17 Because endotoxin is not well retained after tissue fixation, intra vital 2-photon microscopy was essential in proving the accessibility of systemic endotoxin to renal tubular cells.…”

Tubular cross talk in acute kidney injury: a story of sense and sensibility

“…Kidney injury is frequently seen in sepsis, especially with Gram-negative bacteria (13,53,59,72). The histology of the kidney in septic patients reveals a wide spectrum of abnormalities, ranging from minimal changes to widespread cortical foci of apoptosis, necrosis, and inflammation (65).…”

“…The histology of the kidney in septic patients reveals a wide spectrum of abnormalities, ranging from minimal changes to widespread cortical foci of apoptosis, necrosis, and inflammation (65). These cortical lesions are also observed in various animal models of sepsis and are a function of the duration and severity of a particular model (7,9,13,70). The underlying pathophysiological mechanisms are likely multifactorial, but widespread endothelial Fig.…”

“…Inset: ϫ50,000 magnification showing an area where the basement membranes of TAL and S3 segments are in direct contact. and epithelial oxidative stress seems to play a key role in renal injury (13,23,39).…”