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• W2045806812 abstract "Sepsis is the most common cause of acute kidney injury (AKI) (1). The expanding population of patients with sepsis and AKI and the associated excess in mortality provide strong basis for basic research aimed at elucidating mechanisms underlying their complex pathophysiology. Both hemodynamic and nonhemodynamic pathogenic pathways contribute to development of septic AKI (2). Renal microcirculation has recently received considerable attention as a possible causative feature in septic AKI, and several experimental studies provided direct evidence for the role of renal microvascular injury in septic AKI (3). Although damage to the renal microcirculation and resulting tissue hypoxia may constitute early critical steps in the development of septic AKI, the precise understanding of the role and fate of kidney tissue oxygenation in sepsis remains enigmatic. In particular, lack of techniques enabling to directly visualize the unique architecture of the kidney microcirculation both in the cortex and medulla and exact online measurements of oxygen tension in the corresponding areas represent the main impediments to the study of intrarenal oxygenation. A welcome step further in the challenge of in vivo monitoring of renal oxygen kinetics and microcirculation has been made by Dyson et al. (4) in this issue of Shock. In their 4-h rat model, the authors simultaneously studied renal artery blood flow, microvascular and interstitial oxygen tensions in the renal cortex and medulla using ultrasonic flowmetry, dual wavelength phosphorimetry, and tissue oxygen tension, respectively. The aim was to examine the response of microvascular and interstitial oxygenation in the cortex and medulla to an endotoxin challenge. The authors found that after a short drop of medullar oxygen tension with subsequent return to baseline levels, both cortical and medullar microvascular and interstitial oxygen tensions decreased following the decline in renal blood flow. Despite this decrease in renal blood flow and oxygen delivery as well as a fall in urine output, renal oxygen consumption was maintained, and the microvascular (μpO2)-interstitial (tpO2) oxygen gradient was not affected. The authors conclude that unaltered gradient between μpO2 and tpO2 in parallel to reduced urine output could reflect either a functional or an adaptive response. The article by Dyson et al. (4) is innovative in that it is one of the first to exploit the information contained in the simultaneous assessment of oxygen kinetics in different renal tissue compartments and within different tissue levels (i.e., microvascular and interstitial) during endotoxemia. However, the real question is what do these results imply? Generally, oxygen gradients in the tissue are determined by the combined effects of cellular metabolism and the diffusion coefficient of oxygen in the interstitial fluid and intracellular milieu (5). Assuming that the diffusion coefficient of oxygen in the extracellular and intracellular compartments is relatively stable for a given tissue (5), the cellular energy metabolism should create the main driving force for cellular oxygen uptake. The unchanged and relatively large oxygen gradient between intravascular and extravascular compartments together with significantly increased tissue oxygen extraction suggests well maintained capacity of cells to utilize oxygen in this early phase of endotoxemia. The ability to increase oxygen extraction under endotoxemic conditions of diminished oxygen delivery is in agreement with the results of Heemskerk et al. (6), where oxygen kinetics was based on measurements of arterial oxygen content and appropriate calculation of renal oxygen consumption from arteriovenous difference and renal plasma flow. Similarly, we could demonstrate well-maintained renal oxygen consumption despite an apparent tissue metabolic stress as evidenced by gradually worsened renal venous lactate/pyruvate ratio and regional acidosis in a long-term porcine sepsis (7). Although one could interpret the unaltered μpO2-tpO2 oxygen gradient as an indicator of sufficient microvascular oxygenation, the opposite is probably true. Indeed, in endotoxemic rats, the same group of authors provided evidence for the presence of microvascular hypoxic areas, albeit renal oxygen consumption was not significantly reduced and no hypoxia was detected in the average microcirculatory PO2 measurements (8). Nevertheless, to fully understand the fate of renal oxygenation, several factors regulating intrarenal oxygenation have to be taken into consideration: local perfusion, local oxygen consumption, arterial-to-venous oxygen shunting, and cellular energetic status (9). The second interesting question is: Where does the oxygen go? As approximately 80% of renal oxygen consumption is used to drive tubular transport processes (10), one would expect oxygen uptake to drop in conjunction with a fall in urine output. Interestingly, renal oxygen consumption remained unchanged in the study by Dyson et al. (4). In addition to the putative factors discussed by the authors themselves, namely, an increased workload due to more back-flux of sodium, consumption by activated inflammatory cells, the contribution of vascular walls to the total oxygen uptake could be taken into account. Indeed, the vascular wall, in particular under inflammatory conditions, might consume sufficient amount of oxygen to support vasomotion and synthesis of endothelial vasoactive substances (11). But where can this information lead us? Although the present study shows feasibility of such demanding techniques as phosphorimetry in small animal models, several challenges remain, and some critical aspects of the study need to be addressed. The most important limit is that of low translational potential of this study: First, the results are applicable only to this very short-term rat model of acute endotoxicosis, resulting in hypodynamic and markedly hypotensive hemodynamics. In this view, the observed decline in both cortical and medullar oxygen tension is not surprising. Second, because microvascular anatomy of rat kidney differs from that of higher-order species, the observed changes might not be replicated in other models or even humans (12). Finally, whether the interplay between unaltered renal oxygen consumption and reduced urine output indicates a functional or adaptive kidney response remains an important yet unresolved question (13). One could regard reduced glomerular filtration as an adaptive, i.e., protective, measure aimed at preventing medullary oxygen imbalance and tubular damage. However, this intriguing hypothesis has recently been challenged by a clinical study (14). In that study, renal oxygen consumption was not proportionally reduced despite 60% decrease in glomerular filtration and renal sodium resorption. Although leaving important aspects open to speculation, the studies by Dyson et al. provide further insights into the dynamic properties of intrarenal oxygen transport under pathologic conditions. In the light of their study and the methodology used, the field is ripe for continued focused investigations to unveil the complex mechanisms through which sepsis impairs renal vascular functions to engender AKI. ACKNOWLEDGMENTS This work was supported by a research grant MSM 0021620819 (replacement of and support to some vital organs)." @default.
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• W2045806812 title "Sepsis, Kidney, and Tissue Oxygenation" @default.
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