REVIEwS

Immunopathophysiology of
trauma-​related acute kidney injury
David A. C. Messerer 1,2, Rebecca Halbgebauer 1, Bo Nilsson3, Hermann Pavenstädt4,
Peter Radermacher5 and Markus Huber-​Lang 1 ✉
Abstract | Physical trauma can affect any individual and is globally accountable for more than
one in every ten deaths. Although direct severe kidney trauma is relatively infrequent, extrarenal
tissue trauma frequently results in the development of acute kidney injury (AKI). Various causes,
including haemorrhagic shock, rhabdomyolysis, use of nephrotoxic drugs and infectious
complications, can trigger and exacerbate trauma-​related AKI (TRAKI), particularly in the
presence of pre-​existing or trauma-​specific risk factors. Injured, hypoxic and ischaemic tissues
expose the organism to damage-​associated and pathogen-​associated molecular patterns, and
oxidative stress, all of which initiate a complex immunopathophysiological response that results
in macrocirculatory and microcirculatory disturbances in the kidney, and functional impairment.
The simultaneous activation of components of innate immunity, including leukocytes, coagulation
factors and complement proteins, drives kidney inflammation, glomerular and tubular damage,
and breakdown of the blood–urine barrier. This immune response is also an integral part of the
intense post-​trauma crosstalk between the kidneys, the nervous system and other organs, which
aggravates multi-​organ dysfunction. Necessary lifesaving procedures used in trauma management
might have ambivalent effects as they stabilize injured tissue and organs while simultaneously
exacerbating kidney injury. Consequently, only a small number of pathophysiological and
immunomodulatory therapeutic targets for TRAKI prevention have been proposed and evaluated.

1
Institute of Clinical and
Experimental Trauma
Immunology, University
Hospital Ulm, Ulm, Germany.
2
Department of
Anaesthesiology and
Intensive Care Medicine,
University Hospital Ulm,
Ulm, Germany.
3
Department of Immunology,
Genetics and Pathology,
Rudbeck Laboratory Uppsala
University, Uppsala, Sweden.
4
Internal Medicine D,
University Hospital Muenster,
Muenster, Germany.
5
Institute of Anaesthesiological
Pathophysiology and Process
Development, University
Hospital Ulm, Ulm, Germany.
✉e-​mail: markus.huber-​lang@
uniklinik-​ulm.de
https://doi.org/10.1038/
s41581-020-00344-9
Physical trauma is a major cause of hospital admission.
Despite effective diagnostic and therapeutic strategies,
trauma remains accountable for more than one in ten
deaths worldwide1,2. The brain, thorax and extremities
are frequent trauma injury sites, followed by the abdo-
men and spinal cord (Fig. 1). A major complication of any
severe injury pattern is the progression to post-​traumatic
multi-​organ dysfunction syndrome (MODS), which fre-
quently results in kidney failure and death3–5. Acute kidney
injury (AKI) induced by severe injuries is as prevalent in
patients with trauma as coagulopathy — 24% of patients
with trauma who require intensive care develop AKI, of
whom ~10% require kidney replacement therapy5,6.
The severity of trauma-​induced injury depends
on the extent of the structural tissue damage inflicted by
the trauma force vector. Intracellular damage is sensed
by cytosolic receptors, including nucleotide-​binding
oligomerization domain-​like receptors7, which trig-
ger an inflammatory response. Traumatized or dying
cells also release various damage-​associated molecular
patterns (DAMPs) into the extracellular milieu. These
mediators are sensed by pattern-​recognition recep-
tors, including Toll-​like receptors (TLRs), purinergic
receptors, proteinase-​activated receptors, receptors
for advanced glycation end products and complement
receptors. Activation of these receptors rapidly induces
complex neuronal, coagulation and immune responses
that might also affect organs that were not directly dam-
aged by the primary trauma8. Post-​trauma responses are
therefore multifaceted and include pain, neurological
defects, psychological stress, haemodynamic changes
and increased susceptibility to infection (Fig. 1).
Acute trauma-​induced coagulopathy, hypothermia
and acidosis are considered a ‘lethal triad’ (Fig. 1). Major
surgery also constitutes tissue trauma and is associated
with an incidence of perioperative AKI of up to 50%9.
Of note, impairment of kidney function interferes with
multiple organ systems, which exacerbates early organ
dysfunction induced after trauma10,11 and is associated
with multiple adverse long-​term consequences12. Few
clinical studies have investigated the mechanisms under-
lying trauma as a trigger for AKI, although numerous
small animal studies have simulated singular aspects
of trauma, including isolated haemorrhagic shock and
ischaemia–reperfusion injury (IRI). Furthermore, only
a few studies of experimental post-​traumatic AKI take
into consideration the complicated processes that occur
during a stay in the intensive care unit (ICU). Moreover,

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Key points
• Trauma is a major cause of death worldwide. Although direct kidney injury is infrequent,
one in four patients with severe injuries subsequently develops trauma-​related acute
kidney injury (TRAKI).
• Trauma management prioritizes stabilizing vital physiological functions; however,
several therapeutic interventions, such as mechanical ventilation, mass transfusion or
the use of nephrotoxic drugs, which are used to stabilize the patient, often aggravate
kidney injury.
• TRAKI is a multifaceted syndrome that develops owing to numerous trauma-​
associated drivers of kidney injury — local and remote tissue damage, hypoxia,
microcirculatory disturbances and ischaemia–reperfusion injury, as well as exposure
to debris, pathogens and toxins.
• Trauma-​induced activation of innate immunity also promotes kidney injury — the
complement system, the coagulation cascade, leukocytes and platelets function as
a first line of defence to limit tissue damage but might also aggravate TRAKI.
• The post-​trauma immune response can disrupt organ barriers, including the blood–
urine barrier, and both the innate immune and the autonomic nervous system are
key components of kidney–remote organ crosstalk in TRAKI.
kidney structure and function differ between species,
and experimental findings must therefore be translated
into the clinic with caution13.
In this Review, we address the complex pathophysio­
logy of trauma, with a focus on kidney alterations, and
then examine the links between innate immune activa-
tion and trauma-​related AKI (TRAKI). We also discuss
the extensive crosstalk between the kidney and remote
organs, with emphasis on the neurological–renal axis.
Finally, we address challenges in monitoring the clinical
course of TRAKI and potential therapeutic targets.
Kidney injury in patients with trauma
Haemorrhagic shock Patients with trauma rarely suffer from extensive direct
Life-​threatening blood loss kidney trauma (Box 1). Therefore, our discussion is
with subsequent reduced mainly focused on indirect kidney injury caused by the
tissue perfusion and
pathophysiological and immunomodulatory effects of
inadequate oxygen supply
relative to oxygen requirement. trauma and trauma management.
Positive end-​expiratory Trauma management can promote AKI
pressure Treatment of severe trauma requires a multidisciplin­
The level of airway pressure
in the lungs above ambient
ary team that consists of emergency physicians, sur-
pressure at end-​expiration. geons, anaesthesiologists, radiologists, nephrologists
and affiliated specialists14. As a standardized approach
Mass transfusion in the synchronous diagnosis and treatment of patients
Transfusion of ≥10 units
with trauma, the advanced trauma life support system
of packed red blood cells
within 24 h. has been disseminated globally. This regimen includes
a ‘treat first what kills first’ management guided by an
Restrictive transfusion ABCDE mnemonic — airway, breathing, circulation,
Transfusion initiated when disability and exposure15. However, although lifesaving,
the patient has a total
haemoglobin concentration
some of these procedures are potentially harmful to the
≤80 g/l and/or the patient kidneys and promote TRAKI (Box 2).
develops symptoms of The ABCDE approach means that priority is given to
anaemia. securing the airway and ensuring appropriate oxygena-
tion, which is frequently achieved by endotracheal intu-
Liberal transfusion
Transfusion initiated when bation and mechanical ventilation. These procedures
the patient has a total fundamentally change intrathoracic physiology as they
haemoglobin concentration require application of positive end-​expiratory pressure.
≤100 g/l. This procedure inevitably reduces venous return,
Crush injury
thereby possibly further reducing cardiac output and
Compression of the limbs increasing renal venous congestion, which potentially
and/or torso due to trauma. compromises microcirculation in the kidney16.
The next aim is to stabilize the circulation to prevent
tissue ischaemia and restore organ perfusion. However,
fluid administration requires a delicate balance between
hypovolaemia and fluid overload — both extremes are
associated with risks, including organ hypoperfusion
and consequent kidney dysfunction, but also impaired
pulmonary gas exchange and generalized organ or kid-
ney congestion due to hyperperfusion17,18. In patients
with critical illness, balanced crystalloid solutions for
resuscitation are preferred over saline to reduce kidney
dysfunction19. Of note, modern ‘damage control resusci­
tation’ regimens recommend restricted administration
of crystalloids20 because excessive volume resuscita-
tion prompts intracellular swelling, as well as increased
generation of reactive oxygen species (ROS) with subse-
quent advancement of inflammation21. Colloids can sta-
bilize the intravascular volume; however, hydroxyethyl
starch, which was once commonly used, has since been
widely withdrawn because various studies reported that
it was associated with an increase in the incidence of AKI
and mortality22. Other plasma expander solutions (for
example, gelatine-​based solutions) also tend to increase
the risk of AKI23.
Almost 10% of polytraumatized patients require
mass transfusion24. Various transfusion types and algo-
rithms are used to stabilize haemodynamics and
coagu­lation after trauma25. Transfusions target gene­ral
parameters (for example, haemoglobin concentra­tion)
and the use of different regimens, including restrictive
transfusion and liberal transfusion, and their effects on
the kidney are still debated25,26. Although the rates of
complications due to transfusions are generally low25,
transfusion of red blood cells represents a risk factor
for TRAKI5. Mechanistically, hyperkalaemia due to the
injury itself and/or due to transfusion of old red blood
cell units, and the release of free haem that is associ-
ated with blood transfusions, can contribute to kidney
inflammation and dysfunction24,27. In a crush injury
model of AKI, haem-activated platelets triggered the
formation of macrophage extracellular traps (METs),
which contri­buted to tubular injury28. Free haem was
also cytotoxic in experimental kidney IRI, but adminis­
tration of the haem scavenger serum albumin reduced
the expression of pro-​inflammatory cytokines and
improved tubular function after injury29.
The use of vasopressors, including noradrenaline,
is frequently required to restore the mean arterial pres-
sure (MAP) in the acute phase of shock and thereafter.
Although the ideal vasopressor is still a matter of debate,
stabilizing MAP is known to be relevant to TRAKI
prevention30,31. However, the effects of noradrenaline
add to the increase in sympathetic drive and vasocon-
striction in kidney microvessels, which might further
compromise renal blood flow (RBF)31.
Advanced CT-​based imaging for the rapid assessment
of morphological damage in severely injured patients
regularly requires the use of iodinated contrast agents,
which are potentially nephrotoxic. However, the risk of
AKI associated with these agents seems to be relatively
minor32, including in children after major trauma33 —
this patient group normally lack pre-​existing risk factors
for AKI. Another iatrogenic challenge to the kidney is
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Polytrauma
Multiple traumatic injuries,
of which at least one injury
or the combination thereof
is life-​threatening.
the use of potentially nephrotoxic antibiotics in patients
with open fractures or polytrauma, or for the treatment
of post-​trauma infections.
Indirect kidney trauma
In striking contrast to infrequent direct kidney trauma
(Box 1), the kidney is a frequently affected secondary
target organ after trauma. AKI develops in 24% of
patients with severe injuries and is associated with
infectious complications, elevated mortality rate and
increased costs5,34,35. When haemorrhagic shock is pre­
sent, AKI is diagnosed in more than 40% of cases3.
Of note, AKI is characterized by an abrupt (that is,
within 24 h) functional decrease in the glomerular
filtration rate (GFR), which is associated with high
morbi­dity and mortality36,37. In clinical practice, AKI is
mainly defined according to Kidney Disease Improving
Global Outcomes37 criteria, which are based on param-
eters that include an increase in serum creatinine or a
rapid reduction in urine output.
TRAKI has a complex immunopathophysiology and
might be considered a hybrid of different AKI pheno-
types (Fig. 2). Both shock and inflammation promote the
development of TRAKI, but the proportional contri­
bution of the different haemodynamic, inflammatory
and toxic insults that can lead to TRAKI can vary consid­
erably because trauma patterns and patient manage-
ment can be very heterogeneous. Accordingly, AKI in
general is currently viewed as a heterogeneous clinical
syndrome38, and transcriptomic findings support the
existence of different AKI subtypes39.
Both patient-​derived and trauma-​specific AKI risk
factors have been identified in patients with trauma
admitted to the ICU5 (Fig. 2). Of note, single nucleo-
tide polymorphisms, including in the tumour necrosis
factor (TNF) gene and the serine proteinase inhibi-
tor family of genes, might predispose patients to AKI
and adverse outcomes in the settings of perioperative
trauma and sepsis, respectively40–42. Below, we discuss in
more detail the systemic and kidney-​specific immune
and non-​i mmune pathophysiological responses to
trauma — especially shock and inflammation — that
underlie the development of TRAKI.
Systemic pathophysiological response
Trauma can be accompanied by several types of shock,
which in general reflect an imbalance between oxygen
supply and demand43. Shock can result from a defect in
oxygen transport, for example, due to hypovolaemia,
myocardial infarction or pulmonary embolism, all
of which are characterized by reduced cardiac output
and profound systemic vasoconstriction. By contrast,
distri­butive shock (for example, septic shock) is charac­
terized by a systemic decrease in vascular resistance
and abnormal tissue perfusion43. Moreover, the haemo­
dynamic and metabolic responses to trauma and

Loss of consciousness
• Stress Traumatic Mental Psychomotor
• ↑ Sympathetic drive brain injury alterations disorder

Spinal shock Spinal cord

Paralysis injury Hypoxia
Thorax
trauma • ↓ Cardiac output
• IRI

Wounds
Direct organ Soft tissue
• Infection
trauma injury
• Sepsis
• Spleen Abdominal
• Liver trauma
• Gastrointestinal
tract Acidosis
• Kidney
Hypothermia
Lethal
triad

Coagulopathy

Pain
Immobilization Fracture
Bleeding Shock

Fig. 1 | Frequent trauma sites and complications. Frequent injury patterns in patients with trauma include traumatic
brain injury, thorax trauma, soft tissue injury, fractures, abdominal trauma and spinal cord injury. Soft tissue injury is often
underestimated clinically, although it contributes to systemic inflammation through the accumulation of tissue debris
and damage-​associated molecular patterns, as well as bleeding; trauma-​induced haemorrhage leads to shock. Major
complications of trauma include loss of consciousness, hypoxia, external and internal tissue damage, localized and
systemic infection, as well as pain, stress and mental disorders. Hypothermia, acidosis and coagulopathy — known as
the lethal triad — are highly predictive of unfavourable patient outcomes, especially during the first 24 h after trauma.
Bleeding with the development of shock remains the principal cause of early death. Late trauma-​caused lethality is
mainly due to traumatic brain injury and multi-​organ dysfunction1, including trauma-​associated acute kidney injury.
IRI, ischaemia–reperfusion injury.

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Box 1 | Direct kidney trauma

tissue injury52,53 and in cardiogenic shock54. Of note, in
healthy volunteers, a single intravenous dose of 2 ng/kg
The kidneys are surrounded by a firm fibrotic and thick perirenal adipose capsule, and are body weight (corresponding to ~25 pg/ml blood) of
well embedded in the retroperitoneum. Therefore, direct kidney trauma is infrequently lipopolysaccharide (LPS) induced only transient subtle
observed and is caused, in most cases, by blunt injury and high-​velocity deceleration257. changes in kidney biomarkers without clinical manifes-
Clinically, kidney trauma can be masked, although it is frequently associated with macro-
tation of AKI55. This threshold of LPS exposure is barely
or micro-​haematuria, flank and/or abdominal pain, abdominal and/or retroperitoneal
haematoma, rib fractures, urogenital trauma and/or pelvic fractures. Classification of reached in most human trauma settings53. However, in
direct kidney trauma is based on the anatomical extent of the injury and ranges from the case of traumatic-​haemorrhagic shock, endotoxin
subcapsular haematoma and minimal parenchymal lacerations to a completely shattered levels can increase to approximately 100 pg/ml, which
and devascularized kidney. 2019 guidelines state that, in the presence of additional likely promotes kidney injury52. Pro-​inflammatory
haemodynamic instability due to traumatic-​haemorrhagic shock, any injury to the kidney IL-6 reaches peak values in septic shock56, whereas
is classified as severe kidney injury, irrespective of the degree of the anatomical damage lower values are detected early after severe trauma and
to the kidney257. haemorrhagic shock57 and, to a lesser extent, during
Capsula fibrosa cardiogenic shock58. These apparently different profiles
suggest that different forms of shock might differentially
Perirenal promote AKI and suggest that traumatic-​haemorrhagic
1 Subcapsula haematoma 2
haematoma shock has a major role in TRAKI (Fig. 2).
Minor Minor
trauma trauma
Contusion Cortex Pathophysiological kidney changes
laceration In addition to the systemic effects of both traumatic
<1cm
shock and the subsequent inflammatory response, the
3 kidneys are also challenged by local pathophysiological
Cortex alterations (Fig. 3). The kidneys receive high blood flow
Moderate
Renal laceration
trauma (approximately 4 l/kg/min59), which accounts for ~20%
pelvis >1cm
of total cardiac output. Kidney oxygen consumption is
high60 but oxygen extraction in the healthy kidney is low
Ureter Laceration due to the high blood flow. However, despite its physio­
involving 4 logical low oxygen levels, the kidneys are particularly
renal cortex, susceptible to hypoxic injury60, which presents a major
medulla and Severe
collecting trauma post-​trauma problem.
system and/or RBF is most prominent in the kidney cortex to ensure
main renal
artery or vein filtration and reabsorption, whereas medullary RBF is
5 less than 50% of that in the cortex. Therefore, oxygen
Avulsion of renal hilum Severe + Haemodynamic Most severe availability is low in the outer medulla, already close to
and/or completely
shattered kidney
trauma instability injury hypoxia under normal conditions and may fall further
after trauma. Autoregulation maintains RBF over a wide
range of MAP and renal perfusion pressures, but the
haemorrhage are characterized by a hypometabolic medulla responds poorly to autoregulation as medullary
phase, which is followed by a hypermetabolic phase after perfusion is pressure dependent61 and arterial pressure
resuscitation44,45. Upon restoration of tissue perfusion, is frequently depressed after trauma. Tubular solute
the hypermetabolic phase results in IRI due to the reabsorption — mainly of Na+, but also of glucose and
formation of ROS and reactive nitrogen (RNS) species46. amino acids, among others — accounts for ~80% of kid-
Shock seems to be an important general AKI driver ney oxygen uptake, and both GFR and tubular Na+ reab-
(Fig. 2), irrespective of its underlying cause. However, sorption are linearly related to kidney oxygen uptake62.
ample evidence suggests that the contribution of Under pathological conditions, autoregulation can be
DAMPs, pathogen-​a ssociated molecular patterns impaired and even exhausted63,64. Therefore, increasing
(PAMPs) and their associated inflammatory profiles MAP will affect GFR65 and thereby kidney oxygen
differs across distinct shock aetiologies. For example, extraction, depending on the effect on RBF63,64 and/or the
levels of the classical DAMP high-​mobility group protein site of vasoconstriction (that is, vas afferens versus vas
B1 (HMGB1) are highest in traumatic-​haemorrhagic efferens) (Fig. 3); for example, despite a rise in MAP, equal
shock (likely due to the magnitude of tissue damage), constriction of the vas afferens and efferens might reduce
lower in septic shock and lowest in cardiogenic shock. GFR owing to a reduction in RBF. Increasing MAP
Of note, after severe trauma, the presence of additional resulting from preferential constriction of the vas effer-
abdominal trauma47, AKI or acute lung injury48 leads to ens will increase GFR, even with unchanged RBF owing
a further increase in HMGB1 levels. Different patterns to the rise in filtration pressure. However, this post-​
are observed for other DAMPs, such as histones. In one glomerular vasoconstriction (that is, in the vas efferens)
comparative study, histones were highest in septic shock, might in turn increase kidney oxygen demand due to the
followed by trauma and then by other aetiologies49; rise in tubular sodium load64. By contrast, predominant
histone concentrations correlated with trauma sever- efferent vasodilation will increase RBF without affecting
ity and signs of coagulopathy50. As expected, PAMPs filtration pressure and, consecutively, GFR65.
such as endotoxins are highest in septic shock51, but Trauma and haemorrhage activate the autonomic
are also found at lower concentrations after severe nerve system, particularly the sympatho-​adrenergic

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drive, the renin–angiotensin–aldosterone system and
vasopressin release, all of which induce renal vasocon-
striction (Fig. 3). This regional vasoconstriction is dispro­
portionately high when compared with the systemic
effect66, even during conditions of moderate haemor-
rhage that do not affect oxygen uptake in the kidney67.
Moreover, in a porcine model of haemorrhagic shock,
RBF was not restored even after 24–48 h of resuscita-
tion, which comprised retransfusion of shed blood,
fluid resuscitation and noradrenaline to restore systemic
haemodynamics66. Sustained hypoperfusion due to
haemorrhagic shock can therefore reduce GFR without
apparent tissue injury, and failure to restore adequate
perfusion leads to ischaemic tubular necrosis and AKI18.
Of note, in contrast to complete ischaemia (induced,
for example, by aortic cross-​clamping), transitory kid-
ney hypoperfusion alone, which might best simulate
early post-​trauma conditions and can be modelled, for
example, by incremental occlusion of the kidney artery
with up to an 80% reduction of RBF, does not cause per-
sistent AKI, even when severe68. Therefore, additional
mechanisms, including post-​trauma activation of innate
immunity8 and metabolic alterations, might underlie
TRAKI induction. Tissue hypoxia due to progressively
increased severity of haemorrhagic shock might modu­
late kidney metabolism according to the oxygen and
substrate supply69, and consequently lead to metabolic
dysfunction (for example, impaired lactate clearance)
and AKI.
Kidney dysfunction is not only exacerbated by the
effects of trauma and/or haemorrhagic shock per se
but also by alterations associated with essential anaes­
thesia and surgical interventions. The inherent effects
of anaesthetics (for example, myocardial depression
and peripheral vasodilation caused by reduced vascular
tone) and/or fluid losses into the interstitial space due
to post-​trauma impairment of endothelial and epithelial
barriers8 contribute to post-​trauma kidney pathophysio­
logy. IRI following restoration of cardiac output, which
is characterized by enhanced release of ROS and RNS,
and/or by a decrease in the intravascular oncotic pres-
sure from crystalloid infusion-​related haemodilution,
also exacerbates AKI18.
In this context, the relatively uncompliant kidney cap-
sule renders the kidney particularly sensitive to venous
congestion with high central venous pressures70 and/or
intra-​abdominal hypertension71, which are induced, for
example, after retroperitoneal haemorrhage or fluid
overload; intra-​abdominal pressures >12 mmHg inde-
pendently predicted the occurrence of AKI72. Moreover,
the adaptive, catecholamine-​related kidney vasocon-
strictor response can further disrupt the delicate oxygen
supply–demand relationship in the kidney. Noradrenaline
and adrenaline not only decrease cortical and medullary
microcirculatory blood flow and capillary partial pressure
of oxygen (pO2), even in the absence of alterations in RBF
and whole-​organ oxygen delivery and uptake73, but they
can also enhance whole-​organ metabolic load (Fig. 3).
During post-​trauma adrenergic stimulation, kidney glu-
cose release might double, which would account for up
to 50% of total gluconeogenesis74 and markedly enhance
oxygen demand in the kidney. Overall, trauma-​induced
hypoxic and/or ischaemic insults, and perfusion distur-
bances can lead to epithelial damage, inflammation and
failure of the blood–urine barrier (Fig. 3); these effects are
accompanied by a complex immune response.

Box 2 | early trauma management and potential risk of kidney injury

Immediately after trauma, the time period elapsed before successful
rescue is associated with a high risk of hypoxia and ischaemia. Early
trauma management, from the scene of the accident via the emergency
room (ER) and operating theatre (OR) to the intensive care unit (ICU),
requires a multidisciplinary team effort to secure timely synchronic
diagnostics and therapy. Various stabilizing interventions that ensure
oxygen transport to body cells can be lifesaving but might also promote
acute kidney injury (AKI). ARDS, acute respiratory distress syndrome;
DAMPs, damage-​associated molecular patterns; ECMO, extra-​corporal
membrane oxygenation; PEEP, positive end-​expiratory pressure.

Trauma Preclinical ER OR ICU Drivers of AKI

Rescue team Hypoxia, ischaemia and bleeding

Rescue efforts/time
elapsed until rescue
Anaesthesiology
• Airway Airway management and intubation Oxygenation problems

• Breathing Mechanical ventilation → PEEP ↑ ARDS → PEEP ↑ Renal venous congestion

Pneumonia Nephrotoxic antiboitics

• Circulation Infusion → fluid overload Oedema and coagulopathy

Colloids Osmotic problems
(Mass) transfusion → antigenic load ↑ ↑ Free haem

• Organ replacement Kidney replacement therapy

ECMO Artificial surfaces and inflammation

Radiology CT scan → contrast agents Nephrotoxins

Surgery Life saving procedures Damage control ↑ DAMPs and ↑ debris
Early total care ↑↑ DAMPs and ↑↑ debris

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Subtypes Main triggers Perfusion Risk factors

Ischaemic ROS and/or RNS 0 General

• Comorbidities
• Fragility
• Male sex
AKI Trauma-related DAMPs ↓ • Hypertension
• ↑ Age

Shock
Trauma-specific Inflammation
• ↓ Blood pressure
Septic PAMPs = or ↑ • Mass transfusion
• ↑ Injury Severity Score
• ↑ Glasgow Coma Scale due
to traumatic brain injury
• Abdominal injury
Toxic Renal toxins = or ↑ or ↓ • Sepsis

Fig. 2 | TrAKI as a hybrid of heterogeneous AKI types. Various entities of
acute kidney injury (AKI) have been described based on its major underlying
immunopathophysiological drivers — ischaemic AKI associated with
reactive oxygen species (ROS)-induced injury255, septic AKI in which
microorganisms and pathogen-associated molecular patterns (PAMPs) are
the sources of damage256, and toxic AKI triggered by nephrotoxic contrast
agents and drugs32. Early after trauma, tissue debris and the release of
damage-associated molecular patterns (DAMPs), as well as the presence
of hypoxia and reductions in macro and micro kidney perfusion, represent
main causes of trauma-related AKI. However, all other immunopathophys-
iological drivers of different AKI subsets can also contribute to post-trauma
kidney impairment — warm ischaemia–reperfusion injury in the kidneys or
remote organs, exposure to PAMPs via wounds or damaged organ barriers8,
or exposure to iodinated radiocontrast media for essential CT scans32.
Patient-derived factors, including pre-existing comorbidities, male sex and
older age, are risk factors for AKI development in patients with trauma in
intensive care untis5. Of note, trauma-specific risk factors have also been
identified for post-trauma AKI5. Multiple immune and pathophysiological
changes after trauma seem to culminate in trauma-related AKI, with
trauma-induced shock, as well as pre-existing and/or trauma-induced
inflammation emerging as major risk factors. RNS, reactive nitrogen species;
TRAKI, trauma-related AKI.

Immunothrombosis
Formation of thrombi initiated
by the innate immune response
to invading bacteria aimed at
local infection control.
Systemic post-​trauma immune response
Within minutes of trauma, the innate immune response
is triggered by the autonomic nerve system and the
fluid-​phase system8. Rapid immunothrombosis at the site
of external and internal wounds is an ancestral lifesaving
process and attenuates the danger of further blood loss
and the invasion and expansion of microorganisms75.
In this process, traumatized renal and extrarenal tissues
release neo-​antigens and DAMPS, including nucleo­
somes, histones, RNA, HMGB1, ATP, ADP, mitochon-
drial DNA (mtDNA) and uric acid8,76–78. DAMPs activate
cross-​talking protease cascades, including the coagula-
tion and complement systems75,79, which leads to rapid
activation and consumption of zymogenic factors after
polytrauma80. Resident and inflammatory cells sense
these danger molecules, which triggers synchronous
pro-​inflammatory and anti-​inflammatory cytokine
and chemokine responses8. In patients with trauma,
those with AKI had higher plasma concentrations of
anti-​inflammatory IL-1 receptor antagonist (IL-1Ra)
and pro-​inflammatory IL-6, IL-8 and CC-​chemokine
ligand 2 (CCL2; also known as MCP1) early after injury
than those without AKI, regardless of the development
of infectious complications81. Elevated serial levels of
CXC-​chemokine ligand 1 (CXCL1) and CCL4 (also
known as MIP1β) were detected only in patients with
trauma and AKI who developed nosocomial infections81.
The rapid pre-​programmed cellular responses of
chemo­attracted leukocytes included not only cytokine
production but also phagocytosis, oxidative burst, pro-
tease release and the formation of extracellular traps
(for example, neutrophil extracellular traps (NETs) and
macrophage extracellular traps), all of which have a role
in the clearance of damaged tissue, as well as pathogens,
and the induction of regenerative processes8.
Haemostasis — a process coordinated by the coagu­
lation system and >1 trillion platelets that function as
sentinels of vascular and tissue integrity75 — is vital for
rapid repair of injured blood vessels and to ensure fast
reperfusion of traumatized hypoxic tissue. Following
trauma, rapid adhesion, aggregation and activation
of platelets occurs at the damaged endothelial barrier,
where usually concealed sub-​endothelial structures,
including collagens and tissue factor, become exposed
to the circulation. The coagulation cascade is trig-
gered in parallel — thrombin and fibrin further acti-
vate and mediate platelet adhesion. This orchestrated
response results in mechanically stable sealing of the
wounds75. However, after severe tissue trauma and
haemorrhagic shock, platelets and coagulation factors
might become excessively activated, dysfunctional
or depleted, which manifests clinically as a reduction
in platelet counts, histone-​dependent ballooning of
platelets and the development of life-​threatening acute
trauma-​induced coagulopathy82,83. Even in untrauma-
tized endothelium, inflammatory mediators can induce
a switch towards a pro-​inflammatory, pro-​oxidative, pro-​
adhesive, pro-​platelet and pro-​coagulative endothelial
phenotype77.
Post-​trauma kidney immune response
The consequences of remote trauma in the kidneys are
not well investigated. Findings to date are most fre-
quently based on studies of warm IRI but also include
trauma-​relevant haemorrhagic shock conditions,
which have been shown to drive damage to multi-
ple organs and exacerbate kidney dysfunction after
experimental and clinical polytrauma57,84.
Glomerular changes
In addition to the systemic post-​t rauma immune
response, several studies suggest that kidney injury
directly promotes pro-​inflammatory changes in the glo-
merulus. In the glomerular endothelium, RBF reduction

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 Reviews

modelled by warm renal IRI resulted in strong upreg-
ulation of P-​selectin within 24 h (ref.85). In rodent IRI,
a decrease in constitutive endothelial nitric oxide syn-
thase (eNOS) activity in the kidney reduced nitric oxide
(NO)86, which led to vasoconstriction and reduced
antioxidant activity87. Trauma also induces the produc-
tion of the endogenous catecholamines adrenaline and
noradrenaline8,88, as well as the eicosanoid thromboxane
A2 (TXA2)89,90, all of which contribute to vasoconstric-
tion of the kidney arterioles and thereby compromise
glomerular haemodynamics91 (Fig. 4).
Glomerular endothelial cells are also robustly acti-
vated by trauma and haemorrhagic shock, which induce
nuclear factor-​κB (NF-​κB)-​dependent expression of
inflammatory mediators and adhesion molecules,
including E-​s electin and vascular cellular adhesion
protein 1, which recruit inflammatory cells92. However,
the relevance of leukocyte migration into the glomer­
ulus after trauma remains unclear. Glomerular neutro-
phil numbers increased early after LPS-​induced AKI93
but their exact glomerular role in trauma is poorly
understood.
Complement activation might also have an important
role in the kidney response to trauma-​induced damage.
Glomerular and tubular cells express key complement
factors, including C1q and C3 (ref.94). In vitro, exposure
of mesangial cells to the anaphylatoxin C3a at concen-
trations observed after trauma80,95 induced a switch from
a contractile to a secretory phenotype, which promoted
kidney fibrosis and a concomitant loss of blood flow
regulation96. Upon contact with non-​lytic concentra-
tions of the C5b–9 complex, mesangial cells genera­
ted growth factors and vasodilatory prostaglandins97
(Fig. 4). In human podocytes, deposition of C5b–9 also
induced synthesis of profibrotic factors and collagen98.
Moreover, the rise in systemic C5a during experimental
sepsis-​induced AKI resulted in fusion of podocyte foot
processes, which affected glomerular filtration99. In warm
kidney IRI, fusion of podocyte foot processes, as well as
exfoliation and exposure of the glomerular basement

Macula Loss of autoregulation

Trauma densa
↓ MAP
↑ Renin Venous
• Haemodynamics: ↓ MAP, congestion
↓ cardiac output
• Oxygenation: ↓ pO2 Angiotensin II
• Release of DAMPs and/or Vasoconstriction:
presence of PAMPs noradrenaline,
adrenaline and ↓ RBF
vasopressin Hypoperfusion
Monocyte and hypoxia

Neutrophil
↓ Primary ↓ O2 and
Primed innate urine nutrients
immunity
• ↑ Oxygen ↓ ATP- Casts
dependent ↓ ATP
demand ↓ Reabsorption
• ↓ RBF transport
of electrolytes,
↓ Blood toxin • ↓ Glomerular glucose and ↓ Urine
clearance filtrationa amino acids output
• ↓ Tubular Metabolic IRI
secretion changes
Venous • ↓ Metabolic
congestion ↑ Pressure
capacity ROS • Proteinuria
↓ Toxin • ↓ FENa
Casts excretion
Epithelial
and/or • Apoptosis
Oedema ↑ Pressure endothelial • Necrosis
barrier
Debris dysfunction
• ↑ BUN
• ↑ Creatininea
• ↓ Urine outputa Platelet activation Microthrombi
Thrombo-
inflammation

Fig. 3 | pathophysiological response of TrAKI. Trauma can induce
haemodynamic disturbances, changes in oxygenation that lead to
ischaemia and hypoxia, as well as the release of damage-associated
molecular patterns (DAMPs) and/or the presence of pathogen-
associated molecular patterns (PAMPs) that activate innate immunity.
Collectively, these changes can result in constriction of blood vessels in
the kidney, decreased renal blood flow (RBF), glomerular filtration rate,
tubular secretion and urine output. Congestion of the tubular lumen
by tissue debris enhances tubular pressure, which further decreases urine
output and facilitates the development of oedema. Under conditions of
trauma-induced hypoxia and/or hypoperfusion, oxygen and nutrient
supply–demand is unbalanced, which leads to reduced ATP generation and,
thus, defective energy-dependent reabsorption and transport mechanisms.
Ischaemia–reperfusion injury (IRI) leads to production of reactive oxygen
species (ROS). Metabolic changes and ATP depletion, combined with
ROS-induced cellular apoptosis and necrosis, damage the urine–blood
barrier. Trauma-induced platelet activation, endothelial alterations and
thromboinflammation promote formation of microthrombi, which further
compromise microperfusion and aggravate venous congestion. BUN, blood
urea nitrogen; FENa, fractional excretion of sodium; MAP, mean arterial
pressure; pO2, partial pressure of oxygen; TRAKI, trauma-related acute
kidney injury. aDiagnostic parameters of acute kidney injury.

Nature Reviews | Nephrology

Reviews

Trauma
↑ Sympathetic drive Ischaemia

↑ TXA2 ↑ Noradrenaline Hypoxia ↓ pO2

and adrenaline
Activation
Vas Cellular Vas
afferens ↓ RBF Coagulation defence Activated efferens
platelets
Thrombin
Complement
↓ NO
↓ endothelin Anti-inflammatory → pro-inflammatory
Fibrin • ↓ Anti-thrombotic activity
• ↓ Anti-oxidant activity
C3a
C5a ?
Crush syndrome
C5b–9

Thrombus Deposition of debris

and myoglobin
↑ Myoglobin
↑ Haem
↑ K+
↑ TF

Mesangium
Myoglobin
DAMPs

Fusion of foot
processes ↑ P-selectin
↑ MMP ↓ Hb
Exposure Haemorrhagic
Ischaemia Inflammation
of BM shock
BM alterations ↓ ZO1
ROS

Detachment
↑ Adhesion
molecules

Efflux of albumin
Glomerular filter and other proteins
dysfunction Bowman’s
• (Micro)albuminuria capsule
• (Micro)proteinuria ↓ GFR

Endothelial Mesangial cell

cell

Macrophage Pro-fibrotic
mesangial cell

Monocyte Podocyte
Necrosis and/or
Neutrophil Pro-fibrotic
detachment
podocyte

PTEC Parietal cell

membrane have also been reported; these changes were
dependent on the severity of the injury100. Moreover, the
expression of key slit membrane proteins, including syn-
aptopodin and nephrin, was reduced, and this effect was
also dependent on the length of the ischaemic period100.
In another study of kidney IRI, metalloproteinase levels
and degradation of the key scaffold protein tight junc-
tion protein ZO1 increased101 (Fig. 4). Collectively, these
data indicate that kidney IRI results in impairment of the
glomerular barrier.
IRI-​induced defects in glomerular filtration might
allow the passage of inflammatory mediators through
the glomerular filter. Once in the glomerular filtrate,
these mediators might induce an intraluminal chemo­
tactic and pro-​inflammatory response. Of note,
microalbuminuria — indicated by an enhanced urinary

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◀ Fig. 4 | Innate immune response in the glomerulus during TrAKI. Trauma increases
sympathetic activity, which promotes activation of the innate immune system and drives
vascular changes that reduce renal blood flow (RBF). In the glomerulus, the release of
damage-​associated molecular patterns (DAMPs), such as high-​mobility group protein
B1 (HMGB1) and histones, and the activation of the coagulation and complement
systems induce changes in the endothelium to create a pro-​coagulant, pro-​adhesive and
pro-​inflammatory platform. Complement activation products can furthermore induce
a pro-​fibrotic phenotype in mesangial cells and podocytes. The generation of reactive
oxygen species (ROS) induced by hypoxia and ischaemia contributes to morphological
alterations of the glomerular filter and glomerular dysfunction. The presence of additional
haemorrhagic shock exacerbates endothelial changes and inflammation, including the
upregulation of adhesion molecules. In the case of crush syndrome, severe compression
of musculoskeletal areas exposes the patient to excessive amounts of debris, myoglobin,
free haem and potassium. These by-​products of tissue damage can accumulate at the
glomerular filter and trigger thrombus formation. Apoptotic or necrotic epithelial cells
released into Bowman’s capsule and tubular system can increase intratubular pressure,
which, in combination with microperfusion disturbances, reduces the glomerular
filtration rate (GFR). BM, basement membrane; C3a, activated complement protein 3;
C5b–9, membrane attack complex; Hb, haemoglobin; MMP, matrix metalloproteinase;
NO, nitric oxide; pO2, partial pressure of oxygen; PTEC, proximal tubule epithelial cell;
TF, tissue factor; TRAKI, trauma-​related acute kidney injury; TXA2, thromboxane A2;
ZO1, tight junction protein ZO1.
albumin-​to-​creatinine ratio — was detected as early as
24 h after trauma102, and albumin is thought to induce
podocyte injury via cylooxygenase-2 (ref.103).
Trauma-​induced rhabdomyolysis occurs after crush
injury of muscle tissue with a prolonged period of com-
pression and ischaemia, for example, during rubble
entrapment. The injured and necrotic muscle exces-
sively releases myoglobin, potassium, creatinine and
creatinine kinase, as well as phospholipids and tissue
factor104 (Fig. 4). Rapid decompression might exacer-
bate the pathophysiology owing to reperfusion injury,
ROS generation and flooding of the body with debris
as well as metabolites, such as lactate, released from a
hypoxic and acidotic environment104. Clinically mani-
fest crush syndrome is characterized by major shock and
AKI with myoglobinuria. In experimental crush injury,
fibrin-​rich glomerular microthrombi occluded a variable
number of glomerular capillary loops105, and podocyte
swelling was also detected105. Nevertheless, because myo-
globin (~17 kDa) is small enough to pass through the
glomerular filter, it probably mainly affects the proximal
tubular system.
Of note, the glomerulus is protected by multiple
innate defence systems, including anti-​inflammatory
mediators, complement-​regulatory proteins, anti-
thrombotic molecules, antioxidants and protease
inhibitors106. By contrast, the tubular system has limi­
ted defences and its lower peritubular oxygen tension
renders it more vulnerable to trauma-​induced changes
than the glomerulus.
Tubular changes
In the tubular system, post-​trauma AKI is mainly driven
by low-​f low hypoxia and ischaemic tissue damage.
Crush syndrome Tubular epitheliopathy is a general feature of AKI and is
Syndrome characterized characterized by cellular swelling, villi degradation, loss
by degradation of muscle of polarization (for example, of the Na+–K+–ATPase),
tissue (that is, rhabdomyolysis)
accompanied by the
vacuolization, tubular dilation, focal apoptosis and
accumulation of tissue necrosis; these changes are accompanied by sloughing
debris and myoglobin. of viable, apoptotic and necrotic cells107,108. Functionally,
Nature Reviews | Nephrology
Reviews
these morphological changes result in impaired Na+
reabsorption, decreased clearance of cytokines and
toxins, and increased intraluminal pressure, which, in
combination with hypoxia, lead to further stress and cell
loss (Fig. 5).
Complement. In experimental kidney IRI, generation
and deposition of complement C3 on tubule epithelial
cells (TECs) was enhanced, whereas the expression of
the complement regulator factor H was decreased109.
The basolateral side of TECs seems to be the main tar-
get of complement attack110. Enhanced C3d deposition
on TECs was also detected in a patchy pattern in human
biopsy samples of acute tubular necrosis111. Hypoxic or
hypothermic stress, which are early cardinal features
of trauma, lead to disorganized patterns of l-​fucose on
post-​ischaemic proximal TECs. l-​fucose is recognized
by the C-​type lectin collectin-11, which activates the
lectin pathway, generating pro-​inflammatory comple-
ment mediators112. In a rat model, internalization of
circulating mannose-​binding lectin directly damaged
tubular cells113. In experimental kidney IRI, C5a receptor
(C5aR) was upregulated in proximal TECs, which
induced a pro-​inflammatory response114. Accordingly,
mice deficient for C3aR and/or C5aR in the kidney
had reduced kidney damage, which was reflected by an
improved histological score and reduced generation of
inflammatory mediators such as TNF and IL-1β, as well
as reduced blood urea nitrogen levels, compared with
wild-​type controls115.
In cases of severe tissue trauma, excessive comple-
ment activation leads to zymogen depletion, accom-
panied by a reduction in the haemolytic activity of
complement and the development of complementopa-
thy in synergy with coagulopathy80. Post-​trauma, local
complement activation might be organ-​dependent.
In a model of severe porcine traumatic-​haemorrhagic
shock, complement haemolytic activity was lower in
the renal vein than in systemic blood, which suggested
extensive complement activation and consumption
in the kidneys116. Elevated systemic C5a concentra-
tions after trauma 80 can upregulate key adhesion
molecules on endothelial cells, attract and activate
leukocytes and enhance endothelial permeability 8
(Fig. 5) . Upregulation of P-​s electin and E-​s electin in
peritubular capillary plexus cells within 24 h of an
ischaemic insult in combination with local neutro-
phil recruitment are hallmarks of IRI-​induced AKI117.
In neutrophils, signalling through C5aR induces
the expression of pro-​coagulant tissue factor118 and
functions as a metabolic master switch by inducing
lactate release and generating an acidic extracellular
microenvironment119. Moreover, neutrophil exposure
to C5a induces NET release and proliferation of
kidney fibroblasts, which can promote the develop-
ment of kidney fibrosis120–122. In kidney IRI models,
C5a–C5aR1 interaction contributed to the develop-
ment of kidney fibrosis by recruiting and activating
inflammatory cells, promoting tubular epithelial-
to-​mesenchymal transition, and directly activating
interstitial fibroblast proliferation and the production
of extracellular matrix120.
Reviews

Trauma

Renal tubule Interstitium Capillary

Loss of villi: Hypoxia and/or ischaemia Necrosis DAMPs Coagulation

• ↓ Polarization
• ↓ Na+–K+–ATPase
• Vacuolization PRR
Thrombin
Resident
macrophage
Platelet
TF activation
Necrosis

Apoptosis GAG
Activation P-selectin shedding
DAMPs and ICAM1
BM Endotheliopathy
Inflammation Endothelial
Necroptosis?
cell ↑ Adhesion Complement

TEC ↑ Clearance C3a

of dead cells Phagocytosis
DAMPs TLR4
C5a
HMGB1 C5b–9
↑ KIM1
Chemotaxis NETs METs

• ↓ Toxin clearance
• ↓ Cytokine clearance
Cytokines
ROS Cytokines
Neutrophil Migration
TIMP2 and G1 cell
IGFBP7 cycle arrest IL-8 Phagocytosis
H2O shift H2O shift
Loss of tight junctions
Barrier Barrier
Oedema ↑ Circulating
dysfunction dysfunction
tight junctions
• Hyaline
casts Thrombin Thrombus
• Debris Renal lymph Fibrin
RBC
Adaptive
immunity
↑ TNF
Congestion
Rouleaux
formation
Apoptosis
Antigen Pericyte
presentation dissociation Congestion

↓ Urine output ↓ Microperfusion

DC
↓ Vascular Hypoxia and ischaemia
Pericyte homeostasis

Marginated neutrophils
Neutrophils from the circulating
cell pool that attach to surfaces
such as the endothelium.
Immune cells. Neutrophils function as a first line of
cellular defence after trauma8. A 2019 study of patients
with trauma revealed that an elevated neutrophil-​to-​
lymphocyte ratio (NLR) over the first 48 h following
hospital admission was predictive of severe AKI as well
as MODS123, which suggests a more important role for
neutrophils in TRAKI than appreciated thus far.
In a kidney IRI model, neutrophils were mainly
recruited to the kidney interstitium, and their num-
bers peaked 24 h after reperfusion. These infiltrating
neutrophils were phenotypically different from the low
number of marginated neutrophils found on the vascular
endothelium124. Recruitment of neutrophils into tis-
sues via the endothelium involves capture and rolling,
slow rolling, arrest, adhesion and transmigration —
multiple AKI-​related changes might interfere with this
process. Acute loss of kidney function in experimental
IRI, reflected by an increase in creatinine, abolished
selectin-​dependent slow rolling of neutrophils and
impaired their recruitment125. Experimental rhabdo-
myolysis also impaired neutrophil migration as early
as 4 h after injury by inhibiting the phosphoinositide

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◀ Fig. 5 | Innate immune response in the tubular system during TrAKI. The innate
immune response in the kidney tubular system after trauma is multidimensional.
Trauma-​induced endotheliopathy involves shedding of glycocalyx structures such as
glycosaminoglycans (GAGs), exposure of subendothelial pro-​coagulant proteins such
as tissue factor (TF), and activation of platelets and the coagulation system — all of these
changes contribute to thrombus formation in the perivascular system. The consequent
reduction in blood flow can aggravate hypoxia and ischaemia in the tubules. Activated
systemic leukocytes migrate to the peritubular interstitium, where, in combination with
activated resident macrophages, they mount an inflammatory response by releasing
cytokines, reactive oxygen species (ROS), proteases and extracellular traps. The
inflammatory fluid phase and cellular response can promote the clearance of soluble
mediators and cellular debris but might also further damage tubule epithelial cells
(TECs). TECs themselves contribute to the inflammatory response by generating damage-​
associated molecular patterns (DAMPs) and releasing cytokines. Shedding of apoptotic
and necrotic TECs into the tubular lumen leads to tubular congestion and thus further
damage, which ultimately reduces urine output. Blood–urine barrier disturbances can
also develop owing to the inflammatory response and might cause kidney oedema.
Resident dendritic cells (DCs) can sense DAMPs and pathogen-​associated molecular
patterns and migrate through the kidney lymphatics to activate the adaptive immune
system. These acute inflammatory changes are required to activate subsequent kidney
repair mechanisms. BM, basement membrane; C3a, activated complement protein 3;
C5b–9, membrane attack complex; HMGB1, high-​mobility group protein B1; IGFBP7,
insulin-​like growth factor-​binding protein 7; KIM1, kidney injury molecule 1; METs,
macrophage extracellular traps; NETs, neutrophil extracellular traps; PRR, pattern
recognition receptor; RBC, red blood cell; TIMP2, metalloproteinase inhibitor 2;
TLR4, Toll-​like receptor 4; TNF, tumour necrosis factor; TRAKI, trauma-​related acute
kidney injury.
3-​kinase (PI3K) pathway, as well as intracellular actin
polymerization and translocation126. Mechanistically,
elevated concentrations of the uraemic toxin resistin —
as observed after trauma127 and during AKI126,128 — have
been proposed to induce neutrophil dysfunction, includ-
ing impaired migration, ROS production and bacterial
killing, with potential septic complications128,129. Of note,
an AKI-​induced impairment of neutrophil recruitment
would affect not only the kidneys but also remote organs,
including the lungs130. In some IRI models, inhibition
of neutrophils has been proposed to protect from AKI,
whereas others found no significant effects131. However,
whether modulation of neutrophils protects from AKI,
especially in the context of trauma, remains unclear131.
The kidney mononuclear phagocytic system, which
comprises macrophages and dendritic cells (DCs), can
sense and clear tissue debris132,133. Kidney-​resident inter-
stitial macrophages act as innate sentinels and sample
DAMPs and PAMPs from the tubular environment via
pattern recognition receptors, such as TLR4, and can
also process antigens for presentation to T cells (Fig. 5).
Beyond their role in immunosurveillance, macrophages
can also mount inflammatory responses to DAMPs and
PAMPs that involve the release of cytokines, as well as
pro-​angiogenic and regenerative factors required for
tissue repair134. In experimental IRI, monocytes are
recruited from the circulation into the kidney, particularly
around post-​capillary venules in the outer medulla135.
There, they can be polarized to a pro-​inflammatory
phenotype by trauma-​relevant mediators such as TNF
and IFNɣ136. Furthermore, inflamed blood monocytes
traffic towards a chemokine gradient released from IRI
kidneys in mice and, upon infiltration of the kidneys,
they secrete pro-​inflammatory cytokines, as well as ROS
and RNS, which can further damage the surrounding
kidney tissue132,137,138. However, macrophages were also
Nature Reviews | Nephrology
Reviews
a major source of haem oxygenase-1 under hypoxic
conditions (for example, 24 h after IRI), which pro-
tected the kidney against oxidative stress and improved
local blood flow139. Moreover, in later stages (that is,
>3 days after trauma) macrophages tend to polarize
towards an anti-​inflammatory phenotype to promote
tissue repair128,140. This phenotypic switch is promoted
by phagocytosis of apoptotic neutrophils141 and by the
release of retinoic acid by damaged epithelial cells, which
seem to reactivate this embryonic signalling pathway in
experimental IRI142. Anti-​inflammatory macrophages
mainly adhere to the basal membrane of damaged
tubular cells, where they orchestrate the resolution of
inflammation and tissue repair140. Along the polarization
continuum, several stimuli can induce different subtypes
of anti-​inflammatory macrophages, which have distinct
chemokine secretion patterns and metabolic character-
istics, and are involved in distinct immune functions and
regulatory processes143. Of note, increased expression of
suppressor of cytokine signalling 3 induced by damage
in proximal TECs inhibited macrophage polarization
towards an anti-​inflammatory phenotype, resulting in
an impaired reparative response144.
Resident DCs are mainly located between the tubu-
lar system and the peritubular vasculature, where they
sample DAMPs and PAMPs for subsequent antigen
presentation to T cells128. DCs can be recruited to the
kidney by fractalkine expressed on injured endothelium
after IRI131,145. Immature DCs mature within a few hours
after ischaemia, which results in loss of phagocytic activ-
ity and changes in gene expression that enable them to
migrate to secondary lymphoid organs to induce T cell
activation146. Under hypoxic and/or ischaemic condi-
tions, DCs can generate chemokines, TNF, IL-6, CCL2
and CCL5 (also known as RANTES)147, and rapidly
attract neutrophils148. The excessive release of TNF by
DCs early during renal IRI is a major contributor to the
inflammatory response, tubular epithelial apoptosis and
endothelial dysfunction128.
Mast cells have been mainly implicated in allergy
responses but have also been investigated in preclini­
cal studies of AKI. Genetic depletion of mast cells
or mast cell chymase prevented systemic inflamma-
tion and fibrosis in murine partial unilateral ureteral
obstruction149. In a rat model of IRI, pharmacological
inhibition of mast cell function and histamine release
markedly reduced AKI150. These detrimental effects of
mast cell activation appear to be limited to the early
phase after injury151. By contrast, murine mast cell pro-
tease 4, a functional counterpart of human mast cell
chymase, regulated neutrophil expression of adhesion
molecules and its genetic deletion resulted in increased
neutrophil migration and activation, which was asso-
ciated with exacerbation of kidney injury, as indicated
by increased blood creatinine and tubular necrosis in
experimental renal IRI152.
Innate lymphoid cells are rare tissue-resident
immune cells but can be potent modulators of the local
inflammatory response153. Type 2 innate lymphoid cells
responded to administered IL-33 and prevented kidney
injury by increasing local and systemic levels of IL-4
and IL-13, which promoted the expansion of regulatory
Reviews
T cells and the polarization of macrophages towards an
anti-​inflammatory phenotype in murine IRI154.
B and T cells have been linked to non-​TRAKI and,
in animal studies, the absence of these cells ameliorated
IRI-​induced AKI155. The role of B cells in TRAKI is elu-
sive but the trauma-​induced release of macromolecules
with repetitive epitope patterns, including DNA, histones
and other DAMPs, might crosslink the antigen receptor
on B cells and stimulate the release of poly­reactive natu-
ral immunoglobulin M (IgM) autoantibodies that might
bind and opsonize neo-​antigens released by damaged
cells (that is, DAMPs) and thereby exacerbate AKI. This
is underscored by the fact that the lack of IgM antibod-
ies and B cells in murine IRI-​induced AKI improved
creatinine serum concentration, histological tubular
damage and survival up to 72 h after injury156. Further
investigations are warranted for elucidating the specific
involvement of adaptive immunity in TRAKI.
Tubule epithelial cells. As previously discussed, TECs
have high metabolic activity and function in a low base-
line oxygen microenvironment that can be exacerbated
by trauma. Stressed and damaged TECs not only gene­rate
cytokines, chemokines and DAMPs but are also targets
for these inflammatory mediators157. For example, TLR2
and TLR4, which are mainly expressed on the luminal
site of TECs, were upregulated after rodent IRI and can
be activated by DAMPs and PAMPs158. As previously
mentioned, patients with trauma who develop AKI have
an altered serum cytokine profile81. Although the source
of many cytokines is systemic, their production can
also be induced in the kidney159, for example, in TECs.
Transcriptomic analysis of the kidneys after murine IRI
also revealed altered expression of genes involved in
several immune signalling pathways, including IL-10,
IL-6, TLR, LPS and/or IL1-​mediated inhibition of the
retinoid acid receptor RXR, and Janus kinase–signal
transducer and activator of transcription (JAK–STAT)
pathways160. In murine kidney IRI, TECs produced
IL-34, which promoted macrophage-​mediated tubule
injury161. Moreover, epithelial expression of hypoxia-​
inducible factors (HIFs), including HIF1α, increased
within 1 h of segmental rodent ischaemia compared
with regularly perfused kidney segments and promoted
macrophage recruitment162. Of note, reduced clearance
of cytokines and toxins in the kidneys during AKI might
enhance local and systemic levels of these soluble media-
tors in trauma. For example, the clearance of the trauma-​
relevant mediators HMGB1, IL-6, IL-10 and TNF was
impaired in mice with either septic AKI or with reduced
kidney function owing to 5/6 nephrectomy163.
Circulating mtDNA has been defined as a strong
DAMP and a driver of inflammation in patients with
trauma78, but seems to be less involved in the development
of post-​trauma AKI164. By contrast, urinary mtDNA levels
correlated with an elevated albumin-​to-​creatinine ratio
and TEC exposure to mtDNA induced an inflammatory
response164.
Kidney injury molecule 1 (KIM1) is markedly upreg-
ulated and shed into the proximal tubular lumen during
IRI-​induced AKI165. In patients with combat-related
injuries, increases in urinary KIM1 levels correlated
positively with injury severity and were higher in
patients with blast injuries compared with those who
sustained gunshot wounds166. At the cellular level,
KIM1 is expressed in injured TECs after experimental
IRI and enables them to detect the apoptosis-​associated
epitopes phosphatidylserine and oxidized lipoprotein167.
This mechanism functionally transforms TECs into
semi-​professional phagocytes early after injury, which
supports tubular clearance of apoptotic and necrotic
cells, and regulates the ensuing immune response167,168
(Fig. 5). Dickkopf-3 (DKK3) is also released into the urine
by stressed kidney cells and is elevated after major car-
diac surgery. Also, preoperative urinary DKK3 to creati-
nine ratio was reported to be predictive of postoperative
AKI development and concomitant long-​term reduction
in estimated GFR169.
Maladaptive repair of the kidney epithelium after
AKI involves various mechanisms, including the induc-
tion of cellular senescence170, G2/M arrest in tubule
cells, persistence of pro-​inflammatory macrophages and
production of pro-​fibrotic cytokines165. Levels of tissue
metalloproteinase inhibitor 2 (TIMP2) and insulin-​like
growth factor binding protein 7 (IGFBP7) are elevated
in urine samples of patients in ICUs, including patients
with trauma, and these cell cycle arrest biomarkers
help to stratify these patients according to the risk of
develo­ping AKI171. Of note, despite the absence of pro-
genitor cells, the remaining functional TECs are able to
repopulate the epithelium after trauma172.
Vasculature. Pericytes, which maintain endothelial and
vascular stability by producing angiogenic factors (for
example, angiopoietin, platelet-​derived growth factor
(PDGF), sphingosine-1-​phosphate (S1P) and vascular
endothelial growth factor (VEGF)) are also activated
during AKI. These cells dissociate from the vasculature
and acquire myofibroblast features in models of IRI or
ureteral obstruction165,173 (Fig. 5).
Sympatho-​a drenal activation, as well as release
of DAMPs, proteases and inflammatory mediators,
induced by trauma and shock, can lead to degradation of
the protective endothelial glycocalyx and release
of glycosaminoglycans — these effects are hallmarks of
trauma-​induced endotheliopathy57,174,175 (Fig. 5). The
serine protease thrombin was shown to contribute to
endotheliopathy in the kidney by inducing endothelial
barrier breakdown in kidney microvessels176.
Reduced endothelial eNOS expression177 and blunted
kidney NO generation contribute to impaired vascular
function, and thus, microperfusion, in IRI-​stressed
kidneys178. Furthermore, the release of platelet inhibi­
tors, including NO and prostacyclin, and the hydrol-
ysis of ATP-​d erivatives to produce adenosine are
compromised, which creates a pro-​coagulant endothelial
microenvironment77 (Fig. 5). In addition, DAMPs such
as uric acid stimulate exocytosis of endothelial Weibel–
Palade bodies within the kidneys early after IRI179.
Weibel–Palade bodies have been described as ‘vascu-
lar emergency kits’180 because they provide preformed
haemostatic, inflammatory and angiogenic mediators,
including the adhesion molecules von Willebrand factor
(vWF) and P-​selectin77. These changes in the endothelial
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Post-​traumatic abdominal
compartment syndrome
Syndrome characterized
by post-​traumatic
intra-​abdominal hypertension
(that is, intra-​abdominal
pressure >20 mmHg) and
de novo visceral organ
dysfunction or failure.
Nature Reviews | Nephrology
microenvironment initiate platelet adherence, accumu-
lation and activation. Activated platelets subsequently
release further DAMPs, including mtDNA and HMGB1
(ref.181), as well as key activators of the coagulation sys-
tem, including tissue factor and polyphosphates, which
support the formation of a stable clot. Thrombin can
also stimulate resting platelets to release mitochondria,
further increasing the local DAMP load77. HMGB1 was
markedly elevated on platelets from patients with severe
blunt trauma compared with healthy controls; accord-
ingly, platelet HMGB1 was crucial for the formation of
thrombi in a murine model of multiple injury181. The
damaged endothelium also facilitates the recruitment
of leukocytes and rouleaux formation of erythrocytes38,
which further compromise RBF in peritubular capillaries
after renal ischaemia128,165,182 (Fig. 5).
Increased vascular inflammation and permeability
are key features of early AKI. These changes are con-
trolled by, among others, the endothelial angiopoietin–
angiopoietin receptor (Tie2) system. Activation of
Tie2 by the agonist angiopoietin 1 propagates anti-​
inflammatory, anti-​apoptotic and anti-​leakage effects
(including stabilization of inter-​e ndothelial junc-
tions, for example, through the inhibition of vascular
endothelial cadherin)183. By contrast, angiopoietin 2
functions as a competitive antagonist of Tie2 resulting
in inflammation and enhanced endothelial perme­
ability. Furthermore, soluble Tie2 (that is, the cleaved
extracellular domain of Tie2) acts as a decoy recep-
tor for angiopoietin and can therefore modulate the
endothelial response183. Haemorrhagic shock in rodents
enhanced levels of circulating angiopoietin 2 and sol-
uble Tie2, induced microcirculatory perfusion distur-
bances and reduced Tie2 expression and activation in
the kidneys184. Moreover, the Tie2 agonist vasculotide
was renoprotective in IRI-​induced AKI185.
Intense endothelial–epithelial communication is
thought to promote a ‘vicious triad’ — DNA derived
from necrotic TECs induces platelet aggregation and
activation, platelets interact with neutrophils and trig-
ger the formation of NETs, which in turn further dam-
age TECs by exposing them to cytotoxic histones186.
Moreover, ROS generation induces endothelial TLR4
upregulation within 4 h of IRI; TLR4 is only upregu­
lated later (within 24 h) in the tubule epithelium.
HMGB1, which is generated by TECs179 or systemically,
can therefore signal through TLR4 in a temporo-​spatial
manner — HMGB1 initially induces the expression of
endothelial adhesion molecules that recruit inflamma-
tory cells, followed by induction of cytokine production
by TECs187. In addition, binding of HMGB1 to TLR4 on
macrophages activates these cells and induces the release
of IL-6, which exacerbates endotheliopathy and kidney
dysfunction128,188.
Neuroinflammatory response in TRAKI
Within milliseconds of a traumatic event, injured
regions react with a neuronal response that causes
pain, induces the release of stress hormones and trig-
gers haemodynamic adaptation responses, as well as
excitatory and inhibitory brain–kidney crosstalk and
renal–renal neuronal connections (Fig. 6). Sympathetic
Reviews
efferents interact directly with the kidney vasculature,
tubules and juxtaglomerular granular cells189. Tissue
injury, hypoxia and trauma-​relevant cytokines, includ-
ing IL-1β and IL-6, can activate medullary neurons in
the brain, which enhances the sympathetic efferent drive
to the kidneys189. This results in increased production
of noradrenaline and renin in the kidney, enhanced
Na+ and water reabsorption, and a decrease in RBF, GFR
and urine output190,191. Accordingly, blockade of kidney
sympathetic nerve activity improved histomorphological
damage in rodent IRI190.
Afferent sensory neurons in the kidney, which
are mechanosensitive and chemosensitive, project
mainly from the renal pelvis to the brainstem and
hypothalamus189. These neurons might sense altera-
tions in urine composition and pelvic stretch189 after an
injury to the ureter or retroperitoneum, or during post-​
traumatic abdominal compartment syndrome. However, the
exact function of these neurons after trauma remains
unclear.
Neuroinflammatory reflexes of the vagal nerve sys-
tem for various organs and the protective effects of vagal
stimulation on visceral organs have both been described
in trauma and haemorrhagic shock192. However, the
existence and potential function of direct vagal efferent
activity in the kidneys remain uncertain193. Nevertheless,
vagal drive can indirectly modulate the immunopatho-
physiological responses in the kidney — stimulation
of the efferent vagal nerve induces acetylcholine pro-
duction in splenic CD4+ T cells, which prompts an
anti-​inflammatory response in splenic and peritoneal
macrophages191,194. Of note, activation of this pathway is
also protective in IRI-​induced AKI194.
In addition, severe trauma activates the hypotha-
lamic–pituitary–adrenal (HPA) axis, which initially
leads to enhanced corticosteroid levels that sup-
press the inflammatory response (Fig. 6). However, in
humans, this increase persists for less than 24 h after
trauma195,196. In experimental rhabdomyolysis-​induced
AKI, systemic and urine cortisol concentrations were
also increased197. In murine kidney IRI, intraperito-
neal administration of a transactivator of transcription
(Tat)–glucocorticoid-​induced leucine zipper (GILZ)
peptide resulted in a shift from a pro-​inflammatory to
a suppressive neutrophil phenotype and promoted the
development of regulatory T cells. These changes were
associated with improved kidney perfusion and mito-
chondrial function, as well as a reduction in kidney
oedema and cell necrosis198, suggesting that glucocorti-
coids might have some renoprotective effects. However,
further studies are needed to define the role of the HPA
axis and glucocorticoids in the kidney after trauma.
Kidney–organ crosstalk during TRAKI
The kidney is interconnected with almost every other
organ system (Fig. 7). Nevertheless, research data on
kidney–remote organ interactions in trauma and IRI
are currently lacking11. Experimental evidence, mainly
from IRI models, suggests that AKI augments leuko-
cyte infiltration, ROS generation and other outcomes
linked to kidney inflammation, barrier dysfunction and
congestion, in almost all parenchymal organs10,11,199,200.
Reviews

Trauma

• Tissue damage
• Pain
• Hypoxia HPA axis
• Haemorrhage
• Cytokines
Brain (IL-1β, IL-6, TNF)

Adrenal gland
Vagal Sensory Sympathetic
efferents afferents efferents Corticosteroids

Adrenaline
Spleen and/or
noradrenaline
• ↑ Noradrenaline →
↑ leukocytes →
inflammation
Reno–renal reflexes
• ↑ Renin
• ↓ RBF
Inflammatory ↑ Noradrenaline • ↓ GFR
reflexes • ↓ Na+ excretion

Changes in:
• Pelvic pressure
T cell β2R and stretch
• Vasculature
• Urine flow
• Urine concentrate
α7nAchR
Cholinergic
anti-inflammatory Anti-inflammatory
pathway action

Macrophage

Fig. 6 | Neuroinflammatory axis underlying TrAKI. Early after trauma, the balance between sympathetic and vagal
activity undergoes a substantial shift towards sympathetic stimulation, which can exacerbate kidney dysfunction and
inflammatory processes through direct action in the kidney. Mechanic and chemosensitive signals are transmitted via
kidney sensory afferents to the brain. Conversely, trauma-​induced stimulation of the hypothalamic–pituitary–adrenal
(HPA) axis not only induces the release of adrenaline and noradrenaline, but also corticosteroid production, which
supports an anti-​inflammatory response. The neuroinflammatory reflex induced by vagal stimulation of the spleen
ultimately results in an anti-​inflammatory response in various organs, including the kidneys. Vagal stimulation of the
splenic nerve results in noradrenaline release, which is sensed by the β2-​receptor (β2R) of splenic CD4+ T cells that
respond by secreting acetylcholine. In turn, acetylcholine binding to the α7 nicotinic acetylcholine receptor (α7nAchR)
on splenic macrophages promotes an anti-​inflammatory response in the kidney. Vagal stimulation can also activate
peritoneal macrophages directly via α7nAchR to drive an anti-​inflammatory response in acute kidney injury (AKI)
induced by ischaemia–reperfusion injury. GFR, glomerular filtration rate; RBF, renal blood flow; TNF, tumour necrosis
factor; TRAKI, trauma-​related AKI.

Brain Conversely, AKI has detrimental effects on the brain

Neuronal pyknosis
An early hallmark of neuronal
cell death characterized by
irreversible condensation of
chromatin.
Traumatic brain injury (TBI) is a risk factor for fatal out-
comes and the development of TRAKI5. Interestingly,
both the brain and kidney possess a tightly controlled
autoregulation system regarding blood flow, challenged
by systemic hypotension. Post-​trauma sympathetic
stimulation, activation of the HPA axis and neuroin-
flammation represent major drivers of the brain–kidney
axis199,201,202. Several neurotransmitters can modulate
kidney physiology following trauma. Endogenous88 or
administered catecholamines result in increased renin
secretion by the juxtaglomerular cells, which is driven
by activation of β1-​adrenergic receptors, whereas RBF
is decreased through stimulation of α1-​adrenergic
receptors199,201. TBI also alters Na+ handling in the kidney
— both cerebral Na+ wasting or excessive secretion of
anti-​diuretic hormone can contribute to hyponatraemia,
but are often difficult to distinguish202,203.
by altering its water content and disrupting the blood–
brain barrier202. Dysfunction of the blood–brain barrier
itself might facilitate an influx of inflammatory medi-
ators and toxic substances released from the injured
kidney204. Increased neuronal pyknosis, activation of
brain microglia and a decline in locomotor activity
were all reported in bilateral kidney murine ischaemia205.
Furthermore, kidney IRI induced a rise in the expression
of chemokines and glial fibrillary acidic protein in the
brain, which suggests that substantial pro-​inflammatory
and functional cerebral alterations occur during AKI205.
Heart
Optimal cardiocirculatory function is crucial to sus-
tain kidney perfusion. In murine IRI, AKI was associ-
ated with an elevated cardiomyocyte apoptosis rate and
impaired left ventricular function206. Furthermore, AKI

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resulted in increased cardiac IL-1β and TNF production,
myeloperoxidase activity and expression of intercellular
adhesion molecule 1, which are indicative of leukocyte
infiltration206. In this context, in a murine model of IRI,
the kidney injury promoted cardiac injury in a galectin-3
dependent manner by enhancing systemic cytokines
such as IL-1β, IL-6, IL-10 and TNF, as well as promot-
ing immune cell recruitment from the bone marrow and
cardiac macrophage invasion207.
Lungs
Kidney IRI resulted in the downregulation of pulmonary
ion channels and transporters, and increased alveolar
fluid leakage with subsequent pulmonary oedema and
caspase-​dependent apoptosis200,208–210. AKI is also associ-
ated with the upregulation of various pro-​inflammatory
cytokines in the lung (for example, TNF, IL-1β, IL-6 and
IL-8), leading to a pronounced influx of inflammatory
cells124,159,200,211. Among others, the DAMPs HMGB-1
and haem represent key mediators in AKI-​induced
pulmonary inflammation212,213.
Lung trauma, frequently caused by blunt chest
injury, might also induce TRAKI. Although broad evi-
dence exists for a lung–kidney crosstalk in patients with
critical illness, for example, the presence of blood–gas
disturbances and fluid overload214, data on isolated lung
trauma and its consequences for the kidneys are scarce.
Of note, inflammation in both the lungs and the kid-
neys can also be induced by mechanical ventilation16.
A study of patients with trauma revealed that acute
lung injury requiring mechanical ventilation was a
risk factor for AKI215; mechanical ventilation per se
is also independently associated with progression of
early AKI216. Patients with thoracic trauma who did
not require mechanical ventilation had an elevated
albumin-​to-​creatinine ratio, which suggested increased
kidney permeability, compared with patients with
trauma without thoracic trauma217. Furthermore, pulmo-
nary dysfunction in patients receiving mechanical ven-
tilation, which was indicated by an elevated fraction of
inspired oxygen (FiO2):partial pressure of oxygen ratio,
correlated with increased albumin-​to-​creatinine ratio217.
Liver
The kidneys and liver share important functions after
trauma, including clearance of metabolites and drugs,
as well as stabilization of blood glucose and amino acid
levels. In various kidney IRI models, AKI caused hepatic
damage evidenced by increased plasma concentrations
of liver enzymes. Hepatic inflammation, periportal
hepatocyte vacuolization and apoptosis were observed
after AKI, whereas systemic antioxidant levels were
decreased compared with sham animals218–220. Moreover,
kidney IRI altered drug metabolism in the liver221,222.
Following kidney IRI, increased production of various
cytokines such as IL-6, IL-10, IL-17A and TNF in the
liver drove hepatic damage218,219. Interestingly, induction
of the sphingosine kinase–S1P pathway by isoflurane
protected against hepatic and intestinal dysfunction
after IRI-​induced AKI in mice, at least partly through
the downregulation of TNF, CCL2 and IL-17A in the
liver and intestine220.
Nature Reviews | Nephrology
Reviews
Gastrointestinal tract
Gastrointestinal trauma and IRI can disrupt the gut–
blood barrier, which might allow pathogens and toxins
to enter the body and drive inflammation and MODS
after injury8,223,224. In experimental models, kidney IRI
led to apoptosis of intestinal epithelial and endothelial
cells, epithelial cell necrosis, upregulation of TNF, IL-6
and IL-17, and increased tissue oedema, all of which can
exacerbate damage to the intestinal barrier218,220. The
retention of metabolites and urea due to reduced kidney
excretion has been suggested to disrupt tight junctions
between intestinal epithelial cells225. Furthermore, ample
evidence supports a close link between kidney injury
and the intestinal microbiome, particularly in chronic
kidney disease 226; many uraemic toxins, including
indoxyl sulfate, are of microbial origin227,228. By contrast,
gut-​derived d-​serine was renoprotective in murine IRI
and human AKI229. Similarly, short-​chain fatty acids,
including propionate and butyrate, but in particular
acetate, which are produced by gut microbiota during
the fermentation of dietary fibres, have been shown
to prevent kidney injury and dysfunction in murine
IRI230. This is presumably mediated, at least in part,
by attenuated histone deacetylase activity and restored
oxidant–antioxidant balance in T cells, as demonstrated
in murine septic AKI231. However, further studies are
warranted to assess the benefits and risks of long-​term
short-​chain fatty acid treatment232, especially in the
context of trauma.
Spleen
The spleen functions as a blood filter and has a key role
in the clearance of debris and infectious agents. Splenic
cells, particularly monocytes, secrete IL-6, IL-8, IL-10
and TNF early after ischaemic AKI233,234. Splenectomy
directly before kidney murine IRI resulted in elevated
serum IL-6 concentrations as well as increased pulmo-
nary capillary leakage and neutrophil infiltration234.
These detrimental effects were attributed to a reduction
in spleen-​derived IL-10 and could be reversed through
administration of IL-10, which emphasizes the role of
the spleen in resolving inflammation during AKI234.
By contrast, splenectomy in the context of liver IRI
in rats seemed to have a protective effect on the liver
and kidneys235. Of note, the anti-​inflammatory drive of
vagal stimulation in the spleen might have therapeutic
potential233,236,237. In humans, splenectomy post-​trauma
has been associated with enhanced infectious and
hypercoagulation complications238,239, but little has been
reported about kidney complications.
Bone
The kidneys are involved in regulating bone forma-
tion and repair by modulating calcium and phosphate
homeostasis, and by producing growth factors such as
active vitamin D, erythropoietin and bone morphogenic
protein 7 (ref.240). Hip fractures and long bone fractures
are a risk factor for the development of AKI215,241,242,
and post-​fracture changes in kidney perfusion were
proposed as an early predictor of AKI243. In rabbits,
AKI was absent or only mild following bilateral femur
fractures with haemorrhagic shock that were treated
Reviews

Acutely injured organ → kidney Spleen Brain

• TBI
Spleen trauma • ↓ GCS
• ↑ ICP

Splenectomy

CAP IL-10 • ↑ Sympathetic drive

• HPA activation
Anti-inflammatory action • Neuroinflammatory reflexes
Lungs
Gut • ↑ Renin
Kidney • ↓ RBF Thoracic
• Gut trauma • Hyponatraemia Hypoxia trauma
• PAMPs and/or
• Gut barrier • Bacteria • ↑ UACR
dysfunction • Epithelial mechanic
necrosis ventilation

↓ Macro and micro-circulation DAMPs

↓ Clotting Heart
Liver factors

Haemorrhagic Heart contusion

Haemorrhagic ↑ NLR and/or trauma
shock shock
• ↓ Cardiac
output
Bone • ↓ MAP
marrow
Fracture

Acutely injured kidney → remote organ

• ↑ GFAP
IL-6, IL-8 and • ↑ Cerebral chemokines
TNF secretion • Neuronal pyknosis
• ↑ Oedema
• Blood–brain barrier dysfunction

• ↑ IL-6, IL-17 and

TNF
• ↑ Oedema • ↑ Inflammatory cells
• Epithelial necrosis • ↑ Phagocytosis
• ↑ Epithelial and • ↑ Alveolar fluid
AKI • ↑ Oedema
endothelial cell
apoptosis
• ↓ Gut–blood barrier

• ↑ Cardiac cytokines
• ↑ Hepatic • Leukocyte infiltration
cytokines Immune cell • ↑ Cardiomyocyte
• ↑ Neutrophil recruitment apoptosis
recruitment
• ↑ Apoptosis
• ↓ Drug clearance Bone
• ↓ Antioxidant marrow
enzymes

with either intramedullary nails or external fixators244. Bone marrow

However, in the clinical setting, definitive osteosyntheses
scheduled 24–48 h after trauma to treat lower extremity
fractures reduced the incidence of AKI, whereas earlier
or later definitive surgical intervention was associated
with higher AKI rates245. AKI also predisposes to sub-
sequent chronic kidney disease246, which contributes
to renal osteodystrophy and increases the risk of bone
fractures247.
Trauma has long been known to significantly affect
haematopoietic function in bone marrow248; however,
data regarding a direct interaction between TRAKI
and haematopoiesis in bone marrow are scarce.
Nevertheless, in addition to the previously mentioned
study in patients with trauma123, elevations in the sys-
temic NLR have also been proposed as a diagnostic
marker for AKI249 based on data from patients who

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◀ Fig. 7 | Kidney as target and effector of TrAKI-associated organ crosstalk. Intense
immunopathophysiological crosstalk exists between acutely injured organs and the
kidney, which is often not directly injured by trauma but is a common secondary target
organ of trauma. Conversely, kidneys with acute injury, induced by trauma or other
conditions, interact closely with several organs. Immediately after the onset of shock, the
kidney is affected by remote organ dysfunction, which disturbs the kidney macro- and
microcirculation. Consequently, trauma-​related acute kidney injury (TRAKI) amplifies
remote organ damage, for example, due to electrolyte–water imbalance, which drives
parenchymal oedema and breakdown of the blood–organ barrier. This effect increases
O2 transport distances and promotes cardio-​respiratory failure. The immunopathophysi-
ological response of TRAKI generally enhances levels of inflammatory cytokines, such as
IL-1, IL-6, IL-8 and tumour necrosis factor (TNF), as well as the infiltration of remote organs
with activated leukocytes. CAP, cholinergic anti-​inflammatory pathway; DAMPs, damage-​
associated molecular patterns; GFAP, glial fibrillary acidic protein; GCS, Glasgow Coma
Scale; HPA, hypothalamic–pituitary–adrenal; ICP, intracranial pressure; MAP, mean
arterial pressure; NLR, neutrophil-​to-​lymphocyte ratio; PAMPs, pathogen-​associated
molecular patterns; RBF, renal blood flow; TBI, traumatic brain injury; UACR, urine
albumin-​to-​creatinine ratio.
underwent cardiac surgery250. A 2019 study of mice with
adenine-​induced nephropathy reported an increase
in the generation of myeloid progenitor cells and a
decrease in common lymphoid progenitor cells in the
bone marrow, which significantly increased the NLR.
Mechanistically, these alterations were mediated by
gut-​derived indoxyl sulfate251. NLR elevations followed
by neutrophil-​mediated kidney injury might also occur
in TRAKI.
Monitoring of TRAKI
Monitoring of TRAKI is challenging. Severe trauma
in one kidney does not necessarily result in enhanced
serum creatinine levels or impaired urine output
because the collateral uninjured kidney might com-
pensate for lost function. By contrast, untraumatized,
morphologically intact kidneys might be severely func-
tionally compromised owing to extrarenal injuries,
especially haemorrhagic shock or TBI. Further contri­
butors to functional deterioration include pre-​existing
risk factors (such as advanced age or type 2 diabe-
tes mellitus) or exposure to nephrotoxins, volume
depletion, mechanical ventilation or vasopressor appli-
cation, all of which add to the presence of renal angina,
which is indicated clinically by the presence of oliguria,
any increase in serum creatinine and fluid overload252.
Early detection of biomarkers of kidney tubule injury
might create a window of opportunity to prevent further
kidney damage after TRAKI. Perioperative increases
in biomarker levels were associated with postopera-
tive development of AKI. For example, the two urine
biomarkers IGFBP7 and TIMP2, which are expressed
in TECs and induce cell cycle arrest 171, can predict
moderate or severe AKI (Kidney Disease Improving
Global Outcomes stage 2 or 3) within 12 h of sample
collection253. Interestingly, IGFBP7 was superior to
TIMP2 in patients after surgery, whereas TIMP2 was
best at predicting sepsis-​induced AKI; such differences
might reflect distinct underlying biological mecha-
nisms. These biomarkers also improved AKI risk strati-
fication when added to a nine-​variable clinical model254,
and are thus important tools for AKI detection and
patient management253. Future diagnostics should also
enable micro-​spatial differentiation of kidney injury
Nature Reviews | Nephrology
Reviews
to ensure that therapeutic strategies are targeted to the
relevant pathogenic mechanisms that affect specific
kidney compartments.
Therapeutic targets of TRAKI
Therapy of TRAKI is equally complex. Various patho-
physiological and immunological strategies have
been proposed and evaluated to ameliorate TRAKI
in different experimental and clinical settings. These
approaches mainly address trauma-​induced generation
of DAMPs and PAMPs, metabolic and radical stress,
alterations in micro-​perfusion, hypoxia and ischae-
mia. The systemic as well as the fluid phase and cellular
immune responses in the kidney also offer promising
targets (Supplementary Table 1).
Increased awareness of TRAKI in combination
with reliable monitoring and early, effective thera-
peutic interventions represent major prerequisites to
successfully treating or even preventing TRAKI.
Conclusions
TRAKI occurs frequently after severe tissue trauma and
represents a hybrid of various aetiologies. Low-​flow per-
fusion, hypoxia, ischaemia, release of DAMPs, PAMPs
and toxins, and the presence of direct and remote tissue
debris can differentially modulate the early pathophysio­
logical and immune response in the kidneys. Rapid
activation of the central neuronal system with a pre-
dominant sympathetic drive post-​injury, as well as
activation of the coagulation and complement system
in concert with leukocyte stimulation and endothelial
alterations, mount an inflammatory response in both
the glomerular and tubular systems of the kidney. The
consequences are glomerular filter dysfunction, deve­
lopment of microthrombi and GFR decline. Further
downstream, TECs adopt a pro-​inflammatory pheno­
type, lose their resorption and clearance function,
undergo morphological changes and might become
apoptotic or necrotic, thus obstructing the tubular
lumen. The resulting breakdown of the urine–blood
barrier leads to ion and water imbalances, which lead
to oedema in the kidney and remote organs, further
aggravating multiple organ dysfunction. The kidneys
are involved in crosstalk with multiple organs and, con-
sequently, are not only highly susceptible to damage
caused by systemic responses to remote trauma but,
following TRAKI, the kidneys can also act as a major
instigator of remote organ dysfunction.
Haemorrhagic shock is also a potent driver of TRAKI
in combination with individual pre-​e xisting and
trauma-​specific risk factors. Therefore, therapeutic
strategies must address the initial causes of shock, limit
further tissue damage, and address the systemic and
kidney consequences of trauma through interdiscipli-
nary management of intensive care and the proposal of
future immunomodulatory approaches. Further research
on TRAKI and the corresponding crosstalk with other
organs affected by trauma is necessary to understanding
the underlying mechanisms of organ dysfunction and
ultimately improve trauma management.
Published online xx xx xxxx
Reviews
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Acknowledgements
This review was supported by funding from the German
Research Foundation (DFG) to M. H.-​L. (CRC 1149, project
numbers INST 40/479-2 and INST 40/487-2).
Author contributions
D.A.C.M., R.H., B.N. and M.H.-​L. made substantial contribu-
tions to discussions of the content of the article. D.A.C.M., R.H.,
P.R. and M.H.-​L. researched data for the article. D.A.C.M.,
R.H., H.P., P.R. and M.H.-​L. wrote the manuscript. All authors
reviewed or edited the manuscript before submission.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Nephrology thanks the anonymous reviewers
for their contribution to the peer review of this work.
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