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org

Sepsis and Acute Kidney Injury

Abolfazl Zarjou and Anupam Agarwal
Department of Medicine, Division of Nephrology, Nephrology Research and Training Center and Center for Free
Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama

ABSTRACT
Sepsis is a severe and dysregulated inflammatory response to infection character- causes of AKI in critically ill patients, ac-
ized by end-organ dysfunction distant from the primary site of infection. Develop- count for 50% or more of cases of AKI in
ment of acute kidney injury (AKI) during sepsis increases patient morbidity, pre- ICUs, and associate with a very high
dicts higher mortality, has a significant effect on multiple organ functions, is mortality.9 Furthermore, there is evi-
associated with an increased length of stay in the intensive care unit, and hence dence that even less severely ill patients
consumes considerable healthcare resources. When compared with AKI of non- with infection (patients with nonsevere
septic origin, septic AKI is characterized by a distinct pathophysiology and there- pneumonia) have a significantly higher
fore requires a different approach. Despite impressive advances in several fields of incidence of AKI and increased immune
medicine, the pathophysiology, diagnostic procedures, and appropriate therapeu- responses.10 Although septic shock is a
tic interventions in sepsis are still highly debatable. Numerous immunomodulatory leading cause of AKI, the underlying
agents showing promise in preclinical studies fail to reduce the overwhelmingly mechanisms are not completely known.
high mortality rate of sepsis and provoke AKI when compared with other critically Despite extensive research and progress
ill patients. Major impediments to progress in understanding, early diagnosis, and in several other fields, the incidence, as
application of appropriate therapeutic modalities in sepsis-induced AKI include well as mortality of septic AKI, remains
limited histopathologic information, few animal models that closely mimic human unacceptably high.11 Perhaps an impor-
sepsis, and a relative shortage of specific diagnostic tools. Here we discuss the tant factor in this dilemma is the relative
most recent advances in understanding the fundamental mechanisms of sepsis- lack of histopathologic information and
induced AKI, characteristics of relevant animal models available, and potential reliance on creatinine measurements for
therapies. assessment of kidney function.
J Am Soc Nephrol 22: 999 –1006, 2011. doi: 10.1681/ASN.2010050484
Pathogenesis of Sepsis-induced AKI
Sepsis develops when the initial, appro-
priate host response to an infection be-
Sepsis is a serious medical condition bands).1,2 Except for the discovery of an- comes amplified and then dysregulated.
characterized by a whole-body inflam- timicrobial agents in the mid-1900s, little Because of very high mortality rates, it is
matory state (systemic inflammatory-re- progress has been made in the manage- fundamental to promptly recognize sep-
sponse syndrome) and the presence of a ment of sepsis, which remains a particu- sis-induced AKI and to choose the most
known or suspected infection that has se- larly serious problem for patients with appropriate therapeutic modality. This
vere consequences, including multiple ESRD.3 In fact, there are approximately task, however, is still far from certain be-
organ failure.1 The clinical diagnosis of one million reported cases and more cause of a lack of general consensus and
sepsis requires finding a focus of infec- than 200,000 deaths each year attribut- conflicting data. It is well established that
tion as well as at least two signs of sys- able to sepsis in the United States alone.4
temic inflammatory-response syn- This is a significant burden on health re-
drome that comprise abnormal body sources, with costs exceeding $10 billion Published online ahead of print. Publication date
temperature (higher than 38°C or less per year in the United States.5,6 available at www.jasn.org.

than 36°C), heart rate ⬎90 beats/min,
respiration ⬎20 breaths/min or arterial
partial pressure of CO2 ⬍32 mmHg, and
deranged white blood cell counts
(greater than 12 ⫻ 103/mm3, less than
4 ⫻ 103/mm3, or greater than 10%
Acute kidney injury (AKI) is a fre-
quent and serious complication of sepsis
in intensive care unit (ICU) patients,7
particularly in the elderly.8 Moreover,
there is strong evidence that sepsis and
septic shock are the most important
Correspondence: Dr. Anupam Agarwal, Division of
Nephrology, THT 647, University of Alabama at Bir-
mingham, 1900 University Boulevard, Birmingham,
AL 35294. Phone: 205-996-6670; Fax: 205-996-
6650; E-mail: agarwal@uab.edu
Copyright © 2011 by the American Society of
Nephrology

J Am Soc Nephrol 22: 999–1006, 2011 ISSN : 1046-6673/2206-999 999

 BRIEF REVIEW www.jasn.org

the kidney is a commonly affected organ tory phase is followed by a compensatory alerting the innate immune system.27,28
during sepsis, and its involvement carries anti-inflammatory immune response, an They are single membrane-spanning
a high risk of mortality.12,13 The patho- immunosuppressed state characterized noncatalytic receptors that recognize
physiology of AKI in sepsis is complex by altered cytokine production and anti- structurally conserved molecules derived
and multi-factorial and includes intrare- gen presentation by monocytes, de- from invading pathogens. TLR-4 ap-
nal hemodynamic changes, endothelial creased lymphocyte proliferation, and pears to play a key inflammatory role in
dysfunction, infiltration of inflamma- increased apoptosis. It must be noted AKI.29 There is a significant up-regula-
tory cells in the renal parenchyma, intra- that these stages can overlap tempo- tion of monocytic TLR-2 and TLR-4 ex-
glomerular thrombosis, and obstruction rally.21 pression in septic patients when com-
of tubules with necrotic cells and debris Several pro-inflammatory cytokines pared with healthy individuals.30,31 In
(Figure 1).14 A growing body of evidence contribute to the development of sepsis, addition, the expression of TLR-2 and
now suggests that the sepsis-induced im- and others may be identifiable from TLR-4 in hepatic and splenic macro-
mune responses involve the activation, other kinds of genetic screens.22 For in- phages is significantly increased in mice
in a sequential manner, of both pro- and stance, administration of recombinant with experimental peritonitis induced by
anti-inflammatory mechanisms.15,16 IL-1 or TNF-␣ induces many of the fea- cecal ligation and puncture.31,32 These
After initial host-microbial interac- tures observed after lipopolysaccharide and other findings suggest that modula-
tions, there is widespread activation of exposure or sepsis itself.18,19 Further- tion of TLRs may become a novel thera-
the innate immune response, which co- more, anti-TNF monoclonal antibodies peutic target especially in the treatment
ordinates a defensive response involving have beneficial effects in several animal of organ injury accompanying sepsis. Al-
both humoral and cellular compo- models of sepsis.23 Nonetheless, these though this is an interesting approach, it
nents.17 This in turn leads to secretion and other cytokine-blocking experi- is imperative to note that apart from TLR
of various cytokines, most importantly ments have not been conclusive and have modulation, sepsis also affects several
IL-1,18 TNF-␣,19 and IL-6,20 that prog- also failed in clinical trials.24 Recent pre- other pathways including injury caused
ress to a state of cytokine storm, hemo- clinical studies suggest an anti-inflam- by endotoxin, complement cascade, co-
dynamic instability, and eventually or- matory role for soluble thrombomodu- agulation pathway activation, release of
gan dysfunction and septic shock. The lin in AKI,25 and release of stem cell arachidonic acid and nitric oxide, vascu-
precise nature of such hemodynamic in- factor by MMP-9 has an antiapoptotic lar injury, and others that mediate the
stability and its consequence on renal effect through activation of cKit.26 development and course of sepsis. Such
blood flow (RBF) will be discussed in Toll-like receptors (TLRs) are a class complexity may have been an important
more detail below. This pro-inflamma- of proteins that play an important role in contributor to the failure of clinical trials
targeting just one of these pathways.
Microbial insult
(endotoxin-LPS/exotoxin-peptidoglycan)
Biomarkers in Sepsis-induced AKI
When compared with AKI of nonseptic or-
Pro-inflammatory state igin, septic AKI is characterized by a dis-
tinct pathophysiology,14,33,34 and there-
Complement and Protease activation: Free Cytokine secretion: Cellular involvement:
fore important differences exist in
coagulation Heparan sulfate, radical IL-1, IL-6, Neutrophils, macrophages, patient characteristics, response to inter-
pathway activiation hyaluronic acid, elastase formation PAF, TNF-α DG, platelets, endothelial cells
ventions, and clinical outcomes. This
may also extend to unique patterns of
plasma and urinary biomarkers in septic
Anti-inflammatory state
AKI. For instance, the excretion of IL-18
is higher in septic AKI than in nonseptic
Increased Poor Deranged immune Impaired Lymphocyte AKI.35,36 Moreover, an increased level of
IL-10 phagocytosis function chemotaxis apoptosis IL-18 predicts deteriorating kidney func-
tion approximately 24 to 48 hours before
clinically significant AKI. AKI can be di-
Mitochondrial dysfunction Apoptosis and necrosis Endothelial dysfunction
Metabolic acidosis Capillary leakage Thrombosis
agnosed by small changes in serum cre-
Oliguria Impaired vascular tone atinine37 or acute reductions in urine
output.38 Nevertheless, rising creatinine
and oliguria during sepsis often appear
ACUTE KIDNEY INJURY after the window of opportunity for ef-
MULTIPLE ORGAN FAILURE AND DEATH
fective therapy has already passed. More-
Figure 1. Key pathogenic pathways involved in the clinical course of sepsis that also have over, sepsis decreases production of cre-
implications in the pathophysiology of sepsis-induced acute kidney injury. atinine without major alterations in

1000 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 999 –1006, 2011
 www.jasn.org BRIEF REVIEW

body weight, hematocrit, or extracellular
fluid and creates further limitations on
using changes in creatinine levels as a re-
liable marker of AKI.39 Hence, it is essen-
tial to have markers that enable early de-
tection. Molecules such as kidney injury
molecule-140 or neutrophil gelatinase-
associated lipocalin41 demonstrate excit-
ing potential for this reason. Table 1
summarizes a partial list of emerging
biomarkers that are in various phases of
validation in AKI.
A recent study demonstrated that sep-
tic AKI patients have higher detectable
plasma and urine neutrophil gelatinase-
associated lipocalin compared with non-
septic AKI patients.42 The utility of these
and other novel biomarkers including
cystatin C, liver fatty acid– binding pro-
tein, and netrin-1 for early detection of
sepsis-induced AKI is very encouraging
and may have prognostic as well as
pathogenetic implications.43 For in-
stance, urinary liver fatty acid– binding
protein is significantly higher in AKI
than non-AKI in adult ICU patients.44,45
On the other hand, netrin-1, a laminin-
like protein with possible roles in neovas-
cularization, cell adhesion, and tumori-
genesis, is excreted in the urine as early as
1 hour after injury reaching approxi-
mately 30-fold increase by 3 hours and
Table 1. A partial list of emerging biomarkers for early detection of acute
kidney injury
Biomarker Source of Sample
Cystatin C Plasma
L-FABP Urine
IL-18 Urine
NGAL Plasma
KIM-1 Urine
Netrin-1 Urine
L-FABP, L-type fatty acid– binding protein; NGAL, neutrophil gelatinase-associated lipocalin; KIM-1,
kidney injury moleclue-1.
peaking at 6 hours after the insult.46,47
This window of opportunity to imple-
ment potential therapeutic interventions
is indeed well before any detectable
changes in blood urea nitrogen and se-
rum creatinine would occur. The utility
of such biomarkers may be of particular
importance because early detection of
AKI will allow for appropriate and timely
interventions that would significantly
decrease morbidity and mortality related
to AKI.13
Advances and Limitations of Animal
Models of Sepsis
An ideal animal model of sepsis ought to
consistently translate pertinent informa-
tion from animal research to the human
condition. As in many other fields of in-
vestigation, rodents have been a highly
favored species in sepsis research. This is
mainly because they are small, relatively
inexpensive, and permit a large number
of animals to be studied.48 –50 Despite
these advantages, certain rodent strains
are quite resistant to endotoxin, have dis-
tinct hemodynamic profiles, and have
smaller blood volume in comparison
with humans, limiting the number of re-
peat samples that can be obtained from
these species. The fact that there are dif-
ferences between TLRs in mice and in
Elevation in
Reference
Sepsis-induced AKI
Intermediate 44,76
Early 45,49
Intermediate 35,36
Early 42,77
Intermediate 44,48,76
Early 46,47,78
humans could also affect interpretation
of sepsis studies in the two species.51
Parameters such as cardiac output
and pulmonary artery pressure are mea-
sured more easily in larger species.52–54
There have been other animal species of
induced sepsis that include rabbits, cats,
dogs, pigs, sheep, and nonhuman pri-
mates (Tables 2 and 3).52 Unfortunately,
none of the large or small animal species
can completely reproduce the patho-
physiology, immunology, and conse-
quences of human sepsis. The majority
of animal studies use young, healthy an-
imals, and in most cases, the animals
have no comorbidities and start with
normal leukocyte counts. In addition,
the clinical course of sepsis in humans is
usually prolonged, taking days to weeks
to manifest progressive organ failure. By
contrast, the time course of illness in an-
imal models ranges from hours to days,
which may suggest a different set of
pathophysiologic conditions. There is
much to be improved in animal models
of sepsis, and several key factors must be
taken into consideration. These factors
include the need for long-term studies
with ICU-like conditions to simulate the
often-delayed onset of organ dysfunc-
tion in the clinical setting and using sep-
sis or organ dysfunction criteria to start
treatment instead of a fixed time sched-
ule. Indeed, recent progress has been
very encouraging and has led to several
new clinically relevant animal models.48
Animal models will remain essential in
the development of the testing and vali-
dation of all new therapies for sepsis and
septic shock because they provide funda-
mental information about the pharma-
cokinetics, toxicity, and mechanism of
drug action that cannot be duplicated by
other methods.

Table 2. Most common animal models of sepsis

Species Advantages Disadvantages
Rodents Small, inexpensive, defined genetic Difficult measurement of physiological parameters such as
characteristics and transgenic strains cardiac output, limited samples, major immunological
differences
Sheep and pigs Superior physiological, hemodynamic mimicry, More expensive, labor intensive
easier to monitor important parameters, docile
Nonhuman primates Closely resemble human anatomy and replicate Substantial expenses, ethical limitations, higher potential
inflammatory response for zoonotic disease

J Am Soc Nephrol 22: 999 –1006, 2011 Sepsis and AKI 1001
 BRIEF REVIEW www.jasn.org
Table 3. Animal models of sepsis and acute kidney injury
Animal model
Endotoxin injection
Intravascular infusion of live bacteria
Peritonitis models
(CLP, fecal inoculation, and CASP)
CLP, cecal ligation and puncture; CASP, colon ascendens stent peritonitis.
RBF Alterations during Sepsis
Arterial vasodilation with an associated
decrease in systemic vascular resistance is
a fundamental hallmark of sepsis, and
until recently, it was generally believed
that like other causes of shock (hypovo-
lemic or cardiogeneic), sepsis-induced
AKI was mainly due to hypoperfusion of
kidneys. If true, this would imply resto-
ration of such hypoperfusion, and RBF
should be the primary means of renopro-
tection in sepsis.55
Most of our understanding regarding
RBF during sepsis relies on animal mod-
els. Across these studies, the heteroge-
neous nature of animals used, methods
of inducing sepsis, and observed changes
in RBF that vary from unchanged, de-
creased, and markedly increased all
translate to uncertainty regarding their
applicability to humans.55,56 The charac-
teristic pattern of RBF in human sepsis is
for the most part largely unknown be-
cause RBF cannot be measured continu-
ously in humans, and even its intermit-
tent measurement requires a high level of
invasiveness.55,57 However, a small co-
hort study where RBF was measured in
patients with sepsis reported that RBF
was either preserved or increased in these
patients.58 This study and some others
that followed seriously challenge the
long-standing presumption that sepsis-
induced AKI is mainly, if not completely,
dictated by renal hypoperfusion.
In another study, investigators stud-
ied a percutaneously placed thermodilu-
tion RBF catheter in eight critically ill pa-
tients with AKI. Their major observation
revealed that sepsis-induced AKI oc-
curred despite normal RBF.59 These
findings and the fact that septic patients
typically show a high cardiac output and
1002 Journal of the American Society of Nephrology
Advantages
Sterile, simple, relatively stable, inexpensive, Restricted to Gram-negative bacteria, variable
accurate dose can be measured
Mimics extreme clinical sepsis, produces early Strain specific effects, large doses are required,
hyperdynamic state, permits the study of
the acute effects of early interventions
Relatively simple and reproducible, mixed Difficult to control the magnitude of sepsis, age,
bacterial flora
hyperdynamic circulation imply that ob-
servations in hyperdynamic models of
sepsis are much more relevant to human
septic shock.60 A major challenge to the
conventional presumption that renal va-
soconstriction is an essential prerequisite
for AKI during hyperdynamic sepsis
came from a study where the authors stud-
ied the effects of sustained Gram-negative
bacteremia and sepsis on RBF, renal vascu-
lar conductance, and renal function in fe-
male Merino sheep. They demonstrated
that in addition to generalized peripheral
vasodilation with increased cardiac output
and decreased mean arterial pressure, there
was renal vasodilation accompanied by a
prominent increase in RBF. Despite this
increase in RBF, however, creatinine clear-
ance decreased significantly, and serum
creatinine increased approximately four-
fold.61
By monitoring the recovery phase and
accompanying hemodynamic alterations,
the same group of investigators took this
concept one step further. In a well-con-
trolled and comprehensive study, nine fe-
male sheep were instrumented to continu-
ously record systemic hemodynamics and
RBF.62 Most importantly, the hyperdy-
namic and normotensive circulation that
was induced by bacterial (Escherichia
Coli) challenge and fluid administration
was accompanied by significant renal va-
sodilation and increased RBF. In spite of
well-maintained renal perfusion, GFR
deteriorated. In contrast, recovery from
sepsis was characterized by normaliza-
tion of GFR despite a renal vasoconstric-
tive response and return of the RBF back
to control values. Such reduction of RBF
and functional improvement in this
model is an important finding, and the
results indicate that the renal vascular
Disadvantages
sensitivity among species, brief increase in
inflammatory mediators
difficulty in analyzing pathophysiological
pathways
and strain variability
bed participates in the systemic hemody-
namic alterations not only during sepsis
but also during its resolution. Previously,
similar findings were observed in a pig
model of sepsis that showed an increase
in global RBF and an increase in medul-
lary blood flow.63 These findings strongly
suggest that the actual AKI that occurs
during sepsis is a hyperemic injury.
A plausible explanation for these
results could relate to the following con-
siderations. Identical to the systemic ar-
terioles that account for approximately
two-thirds of total peripheral resistance,
afferent and efferent arterioles are essen-
tial regulators of renal perfusion. Simul-
taneous dilation of both arterioles (with
greater efferent than afferent dilation)
can lead to decreased glomerular capil-
lary pressure and subsequent decrease in
filtration. This is very similar to the ob-
served effects of angiotensin-converting
enzyme inhibitors and may account for
the AKI that accompanies sepsis.
Therapeutic Options for the
Present and Future
Apart from supportive treatment (fluid
management, antibiotics, vasopressors,
diuretics, and dialysis), there have been a
number of pharmacologic attempts di-
rected at limiting and reversing sepsis-
induced AKI. Anti-TNF therapy gained
popularity particularly because of prom-
ising results in different animal mod-
els64 – 66 and the fact that elevated levels of
soluble TNF receptors can indepen-
dently predict the development of AKI
and mortality.67 Nonetheless, several
large clinical trials with neutralizing
monoclonal anti-TNF antibodies and
soluble TNF receptor fusion proteins
failed to show survival benefits in pa-
J Am Soc Nephrol 22: 999 –1006, 2011
 www.jasn.org BRIEF REVIEW

tients with sepsis.64 The same level of en-
thusiasm accompanied many other mol-
ecules that suggested their beneficial
effects in preclinical models of sepsis. For
example, inhibition of platelet-activating
factor, endothelin, anti-thrombin, tissue
factor pathway, leukocyte adhesion, and
administration of natriuretic peptides
and growth factors were all promising
novel therapeutic approaches that unfor-
tunately either never made it to clinical
trials or failed to produce the desired ef-
fects in large clinical trials.23 Indeed, only
one therapeutic agent, activated drotre-
cogin alfa, also known as recombinant
human activated protein C, has been
shown to improve survival in patients
with severe sepsis and septic shock.68
Mesenchymal stem cells (MSCs) are
another novel approach that recently
sparked great interest in the scientific com-
munity. MSCs69 or their microvesicles70
prove effective in various animal models of
diseases including AKI. In addition to be-
ing immunosuppressive, their renopro-
tective effects are complex but are mainly
mediated by paracrine mechanisms that
act on surviving tubular cells by stimu-
lating proliferation, migration, and ulti-
mately differentiation into mature epi-
thelial cells as well as by stimulating
expansion and differentiation of resident
progenitor stem cells. An ongoing clini-
cal trial evaluating the safety and efficacy
of MSCs in cardiac surgery-related AKI
(clinicaltrials.gov, NCT00733876) re-
ported the exciting initial results of their
Phase I study at the American Society of
Nephrology meeting in 2009. The suc-
cessful delivery of MSCs to humans and
the fact that they may be used allogenei-
cally offer a novel therapeutic approach.
Recently, MSCs have been reported to
have beneficial effects in sepsis-induced
AKI in mice. These effects were attrib-
uted to prostaglandin E2-dependent re-
programming of host macrophages to
increase their IL-10 production.71
Another interesting approach has
been the utilization of the stress-re-
sponsive heme oxygenase-1 (HO-1)
enzyme system72 and the products of
heme catabolism, including carbon
monoxide, biliverdin, and bilirubin.
These products have important antiox-
idant, anti-inflammatory, and antiapo-
ptotic properties. For instance, HO-1-
derived carbon monoxide enhances the
host defense response to microbial sep-
sis in mice.73 A recent study demon-
strated that high-mobility group box 1
contributes to lethality of endotoxemia
in HO-1-deficient mice.74 A significant

Table 4. Partial list of emerging therapeutic targets tested in animal models

Target Primary mechanism Agent Reference
HMGB1 HMGB1 is released from damaged cells in sepsis, Neutralizing Ab 79
HMGB1 activates NF-␬B via RAGE, TLR2, and TLR4
Lymphocyte apoptosis Apoptosis induces depletion of immune cells, apoptosis Caspase inhibitor CD95 80
impairs immunity by inducing anergy fusion-protein/siRNA
Pathogen recognition E. coli sepsis induces cytokine production via TLR4; Neutralizing Ab ODN TLR9- 81–83
(TLR4 and TLR9) bacterial DNA induces cytokine production via TLR9 inhibitor Chloroquine
End-organ damage Soluble Flt1
VEGF Systemic VEGF level increases in sepsis, VEGF-induced 84–88
vascular leakage
C5a C5a induces lymphocyte apoptosis and coagulation
system failure, C5a induces HMGB1 release via C5L2
Neuroimmune axis Vagus nerve stimulation attenuates an inflammatory Neutralizing Ab to C5a 89
(parasympathetic response via ␣7nAChR; acetylcholine inhibits HMGB1
nerve system) release via ␣7nAchR
Pituitary hormones 90,91
␣-MSH ␣-MSH decreases inflammatory cytokines and NO ␣-MSH analog
production
Ghrelin Ghrelin decreases HMGB1 release and has antibacterial Ghrelin
activity
Cell-based therapy 71,92
NETs NETs trap and kill bacteria in blood and tissue Eritoran (TLR4 antagonist)
MSCs TLR4 activation induces NET formation; MSC MSC
reprograms macrophage to produce IL-10
Heme oxygenase-system 73–75
Carbon monoxide Carbon monoxide acts as a potent anti-inflammatory Inhaled carbon monoxide
molecule
Bilirubin Bilirubin is one of the most powerful antioxidants of the Atazanavir (UGT1A1 inhibitor)
human body

This table has been modified and reproduced with permission from Reference 48. HMGB 1, high mobility group box 1; RAGE, receptor of advanced glycation
end product; ODN, oligonucleotides; nAChR, nicotinic acetylcholine receptor; ␣-MSH, ␣-melanocyte-stimulating hormone; NET, neutrophil extracellular trap;
Flt1, Feline McDonough Sarcoma (FMS)-like tyrosine kinase 1 (also known as VEGF receptor 1); UGT1A, 1 Uridine diphosphate glucuronosyl transferase
enzyme; Ab, antibody; siRNA, small interfering; TLR, Toll-like receptor.

J Am Soc Nephrol 22: 999 –1006, 2011 Sepsis and AKI 1003
 BRIEF REVIEW www.jasn.org

Table 5. Focus areas of interest in sepsis-induced acute kidney injury (AKI)
research
1. Optimization of animal models that closely mimic human sepsis and AKI
2. Role of immune modulation in sepsis-induced AKI
3. Identification of specific biomarker profile for sepsis-induced AKI 11.
4. Appropriate fluid management in sepsis-induced AKI
5. Retesting therapeutic interventions in sepsis-induced AKI using novel biomarkers
rather than creatinine based changes
6. Key endpoints in clinical trials of sepsis-induced AKI 12.
reduction of high-mobility group box DISCLOSURES 13.
1 was noted after administration of We acknowledge the UAB-UCSD O’Brien Cen-
carbon monoxide and biliverdin, ter for Acute Kidney Injury research and support
products of the HO-1 enzymatic path- from National Institutes of Health Grants
way. Moreover, HO-1 suppresses the DK059600, DK075332, and DK079337 (to A.A.).
We thank Dr. Paul Sanders, Ravi Mehta, and Mark
infiltration of neutrophils in rat liver
Okusa for their valuable input for this work. 14.
during sepsis.75 These and other find-
ings have led to ongoing clinical trials
that are examining the beneficial ef-
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