Sepsis-induced acute kidney injury

Abstract

Purpose of review: Sepsis is a common and frequently fatal condition in which mortality has been consistently linked to increasing organ dysfunction. For example, acute kidney injury (AKI) occurs in 40-50% of septic patients and increases mortality six to eight-fold. However, the mechanisms by which sepsis causes organ dysfunction are not well understood and hence current therapy remains reactive and nonspecific.

Recent findings: Recent studies have challenged the previous notion that organ dysfunction is solely secondary to hypoperfusion, by showing, for example, that AKI occurs in the setting of normal or increased renal blood flow; and that it is characterized not by acute tubular necrosis or apoptosis, but rather by heterogeneous areas of colocalized sluggish peritubular blood flow and tubular epithelial cell oxidative stress. Evidence has also shown that microvascular dysfunction, inflammation, and the metabolic response to inflammatory injury are fundamental pathophysiologic mechanisms that may explain the development of sepsis-induced AKI.

Summary: The implications of these findings are significant because in the context of decades of negative clinical trials in the field, the recognition that other mechanisms are at play opens the possibility to better understand the processes of injury and repair, and provides an invaluable opportunity to design mechanism-targeted therapeutic interventions.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1

The figure summarizes the mechanisms that are thought to participate in the development of microvascular dysfunction. Damage-associated molecular patterns and pathogen-associated molecular patterns resulting from invading pathogens and the subsequent immune response activate leukocytes and endothelial cells. Activation of, and injury to endothelial cells directly or through oxidative stress, induces alterations in protective mechanisms (see text). In addition, damaged or activated endothelial cells undergo shedding of their glycocalyx which exposes adhesion molecules to circulating leukocytes and platelets, promoting adhesion of both, and rolling and transmigration of leukocytes; alters the barrier function of the capillary, resulting in capillary leak and formation of edema; alters sensing of shear stress forces which are necessary to regulate tone and couple blood flow to changing circumstances; and causes profound alterations in blood flow distribution. DAMPs, damage-associated molecular patterns; eNOS, endothelial-derived nitric oxide synthase; iNOS, inducible nitric oxide synthase; NO, nitric oxide. Adapted with permission from [19].

FIGURE 2

The figure represents a potential model to explain how the interactions between sepsis-induced microvascular dysfunction, inflammation and the metabolic response from TECs interact. It is still unknown if these are the only interactions, if the directions of the interactions are correct, and what is the sequence of events that spins this injury-response cycle into reverberation. Here, the response of the TEC to injury is governed by metabolic reprogramming. Through this, the TEC is able to optimize energy production and prioritize energy expenditure, while supporting the necessary supply of carbon, nitrogen and other components for the synthesis of proteins and structural components necessary to mount an innate immune response. This may be achieved early on by activating a series of master regulators of cellular metabolism that ultimately are capable of switching between aerobic glycolysis and OXPHOS, and engaging other processes necessary for the survival of the cell such as autophagy (mitophagy) and biogenesis. In addition, cell cycle arrest may be a complementary important protective strategy to avoid the overtaxing energy expenditure and the risk of replicating damaged DNA during mitosis, particularly in the context of scarce energy resources. AKI, acute kidney injury; DAMPs, damage-associated molecular patterns; OXPHOS, oxidative phosphorylation; TEC, tubular epithelial cell. Bottom panel is adapted with permission from [37], and cell cycle panel is adapted with permission from [38■].