https://helda.helsinki.fi
Acute kidney injury in sepsis
Bellomo, Rinaldo
2017-06
Bellomo , R , Kellum , J A , Ronco , C , Wald , R , Martensson , J , Maiden , M , Bagshaw , S
M , Glassford , N J , Lankadeva , Y , Vaara , S & Schneider , A 2017 , ' Acute kidney injury in
sepsis ' , Intensive Care Medicine , vol. 43 , no. 6 , pp. 816-828 . https://doi.org/10.1007/s00134-017-4755-7
http://hdl.handle.net/10138/237045
https://doi.org/10.1007/s00134-017-4755-7
unspecified
publishedVersion
Downloaded from Helda, University of Helsinki institutional repository.
This is an electronic reprint of the original article.
This reprint may differ from the original in pagination and typographic detail.
Please cite the original version.
Intensive Care Med (2017) 43:816–828
DOI 10.1007/s00134-017-4755-7
REVIEW
Acute kidney injury insepsis
Rinaldo Bellomo
1,2*
, John A. Kellum
3
, Claudio Ronco
4,5
, Ron Wald
6,7
, Johan Martensson
8
, Matthew Maiden
9,10
,
Sean M. Bagshaw
11
, Neil J. Glassford
12,13
, Yugeesh Lankadeva
14
, Suvi T. Vaara
15
and Antoine Schneider
16
© 2017 Springer-Verlag Berlin Heidelberg and ESICM
Abstract
Acute kidney injury (AKI) and sepsis carry consensus definitions. The simultaneous presence of both identifies septic
AKI. Septic AKI is the most common AKI syndrome in ICU and accounts for approximately half of all such AKI. Its
pathophysiology remains poorly understood, but animal models and lack of histological changes suggest that, at
least initially, septic AKI may be a functional phenomenon with combined microvascular shunting and tubular cell
stress. The diagnosis remains based on clinical assessment and measurement of urinary output and serum creatinine.
However, multiple biomarkers and especially cell cycle arrest biomarkers are gaining acceptance. Prevention of septic
AKI remains based on the treatment of sepsis and on early resuscitation. Such resuscitation relies on the judicious use
of both fluids and vasoactive drugs. In particular, there is strong evidence that starch-containing fluids are nephro-
toxic and decrease renal function and suggestive evidence that chloride-rich fluid may also adversely affect renal
function. Vasoactive drugs have variable effects on renal function in septic AKI. At this time, norepinephrine is the
dominant agent, but vasopressin may also have a role. Despite supportive therapies, renal function may be tempo-
rarily or completely lost. In such patients, renal replacement therapy (RRT) becomes necessary. The optimal intensity
of this therapy has been established, while the timing of when to commence RRT is now a focus of investigation. If
sepsis resolves, the majority of patients recover renal function. Yet, even a single episode of septic AKI is associated
with increased subsequent risk of chronic kidney disease.
Keywords: Sepsis, Acute kidney injury, Biomarkers, Creatinine, Renal replacement therapy, Recovery
Introduction
Septic acute kidney injury (AKI) is a syndrome of acute
impairment of function and organ damage linked with
long-term adverse outcomes depending on the extent of
acute injury superimposed on underlying organ reserve.
Implicit in this concept is that dysfunction should be
reversible and rescue is possible, but that duration of the
insult and underlying renal reserve may limit restoration
of renal function. us, septic AKI is a clinical diagno
-
sis based on specific, context-dependent, and imperfect
definitions [
1] with azotemia and oliguria still its key
diagnostic criteria [
2]. In this article, we aim to review
recent developments and key aspects of the epidemiol
-
ogy, pathogenesis, prevention, and treatment of sep-
tic AKI with the goal of increasing understanding and
awareness among clinicians of this increasingly common
intensive care syndrome.
Denition anddiagnosis ofseptic AKI
e RIFLE criteria (Risk Injury Failure Loss End-stage
renal disease) were proposed by the Acute Dialysis
Quality Initiative [
1]. More recently, the Kidney Disease
Improving Global Outcomes (KDIGO) group produced
a unified version of all key criteria (Table
1) [2], which
now represent global consensus. Similarly, a new global
consensus definition of sepsis has emerged and is likely
to be used for epidemiologic and clinical purposes [
3].
Logically, septic AKI (or sepsis-associated AKI or AKI in
*Correspondence: Rinaldo.bellomo@austin.org.au
2
Department of Intensive Care, Austin Hospital, Heidelberg, VIC 3084,
Australia
Full author information is available at the end of the article
Take-home message: Septic acute kidney injury is no longer
considered a disease of the macrocirculation, but rather a disorder of the
renal microcirculation with associated inflammatory tubular injury. These
new ideas have profound diagnostic and therapeutic implications.
817
sepsis) should describe a syndrome characterized by the
simultaneous presence of both Sepsis-3 and KDIGO cri
-
teria. Nonetheless, clinical judgment is still required [
4],
and a more modern framework for rapid clinical diag
-
nosis is evolving which is based on novel biomarkers of
renal injury (Table
2). us, future definitions of AKI may
soon include such biomarkers. Irrespective of definition,
knowledge of baseline renal function remains important
and is needed to apply the KDIGO diagnostic criteria.
Unfortunately, a baseline creatinine may not be available,
and a patient with suspected septic AKI and unknown
baseline function might have sepsis with chronic kidney
disease (CKD), septic AKI, or both. Ancillary tests and
checklists might be helpful to make the correct diagno
-
sis [
4]. In the absence of baseline information, however,
an estimated GFR using the Modification of Diet in Renal
Disease (MDRD) equation has been used in patients
without a history of CKD (Table
2) [1]. Finally, although
urinalysis and urinary biochemistry have limited clinical
utility [
5], urine output remains important not only for
diagnosis but also for risk prediction [
6]. However, uri
-
nary output and creatinine are increasingly being com-
plemented by novel biomarkers of AKI.
Novel biomarkers
Over the last decade several biomarkers have been evalu-
ated for their capacity to detect kidney “stress” and/or
“damage” and to predict the development of AKI. ey
apply to septic AKI as well. e strong interest in bio
-
markers relates to the desire to achieve early diagnosis
in order to deliver prevention and early therapy when it
may be most effective. Biomarkers can provide additional
insights into AKI pathophysiology and are complemen
-
tary to functional tests [
7]. ese biomarkers might also
detect renal stress or damage before functional change
is evident (preclinical AKI) or even in the absence of
functional change (subclinical AKI). In other cases, low
biomarker levels may help diagnose physiologic in con
-
trast with pathologic oliguria. eir role in different renal
syndromes including septic AKI is a rapidly evolving area
of research. Neutrophil gelatinase-associated lipoca
-
lin (NGAL) has been the most extensively investigated
renal biomarker [
8]. NGAL is upregulated in kidney tis
-
sue exposed to nephrotoxic or inflammatory stress, but
also released by activated neutrophils with specific forms
of the molecule released from the kidney (monomeric)
and neutrophils (dimeric) [
9]. Unfortunately, commer
-
cial assays only measure a mixture of the different forms
making their specificity, reproducibility, and diagnostic
accuracy unclear and creating uncertainty regarding the
role of NGAL as a biomarker of AKI. In a pooled analysis
of>2000 critically ill patients, one-fifth were NGAL-pos
-
itive without an increase in serum creatinine (subclini-
cal AKI or false positive results). Yet, these patients were
at greater risk of subsequent renal replacement therapy
(RRT), longer ICU and hospital stay, and death [
10].
Similar findings were observed in emergency depart
-
ment patients [
11] and support the existence of a state of
subclinical damage, which is associated with worse renal
outcomes, and can only be detected by novel biomarkers.
Other molecules have been studied as biomarkers of AKI.
Among these, kidney injury molecule (KIM-1) appears to
perform similarly to NGAL [
7] but has not been studied
in a large cohort of septic ICU patients. Cell cycle arrest
may be protective during cellular stress. Two major regu
-
latory proteins involved in initiating cell cycle arrest were
recently discovered to play a role in AKI: tissue inhibi
-
tor of metalloproteinases-2 (TIMP-2) and insulin-like
growth factor binding protein-7 (IGFBP-7). In 2013, a
prospective, observational, international investigation
Table 1 Criteria andstaging foracute kidney injury
Minimum criteria for acute kidney injury include an increase in SCr by≥0.3mg/dl (>26.5µmol/l) observed within 48h; or an increase in SCr to≥1.5 times baseline,
which is known or presumed to have occurred within the prior 7days; or urine volume<0.5ml/kg/h for 6h
Stage Serum creatinine Urine output
1 1.5–1.9 times baseline
OR
≥0.3 mg/dl (>26.5 µmol/l) increase
<0.5 ml/kg/h for 6–12 h
2 2.0–2.9 times baseline <0.5 ml/kg/h for ≥12 h
3
3.0 times baseline <0.3 ml/kg/h for ≥24 h
OR OR
Increase in serum creatinine to ≥4.0 mg/dl (353.6 µmol/l) Anuria for ≥12 h
OR
Initiation of renal replacement therapy
OR
In patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m
2
818
of critically ill patients, including many with septic AKI
[
12], found an area under the receiver operating charac
-
teristic curve (AUC) of 0.80 for [TIMP-2]·[IGFBP-7] for
the prediction of KDIGO stage 2 and 3 AKI. ese mark
-
ers were significantly superior to all previously described
biomarkers. Moreover, tubular cells may undergo cell
cycle arrest (as demonstrated by cell cycle arrest bio
-
markers in the urine) [
12] to decrease energy consump-
tion and protect themselves. is phenomenon may then
result in activation of the tubulo-glomerular feedback
mechanism [
13], which would contribute to a decrease
in GFR aimed at attenuating ultrafiltration. However, this
theoretical framework, like others, remains speculative.
ese biomarkers may also help change the definition
of AKI in the future and contribute to a better under
-
standing, diagnosis, prevention, and treatment of septic
AKI (Fig.
1). Other approaches to assess renal function
have been considered. ey include the furosemide stress
test, and assessment of the response to protein loading
[
14] and the application of real-time GFR measurements
[
15]. None of these approaches have yet been tested for
their accuracy and robustness in large multicenter stud
-
ies and remain investigational in nature. However, there
is no evidence at this time that knowledge of biomarker
values in septic AKI allows better and more successful
early treatment. us, current epidemiologic information
remains linked to traditional diagnostic criteria.
Epidemiology ofseptic AKI
Several cohort studies have described the frequency
of sepsis among patients with AKI. e multinational
Beginning and Ending Supportive erapy for the Kidney
(BEST Kidney) [
16] found sepsis in nearly half the cohort.
Septic AKI was associated with higher risk of in-hospital
mortality. More recently, an international consortium
confirmed these findings [
17]. Angus et al. examined
192,980 patients with severe sepsis from seven US states
using diagnostic codes [
18]. AKI occurred in 22% and
was associated with a mortality of 38.2%. e Sepsis
Occurring in Acutely ill Patients (SOAP) cohort study
recruited patients admitted to 198 ICUs across Europe
[
19]. Of 3147 patients, 37% had sepsis. AKI occurred in
51% of cases and was associated with an ICU mortality of
41%. e FINNAKI study enrolled 2901 critically ill con
-
secutive patients from 17 Finnish ICUs [
20]. Among the
918 patients with severe sepsis, 53% met the KDIGO cri
-
teria for AKI. In the recent Vasopressin vs. Norepineph-
rine as Initial erapy in Septic Shock (VANISH) trial,
AKI occurred in about 45% of patients, and AKI requir
-
ing RRT developed in 30% of patients [
21].
ere may also be genetic susceptibility to AKI in
general and to septic AKI specifically. Polymorphism
of cytokine-controlling genes has been associated with
Table 2 Criteria fordiagnosing AKI
CKD chronic kidney disease, AKI acute kidney injury, uKIM-1 urinary kidney injury molecule-1, uNGAL urinary neutrophil gelatinase-associated lipocalin, uTIMP-2 urinary tissue inhibitor of metalloproteinase-2, IGFBP-7
insulin-like growth factor binding protein-7, pNGAL plasma neutrophil gelatinase-associated lipocalin
Criterion/test Utility Limitations Comments
Serum creatinine Cheap, easily measured, readily available, well-known
relationship to disease
Slow to change in response to injury, insensitive—no
changes until >50% loss of function
Increases of ≥50% over ≤1 week or ≥0.3 mg/dl
over ≤48 h used as consensus criteria for AKI
Urine output Faster to change than creatinine, cheap and easy to
measure
Non-specific, insensitive to certain forms of AKI, not
reliably measured outside the ICU
<0.5 ml/kg/h ≥ 6 h used as consensus criteria for AKI
Serum cystatin C Experience from CKD Similar to creatinine
Urine sediment Can help identify specific causes of AKI (e.g., glomeru-
lonephritis)
Not standardized and usually non-specific
Kidney damage markers Measure cellular injury rather than organ function Not standardized nor completely validated in humans uKIM-1, uNGAL, others
AKI risk markers Measures of kidney stress or systemic inflammatory
states rather than injury per se
Measures of kidney stress or systemic states rather than
injury per se
u[TIMP-2]·[IGFBP-7], pNGAL
Functional stress tests Examine capacity for increases in function by stressing
the system
Test are not well standardized Protein load, furosemide
819
sepsis and polymorphism of catechol-O-methyl trans-
ferase activity has been associated with AKI risk [22].
More recently a genome-wide association study of
patients with AKI (including septic AKI) found that
polymorphism of the likely controller of a transcription
factor (on chromosome 4) involved in innate immunity
pathways was associated with greater risk of AKI. Simi
-
larly, another gene involved in the likely control of trans-
forming growth factor beta (on chromosome 22) was also
associated with greater risk [
23].
e outcomes of critically ill patients with sepsis [
24]
and AKI requiring RRT [
25], however, have improved
in recent years. It remains unclear if these improve
-
ment reflect a true decline in mortality or greater diag-
nostic sensitivity or more liberal indications to initiate
RRT. Moreover, little is known about AKI in septic gen
-
eral ward patients. e advent of the Sepsis-3 definitions
will force a reassessment of the characteristics and out
-
comes of sepsis-associated AKI. However, such assess-
ment must logically be based on an understanding of its
pathophysiology.
Pathophysiologic theories
Our understanding of the pathogenesis of septic AKI is
limited, but it is now clear that septic AKI is profoundly
different from ischemic AKI both in the experimental
setting and in the clinic. It is markedly affected by our
inability to monitor renal blood flow (RBF), microvas
-
cular flow, cortical and medullary perfusion and oxy-
genation, and tubular well-being. us, animal models of
septic AKI have been developed to enable sophisticated
and invasive measurements that cannot be performed
in humans. In early experimental studies of septic AKI,
global RBF was reported to decline after the administra
-
tion of endotoxin [
26]. ese endotoxin-based experi-
ments, which were associated with a hypodynamic
systemic circulation, led to the view that human septic
AKI must be due to renal vasoconstriction and ischemia
[
26]. More recent studies of hyperdynamic sepsis have
demonstrated that the renal circulation participates in
the systemic vasodilatation of sepsis. us, in such mod
-
els, septic AKI develops in the presence of increased RBF
[
27, 28].
In a study of 160 original articles of animal models
[
29], if the model reported a high cardiac output (CO),
RBF was either preserved or increased. However, despite
such global renal hyperemia, oliguria and AKI develop
rapidly (hours) and are marked. is phenomenon,
where RBF is dissociated from glomerular filtration
rate (GFR), requires explanation. Changes in intrarenal
Fig. 1 Potential contribution of novel renal injury biomarkers to the detection, prevention, and treatment of septic AKI