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Journal of Clinical Anesthesia (2015) 27, 175180


New insights into the mechanisms of acute

kidney injury in the intensive care unit
Seth D. Glodowski MD (Resident), Gebhard Wagener MD (Associate Professor)
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Received 26 November 2013; revised 22 August 2014; accepted 3 September 2014

Renal blood flow;
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

1.1. Definition and incidence

Evaluating renal function in the context of systemic

hemodynamics is a cornerstone of intensive care medicine.
Interventions taken in the intensive care unit (ICU) such as
use of fluids or vasoactive and inotropic agents are often
instituted with the goal of effectively resuscitating or
supporting a failing kidney and preventing acute kidney
injury (AKI). The diagnosis of AKI has been hampered by
imperfect, insensitive, and slow laboratory tests. The absence
of early sensitive markers of AKI is, in part, related to limited
understanding of AKI and affects of the ability to intervene
early and successfully. The traditional differentiation
between prerenal azotemia and AKI is a simplification that
has been challenged by recent preclinical and clinical studies.

Acute kidney injury represents an abrupt and sustained

decrease in kidney function [1]. It manifests as a decrease in
urine output followed by an increase in serum creatinine.
Most definitions of AKI are based on these 2 variables,
serum creatinine and urine output, and for a long time, there
were many different definitions of AKI that complicated the
comparison of studies and hampered clinical research. The
RIFLE (risk, injury, failure, loss of function and end-stage
kidney disease) criteria have emerged as a commonly
accepted way to define and grade the severity of AKI in
the ICU [2] (Fig. 1). Another commonly used definition was
derived from the observation that even smaller changes in
serum creatinine, for example, after cardiac surgery, affect
outcome [3]. The Acute Kidney Injury Network (AKIN)
definition defines AKI as an abrupt (within 48 hours)
reduction in kidney function with an absolute increase in
serum creatinine 0.3 mg/dL ( 26.4 mol/L) or 50%
(1.5-fold from baseline), or a reduction in urine output less
than 0.5 mL/kg per hour for more than 6 hours [4]. Both
definitions have limitations, and a third definition proposed
more recently by the Kidney Disease Improving Global

None of the authors have any conflict of interest to report.

Corresponding author at: Department of Anesthesiology, Columbia
University, P&S Box 46 (PH-5), 630 West 168th St, New York, NY
10032-3784, USA. Tel.: + 1 212 305 6494 (Office); fax: + 1 212 305 2182.
E-mail address: gw72@columbia.edu (G. Wagener).
0952-8180/ 2014 Elsevier Inc. All rights reserved.


Fig. 1 Levels of acute kidney injury as defined by the Second

International Consensus Conference of the Acute Dialysis Quality
Initiative Group: the RIFLE (Risk, injury, failure, loss of function
and end-stage kidney disease) criteria. UO = urine output; GFR =
glomerular filtration rate; SCreat = serum creatinine; ARF = acute
renal failure; ESKD = end-stage kidney disease. With open access
permission from Crit Care 2004;8(4):R20412.

Outcomes group aims to combine the advantages of RIFLE

and AKIN definitions [5]. KIDGO defined AKI as either an
increase in serum creatinine by 0.3 mg/dL within 48 hours or
an increase of serum creatinine by 1.5 times baseline, which is
known or presumed to have occurred within the prior 7 days or
a decrease of urine volume to less than 0.5 mL/kg per hour for
6 hours. The group further defined 3 stages of AKI: stage 1 is
defined as either an increase of serum creatinine by 1.5 to
1.9 times or by 0.3 mg/dL above baseline or a decrease of urine
output to less than 0.5 mL/kg per hour for 6 to 12 hours. Stage 2
is defined as an increase of serum creatinine by 2.0 to 2.9 times
baseline or a decrease of urine output to less than 0.5 mL/kg/h
for more than 12 hours. Stage 3 is defined by a tripling of
serum creatinine or an increase of serum creatinine to more
than 4.0 mg/dL or the initiation of renal replacement therapy or
anuria for more than 12 hours.
The incidence of AKI in a general surgery population has
been reported as 0.8% when AKI was defined as a
postoperative estimated creatinine clearance of 50 mL/min or
less [6]. After major surgery, however, the incidence of AKI
defined by RIFLE criteria can be as high as 36.7% and is
associated with an increase of 90-day mortality from 3%
without AKI to 11 % with any stage AKI [7]. After elective
cardiac surgery, the incidence of AKI defined by AKIN criteria
is 27.9% and the 5-year risk of death in patients with AKI was
26.5% compared with 12.1% in patients without AKI [8].
The incidence in ICU patients is significantly higher. Using
RIFLE criteria to identify the incidence of AKI, Mandelbaum
et al in 2011 [9] found an incidence of AKI of 57% in critically
ill patients and the mortality with stage 1 AKI defined by AKIN
criteria was 13.9% compared with 6.2% in patients without
AKI. Nisula et al [10] described a slightly lower incidence

S.D. Glodowski, G. Wagener

(39.3%) when using the KIDGO definition in 17 Finnish ICUs.
The 90-day mortality of patients with AKI was 33.7% compared
with 16.6% in patients without AKI. These results emphasize
the importance and clinical relevance of AKI in the ICU.
There are some common clinical scenarios that are
associated with a high incidence of AKI. For example,
patients with preexisting renal insufficiency undergoing
major cardiac surgery have a likelihood of developing AKI
after surgery. This may, however, not be evident early in the
postoperative course because hemodilution with the use of
cardiopulmonary bypass also dilutes serum creatinine
concentrations. If mannitol was added to the cardiopulmonary bypass circuit, diuresis may actually be brisk early after
surgery despite a profound renal insult. The diagnosis of AKI
in these patients is frequently delayed. After general surgery,
AKI is rare and the cause is often multifactorial: preexisting
renal insufficiency, intraoperative hypovolemia, vasopressor
use, and nephrotoxic medication may cause sufficient renal
injury to progress toward AKI. However, low urine output in
the early postoperative period may also be caused by
hypovolemia and prerenal azotemia. Early after surgery in
the postanesthesia care unit, it may difficult to differentiate
prerenal azotemia and intrinsic AKI. Serum creatinine is too
slow and insensitive to be useful in this scenario.

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

Mechanism of AKI in the ICU

integrity. The progression of AKI is typically divided into
initiation, extension, maintenance, and recovery phases. The
initiation phase refers to the primary ischemic insult, during
which parenchymal cells are underperfused to the point
where either cellular mechanisms to maintain cell integrity
break down (necrosis) or coordinated cell death pathways
are initiated (apoptosis). Histologic changes that occur
include effacement of proximal tubule brush border, dilation
of distal tubule, and formation of tubular casts [13,12].
These events result in tubular obstruction, increased
glomerular hydrostatic pressure preventing ultrafiltrate
formation, and back leak of ultrafiltrate [15]. Multiple
different pathways have been implicated in this process and
include intracellular calcium handling, xanithine signaling,
and formation of reactive oxidations species [13]. As a result
of cell damage, inflammation occurs which is exacerbated
by reperfusion. This is known as the extension phase and
associated with infiltration of the kidney by inflammatory
cells, mostly neutrophils and release of cytokines [16]. The
maintenance and recovery phases describe the restoration
of normal renal architecture through repair mechanisms
and proliferation.
As an initial response to ischemia, blood flow is
redistributed to the hypoxic medulla. However, with
prolonged or severe ischemia, Na reabsorption breaks
down, and as a result, the macula densa activates the reninangiotensin-aldosterone system and increases the afferent
arteriolar tone to decrease GFR. Without this mechanism,
GFR would remain unchanged even with nonfunctional
reabsorption, and death by dehydration would rapidly ensue.
Oliguric AKI is therefore a mechanism that sacrifices GFR to
keep the body alive and has therefore also been coined acute
renal success (not failure) [17,18].
Furthermore, intrarenal hemostasis is also altered
secondary to alterations of the damaged endothelium
[19], leukocyte activation, and adhesion to renal vascular
endothelial cells. This results in vascular stasis, imbalance between endolthelial vasodilation and vasoconstriction, and activation of complement and coagulation
cascades. The consequence of these mechanisms is
intravascular coagulation and further impediment of
oxygen delivery [19].
A frequently neglected cause of AKI is renal venous stasis
that may lead to increased intracapsular pressure and
therefore decrease perfusion pressure and oxygen delivery.
Chvojka et al [20] demonstrated in a large animal model that
increasing central venous pressures decreases renal perfusion, whereas renal oxygenation consumption remains
stable. Further evidence for increased renal venous pressure
as a cause of AKI is a retrospective study that found that not
low mean arterial pressure but increased central venous
pressure was associated with an increased risk of AKI [21].
These data challenge the current dogma of aggressive fluid
resuscitation as a treatment of AKI and merit further
investigation in prospective trials. Fig. 2 illustrates the
different mechanisms of AKI.


3.2. Septic AKI

Sepsis is the cause of AKI in approximately 33% of ICU
patients [22]. Despite its ubiquity, there is still confusion
regarding the mechanism of AKI. The traditional paradigm
argues that sepsis and septic shock result in vasodilation,
hypoperfusion, and then ischemic injury, as described above.
Renal histology specimens in patients with septic AKI at the
time of death argue for a more complex etiologic basis of
injury than the conventional ischemia/reperfusion model

3.3. Hemodynamic causes of AKI

To evaluate the role of renal perfusion in septic AKI,
Langenberg et al [25] exposed 7 sheep to intraperitoneal
Escherichia coli injection and monitored global and renal
hemodynamics with aortic and renal blood flow probes,
respectively. Over the course of 48 hours, hyperdynamic
sepsis developed with hypotension, tachycardia, and increased cardiac output. During this period, there was a rise in
serum creatinine associated with the onset of oliguria.
Interestingly, despite evidence of worsening renal function
and hypotension, RBF increased. These results confirmed
other studies demonstrating evidence of end-organ dysfunction in sepsis despite adequate or supranormal blood flow
[26]. However, other studies had conflicting results: Benes
et al [27] demonstrated an increase in renal vascular
resistance under similar experimental conditions. In their
study, sepsis was induced with an intravenous infusion of
pseudomonas or by induction of fecal peritonitis. Pigs that
developed septic AKI had a decrease in RBF and an in
increase in renal vascular resistance compared with controls,
regardless of which model of sepsis was used. Rather than
the hyperemic model Langenberg et al described, this study
demonstrated an uncoupling of renal to systemic vascular
resistance: although SVR was decreased, RVR increased.
The incongruity of renal hemodynamic responses to sepsis
between these 2 studies is reflected in a recent literature
review [28]. Of 159 studies reviewed, 99 reported decreased
RBF and 60 reported either increased or unchanged RBF.
Given that sepsis is known to cause microcirculatory
derangements in vascular beds [29], a possible explanation
for this discrepancy between increased RBF and decreased
GFR is that blood is simply being shunted past the glomerulus
secondary to efferent arteriole dilation. This is supported by
animal studies of hyperdynamic sepsis that demonstrated an
increase in urine output and creatinine clearance with
selective efferent arteriole constriction despite a decrease in
RBF [30]. Renal histology specimens from sheep with
induced septic AKI found differential expression of nitric
oxide synthase isoforms between the renal cortex and
medulla 48 hours after induction of septic AKI [31].
Although up-regulation of nitric oxide synthase was apparent
in the cortex, this was not seen in medulla specimens. This


S.D. Glodowski, G. Wagener

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

could possibly explain the pathogenesis of intrarenal

shunting. This same study failed to show significant
differences in histology between sham and septic kidneys.
Therefore, the rise in serum creatinine and oliguria seen in
septic AKI may be a consequence of microvascular
abnormalties rather than direct parenchymal damage.

3.4. Inflammatory causes of AKI

Interestingly, the inflammatory milieu of the sepsis
syndrome has been shown to cause immune cell sequestration in organs independent of preexisting damage to that
organ [32,33]. In this sense, when early hyperdynamic sepsis
develops, renal vasculature dilates similar to other vascular
beds. However, as immune cells begin to stick to renal
endothelium secondary to a systemic inflammatory response,
inflammatory cascades are initiated that result in vascular
occlusion and increased renal vascular resistance despite
continuing systemic hypotension. In other words, the
initiation of inflammatory renal damage in septic AKI is
not RBF dependent contrary to the model of ischemia/
reperfusion injury described above.

One unifying theory described by [34] is that circulating

inflammatory markers alone act directly on renal tubular
cells causing suppression of regular, energy-dependent
functions. This theory argues that microcirculatory perfusion
abnormalities result in differential delivery of toxic plasma
to different regions of the tubule resulting in the heterogeneous tubular cell dysfunction. Compounding the flow
abnormalities is an increase in tubuloglomerular feedback
induced afferent vasoconstriction caused by increased
delivery of Na to distal nephron. This is related to
malreabsorbtion, as described above. Interestingly, the
renal dysfunction in this model is related to altered cellular
function and not necessarily cell death. This is supported by
the bland histology seen in septic AKI [31].
Whether immune cells or septic inflammatory proteins are
directly responsible for the dysfunction in Septic AKI,
evidence argues against global renal blood flow being the
primary insult. The FINNAKI study prospectively examined
the role of fluid balance in all cause 90-day mortality [10].
Fluid overload was described as a value of greater than 10%
from baseline (fluid accumulation in liters divided by weight
in kilograms multiplied by 100%). In this study, there was a

Mechanism of AKI in the ICU

higher crude mortality in those with fluid overload compared
with those without. Importantly, these results were adjusted
for severity of disease and modality of renal replacement
therapy. The FINNAKI study is consistent with others that
highlighted a deleterious role of fluid therapy in septic AKI
[3537]. Therefore, interventions aimed at increasing RBF
during the early phase of septic shock, including aggressive
fluid therapy, may be futile or even counterproductive.

3.5. Nephrotoxity as a cause of AKI

Nephrotoxic drugs are commonly used in the ICU and may
exacerbate AKI. Commonly used nephrotoxic drugs include
antibiotics, especially aminoglycoside, immunosuppressive
calcineurin inhibitors, nonsteroidal anti-inflammatory drugs,
and radiocontrast.
Nonsteroidal anti-inflammatory drugs inhibit prostaglanding synthesis and therefore decrease prostaglandine
(specifically prostaglandin E2 and prostacycline)-induced
renal vasodilation [38]. Acute nephrotoxicity from calcineurin inhibitors is due to profound afferent renal arteriolar
vasoconstriction that results in reduced glomerular blood
flow and decreased GFR [39]. Chronic exposure to
calcineurin inhibitors causes artereliopathy and tubulointerstital fibrosis [40]. Aminoglycosides cause direct injury to
proximal tubular cells. Megalin receptors in the renal tubulis
are responsible for uptake of aminoglycosides and many
other ligands. Competition with these other ligands at the
megalin receptor may result in increased tubular concentrations of aminoglycosides and worsening nephrotoxicty [40].
Radiocontrast causes renal medullary vasoconstriction and a
decrease of renal blood flow [41]; however, direct tubular
toxicity may also play a role as evidenced by histopathologic
tubular necrosis after radiocontrast administration [42].
In themselves, nephrotoxic drugs are rarely the sole cause
of AKI, unless given in high doses over a long period.
Nephrotoxic drugs in combination with preexisting renal
dysfunction, sepsis, dehydration, hypotension, or vasopressor use may, however, be sufficient to cause overt AKI.

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

of a multiple renal insults (hemodynamic, septic, and
nephrotoxic) frequently in combination with preexisting
renal insufficiency.

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