Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344

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Best Practice & Research Clinical

Anaesthesiology
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Biomarkers in acute kidney injury (AKI)

Su Hooi Teo, MD, MRCP (UK), Associate Consultant a,

n Huba Endre, MBBS, PhD, FRACP,
Zolta
FASN, Professor b, c, d, e, *
a
Department of Nephrology, Singapore General Hospital, Singapore
b
Department of Nephrology, Prince of Wales Hospital, High Street, Randwick, Sydney, 2031, Australia
c
Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
d
Department of Medicine, University of Otago-Christchurch; Christchurch, New Zealand
e
School of Medicine, University of Queensland, Brisbane, Australia

Keywords:
Acute kidney injury is common in critically ill patients and por-
acute kidney injury
tends a significant impact on mortality, progressive chronic kidney
biomarkers
biomarkers of function disease, and cardiovascular disease and mortality. Though most
biomarkers of damage physicians alter therapy depending on changes in serum creati-
risk nine, this often represents delayed intervention. Various AKI bio-
diagnosis markers have been discovered and validated to improve timely
prognosis detection, differentiation and stratification into risk groups for
progressive renal decline, need for renal replacement therapy or
death. This chapter will review AKI biomarkers validated over the
past decade. We also describe the clinical performance of the
biomarkers. We suggest that using AKI biomarkers to comple-
ment serum creatinine (or cystatin C) and urine output will better
integrate patient care through earlier recognition and clinical
outcome prediction after AKI.
© 2017 Published by Elsevier Ltd.

Introduction

Acute kidney injury (AKI) frequently complicates critical illness and is associated with a high
incidence of short-term morbidity, dialysis, mortality and prolonged hospitalisation and long-term

* Corresponding author. Sydney Department of Nephrology, Level 3, High St Building, Prince of Wales Hospital, Randwick,
NSW, 2031, Australia. Fax: þ612 9382 4409.
E-mail address: z.endre@unsw.edu.au (Z.H. Endre).

https://doi.org/10.1016/j.bpa.2017.10.003
1521-6896/© 2017 Published by Elsevier Ltd.
332 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344

adverse outcomes including chronic kidney disease and cardiovascular mortality [1e4]. AKI is an
enormous global problem. Recent large-scale meta-analyses, utilising the consensus Kidney Disease
Improving Global Outcomes (KDIGO) definition and incorporating data from over 49 million subjects,
confirm that 1 in 5 adults and 1 in 3 children worldwide experience AKI during a hospital admission
[3,5] including more than 50% of patients admitted to the intensive care unit (ICU). Two percent of
hospital admissions and 11% of all AKI require dialysis [3].

Limitations of serum creatinine and the pressing need for novel AKI biomarkers

Using the KDIGO consensus definitions, AKI is defined as an increase in serum creatinine to
26.5 mmol/L within 48 h, or increase in serum creatinine to 1.5 times baseline within 7 days or
oliguria for 6 h [6]. To date, attempts to launch preventive or therapeutic measures for AKI have failed
to demonstrate consistent protective effects. While serum creatinine and urine output are useful
application tools in the diagnosis of acute kidney injury, serum creatinine is a late marker of kidney
injury. Limitations to serum creatinine as a marker of kidney injury include modulation by age, gender,
diet, muscularity and medication. Additionally, modulation of serum creatinine by hydration status
may further complicate the diagnosis of AKI. These limitations have encouraged the development of
biomarkers of kidney damage to improve risk assessment, early detection, differential diagnosis and
prognosis of AKI [7,8].
An ideal AKI biomarker is one that can predict and diagnose AKI; identify the location, type and
aetiology of injury; predict outcomes; and enable initiation and monitoring of therapeutic in-
terventions [9]. While not yet routine, widespread implementation of damage biomarkers in clinical
practise is imminent. Liver-type fatty acid-binding protein (L-FABP) is approved for use in Japan, local
policies dictate the use of neutrophil gelatinase-associated lipocalin (NGAL) in Europe, and the com-
bination of tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin growth factor binding protein-
7 (IGFBP-7) is FDA-approved in the United States [10]. Nevertheless, many factors such as time after
exposure to injury and baseline renal function usually quantified by the estimated GFR (eGFR) [11] and
subclinical kidney disease [12] modify biomarker temporal profiles and should be considered in
interpreting biomarker performance. We review the AKI biomarkers most commonly studied and
likely to be adopted in clinical practice and some others with either historical or potential roles in AKI
management.

Biomarkers of function (glomerular filtration rate e GFR)

Cystatin C

Cystatin C is a 122-amino acid low-molecular-weight protein (13 kDa). A member of the cysteine
proteinase inhibitor protein superfamily, cystatin C is freely filtered by the glomerulus and almost
completely reabsorbed in the proximal tubule, where it is almost entirely catabolised. Unlike creati-
nine, cystatin C is not secreted by the renal tubules.
This combination of attributes means that serum cystatin C levels are determined almost entirely by
glomerular filtration, and additionally, many of the limitations of serum creatinine such as the influ-
ence of diet, body muscle mass and gender are less likely to affect cystatin C. Because cystatin C is
secreted by cells, the volume of distribution is extracellular and thus one-third that of serum creatinine.
Consequently, the half-life of cystatin C is approximately one-third that of serum creatinine, which
results in cystatin C reaching steady-state equilibrium three-fold more rapidly. These attributes have
facilitated the use of serum cystatin C as an alternative or in combination with serum creatinine as a
surrogate marker of renal function. For example, early studies indicated that serum cystatin C was
superior to serum creatinine as a marker of kidney function [13], while in later studies, the estimated
GFR (eGFR) based on both cystatin C and creatinine outperformed creatinine alone in the evaluation
and monitoring of chronic kidney disease [14]. In addition, the shorter half-life increases the utility of
serum cystatin C after a perturbation of GFR, as might occur in AKI, so that both eGFR and kinetic GFR
estimates based on cystatin C outperformed serum creatinine in the prediction of delayed graft
function after kidney transplantation [15].
 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344 333

Cystatin C in AKI

Serum cystatin C has been superior to creatinine in most studies in the early diagnosis of AKI, with
cystatin C detecting AKI 24e48 h earlier than creatinine [16]. Cystatin C utilisation and performance
has been studied in various clinical settings of patients at high risk of developing AKI. In a meta-
analysis of 30 prospective cohort studies, involving 4247 adults from 15 countries with 982 patients
developing AKI, serum cystatin C showed a high predictive power for all-cause AKI, with an area under
the receiver operating characteristic curve of 0.89 [16]. An interesting feature of the meta-analysis is
comparison of cystatin C performance at different time points after exposure to potential renal injury.
Not surprisingly, the AUC increased from 0.80 at 1e12 h to 0.89 at both 24 and 48 h. After cardiac
surgery, the AUC increased from 0.77 at 0e6 h to 0.90 at 12e24 h. This lag in performance reflects the
fact that even with a shorter half-life than creatinine, under non-steady-state conditions, neither
cystatin C nor creatinine estimate real-time GFR. Under changing conditions, this estimate can be
somewhat improved by calculating the kinetic eGFR [17] either with creatinine or cystatin C [15].
Serum cystatin C was positively predictive of AKI for days 1e3 in patients admitted to the ICU, with
AUCs of 0.885, 0.893 and 0.901, respectively, for diagnosis [18]. Nejat et al. prospectively compared the
detection of functional change of plasma cystatin C and plasma creatinine in critically ill patients and
observed a more rapid relative increase in plasma cystatin C than in plasma creatinine [19]. Within 6 h
of cardiac surgery in adults, Haase Fielitz et al. demonstrated that serum cystatin C had 71% sensitivity
and 53% specificity for the diagnosis of AKI [20] (Table 1). Serum cystatin C level was significantly
higher in patients with traumatic haemorrhagic shock than in normal subjects (1.10 ± 0.36 vs
0.91 ± 0.34 mg/l), and the serum cystatin C AUC for the detection of AKI was 0.728 (95% CI,
0.570e0.886) in nonparametric ROC analysis, suggesting moderate potential utility for the prediction
of AKI in the early stages of traumatic haemorrhagic shock [21].
Other studies suggest that serum cystatin C is a useful marker for the early diagnosis and for
prognosis after contrast-induced acute kidney injury (CI-AKI), both in patients with chronic kidney
disease and in normal subjects. Most studies illustrate this by demonstrating that serum cystatin C
can diagnose CI-AKI at 24 h after contrast, i.e. 24 h earlier than creatinine. Using an increase of 10%
at 24 h as the cutoff, both in subjects with chronic kidney disease and in Western Indians, cystatin C
predicted AKI at 48 h in patients undergoing percutaneous coronary angiography, with an AUC of
0.92[22,23]. An increase greater than 10% in cystatin C with or without an increase in serum

Table 1
Biomarker performance at different clinical times in multicentre studies after cardiac surgery or critical illnessa.

Cardiac Surgery Critical Illness

Preop AKI Risk Early Postop AKI Early Diagnosis Classification of AKI Prediction of
Assessment Diagnosis of AKI Progression of AKI (Transient Versus Dialysis
Intrinsic AKI)

U NGAL N/A þ e þ þ þ
B NGAL e þ þ þ ? e
U Cystatin C N/A e e þ þ þ
Serum Cystatin C þ ? N/A ? N/A ?
U IL-18 N/A þ þ þ þ þ
U KIM-1 N/A þ e þ e e
U protein/albumin þ þ þ ? ? ?
Plasma BNP þ N/A þ N/A N/A N/A

Key: Pre, preoperative; postop, postoperative;

NGAL, neutrophil gelatinase-associated lipocalin; N/A, not applicable
þ, published data supports the ability to detect this aspect of AKI;
e, data published does not support detection of this aspect of AKI;
? no large multicentre data published on this biomarker/aspect of AKI;
B, blood; KIM-1, kidney injury molecule-1; U, urine.
a
Modified from [82]
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creatinine >3 mg/dL also predicted the major adverse outcome of death or dialysis at 12 months with
an OR of 7.2 (95% CI: 2.9e18.1) in the combined group or 4.0 (95% CI: 1.7 to 8.5) in those with only an
increase in cystatin C [22].
Of all causes of AKI in the meta-analysis in adults cited above [24], serum cystatin C had the best
performance in CI-AKI. While other potential reasons are noted, perhaps the most likely is the rela-
tively delayed sampling time of 24 h after insult. While still predictive earlier than serum creatinine,
there is nevertheless sufficient time for the development of a significant increase in the cystatin C
levels for the diagnosis to be made. Pragmatically speaking, the 24-h time point is useful as many
patients are discharged after 24e48 h after coronary angiography and a 48-h time point may be absent
or delay discharge. However, 24 h is quite late if there is a possibility of successful post hoc intervention.
Even earlier detection of a decrease in GFR will require a biomarker with an even shorter half-life or,
preferably, the utilisation of a direct method of measuring GFR such as the use of fluorinated filtration
markers developed using rodent studies [23] and currently undergoing clinical evaluation [25,26]. The
use of damage biomarkers in preference to functional markers or perhaps to complement them is a
clear alternative to the sole use of functional markers and is considered below.

Galectin-3

Plasma galectin-3, a ß-galactoside-binding protein has been approved by the US Food and Drug
Administration as a prognostic aid in patients with heart failure (see) [27]. Galectin-3 may be involved
in the stiffening of the extracellular matrix, causing myocardial fibrosis, and is closely related to the
lectin family. Its role in heart failure is, however, unclear. Plasma galectin-3 levels are inversely related
to renal function. Consequently, galectin-3 concentrations increase with impaired kidney function.
Therefore, galectin-3 has been linked to incident renal disease, experimental renal fibrosis and ne-
phropathy and may play a role in interstitial fibrosis and progressive kidney disease [28]. In two very
large cohort studies analysed retrospectively, galectin-3 concentration was significantly associated
with a combined endpoint of cardiovascular events [29] in participants with impaired kidney function,
including dialysis patients, but galectin-3 was not associated with these clinical end points in partic-
ipants with normal kidney function. Plasma galectin-3 is inversely related to renal function in patients
with and without clinical HF. Concentrations of plasma galectin-3 do not seem to depend on the level of
compensation or type of HF. Furthermore, the relationship between galectin-3 and renal function
seems to be affected little or not at all by the presence or absence of clinical heart failure [27]. Taken
together, these results suggest that galectin-3 is a marker of GFR but is unlikely to be of greater utility
than estimates of GFR in the prediction of cardiovascular outcomes in subjects with kidney disease.
However, there is no evidence to suggest utility in AKI.

Proenkephalin

A recently evaluated novel biomarker of renal function is proenkephalin A. Cardiac cells secrete
enkephalins. These have negative inotropic and chronotropic effects, lowering blood pressure and
heart rate [30]. These local cardiodepressive effects are mediated through opioid receptors. Opioid
receptors are widely distributed, with the highest densities in the kidney [31]. Enkephalins may
therefore be important in the cardiorenal and renocardiac syndromes. However, because enkephalins
have a half-life of 12e15 min in plasma, their role is easier to explore through proenkephalin, a widely
expressed enkephalin precursor molecule that is also much more stable. Recent studies suggest that
proenkephalin may be a useful biomarker as proenkephalin plasma levels are inversely proportional to
GFR [31] and may predict the progression of CKD [32]. Proenkephalin predicts worsening renal
function in acute heart failure and predicts short- and long-term prognosis independent of renal
function [33]. This is exciting, though caveats remain, including the need to define the volume of
distribution and half-life of proenkephalin. There is also considerable overlap with AKI caused by
increased expression of proenkephalin in sepsis [33], one of the most common causes of AKI. Thus,
many steps remain before a role for proenkephalin as a biomarker in the cardiorenal and renocardiac
syndromes can be confirmed [34].
 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344 335

Biomarkers of damage

Neutrophil gelatinase-associated lipocalin

Neutrophil gelatinase-associated lipocalin (NGAL) is also known as siderocalin, or lipocalin 2, and

belongs to the family of lipocalins. NGAL is the most highly upregulated and the most widely studied
biomarker in studies of early AKI. Human NGAL exists in three distinct forms: a 25-kDa monomer, a 45-
kDa homodimer, and conjugated to gelatinase as a 135-kDa heterodimer [35]. The heterodimeric form
is specific to neutrophils [36]. NGAL is expressed at low levels in many cell types, including the uterus,
prostate, salivary gland, lung, trachea, stomach, colon and kidney [37]; increases with age; and levels
are higher in women than men [2]. After AKI, urinary NGAL is predominantly monomeric, whereas the
dimeric form is more frequent in urinary infection [36]. In the kidney, NGAL is produced mainly by
distal tubular epithelial cells but soon appears in proximal tubular cells [38], presumably after filtration
and reabsorption through megalin-cubulin [39,40]. NGAL forms a complex with iron-binding side-
rophores, which may be important in renoprotection, putatively through the chelation of labile Fe
released from damaged tubules, which may prevent the formation of hydroxyl radicals and superoxide
[35,39,41]; this may also facilitate bacteriostasis (by limiting bacterial iron uptake), for example, in
response to urogenital infection [41].
Elevated NGAL levels can be detected in the urine as early as 3 h after renal injury; NGAL peaks at
6e12 h after injury depending on AKI severity [42] and the presence of background CKD [11].

NGAL in AKI

The first study utilising NGAL demonstrated that in 20 of 71 children who developed AKI after
undergoing cardiac surgery, urinary NGAL 2 h after cardiopulmonary bypass (CPB) had an area under
the receiver operating characteristic curve (AUC) of 0.998 and serum NGAL had an AUC of 0.906, both
outstanding AUC values, which suggested that this biomarker was highly predictive of AKI, 1e3 days
before changes in serum creatinine became diagnostic [43].
However, a decrease in biomarker performance is expected in larger validation studies [44]. Context
is critical in the interpretation of biomarker levels. The wide variety of possible sources of NGAL noted
above highlight that there may be problems in the interpretation of biomarker performance when
multiple factors contribute to an increase in NGAL. It is therefore no surprise that there is a wide
disparity in the diagnostic performance of NGAL in different clinical settings, with the widest range of
AUC values probably seen in the general ICU where the range of comorbidities is greater than in other
hospital populations.
Limiting the analysis to a subgroup of patients with an eGFR >75 mL/min/1.72 m2 on admission,
Siew and colleagues observed NGAL AUCs for the development of AKI within 24 and 48 h to be 0.71
(95% CI: 0.63 to 0.78) and 0.64 (95% CI: 0.57 and 0.71), respectively [45]. Even after adjustment for age,
baseline serum creatinine closest to enrolment, illness severity, sepsis and ICU location, NGAL only
marginally improved the predictive performance of the clinical model when used alone [45]. Similarly,
our experimental studies of AKI biomarker performance in the presence of subclinical CKD confirm
slower rates of increase and lower peak values in that setting compared with AKI induced in rodents
without subclinical CKD [12]. Similarly, in yet another context, NGAL performance in the presence of
sepsis is reduced compared with non-septic critically ill patients [46].
NGAL performance improves when the time of renal injury is better defined. For example, 4 h after
kidney transplantation, the AUC for the prediction of delayed graft function, a very common mani-
festation of AKI after renal transplantation, was 0.77 (95% CI: 0.57e0.78) [47]. Nevertheless, despite the
excellent results in children undergoing cardiac surgery [48], the range of AUCs following cardiac
surgery in adults is very wide. A recent meta-analysis of 2906 adult subjects in 26 studies revealed that
the AUCs for urinary NGAL in the first 24 h after cardiac surgery ranged from 0.50 to 0.91, with a
composite AUC of 0.72 (95% CI: 0.66e0.79) [49] (Table 1).
In summary, urinary and plasma NGAL levels are predictive of AKI and AKI outcomes including
mortality and need for dialysis. However, the performance varies with context, and there is a clear need
to determine appropriate cutoffs for different clinical settings and comorbidities.
336 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344

Liver-type fatty acid-binding protein

FABPs are lipocalins, small cytoplasmic proteins involved in binding long-chain fatty acids. FABPs
may also play a role in the reduction of cellular oxidative stress, binding fatty acid oxidation products
and limiting the toxic effects of oxidative intermediates on cellular membranes [50]. FABPs are
expressed in hepatocytes, stomach, lung, intestine and kidneys [51]. Initially identified in hepatocytes,
L-FABP is a 15-kDA protein also expressed in the proximal tubule, a nephron segment that normally
relies on fatty acid metabolism to drive membrane transport but also a critical target for hypoxic injury
in AKI [52,53]. Under normal healthy conditions, L-FABP is undetectable in urine as it is reabsorbed in
the proximal tubule through megalin-mediated endocytosis. Under stress, e.g. after injury in AKI, L-
FABP is excreted into the proximal tubular lumen alongside bound toxic peroxisomal products, in
proportion to the severity of injury [51,54,55]. Its potential antioxidant properties and the presence of
an hypoxia-inducible factor 1a response element in the human L-FABP gene, which facilitates the
induction of gene expression by hypoxia, suggested that L-FABP is was likely to be a renoprotective
protein [56,57]. These and other preclinical studies suggested the potential utility of L-FABP as a marker
of kidney disease, including progression of CKD [58,59], and as an early biomarker of AKI [54].

Liver-type fatty acid-binding protein in AKI

Clinical studies have established L-FABP as a promising biomarker in AKI [54,60e63], and L-FABP
has been used as a guide for clinical intervention in patients at risk for AKI. In a meta-analysis of 7
cohort studies by Susantitaphong and colleagues, urinary L-FABP showed good performance charac-
teristics with high sensitivity and specificity, especially in patients undergoing cardiac surgery [64]. The
estimated sensitivity and specificity of urinary L-FABP in diagnosing AKI was 74.5% and 77.6%,
respectively. The sensitivity and specificity for predicting the need for dialysis was 69.1% and 42.7%,
respectively. Sensitivity and specificity for in-hospital mortality was 93.2% and 78.8%, respectively [64].
Similarly, L-FABP was amongst the top four urinary biomarkers in predicting the progression of AKI or
death in patients with stage 1 AKI within the first 3 days after cardiac surgery and performed well in
combination with KIM-1 as a strong predictor of AKIN 3 or death (AUC ¼ 0.89) [65]. In a more recent
meta-analysis, the composite AUC of six studies of urinary L-FABP for AKI prediction after cardiac
surgery was 0.72 (0.60e0.85), and this improved to 0.75 (0.53e0.97) when only trials using AKIN, RIFLE
or KDIGO definitions of AKI were included [49]. Unfortunately, a limitation of these and most published
studies has been the limited number of patients with positive study outcomes.
Nevertheless, L-FABP is approved as a diagnostic test in Japan [66]. In a prospective study investi-
gating cystatin C, urinary L-FABP, beta 2-microglobulins, N-acetyl-beta-D-glucosaminidase and
microalbumin in predicting the development of CI-AKI after cardiac catheterisation, it was found that
urinary L-FABP levels were significantly higher on days 1 and 2 after cardiac catheterisation. Doi and
colleagues demonstrated that patients with increased L-FABP levels at the time of ICU admission
carried a higher risk of AKI development within the first week of admission [67]. Similarly, in a recent
study in critically ill patients with AKI that examined the ability of L-FABP to predict kidney injury
progression, dialysis or death within 7 days, urinary L-FABP significantly improved the integrative
discriminative index for a clinical prediction model [68]. Interestingly, in the allogeneic stem cell
transplantation population, increased baseline L-FABP may indicate previous incipient kidney injury
and is associated with a high risk of AKI after allogeneic stem cell transplant [69].

Interleukin-18

Interleukin-18 (IL-18) is a 22-kDa proinflammatory cytokine that is activated by caspase-1 and is

produced by renal tubular cells and macrophages. It has been shown to be a mediator of acute
tubular injury in animal studies. In the human kidney, IL-18 is induced in the proximal tubules and
released into the urine in a variety of conditions including ischemia-reperfusion injury, sepsis and
malignancy. It can be rapidly and reliably measured in urine by commercially available ELISA and
microbead-based assays. Urine IL-18 concentration elevates within the first 6 h after renal injury and
peaks at 12e18 h. In the Acute Respiratory Distress Syndrome (ARDS) network trial, urine IL-18
 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344 337

predicted the development of AKI even before 24 and 48 h and the mortality of patient who have
ARDS in ICU [70]. IL-18 was the top urinary biomarker in predicting the progression of AKI or death in
patients with stage 1 AKI within the first 3 days after cardiac surgery and performed well in com-
bination with KIM-1 as a strong predictor of AKIN 3 or death (AUC ¼ 0.93) [65]. In a recent systematic
review of 11 studies covering 2796 patients, urine IL-18 was believed to hold promise as a biomarker
with moderate diagnostic accuracy in the early diagnosis of AKI [71] (Table 1). It is therefore an
attractive target for biomarker-directed therapy of AKI, and more studies on anti-IL-18 therapy are
awaited.

Kidney injury Molecule-1

Kidney injury molecule-1 (KIM-1) is a 38.7-kDa type-1 cell membrane glycoprotein, which contains
a six-cysteine immunoglobulin-like domain, two N-glycosylation sites and a thrombospondin-rich
domain characteristic of mucin-like O-glycosylated proteins [72]. There are several properties sug-
gesting that KIM-1 is ideal as a kidney injury biomarker: the low level or absence of KIM-1 expression
in the normal kidney, marked upregulation and insertion into the apical membrane of the proximal
tubule after ischemia-reperfusion injury and persistence in epithelial cells until recovery [73]. KIM-1
has been shown to be a highly sensitive and specific marker of proximal tubular kidney injury in
several rodent models [73]. It peaks at 2e3 days after injury, and this explains why biomarker per-
formance improved in the EARLYARF trial [9] when samples were stratified according to time after
injury and the presence or absence of underlying CKD [11]. This late timing suggests a role in recovery
and regeneration after AKI, and the urinary KIM-1 concentration could potentially be used as a marker
to differentiate between the extension and recovery phase of AKI [74]. A limited correlation with other
biomarkers after cardiac surgery suggests potential utility in combination with other biomarkers [65],
particularly in triaging patients at high risk of AKI into clinical trials.
Unfortunately, studies evaluating the usefulness of KIM-1 in predicting and prognosticating AKI
have yielded mixed results. In the setting of critical illness-related AKI, KIM-1 provides good value in
the diagnosis of AKI. However, it is less impressive with regard to the prediction of dialysis or death,
although, interestingly, elevated urinary KIM-1 on day 1 after cardiac surgery was associated with
increased duration of AKI [75], which is an independent marker of increased mortality [76]. In the
setting of cardiac surgery AKI, urinary KIM-1 increased at 6e12 h following CPB and remained
significantly elevated up to 48 h after CPB [77]. Furthermore, all the postoperative urinary biomarkers
studied by the Translational Research Investigating Biomarker Endpoints (TRIBE) consortium, partic-
ularly KIM-1 and IL-18 (but also NGAL, albumin and L-FABP), independently predicted long-term
mortality up to 3 years later [78].

Prediction of progression of AKI

In contrast to the modest or variable performance of many biomarkers in early diagnosis prior to
any change in serum creatinine, biomarker performance improves when urinary or plasma damage
biomarkers are used to predict progression to a higher AKI stage at the time of AKI diagnosis using
creatinine. For example, in the TRIBE in AKI consortium studies of biomarkers [79,80], biomarkers
measured on the day of AKI diagnosis in 380 patients, who developed at least AKI Network (AKIN) stage
1 AKI, were assessed for the prediction of progression to a higher AKI stage, which occurred in 45 of
those subjects [81] (Table 1). The biomarkers improved risk stratification and identified patients at
higher risk for progression of AKI and worse patient outcomes. After adjustment for clinical predictors,
compared with biomarker values in the lowest two quintiles, the highest quintiles of three biomarkers
remained associated with AKI progression: IL-18 (odds ratio ¼ 3.0, 95% confidence interval ¼ 1.3e7.3),
ACR (odds ratio ¼ 3.4, 95% confidence interval ¼ 1.3e9.1) and plasma NGAL (odds ratio ¼ 7.7, 95%
confidence interval ¼ 2.6e22.5)[81]. Each biomarker improved risk classification compared with the
clinical model alone, with plasma NGAL performing the best (with a category-free net reclassification
improvement of 0.69, P ¼ 0.0001)[81]. Even better biomarker performance was observed with bio-
markers of cell cycle arrest e see next section.
338 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344

Cell cycle arrest biomarkers

Tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein-7

Cell cycle arrest is a protective mechanism to prevent the cell from entering the cell cycle when it is
injured or in a harmful environment, possibly because proliferation might involve damaged DNA,
although other factors may also be involved. During times of cellular stress or injury, TIMP-2 and
IGFBP-7 are expressed in renal tubular cells. In the setting of ischemic or septic AKI, renal epithelial
cells undergo G1 cell cycle arrest [83]. The cyclin-dependent kinase inhibitor p21 arrests cell cycle
series from G1 to S phase [2]. TIMP-2, a 21-Da protein, is endogenous inhibitor of metalloproteinase
activities. IGFBP-5, a 29-kDa secreted protein, a member of the IGFBP superfamily, has low-affinity
binding and subsequently inhibits signalling through insulin-like growth factor 1 receptors [2]. Both
TIMP-2 and IGFBP-7 induce cell cycle arrest and are upregulated in patients with AKI, suggesting a role
for growth-inhibitory functions as G1 cell cycle arrest is a well-known sequel of AKI.

Tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein-7 in AKI

In the DISCOVERY study (to identify novel biomarkers), urine TIMP-2 and IGFBP-7 were recognised
as the best-performing AKI prediction biomarkers of 340 potential biomarkers studied in a cohort of
522 critically ill adults. Urine TIMP-2 and IGFPBP-7 were superior with AUCs of 0.75 and 0.77,
respectively, compared to other biomarkers including plasma NGAL, cystatin C, urinary NGAL, KIM-1,
IL-18, L-FABP and pi-glutathione-S-transferase (GST) [84]. In terms of prediction of AKI Stage 2 and
3, follow-up validation studies in critically ill patients showed AUCs of 0.82 [85] and 0.79, respectively
[86]. The combination of TIMP-2 and IGFBP-7 demonstrated optimal diagnostic performance in pre-
dicting a doubling of serum creatinine within 12 h in patients with sepsis, with AUC of 0.8 [85,86].
These studies suggest that the combination of IGFBP-7 and TIMP-2 produces robust diagnostic per-
formance, which improves clinical decision-making in AKI risk assessment and stratification and led to
FDA approval of the first point-of-care device to measure the combination of IGFBP-7 and TIMP for the
purpose of predicting the progression of stage 1 AKI within 12 h. In a long-term follow-up study by
Koyner et al., urinary TIMP-2 and IGFBP-7 levels at the time of ICU admission were predictive of an
elevated risk of mortality or renal replacement therapy (RRT) requirement over the next 9 months in
patients with AKI [87,88]. Zarbock and colleagues have also used the device in a successful pilot study
to triage patients at high risk of AKI after cardiac surgery [89].

Biomarkers of nephrotoxicity

Biomarkers of nephrotoxicity include N-acetyl-glucosaminidase (NAG), gamma-glutamyl trans-

peptidase (GGT), GST, alanine aminopeptidase (AAP) and lactate dehydrogenase (LDH).

N-acetyl-glucosaminidase

NAG is a >130-kDa lysosomal enzyme produced in the proximal and distal tubular cells, and it is
detected 12 h after renal injury. In the mice models, it has been shown that there are elevations in
urinary concentrations of NAG in conditions where mice were exposed to gentamicin [90] or lithium
[91]. Hergen-Rosenthal et al. has demonstrated that NAG was significantly higher in patients requiring
RRT in acute tubular necrosis [92].

Gamma-glutamyl transpeptidase and alkaline phosphatase

GGT and ALP are enzymes located in the brush border villi of the proximal tubular cells. They are
released into urine in the event of significant damage to the brush border membrane with loss of the
microvillous structures [93]. The affordability and wide availability the assay of GGT suggested that
GGT could be utilised for identifying patients at high risk of AKI, especially in the ICU setting, although
 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344 339

because GGT is a pre-formed enzyme that is rapidly depleted after renal insult, this leaves only a
narrow window of opportunity for the detection and early diagnosis of AKI [11].
In the first prospective clinical biomarker study in critical care patients, Westhuyzen and colleagues
demonstrated that GGT, ALP, NAG, and alpha- and pi-GST on admission were higher and that when
normalised to urine creatinine, these biomarkers predicted AKI with high AUCs in subjects who
developed AKI [7]. Endre and colleagues later utilised the product of urinary GGT and ALP (normalised
to urinary creatinine) to triage subjects admitted to the ICU to intervention (with high-dose erythro-
poietin) in an adult ICU population study of 528 patients [11]. In that study (the EARLYARF trial),
urinary GGT indexed to urine creatinine performed well in diagnosing AKI only when stratified to both
time after insult and baseline renal function (prior) to entry to the ICU. In CKD patients (eGFR <60 ml/
min), measuring GGT between 12 and 36 h after renal insult yielded an AUC of 0.91. In comparison,
patients with eGFR 60 ml/min and GGT measured within 12 h after insult had AUC 0.67 [11].

Glutathione-S-transferase

GSTs are a family of enzymes that play an important role in detoxification by conjugating various
compounds with reduced glutathione. In the event of damage to renal tubular epithelial cells, this
cytoplasmic enzyme builds up and becomes detectable in the urine. There are four main classes, alpha
and pi being the most studied in AKI.
The earliest clinical study of GSTs by Westhuyzen, Endre and colleagues [7], showed that gamma-
GGT, pi-GST, alpha-GST, AP and NAG (all standardised to urinary creatinine) had excellent discrimi-
nating power for AKI diagnosis (with AUCs of 0.950, 0.929, 0.893, 0.863 and 0.845, respectively) [7]. In a
separate study of 141 cardiovascular surgery patients, which included those undergoing coronary
bypass and valvular operations, urinary alpha- and pi-GSTs were analysed at 3, 6, 9, 12 and 24 h post-
surgery. Urinary pi-GST levels were found to predict advanced AKI or hospital mortality and improve
SOFA outcome assessment specific to AKI [94].

Clinical application of AKI biomarkers

With the advent of biomarkers in the last decade, a biomarker-integrated model of AKI was pro-
posed by the 10th Acute Dialysis Quality Initiative Consensus Conference (ADQI) [95]. The ADQI group
also recommended the use of these biomarkers in the following settings (summarised in Fig. 1) and
contingent on the development of appropriate cutoffs:

1. AKI diagnosis

The early stages of AKI usually remain undiagnosed in most settings as serum creatinine rise lags
the decrease in GFR by 24e36 h. In different clinical settings including sepsis, critical care and CBP
surgery, the damage biomarkers will aid the identification of patients who exhibit kidney injury
without functional change.

2. Differential diagnosis in established AKI

As there is limited intervention to offer in established AKI besides optimising fluid status, treating
sepsis or withdrawing nephrotoxins, biomarkers that focus on precise timing of the onset of renal
injury are desirable. Currently, biomarkers can differentiate between volume depletion and intrinsic
renal injury [96]. Damage biomarkers and biomarkers specific to the cause of injury should be utilised
in differential diagnosis [97].

3. Risk of AKI

Biomarkers can enable risk stratification both prior to an exposure such as surgery or after the
exposure. The risk assessment can be used to activate reno-protective strategies. For example, in the
340 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344

Fig. 1. Use of damage and functional biomarkers for diagnosis and prognosis of AKI.*
*From http://www.ADQI.org, used with permission.

remote ischemic preconditioning and kidney injury in cardiac surgery study of Zarbock et al., the
control group demonstrated significantly higher urinary (TIMP-2 x IGFBP-7) at 4 and 12 h after CPB
[98]. In a separate study, Zarbock and colleagues demonstrated that urinary (TIMP-2 x IGFBP-7) at 4 h
singled out patients who were likely to develop AKI, and in a subsequent study, they successfully used
urinary (TIMP-2 x IGFBP-7) at 4 h to select patients to be randomised to an intervention study that
randomised subjects to implementation of the generic KDIGO recommendations for the management
of AKI.

Prognosis (trajectory) of AKI

Many studies have examined whether AKI can provide insights into the trajectory of AKI, the need
for renal replacement therapy and renal recovery, ranging from a case-control students within the
ARDS network trial, where it was found that median urine IL-18 predicted the onset of AKI 24 and 48 h
later and urine IL-18 on day 0 was an independent predictor of mortality [70]. Most recently, the cell
cycle arrest markers, urinary (TIMP-2 x IGFBP-7), have been validated to predict worsening of AKI stage
in subjects with AKI stage 1 [85]. Similarly, urinary NGAL has been identified as a predictor of in-
hospital mortality [99]. A 3-year follow-up of the TRIBE consortium data shows that urinary bio-
markers in the immediate post-operative period after cardiopulmonary bypass, particularly IL-18 and
KIM-1, provide independent information regarding long-term mortality risk in patients with and
without AKI [78].

Limitations of novel biomarkers studies

An abundance of biomarkers has been recently described. Damage biomarkers define structural
injury; serum creatinine and cystatin C are presently the main available markers of functional change.
Ideally, damage and functional biomarkers can be combined in a matrix to diagnose four different
categories: no AKI, functional AKI, damage AKI and functional plus damage AKI [95]. Both functional
AKI without damage biomarkers (FN þ BM-) and damage AKI without functional biomarker (BM þ FN-)
have similar outcomes in terms of needing dialysis and risks of death [100].
A major limitation lies in comparing the biomarker performance to serum creatinine performance
when serum creatinine is used to define the AKI event. To decide whether an increase in biomarkers
 S.H. Teo, Z.H. Endre / Best Practice & Research Clinical Anaesthesiology 31 (2017) 331e344 341

alone should allow intervention, functional and damage biomarkers should be independently
compared with hard endpoints. The appropriate biomarker cutoffs could thus be identified. While this
requires studies with a high event rate (or very large numbers of subjects), one strategy proposed by
Pickering and Endre is to use the sensitivity of creatinine for dialysis requirement and the incidence of
death to define the sensitivity needed to validate a given threshold or cut-point for novel damage
biomarkers of AKI [101]. These authors reported that urinary NGAL threshold with 62% sensitivity for
death or dialysis was 140 ng/mL. By using these thresholds, the risk of death or dialysis requirement for
combined structural and functional AKI was 3.11 (95% CI: 2.53 to 3.55) compared to those patients with
no AKI [101]. At present, we do not have the ideal biomarkers for the diagnosis or prediction of renal
recovery from AKI, although decreases in biomarkers of damage have been used for this purpose [102].

Conclusion

Biomarkers of kidney damage independently provide risk, diagnostic and prognostic information
before, during and after an episode of AKI, respectively. Damage biomarkers may prove to be even more
powerful when combined in a matrix with biomarkers of glomerular function.

Practice points

Biomarkers of kidney function, such as creatinine, have long half-lives, delaying return to
steady state conditions after a decrease in GFR: this delays the diagnosis of AKI.
Urinary biomarkers of kidney damage are sensitive markers of early AKI with high specificity.
Diagnosis of AKI should use a matrix of markers of functional change versus markers of kidney
damage.
Many damage biomarkers' levels are increased in patients at high risk of AKI, such as in the
presence of CKD. These can be used for AKI risk assessment prior to a potential kidney injury
such as exposure to CPB surgery or intravascular iodine-based contrast agents.

Research agenda

The functional change versus damage biomarker matrix needs to be validated in multiple
cohorts and centres.
Simple interventions based on KDIGO-based guidelines should be validated in multiple centres
in subjects at high risk or with early AKI diagnosed through urinary biomarkers.

Conflicts of interest

None.

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