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Keywords:
Renal blood flow;
Sepsis;
Septic AKI;
Ischemia reperfusion injury;
RIFLE criteria;
Renal autoregulation
Abstract Acute kidney injury is a frequent complication in the intensive care unit that is associated with
increased mortality and morbidity. Traditional models consider reductions of global renal blood flow as
the cause of acute kidney injury. However, a complex interplay between ischemia-reperfusion injury
and inflammation may lead to intrarenal hypoperfusion and acute kidney injury. The role of changes of
global renal blood flow as a cause for acute kidney injury remains controversial, especially in sepsisinduced acute kidney injury.
2014 Elsevier Inc. All rights reserved.
1. Introduction
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2. Renal physiology
The kidney is exquisitely sensitive to hypoxic injury due to
the precarious match of renal blood flow (RBF) to oxygen
utilization. Tubular cells of the renal medullary thick ascending
limb have the highest oxygen extraction ratio (oxygen
consumption [VO2] to oxygen delivery [DO2] ratio) of any
cell in the human body; approximately 80% of delivered oxygen
is used [11]. This results in a relatively hypoxic renal medulla
with a tissue pO2 of around 10 to 20 mm Hg [12]. These high O2
requirements of the medullary thick ascending limb are due to
Na reabsorbtion, which is a highly ATP-dependent process.
Interestingly, Na reabsorption and therefore O2 consumption are
closely correlated with glomerular filtration rate (GFR); the
more ultrafiltrate is delivered to the distal nephron, the more Na
is reabsorbed, and consequently, the more oxygen consumed.
This flow dependence is inherently matched by peritubular
perfusion so that VO2/DO2 relationship does not reach a critical
value under physiologic conditions [11]. In other words,
although increased blood flow to the kidney may increase
GFR, it will also increase peritubular perfusion, and thus,
oxygen consumption and oxygen delivery should be matched.
3. Mechanisms of AKI
3.1. Ischemia/Reperfusion
Renal ischemia secondary to hypoperfusion triggers a
cascade of events that results in loss of renal cellular
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178
Fig. 2 Pathophysiologic mechanisms of ischemic acute tubular necrosis. Tubular injury is a direct consequence of metabolic pathways
activated by ischemia but is potentiated by inflammation and microvascular compromise. The inset shows shedding of epithelial cells and
denudation of the basement membrane in the proximal tubule, with back leak of filtrate (inset, left) and obstruction by sloughed cells in the
distal tubule (inset, right). ATP = adenosine triphosphate; ATPase = adenosine triphosphatase. With permission from N Engl J Med
2007;357:797805.
4. Summary
Renal ischemia-reperfusion causes profound changes of
the intrarenal milieu. The oxygen-starved cells of the thick
ascending loop are most affected by the breakdown of
oxygen delivery. The feedback mechanism of the macula
densa and the renin-angiontensin system is the cause of
nonoliguria and therefore prevents massive fluid loss and
death by dehydration. The main mechanisms of AKI in
sepsis are in many ways similar to the conventional models
of ischemia-reperfusion injury, even if specific inflammatory
signaling may be more prominent with AKI in sepsis. It is
important to remember that any of the causes rarely occur in
isolation and most patients who develop AKI do so because
179
of a multiple renal insults (hemodynamic, septic, and
nephrotoxic) frequently in combination with preexisting
renal insufficiency.
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