REVIEW

CURRENT
OPINION Trauma-associated acute kidney injury
Zane B. Perkins a,b, Ryan W. Haines a,c, and John R. Prowle a,c,d

Purpose of review
A summary of recent research into the epidemiology, cause, management and outcomes of trauma-
associated acute kidney injury (AKI). There is an increasing focus on subtypes of AKI to better target
clinical management and future research.
Recent findings
AKI associated with trauma occurs in 20–24% of patients admitted to ICU. On the basis of creatinine and/
or urine output, AKI occurs in the first few days of traumatic illness. Although various associations have
been identified, shock and high-volume blood transfusion are the most consistent risks for development of
trauma-associated AKI. Short-term outcomes appear worse for patients with AKI, but extent of longer term
kidney function recovery remains unknown. Recent research in the general critical care population is
beginning to better inform AKI management; however, currently, preventive and supportive strategies
remain the mainstay of AKI management after trauma.
Summary
Well-designed, prospective research is required to better understand the phenotype, pathophysiology and
recovery trajectory of trauma-associated AKI. Only then can potentially unique therapeutic targets be
developed for this common subtype of AKI.
Keywords
acute kidney injury, critical care, trauma

INTRODUCTION recovers, and survivors of AKI may be prone to

Trauma is a global public health problem, responsi-
ble for one in 10 deaths, and the leading cause of life
years lost [1,2]. The WHO estimates that trauma
causes 5.1 million deaths per year worldwide, and
is responsible for over 80 million lost disability-
adjusted life years [3]. Although the majority of
trauma deaths occur soon after injury, as a result
of exsanguination or central nervous system injury,
an important group of potentially preventable
deaths occurs weeks to months later as a result of
organ failure [4,5]. Acute kidney injury (AKI) is a
common cause of organ failure in trauma patients
who survive their initial injuries. It is a heteroge-
neous condition comprising a collection of syn-
dromes that are characterized by an abrupt
decrease in kidney function [6]. Each of these syn-
dromes has a specific cause, pathogenesis, and treat-
ment, and may result in kidney dysfunction that
ranges from mild impairment to need for renal
replacement therapy (RRT). Overall, trauma patients
who develop AKI suffer worse outcomes than those
with normal kidney function, and the condition is
consistently associated with higher mortality rates
&& &&
and longer hospital admissions [7 ,8 ]. In addition,
it remains unclear to what degree kidney function
develop chronic kidney disease (CKD) and late mor-
bidity and mortality [9]. As advances in trauma
systems and care improve immediate survival, the
management of organ failure, including AKI, will
likely present a growing challenge to clinicians and
place an increasing demand on hospital resources.
This review aims to summarize the most recent
evidence on trauma-associated AKI and present an
up-to-date understanding of the epidemiology,
pathogenesis, and management of the condition.
EPIDEMIOLOGY
Over the past 15 years, the development and stan-
dardization of consensus definitions of AKI have
a
Adult Critical Care Unit, Royal London Hospital, Barts Health NHS Trust,
b
Centre for Trauma Sciences, Queen Mary University of London, cWilliam
Harvey Research Institute, Queen Mary University of London and
d
Department of Renal Medicine and Transplantation, Royal London
Hospital, Barts Health NHS Trust, London, UK
Correspondence to John R. Prowle, Adult Critical Care Unit, Royal
London Hospital, Barts Health NHS Trust, London E1 1BB, UK.
E-mail: j.prowle@qmul.ac.uk
Curr Opin Crit Care 2019, 25:565–572
DOI:10.1097/MCC.0000000000000655

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Renal system
KEY POINTS
 Trauma-associated AKI is a common complication of
major trauma, occurring in approximately one in 10
injured patients and one in four of those who require
critical care admission.
 All stages of AKI are strongly associated with adverse
patient outcomes, including increased mortality and
longer hospital admissions.
 The vast majority of cases are caused by insults
occurring at, or soon after, the time of injury such as
hypovolaemic (haemorrhagic) shock, rhabdomyolysis
or complications of excessive fluid resuscitation or
massive blood transfusion.
 Current management of trauma-associated AKI is based
on general principles of AKI management in critical
care populations and as yet, has not been tailored to
the unique aspects of the trauma phenotype.
 Research is needed to better understand the unique
characteristics of trauma-associated AKI, and to
develop targeted prevention and therapeutic strategies
that will improve outcomes in this patient population.
enabled more consistent diagnosis and staging of
this condition in injured patients, and allowed
more rigorous study of its epidemiology in trauma
populations.
These definitions include the Risk, Injury, Fail-
ure, Loss of kidney function, and End-stage kidney
disease (RIFLE) [10], later modified to the Acute Kid-
ney Injury Network (AKIN) criteria [11] and then the
Kidney Disease: Improving Global Outcomes
(KDIGO) practice guidelines [12]. Using these defi-
nitions, trauma-associated AKI has been most thor-
oughly studied in populations of injured patients
admitted to critical care units. Two recent systematic
reviews have appraised the existing literature and
&&
pooled the available data in this setting [7 ,8 ].
The pooled incidence of trauma-associated AKI in
injured patients admitted to critical care units is
approximately 20–24%. Of these cases, 56–59%
develop mild (stage 1) AKI, whereas 23–30% develop
moderate (stage 2) and 14–18% severe (stage 3) AKI.
One in 10 patients who develop AKI will require
RRT, corresponding to approximately 2% of the
&& &
total trauma population [7 ,13 ].
The reported incidence of AKI in general trauma
populations is far more variable. This variability is
because of greater clinical (e.g., differences in the
distribution of risk factors and exposures in the
study populations) and methodological (e.g., differ-
ences in the timing and criteria used to diagnose
AKI, and how baseline plasma creatinine is
estimated) heterogeneity between studies. However,
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two recent large observational studies of injured
&
patients in London [13 ] and Paris [14 ] demon-
&
strated an overall AKI incidence of 13%. Approxi-
mately 7–8% of patients developed mild AKI, 1–4%
moderate AKI, and 2–3% severe AKI. In addition, a
recent analysis of the United States National Trauma
Databank (n ¼ 988 988) showed a 0.68% incidence
&
of severe (stage 3) AKI [15 ]. The majority of cases
(75–95%) of trauma-associated AKI develop within
5 days of injury, with a median time from injury to
meeting AKI diagnostic criteria of 3 days in critical
&&
care populations [7 ] and 2 days in general trauma
& &
populations [13 ,14 ].
CAUSE AND RISK FACTORS
Several pathophysiological mechanisms may cause
AKI in trauma patients. In the vast majority (>90%),
AKI develops within the first few days following
injury, suggesting that the causal insult occurred
at, or soon after, the time of injury [7 ,13 ,14 ].
&& & &
These early causes of AKI include hypovolaemic
shock (generally because of haemorrhage following
trauma), rhabdomyolysis, direct kidney trauma, and
as a complication of massive blood transfusion.
Although less common, delayed causes of AKI are
also important, as many cases are potentially pre-
ventable. Late causes of AKI include exposure to
nephrotoxic therapies and complications, such as
sepsis and abdominal compartment syndrome.
Several clinically measurable factors are markers
of these causal mechanisms and demonstrate a
strong association with the development of AKI
(Table 1). For example, clinical markers of hypovo-
laemic shock that are strongly associated with AKI
include prehospital and admission hypotension
&& & & & &
[7 ,13 ,14 ,16 ,17,18 ], tachycardia [14 ], raised
&
& &
admission lactate [13 ,14 ,19], coagulopathy [16 ],
&
hypothermia [19], acidosis [17], volume of resusci-
&&
tation fluid administered [20], volume of blood
products transfused [7 ,13 ,14 ,19,21,22 ,23],
&& & & &&
and vasopressor requirements [14 ,20]. Many factors
&
associated with AKI may be markers of more than
one mechanism. For example, the presence of a
significant abdominal injury [7 ,23] may indicate
&&
an increased risk of hypovolaemic shock, direct
kidney trauma, or abdominal compartment syn-
drome; and treatment with antibiotics may indicate
&&
sepsis [7 ] or, with certain antibiotics, exposure to
&
nephrotoxins [13 ]. Similarly, a high Injury Severity
&& & & & &
Score [7 ,13 ,14 ,16 ,18 ,21] may act as a marker of
the degree of tissue injury, or an increased risk of
haemorrhage and hypovolaemic shock. The trauma
literature consistently shows that one of the most
important factors associated with AKI is large-vol-
ume blood transfusion [7 ,13 ,14 ,22 ]. In most
&& & & &&
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 Trauma-associated acute kidney injury Perkins et al.

Table 1. Causes, pathophysiological mechanisms, and predictors of trauma-associated acute kidney injury

Cause Pathophysiological mechanisms Clinical markers (predictors)

Hypovolaemia 1) Decreased kidney perfusion secondary to Hypotension (Prehospital/admission)

(Haemorrhagic shock)
Rhabdomyolysis
Direct kidney trauma
Massive blood transfusion
Nephrotoxins
Sepsis
Abdominal compartment syndrome
systemic hypoperfusion Tachycardia
2) Marked changes in glomerular haemodynamics Raised admission lactate
secondary to sympathetic and renin– Acute traumatic coagulopathy
angiotensin–aldosterone system activation Hypothermia
3) Kidney tissue hypoxia/ischaemia Acidosis
4) Microvascular and inflammatory responses to Large volume of fluid resuscitation
ischaemia–reperfusion Volume of blood products transfused
Vasopressor requirements
1) Direct myoglobin-mediated proximal tubule Peak serum CK
cytotoxicity Serum myoglobin
2) Intrarenal vasoconstriction-mediated ischaemic Serum phosphate
tubule injury Injury Severity Score
3) Distal tubule obstruction secondary to cast
formation
1) Kidney destruction or avulsion Significant abdominal injury
2) Devascularization of kidney parenchyma with Haematuria
loss of function
1) Direct haem-protein-(haemoglobin, myoglobin) Volume of blood products transfused
mediated proximal tubule cytotoxicity
2) Transfusion-related immunosuppression
1) Direct kidney toxicity Administration of nephrotoxic medication [i.e.,
2) Indirect kidney injury secondary to drug-induced aminoglycosides, amphotericin B,
compromise of kidney perfusion angiotensin-converting enzyme (ACE)
3) Tubular lumen obstruction secondary to inhibitors, angiotensin-receptor blockers, non-
precipitation steroidal anti-inflammatory drugs (NSAIDs),
and diuretics]
1) Decreased kidney perfusion secondary to: Pyrexia
Systemic hypotension and efferent arteriole Tachycardia
vasodilation Tachypnoea
Effects of inflammatory mediators on White cell count (low or raised)
microcirculation Hypotension
2) Endothelial and kidney tubular cell inflammatory Raised lactate
injuries Antibiotic administration
1) External kidney compression by raised intra- Large-volume crystalloid resuscitation
abdominal pressure compromising kidney Significant abdominal injury
perfusion
2) Kidney interstitial oedema secondary to
excessive crystalloid resuscitation

Risk factors

Older age
Diabetes mellitus
Chronic hypertension
Chronic kidney disease
African race
Obesity

cases, the volume of blood transfusion is likely a
surrogate marker of haemorrhagic (hypovolaemic)
shock. Regardless, studies have reported the associ-
ation of blood transfusion over other measures of
injury severity with AKI suggesting additional trans-
fusion specific risk factors, including transfusion-
related immunosuppression [24] and/or exposure
to products of haemolysis, plasma free haem, and
iron [25,26]. Overall, AKI following trauma is
usually multifactorial, with several potential causal
insults exerting a combined effect, and it may not be
possible to differentiate the individual contribution
of each insult.
Exposure to iodinated contrast material is
believed to be an important cause of avoidable
AKI. However, the evidence to support a causal
relationship between current low- or iso-osmolality
contrast agents and AKI is weak. Recent studies

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Renal system
suggest that the risk of contrast-associated AKI has
& &
been overestimated [27 ], and the clinical impor-
tance of this condition, true toxic effects of contrast
materials in current use, and justification for limit-
ing contrast use have all been called into question
&&
[28 ]. Indeed, large meta-analyses of mixed hospital
populations demonstrate no significant difference
in the risk of AKI, need for RRT, or mortality,
between patients who underwent procedures with
IV administration of contrast material and those
&&
who underwent procedures without [29 ,30]. A
recent meta-analysis of trauma populations showed
similar results, with a lower risk of AKI in trauma
patients who received contrast material compared
&&
to those who did not [7 ]. Certainly, there is no
evidence to justify limiting the use of diagnostic and
therapeutic contrast procedures in trauma patients
because of concerns of contrast-associated AKI.
Risk factors
Trauma may affect any member of society, and
while the average trauma patient is young with
no comorbidities, some injured patients may have
preexisting risk factors that make them more sus-
ceptible to developing AKI for a given causal insult.
These risk factors are common to any form of AKI;
however, more robust estimates of the magnitude
of effect in trauma populations have been reported
in recent studies. Important patient factors shown
to increase the risk of developing AKI following
injury are older age (odds ratio (OR) 2.1), diabetes
mellitus (OR 2.4), chronic hypertension (OR 1.8),
CKD (OR 3.9), obesity (OR 2.1), and African race
&& &
(OR 1.6) [7 ,15 ,31]. Female sex is a recognized risk
factor for nonspecific AKI [12]. However, there is
conflicting evidence on the effect of sex in the
trauma literature, with reports of greater risk in
&& & & &&
women [32], men [7 ,18 ], or no effect [13 ,22 ]
in various recent studies. The true effect of sex on
AKI risk is difficult to determine in trauma
populations, as important confounders are not
evenly distributed between male and female
patient groups.
DIRECT KIDNEY TRAUMA
Direct kidney trauma may be caused by blunt or
penetrating mechanisms of injury and severity is
graded (I–V) using the American Association for the
&&
Surgery of Trauma Organ Injury Scale [33 ]. Low-
grade (I–III) injuries are confined to the capsule and/
or parenchyma, whereas high-grade injuries involve
the major renal vessels and/or collecting system.
There is an increasing trend towards managing kid-
ney trauma nonoperatively, which is associated
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with improved kidney preservation and decreased
morbidity [34 ]. However, attempts at kidney pres-
ervation must not take precedence over achieving
rapid haemostasis in the haemodynamically unsta-
&&
ble patient [33 ]. Overall, direct kidney trauma is
associated with a four-fold to eight-fold increase risk
& &
of developing AKI [13 ,14 ], and devascularization
of 25% or more kidney parenchyma is an indepen-
dent predictor of long-term kidney dysfunction
[35,36].
PATHOPHYSIOLOGY
As trauma-associated AKI is a heterogeneous condi-
tion with multiple possible causes, several distinct
pathophysiological mechanisms may be at play
(Table 1). These mechanisms include marked alter-
ations to systemic and glomerular haemodynamics
resulting in decreased kidney blood flow and ischae-
mic kidney injury; local and systemic release of
inflammatory mediators resulting in a kidney
inflammatory response with secondary injury to
endothelium, microcirculation, and tubular cells;
nephrotoxicity; and direct trauma resulting in
devascularized kidney parenchyma (Fig. 1).
MANAGEMENT
The latest evidence evaluating aspects of AKI pre-
vention and management often include none or
relatively few critically ill trauma patients. We can
make inferences regarding management from stud-
ies of other AKI subtypes, including postoperative
AKI, but with the caveat that trauma-associated AKI
has unique aspects and often involves a more het-
erogeneous group of critically ill patients [37]. Early
in the time course of a trauma patient’s journey
from prehospital management to immediate life-
saving surgery, the prevention and management
of AKI is secondary. Modern trauma management,
including permissive hypotension, early use of
blood products, and damage control surgery, has
improved prehospital and in-hospital mortality
[38,39]. These necessary management steps place
significant demands on kidney function and their
marriage with the recommended approach to pre-
vent and manage AKI is often not possible. The
Kidney Disease: Improving Global Outcomes AKI
guideline provides guidance on best supportive care,
but its constituent elements are generally only sug-
gestions with, on the whole, low-quality evidence in
support [40]. This requires clinicians to adapt these
measures appropriately to individual patients and
clinical scenarios. After the initial 24 h of trauma
management, often when patients are managed in
critical care, elements of the best supportive care
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 Trauma-associated acute kidney injury Perkins et al.

FIGURE 1. Principal pathophysiological mechanisms of acute kidney injury following trauma.

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Renal system
need to be tailored to trauma patients diagnosed
with or at high risk of AKI.
Volume and choice of fluid therapy require con-
sideration in the management of trauma patients in
both early resuscitation and in later stages of manage-
ment. Commonly blood products are the preferred
resuscitation choice and crystalloids often avoided
[41]. As discussed previously, high-volume transfusion
requirement is consistently associated with AKI after
trauma. Reducing the exposure to blood products
beyond what is necessary during resuscitation seems
prudent and despite no prospective evidence, may
plausibly lessen AKI. Restrictive versus liberal transfu-
sion targets, in patients who are not actively bleeding,
have been shown to be safe in other critically ill
cohorts, such as cardiac surgery [42].
Modern trauma management restricts the use of
crystalloid therapy in the prehospital and acute resus-
citation setting [41]. Recent observational research
consistently shows increased mortality in patients
with more liberal use of crystalloids during the first
24–48 h of admission in adult [43] and paediatric
trauma patients [44]. There is growing evidence that
more restrictive use of fluid throughout the time
course of critical illness, beyond the initial resuscita-
tion period, could have the potential to be of benefit
[45,46] with more liberal fluid approaches over the
first 7 days of trauma admission associated with worse
morbidity, including ventilatory days and length of
ICU stay [47]. The adoption of more restrictive use of
fluid and impact on morality and AKI is being tested
in multicentre randomised controlled trials (RCTs) of
patients with septic shock (The Conservative vs. Lib-
eral Approach to Fluid Therapy of Septic Shock in
Intensive Care Trial, CLASSIC, NCT03668236). If
ongoing RCTs confirm observational findings, the
application of fluid restriction to trauma patients will
need appropriate investigation. When fluid is
required, crystalloids remain a common fluid choice
both prehospitally and during critical care admission.
The use of balanced solutions compared to isotonic
saline (0.9% salt solution), especially when larger
volumes are required, is seen as a safer option in
general critical care patients [48,49].
Hypotensive resuscitation has been shown to
demonstrate a benefit on mortality and a recent
meta-analysis reported no increase in the incidence
of AKI when this strategy was applied [50]. There are
little data examining blood pressure targets beyond
24 h of traumatic injury. Therefore, clinicians car-
ing for patients after major trauma adhere to gen-
eral, recommended perfusion parameters, often a
mean arterial pressure (MAP) of at least 65 mmHg.
Vasopressors are regularly used in this phase of
illness and ongoing research is awaited to help
guide choice of vasopressors. Most recently, the
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use of angiotensin II in patients with shock showed
a signal that its use compared to other vasopressors
may modify the occurrence and severity of AKI and
offer a potential rescue therapy in refractory
vasoplegia [51].
Rhabdomyolysis is common in trauma patients
with specific management protocols often initiated
when the creatine kinase level is greater than
5000 U/L. Prevention of AKI associated with rhab-
domyolysis involves the recognition and treatment
of the underlying cause (relief of compartment syn-
drome) and maintenance of urine output to limit
the precipitation of casts in the kidney tubules.
Recognition of compartment syndrome in a sedated
polytrauma patient can be difficult and highlights
the importance of secondary and tertiary surveys.
Current practice involves a protocol-driven
approach to achieve a urine output of more than
2 ml/kg/h with the use of loop diuretics and 1.26%
bicarbonate to achieve urinary alkalinization [52].
The evidence for the use of high-volume haemofil-
tration or super high flux haemodialysis remains
limited to case series [53].
The evidence guiding all RRTs in trauma is
limited but until recently this is true of its use in
critically ill patients in general. Timing of RRT initi-
ation is debated and there remain uncertainties
despite recent RCTs [54,55]. Often, immediate or
intraoperative RRT to combat the impact of massive
transfusion is required, commonly at higher than
standard protocol clearance rates to achieve electro-
lyte homeostasis. For this reason, in the most
severely injured patients with high burdens of tissue
injury, frequent venous and/or arterial blood sam-
pling is required coupled with the rapid availability
of RRT, including during emergent surgery. When to
initiate RRT becomes less clear later in the clinical
course, when AKI is present, often more than 24 h
from admission. The ELAIN study (Effect of Early vs.
Delayed Initiation of Renal Replacement Therapy
on Mortality in Critically Ill Patients With Acute
Kidney Injury), for which 12% of patients in both
early and late groups had the admission diagnosis of
polytrauma, suggested a benefit of early RRT [54].
The AKIKI (Artificial Kidney Initiation in Kidney
Injury), which included no trauma patients but
15% of patients in each group had emergency sur-
gery, showed no mortality benefit [55]. Faced with
conflicting outcomes and limited numbers of
trauma patients in trials of RRT, its use in patients
for trauma-associated AKI relies on best practice and
expert recommendation. By using the Acute Dialysis
Quality Initiative recommendations, aspects of
RRT need to be tailored to the needs of each patient
and considered within a supply and demand
framework [56].
Volume 25  Number 6  December 2019

The impact of trauma-associated AKI on patient
outcomes follows the negative association seen in
other critically ill groups. However, the independent
causality of AKI and both mortality and recovery of
kidney function is complex. Two recent, systematic
reviews highlighted the impact of mortality on AKI,
&& &&
worsening with increasing AKI severity [7 ,8 ].
Although liberation from RRT before hospital dis-
charge is usual in the absence of bilateral kidney
infarction, the extent of kidney recovery after
trauma-associated AKI remains uncertain and has
the potential to be influential in long-term
patient outcomes.
CONCLUSION
Trauma-associated AKI is common, predictable, and
associated with poor patient outcomes. Well-
designed research is warranted to better understand
the phenotype, pathophysiology, and long-term
recovery of this complication, and to translate this
knowledge into novel prevention and therapeutic
interventions that will improve outcome in this
patient population.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 25  Number 6  December 2019