Viewpoint

Acute Kidney Stress and Prevention of Acute

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Kidney Injury
Nevin M. Katz, MD1–3; John A. Kellum, MD4; Claudio Ronco, MD5

Abstract: Critical care physicians continue to be challenged to be instituted to prevent the short- and long-term consequences
recognize an environment that has the potential to result in acute of AKI.
kidney injury, with its associated short- and long-term conse- A variety of renal biomarkers have now been identified and
quences. The recent development of cell cycle arrest biomark- have the potential to enhance the understanding and diagnosis
ers that signal the potential development of acute kidney injury is of AKI, particularly as biomarker monitoring is combined with
part of an evolution in the molecular diagnosis and understanding monitoring changes in renal function (2). The identification of
of acute kidney injury. A preinjury phase that may lead to acute cell cycle arrest biomarkers that signal the potential develop-
kidney injury has been described as “acute kidney stress.” This ment of AKI is part of an evolution in the molecular diagnosis
concept has the potential to stimulate research and innovation and understanding of AKI (3). These cell cycle arrest biomarkers
that will lead to early implementation of measures to prevent or are released by kidney cells during injury or stress and have been
reverse acute kidney injury. recognized as potentially valuable markers of renal stress along
Key Words: acute kidney injury; acute kidney stress; cell cycle a path which may lead to AKI (4) (Fig. 1). The release of these
arrest biomarkers; renal ischemia biomarkers has been reported to predict AKI in patients with
sepsis, with and without other organ failures (5). The kinetics
of the cell cycle arrest biomarkers for AKI have been described
relating the rise to the cumulative number of exposures to renal

E
arly diagnosis of acute kidney injury (AKI) continues to insults, as well as the specific type of exposure (6).
challenge clinicians. The delay in elevation of serum cre- A preinjury phase that may lead to AKI has been termed
atinine to approximately 24 to 48 hours after AKI makes acute kidney stress (AKS). The term “AKS” seems appropriate
this standard renal function test inadequate for the early diag- as the understanding of AKI evolves, and provides a concept to
nosis of AKI. This may be especially true in sepsis where large encourage research and technology innovation which address
volume resuscitation or in cardiac surgery patients where the the challenge to detect situations where the kidney is in danger
pump prime dilutes the patient’s plasma. The occurrence of of sustaining injury (7).
AKI has been well documented to be associated with increased
morbidity and mortality in the short term and may result in
chronic kidney disease with its effect on long-term survival (1). THE CONCEPT OF STRESS
Early recognition of an unfavorable “environment,” which can The mechanisms of AKS have been conceptualized in several
lead to AKI, is important so that changes in management can ways with different clinical implications: pre-injury, functional
load, and preconditioning.
All three concepts have grounding in the classic defini-
1
Department of Surgery, Johns Hopkins University, Baltimore, MD. tions of stress—negative stress evolving into strain and injury;
2
Department of Surgery, George Washington University, Washington, DC. stress in an engineering context; and stress leading to protec-
3
Foundation for the Advancement of Cardiothoracic Surgical Care, Mc- tive mechanisms. All three have potential utility at the bedside.
Lean, VA.
Detecting stress might allow the clinician to alleviate it prior
4
Department of Critical Care Medicine, Center for Critical Care Ne-
phrology, University of Pittsburgh, Pittsburgh, PA. to injury. For example, detecting stress due to ischemia, which
5
Department of Nephrology, Dialysis & Renal Transplantation, International can have multiple effects on the nephron, can alert physicians
Renal Research Institute Vicenza (IRRIV), San Bortolo Hospital, Vicenza, to make hemodynamic changes before AKI occurs.
Italy. Some forms of stress may lead to decreased function (e.g.,
Dr. Kellum and his institution received funding from Astute Medical. The dehydration leading to azotemia) while other forms of stress
remaining authors have disclosed that they do not have any potential con-
flicts of interest. increase function, for example, a protein load can lead to
For information regarding this article, E-mail: nevinkatz@aol.com increased glomerular filtration rate (GFR) (8). Inducing stress
Copyright © 2019 by the Society of Critical Care Medicine and Wolters can probe functional capacity and expose vulnerability and
Kluwer Health, Inc. All Rights Reserved. work as a stress test (9) and/or make the organ better prepared
DOI: 10.1097/CCM.0000000000003738 for subsequent challenge (preconditioning) (10).

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Katz et al

provoke a reaction. A positive

reaction meets the demand
while a negative reaction can
reveal pathology. In a cardiac
stress test, a positive reaction
occurs when cardiac output
increases without evidence of
myocardial ischemia. A renal
stress test can be performed
using a protein load (8) where
a positive reaction is an in-
crease in GFR and a negative
reaction is a failure to increase.
The organ that fails to increase
is presumed to be hyper-fil-
tering to achieve a “normal
GFR” at rest. A furosemide
“stress” test probes tubular
function because an intact or-
ganic transporter system must
exist for furosemide to work
(11). However, the action of
furosemide is to block tubular
Figure 1. Depicted is the relationship between acute kidney stress (AKS) and acute kidney injury (AKI). In the “work” rather than increase
early phases of AKS, cell structure is normal and cell function may or may not be impaired (depicted by open
arrows). Organ function is not yet impaired, and hence functional markers will not be increased. However, the it. Increases in function load
stress response will already exhibit molecular changes. If unchecked, AKS may progress to AKI with evolving may lead to kidney stress as re-
cell damage. Still, even at this stage organ function may not be impaired because of the capacity of organ func- flected in cell cycle arrest bio-
tional reserve to compensate. As AKI progresses cell loss, both in the form of cell death, (necrosis, apoptosis
ferroptosis), as well as shedding of injured but viable cells, will inevitably result in organ dysfunction. markers (13).

For the purpose of this review, we define stress to include Preconditioning

all three meanings and examine potential inducers, modifiers, As with exercise, controlled stress can induce a variety of posi-
and markers of stress. We also note that different parts of the tive responses that increase the ability of the organism to cope
nephron may experience stress differently. For example, a pro- with subsequent stress. In medicine, the concept of precondi-
tein load might stress glomerular function (8), whereas a furo- tioning has been advanced to describe a pattern of responses
semide load tests tubular function (11). Finally, we believe it is that are protective and can be invoked by sub-injurious stim-
important to clarify that stress may be associated with stress- uli. For example, a brief episode of ischemia can protect the
gene induction (12) or it may not. A specific stress response kidney from subsequent prolonged ischemic injury. There is
may involve up (or down)-regulation of gene expression, but even evidence that preconditioning can be invoked by stimu-
this expression is not an especial feature of stress. lating distant tissues—remote ischemic preconditioning (10).
The mechanisms underlying this effect are unclear but appear
Pre-Injury to involve both neural and humoral components. Thus, stress
Conceptually, stress will always precede injury (Fig. 1). However, of this sort evokes protective strategies at the cellular level.
many forms of AKI likely result from the accumulation of renal
insults. As these insults accumulate (e.g., hypoperfusion or doses
of a nephrotoxin) the kidney begins to experience stress and then DEVELOPMENT OF AN AKS SCORING
later, becomes injured. The relationship between pre-injury and SYSTEM
function may be variable. There is now robust evidence that the cell An AKS scoring system could be used to alert clinicians that
cycle modulators, tissue inhibitor of metalloproteinase-2 (TIMP- clinical adjustments are needed to prevent AKI, by using goal-
2) and insulin-like growth factor-binding protein 7 (IGFPB7), are directed protocols to address the relevant issues. A variety of
markers of renal stress (4). TIMP-2 and IGFBP7 increase with clinical factors have been associated with the development of
exposure to injurious stimuli and do so before cell death occurs. AKI associated with cardiac surgery (CSA-AKI) (14). Investi-
Thus, they are markers of preinjury stress even though cell cycle gators have recognized that the etiology of AKI is complex and
arrest may be a protective mechanism against AKI. assessment of renal hemodynamics is important (15). Never-
theless, the development of a system of diagnostic criteria for
Functional Load AKS needs to be based on variables that are readily available in
In physics, stress is pressure or tension exerted on a material operating rooms and ICUs, in regards to standard monitoring
object. Demand placed on a biologic system is expected to equipment, laboratory tests, and timely availability.

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 Viewpoint

The variable urine output has been important in AKI clas- AKS alert protocols could also include review of all phar-
sification systems such as Risk, Injury, Failure, Loss of kidney macologic agents to ensure that agents that have nephrotoxic
function, and End-stage kidney disease (RIFLE), Acute Kidney properties are discontinued, or their doses adjusted appropri-
Injury Network classification of AKI, and Kidney Disease: ately. AKS alert protocols could lead to the early institution
Improving Global Outcome classification of AKI. “These cri- of renal replacement therapy (RRT). Early initiation of RRT
teria” have importantly refined the knowledge base of CSA- has been associated with reduced mortality in some critically
AKI and facilitate its early management (16). Importantly, in ill patients (24). The favorable effect of continuous versus in-
adults, technology to monitor renal blood flow has yet to be termittent RRT, in the ICU on renal recovery at hospital dis-
developed. However, urine flow is often dissociated from renal charge, has also been reported (25).
perfusion, and urine output alone, as a variable to predict AKI,
has not been considered adequate (17).
CONCLUSIONS AND RECOMMENDATIONS
Hemodynamics clearly are an important determinant of renal
The detection of AKS remains a challenge and is important so
blood flow. The Acute Dialysis Quality Initiative (ADQI) XIII
that corrective measures can be instituted before the kidney
Work Group described new treatment targets for renal hemo-
sustains injury. Protocols to prevent AKI have been described
dynamics to address the challenges of preventing and treating
and can be enhanced as more studies of AKS are available. In
AKI (15). The use of cerebral oximetry to detect blood pressure
that the physiology and consequences of AKS are complex,
excursions below the cerebral autoregulation threshold represents
the development of an AKS scoring system would be valu-
an innovative technology to alert physicians to hemodynamics
able to alert physicians when the operating room or critical
that may jeopardize flow to various organs and potentially re-
care environment is unfavorable and likely will lead to AKI.
sult in AKI (18). Such technology is now available for monitoring
Such a scoring system could involve criteria for urine output,
patients in the operating room and in ICUs. However, obstructive
mean arterial pressure, oxygen delivery, and elevation of cell
lesions in the renal arterial vasculature and use of vasoconstric-
cycle arrest biomarkers. Studies to test the validity of a scoring
tive agents can impair renal blood flow in the presence of systemic
system could lead to new protocols to prevent or reduce AKI.
blood pressure and cardiac output that are in the normal ranges
Innovative technology to directly measure renal blood flow
for critically ill patients. Oxygen delivery has been identified as an
and/or GFR could also be an important development.
important risk factor for AKI (19, 20).
A variety of renal biomarkers have now been identified and
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