A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury

Abstract

Given that the leading clinical conditions associated with acute kidney injury (AKI), namely, sepsis, major surgery, heart failure, and hypovolemia, are all associated with shock, it is tempting to attribute all AKI to ischemia on the basis of macrohemodynamic changes. However, an increasing body of evidence has suggested that in many patients, AKI can occur in the absence of overt signs of global renal hypoperfusion. Indeed, sepsis-induced AKI can occur in the setting of normal or even increased renal blood flow. Accordingly, renal injury may not be entirely explained solely on the basis of the classic paradigm of hypoperfusion, and thus other mechanisms must come into play. Herein, we put forward a "unifying theory" to explain the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult. We propose that this response is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI.

Figure 1

Sepsis is associated with the release of damage and pathogen associated molecular patterns (DAMPs and PAMPs) into the circulation. These inflammatory mediators are derived from bacterial products as well as from the immune cells which respond to infection. Together, they constitute an alarm “danger signal” that can be recognized by and can potentially injure the tubular epithelial cell. It has been shown recently that these mediators can readily gain access to the tubular space through glomerular filtration. Specifically, LPS has been shown to be filtered through the capsule of bowman, and into the tubular fluid. Once in the tubular space, LPS can directly interact with the tubular epithelial cell which can recognize it through a TLR-4 – dependent mechanism. Alternatively, there is indirect data suggesting that inflammatory mediators released by activated leukocytes in the peritubular capillaries can stimulate the tubular epithelial cell. It is unknown however, if this stimulation occurs by direct migration of these DAMPs through the endothelial and epithelial layers, or if they exert their actions through cellular interactions activating the endothelium, stimulating dendritic cells and ultimately, triggering a response in the tubular epithelial cell.

Figure 2

Sepsis induces profound alterations in microcirculatory flow in the entire organism, and the kidney is not the exception. This alteration is characterized by a significant increment in the heterogeneity of flow, as well as an increase in the proportion of capillaries with sluggish or stop flow (represented in the figure by darker hexagons in the peritubular capillary). We have conceptualized that these areas of sluggish peritubular flow increase the transit time of activated, cytokine spilling leukocytes, and that this may set the stage for an amplification of the “danger signal” in such areas. These areas of sluggish flow have been shown to co-localize with expression of oxidative stress in the tubular epithelial cells, suggesting causation. In addition, immuno-histologic studies have shown that oxidative stress is localized to the apex of the tubular epithelial cell, and that it is associated to the formation of apical vacuoles as represented hereby in the figure. Importantly, this may explain the mechanism by which apical vacuoles are formed during sepsis-induced AKI and also the histologic phenotype. In addition, filtered LPS is recognized by S1 tubular epithelial cells through TLR-4 and is internalized via endocytosis. This event has been shown to trigger an oxidative outburst, not in the S1 segment cells, but rather in the S2 segment cells. This seems to be associated with the expression in S1, but not in S2 epithelial cells of Heme-oxigenase 1 (HO-1) and Sirt1, both highly protective against oxidative damage.^, In addition, expression of TNF receptors in the S2 segment tubular cells has led to the hypothesis that S1 cells may signal distal segments in a paracrine fashion through secretion of TNF-alpha. Finally, there is also data suggesting that this paracrine signal may also include mediators of cell cycle arrest, namely TIMP-2 and IGFBP-7.

Figure 3

Paracrine stimulation from S1 segment tubular epithelial cells produces an oxidative outburst in the S2 and S3 segment tubular epithelial cells, which is histologically appreciated by the generation of apical vacuoles. This oxidative outburst can potentially alter mitochondrial function by uncoupling respiration, which in turn leads to energetic imbalance, radical oxygen and nitrogen species (ROS/RNS) production, and loss of mitochondrial membrane potential. All of these alterations should activate apoptosis, and yet this is not seen during sepsis-induced AKI. Thus we hypothesize that the tubular epithelial cell coordinates a response to this “danger signal” that avoids triggering apoptosis and allows the cell to survive at least for a limited period of time. We submit that this response is orchestrated by mitochondria, and is centered on regulating energy metabolism by different pathways: 1. Re-prioritizes energy utilization, which inhibits electrolyte transport through cytoplasmic membranes and blocks protein synthesis; 2. Induces mitophagy, a process by which dysfunctional mitochondria are engulfed by autophagosomes, and their components are lysed and recycled as a source of energy; 3. Induces cell cycle arrest. The cell cycle is a normal process by which the cell prepares to undergo mitosis. There seems to be specific check-points along this cycle in which the cell “evaluates” whether or not there is sufficient energy to proceed to the next stage. Presumably, in the setting of energy imbalance (such as sepsis), the cell is unable to overcome such check-points and releases mediators that arrest the cycle to avoid undertaking a potentially lethal endeavor. Such mediators (TIMP-2 and IGFBP-7) have been validated as the best predictors of risk of AKI in critically ill patients, and we submit that they may be involved in first, arresting the tubular epithelial cell cycle, and second, the paracrine signaling to distal tubular cells. Finally, we hypothesize that the link between tubular injury and the dramatic decline in glomerular filtration rate is the activation of tubuloglomerular feedback. As the tubular cell down-regulates apical ionic transport, chloride accumulates in the tubular lumen. This increases the chloride load delivered to the Macula Densa, triggering Tubuloglomerular feedback (TGF). The constriction of the afferent arteriole by this mechanism decreases glomerular filtration rate, and thus reproduces the clinical phenotype of sepsis-induced AKI.