American Journal of Emergency Medicine xxx (xxxx) xxx

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

Early prediction of pediatric acute kidney injury from the emergency

department: A pilot study
Holly R. Hanson, MD a,⁎,1, Michael A. Carlisle, MD b,2, Rachel S. Bensman, MD a,b, Terri Byczkowski, PhD a,
Holly Depinet, MD a,b, Tara C. Terrell c, Hilary Pitner c, Ryan Knox c, Stuart L. Goldstein, MD b,c, Rajit K. Basu, MD c,3
a
Division of Pediatric Emergency Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2008, Cincinnati, OH 45229, United States of America
b
Department of General Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, United States of America
c
Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, United States of America

a r t i c l e i n f o a b s t r a c t

Article history: Background: Identifying acute kidney injury (AKI) early can inform medical decisions key to mitigation of injury.
Received 8 October 2019 An AKI risk stratification tool, the renal angina index (RAI), has proven better than creatinine changes alone at
Received in revised form 15 January 2020 predicting AKI in critically ill children.
Accepted 26 January 2020 Objective: To derive and test performance of an “acute” RAI (aRAI) in the Emergency Department (ED) for predic-
Available online xxxx
tion of inpatient AKI and to evaluate the added yield of urinary AKI biomarkers.
Methods: Study of pediatric ED patients with sepsis admitted and followed for 72 h. The primary outcome was
Keywords:
Renal
inpatient AKI defined by a creatinine N1.5× baseline, 24–72 h after admission. Patients were denoted renal angina
Biomarker positive (RA+) for an aRAI score above a population derived cut-off. Test characteristics evaluated predictive per-
Kidney disease formance of the aRAI compared to changes in creatinine and incorporation of 4 urinary biomarkers in the context
Sepsis of renal angina were assessed.
AKI Results: 118 eligible subjects were enrolled. Mean age was 7.8 ± 6.4 years, 16% required intensive care admission.
In the ED, 27% had a +RAI (22% had a N50% creatinine increase). The aRAI had an AUC of 0.92 (0.86–0.98) for pre-
diction of inpatient AKI. For AKI prediction, RA+ demonstrated a sensitivity of 94% (69–99) and a negative pre-
dictive value of 99% (92–100) (versus sensitivity 59% (33–82) and NPV 93% (89–96) for creatinine ≥2× baseline).
Biomarker analysis revealed a higher AUC for aRAI alone than any individual biomarker.
Conclusions: This pilot study finds the aRAI to be a sensitive ED-based tool for ruling out the development of in-
hospital AKI.
© 2020 Elsevier Inc. All rights reserved.

1. Introduction associated with cardiovascular morbidity, anemia, and growth failure,

and hypertension [3,4]. Many interventions, such as medications, proce-
Acute kidney injury (AKI) is a common complication in hospitalized dures, and fluid-overload, in the hospital-setting are known to be neph-
children with recent studies showing the incidence to be nearly 30% in rotoxic and exacerbate AKI [5-7]. Recognizing that the Emergency
the pediatric intensive care unit and 5% in non-critically ill, hospitalized Department (ED) is often the patient's first exposure to hospital care,
children [1,2]. Children with AKI have an increased risk of death, inde- it is an opportune setting to identify children at risk of AKI and to
pendent of underlying disease pathology [2]. Those children who sur- begin limiting nephrotoxic interventions while offering renal support
vive have an increased risk of chronic kidney disease, known to be as necessary.

Abbreviations: AKI, Acute Kidney Injury; aRAI, acute Renal Angina Index; ED, Emergency Department; IL-18, Interleukin 18; KDIGO, Kidney Disease Improving Global Outcomes; KIM-
1, kidney injury molecule-1; L-FABP, liver fatty acid binding protein; NGAL, neutrophil gelatinase-associated lipocalin; RA, Renal Angina; RAI, Renal Angina Index; SCr, serum creatinine.
⁎ Corresponding author at: Division of Pediatric Emergency Medicine, Monroe Carell Jr Children's Hospital at Vanderbilt, 2200 Children's Way, VCH B-319, Nashville, TN 37232-9001,
United States of America.
E-mail addresses: [email protected] (H.R. Hanson), [email protected] (M.A. Carlisle), [email protected] (R.S. Bensman),
[email protected] (T. Byczkowski), [email protected] (H. Depinet), [email protected] (R. Knox), [email protected] (S.L. Goldstein), [email protected]
(R.K. Basu).
1
Division of Pediatric Emergency Medicine, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, 2200 Children's Way, VCH-B-319, Nashville, TN
37232.
2
Division of Pediatric Critical Care Medicine, Children's Hospital Colorado, 13,123 East 16th Ave, Aurura, CO 80045.
3
Division of Pediatric Critical Care Medicine, Children's Healthcare of Atlanta, Emory School of Medicine, 1405 Clifton Rd NE, Atlanta, GA 30322.

https://doi.org/10.1016/j.ajem.2020.01.046
0735-6757/© 2020 Elsevier Inc. All rights reserved.
2 H.R. Hanson et al. / American Journal of Emergency Medicine xxx (xxxx) xxx

Currently the standard measure of AKI in the ED is the elevation of AKI biomarkers, used with the aRAI, to enhance prediction of inpatient
serum creatinine (SCr). There is a large reliance on laboratory “normals” AKI.
to help identify SCr values outside of an acceptable range and, therefore,
indicate a diagnosis of AKI. This method can result in an under diagnosis 2. Methods
of AKI as SCr, dependent on muscle mass, varies greatly between chil-
dren of the same age making these laboratory “normals” unreliable 2.1. Study design and setting
[8,9]. This laboratory test is performed often without adjudication of
AKI risk. Recent literature has proposed a single definition for AKI, This is a prospective, observational cohort study of children aged
termed the KDIGO (Kidney Disease Improving Global Outcomes) N28 days to b25 years performed at a single, high-volume, tertiary pedi-
criteria, that utilizes changes in SCr to diagnose AKI [10]. Any change atric hospital. Enrollment began 8/1/2015 and concluded 5/9/2016. The
in SCr that is 1.5 times above the patient's baseline SCr (defined as the hospital's institutional review board approved this study with a waiver
lowest SCr in the last 6 months) is consistent with a diagnosis of AKI. of informed consent.
In a recent study, only 8% of children were found to have had a SCr mea-
sured in the 6 months prior to their ED visit, therefore, leaving the pro- 2.2. Selection of participants
vider without a baseline SCr for comparison [11]. This highlights the
difficulty in comprehensively identifying AKI in children in the ED. Patients were included in this study if they presented to the
Proper triage of patients by AKI risk may ultimately facilitate a hospital's ED, had a concern for sepsis, were admitted to the hospital,
targeted approach to initial management in the ED. Similar to stroke and had both a SCr measured and urine specimen obtained as part of
and acute coronary syndrome, AKI is associated with known risk factors. routine ED care. Subjects with “concern for sepsis” were identified by
A combination of risk with signs of injury has led to algorithms for rapid a positive electronic health record automatic sepsis alert (screening
management of both stroke and acute coronary syndrome. These syn- tool based on vital signs, perfusion variables and high risk underlying
dromes inspired a parallel model of context-driven adjudication of condition; or hypotension); this screening tool had been implemented
early injury signs that was used to create the renal angina prodrome. several years prior to this study and was developed as part of a national
Tested first in critically ill children, the concept of renal angina (RA) quality improvement collaborative [17]. As this is a screening tool, sub-
demonstrates a higher predictive sensitivity and discrimination for se- jects were also required to have received fluid resuscitation (≥10 ml/kg
vere AKI than risk factors or signs of injury alone [12]. The score for isotonic intravenous fluid) as part of their ED coarse as this would fur-
assessing RA, the renal angina index (RAI), is a simple multiplication ther indicate a higher concern for possible shock. Excluded subjects
of patient risk by creatinine change (Fig. 1) [13,14]. In initial validation were those who had previously been enrolled in this study, had a his-
testing, biomarker assessment in patients positive for RA (RAI ≥ 8) fur- tory of chronic kidney disease stage IV or V, were anephric, or were ac-
ther optimized prediction of severe AKI. This construct is similar to tively receiving dialysis. A report from the automated tool was
how cardiac enzyme testing is utilized in patients presenting with generated each morning identifying all patients seen in the ED in the
chest pain. In acute coronary syndrome, troponin I efficiently and accu- prior 24 h with a positive screen. These potential subjects were further
rately aids in diagnosis in the appropriate patient context. When used in reviewed for inclusion criteria and then, if deemed appropriate, were
a heterogeneous population without further discrimination for acute followed prospectively through their hospital course.
coronary syndrome it becomes much less useful [15,16].
We hypothesized that a modification of the original RAI to include 2.3. Methods and measurements
“acute” components, objectively available in the ED (Fig. 1), would facil-
itate the prediction of in-hospital AKI among children with possible sep- For each eligible subject, a manual chart review of the electronic
sis. Recognizing the limitations of SCr alone, this tool would allow medical record was performed by three of the authors (HRH, MAC,
application of a risk factor stratification to help further discriminate RSB) using a detailed manual of operations. Abstracted data was cap-
change in SCr and aid in AKI prediction. The aims of this study were tured using REDCap (Research Electronic Data Capture) tool hosted at
(1) to compare the performance of the “acute” RAI (aRAI) with SCr Cincinnati Children's Hospital Medical Center [18]. To increase validity
alone to predict inpatient AKI and (2) to evaluated the ability of urinary and reliability, 5% of the charts were separately reviewed and any

Fig. 1. Description of the acute renal angina index contrasted to the original renal angina index.
 H.R. Hanson et al. / American Journal of Emergency Medicine xxx (xxxx) xxx 3

discrepancies in abstracted data prompted a discussion such that all dis- accepted alternative approach was used to impute a baseline SCr [19].
agreement was resolved by consensus review. Variables including de- The imputation was performed using the Schwartz formula which
mographics, past medical history, administered intravenous fluids, takes into account height and assumes a normal creatinine clearance
procedures, length of stay, disposition, and all measured SCr values of 120 ml/min/1.73 m2 [19,20].
were abstracted for each eligible subject. Subjects were followed for
the first 72 h after hospital admission or until discharge, whichever oc- 2.7. Sample size
curred first. SCr was ordered at the discretion of the patient's admitting
physician, was not specifically obtained for research purposes, and, We assumed a 10% incidence of AKI in the reported pediatric popu-
therefore, was not necessarily present each day. The last SCr measured lation with shock and an area under the curve (AUC) for the RAI of
in each 24-h block after admission, was recorded. For example, if the pa- 0.7–0.8 based on previous work [12,21]. To detect a difference in AUC
tient was admitted at midnight on a Sunday then the SCr measurement by 0.10, and a two-sided test at 0.05 alpha, 116 subjects provided 80%
closest to midnight on Monday was recorded. power. For a planned 116 total patients, we expected to have 12 patients
A urine sample (catheter, clean-catch, or bag) was obtained for bio- with AKI and 104 without.
marker testing from left-over urine that was collected as part of the sub-
jects' ED course. Urine was centrifuged and stored in cryovials at minus 2.8. Analysis
80 °C, according to standard laboratory procedure, until the time of bio-
marker analysis. All statistical analysis was made using the software packages SAS
version 9.3 (SAS Institute, Inc., Cary, NC) and StataSE version 14
2.4. Renal angina (StataCorp, College Station, TX). Descriptive statistics were used to iden-
tify and describe the population of children with RA in the ED. Differ-
The modifications made to the original RAI, in forming the aRAI, are ences between those who were RA(+) and RA(−) were assessed
depicted in Fig. 1. These modifications were necessary in order to estab- using chi-square or fisher's exact test and t-tests for categorical and con-
lish an index that could be applied early in the ED course. The derivation tinuous variables, respectively.
of the original variables in the RAI is explained in the manuscript by The aRAI was evaluated as a diagnostic test and compared to un-
Basu, et al [12]. The risk strata variables in the aRAI were intended to stratified changes in SCr measured in the ED. Sensitivity, specificity, pos-
parallel the variables in the original RAI and incorporate variables al- itive predictive value (PPV), negative predictive value (NPV), and
ready present in the automated sepsis alert. receiver-operating characteristic (ROC) analysis were calculated to
RA was calculated for each enrolled subject while in the ED. Subjects evaluate the predictive performance of an aRAI ≥8 (RA definition).
were classified as RA(+) and RA(−) based on the score obtained using AUC was calculated for the model. A sensitivity analysis was performed
the RAI. For the risk component, the number correlating with the excluding all subjects who did not have a SCr measured during inpatient
highest risk category that the subject fulfilled was used (Fig. 1). For ex- admission. Based on the original derivation and validation studies of the
ample, if the subject had both a history of solid organ transplant and was RAI in the critical care setting, we hypothesized an AUC N 0.80 and a
intubated in the ED they received a score of 5. The score from the risk NPV N 90% [12]. Simple and multivariable logistic regression models
component was multiplied by the score from the injury component to were used to predict AKIInpt using aRAI and ED obtained, patient-
produce the aRAI score. The aRAI ranges from 1 to 40 and, based on pre- related variables. Test characteristics of each biomarker were also
vious derivation of the original RAI, an aRAI score ≥8 was used to define assessed, biomarker concentrations were used as continuous variables,
RA(+) [12]. and the increase in AUC was calculated for each model using DeLong's
method [22]. Classification analysis by sequential iteration was per-
2.5. AKI biomarkers formed to separate the entire cohort into terminal node cohorts with in-
dividual probability and risks for the primary outcome (derivation of
Urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney classification and regression tree analysis). A p b 0.05 was considered
injury molecule-1 (KIM-1), interleukin 18 (IL-18), and liver fatty acid significant for all analysis.
binding protein (L-FABP) were each analyzed in the Center for Acute
Care Nephrology Biomarker Core Laboratory by a laboratory technician 3. Results
with no knowledge of study outcomes. Urinary NGAL was assayed using
a human-specific commercially available enzyme-linked immunosor- 3.1. Characteristics of study subjects
bent assay (ELISA, AntibodyShop, Grusbakken, Denmark). IL-18 and L-
FABP were measured using commercially available ELISA kits (Medical There were 128 subjects initially identified for potential study en-
& Biological Laboratories Co., Nagoya, Japan, and CMIC Col., Tokyo, rollment based on information in the automated sepsis alert trigger.
Japan, respectively) per manufacturer's instructions. Urine KIM-1 was After chart review was initiated 10 subjects were found to be ineligible
measured by ELISA using commercially available reagents (R&D Sys- (Fig. 2). Therefore, 118 individual subjects were included in data analy-
tems, Inc., Minneapolis, Minnesota). The a priori cut-off values for sis. Table 1 describes the patient demographics of all subjects in the en-
each biomarker were determined by sensitivity analysis in the initial rolled cohort, as well as, a comparison of those with and without RA in
RAI data sets [12]. the ED. Of all included subjects, 52% were female, 63% were white, and
the mean age was 7.8 ± 6.4 years. 16% were admitted to the intensive
2.6. Outcomes care unit. 69% of subjects were still admitted after 48 h and 47% were
still admitted after 72 h. There were no deaths during the first 72 h in
The primary outcome of this study was AKI anytime between 24 and any patient in this study and no patients required renal replacement
72 h after admission from the ED as defined by KDIGO Stage I-III by el- therapy.
evated SCr (any SCr N1.5 times baseline) [10]. This outcome measure
was termed AKIInpt. The comparison group was all patients in the hospi- 3.2. Elevated SCr in the ED
tal at 24–72 h after admission who were not identified as having AKI (ei-
ther they had a SCr that was unchanged or they did not have a repeat There were 26/118 (22%) of subjects in the ED with a N1.5× increase
SCr obtained). Baseline creatinine, necessary for KDIGO staging, was de- in creatinine above baseline. Of these, 50% were stage 1 (1.5× increase
fined as the lowest measured SCr in the previous 6 months. For all sub- in SCr from baseline), 38% were stage 2 (2× increase in SCr from base-
jects without a baseline SCr from prior laboratory assessment, an line), and 12% were stage 3 (3× increase in SCr from baseline). 41
4 H.R. Hanson et al. / American Journal of Emergency Medicine xxx (xxxx) xxx

Fig. 2. Study flowchart.

subjects (34%) had no SCr measured after the initial measurement in the 4. aRAI
ED, of these none had an elevated SCr in the ED. The rate of AKIInpt was
17/81 (21%). Of the 81 subjects who remained in the hospital after 24 h, aRA(+) occurred in 32/118 (27%) patients while in the ED. Com-
25 subjects had no repeat SCr after their initial ED SCr. These subjects pared with patients who were aRA(−), patients with aRA(+) were
were assumed to have no AKI for primary analysis. more likely to have received N40 ml/kg of isotonic fluid in the ED,
been admitted to the intensive care unit, and to have required a longer
than 72-h hospital admission (Table 1). Additionally, these subjects
were more likely to have had a history of AKI or chronic kidney disease.
Table 1
There were 46/118 (39%) subjects in the cohort who required their
Demographic and clinical information.
baseline SCr to be imputed because they did not have a previous SCr
Characteristic, n (%) Total aRA(+) aRA(−) p-value measured in the 6 months prior to their ED visit. Only 2/46 of these sub-
cohort n = 32 n = 86
jects were RA(+) in the ED and none had AKIInpt.
n = 118

Age, years (mean ± SD) 7.8 ± 6.4 7.6 ± 6.0 7.8 ± 6.6 0.873 5. aRAI versus context free creatinine increases
Body surface area (mean ± SD) 0.97 ± 0.6 0.93 0.98 0.685
± 0.4 ± 0.6
Female 61 (52) 21 (66) 40 (47) 0.065 The aRAI had a NPV of 0.99 (0.92–1.00) and AUC of 0.92 (0.86–0.98)
Race 0.048 for the prediction of AKIInpt (Table 2). Sensitivity was 94% for the aRAI as
White 74 (63) 16 (50) 58 (68) compared to 59% for an elevation in SCr noted to be at least two times
Black 19 (16) 6 (19) 13 (15)
greater than baseline while in the ED (consistent with the consensus
Other 21 (18) 9 (28) 12 (14)
Unknown 4 (3) 1 (3) 3 (3) definition for severe AKI). Additionally, Table 3 shows that aRA fulfill-
Risk strata b0.001 ment is the only variable, of the variables tested, that is independently
Moderate 75 (64) 5 (16) 70 (82) associated with AKIInpt.
High 24 (20) 12 (37) 12 (14)
Very High 19 (16) 15 (47) 4 (4)
Baseline SCr present 72 (61) 30 (94) 42 (49) b0.001
6. aRAI and urine biomarkers
Transplant history 8 (7) 6 (19) 2 (2) 0.002
History of oncologic disease 24 (20) 13 (41) 11 (13) 0.001 AUC estimates from both the aRAI and individual urine biomarkers
History of AKI (n = 114) 6 (5) 4 (14) 2 (2) 0.017 obtained in the ED revealed a higher AUC for aRAI alone than any indi-
History of CKD (n = 114) 6 (5) 4 (14) 2 (2) 0.017
vidual biomarker, followed by NGAL (Table 4). Additionally, the classifi-
ED intubation 2 (2) 1 (3) 1 (1) 0.463
N 40 mL/kg fluid in ED 17 (14) 14 (44) 3 (4) b0.001 cation analysis identified a terminal node of RA(+)/NGAL(+) with a
ICU admission 19 (16) 11 (34) 8 (9) 0.001 probability of inpatient AKI of 60% higher than any of the other nodes.
ICU length of stay 0.952
≤24 h 6 (32) 4 (36) 2 (25) 7. Discussion
N72 h 2 (11) 4 (36) 3 (38)
OR during 1st 72 h 6 (5) 1 (3) 5 (6) 0.555
ED admission Dx Interpreting elevations in SCr without a clinical context in children
Shock/serious infection 109 (92) 31 (97) 78 (91) 0.261 who present to the ED is challenging. Not only can it be difficult to
Medical cardiac 3 (3) 2 (6) 1 (1) 0.119 make a diagnosis of AKI, but it is also difficult to know how to tailor
Respiratory illness 16 (14) 3 (9) 13 (15) 0.418
medical interventions in light of this elevation. A tool that accounts for
Post-surgical/minor 1 (1) 0 1 (1) 0.540
trauma/ortho clinical risk and accurately screens for inpatient AKI in the ED would
CNS dysfunction 11 (9) 0 11 (13) 0.034 better inform early changes in medical inventions in order to help mit-
Pain/sedation management 1 (1) 0 1 (1) 0.540 igate further damage. The aRAI is a sensitive and practical stratification
AKIInpt (n = 81) 17 (21) 16 (50) 1 (1) b0.001 model, and the first of its kind, that improves the ability to identify chil-
Discharged home in b72 h 62 (53) 12 (38) 50 (58) 0.050
dren in the ED at the highest risk for AKI during hospital admission.
 H.R. Hanson et al. / American Journal of Emergency Medicine xxx (xxxx) xxx 5

Table 2
aRAI compared to elevations in creatinine in the ED for prediction of inpatient AKI

n Sensitivity Specificity PPV NPV +LR

aRAI (+) 32 94 84 50 99 5.9

(27%) (71–100) (76–91) (39–61) (92–100) (3.7–9.5)
aRAI (−) 86 6 16 1 50 0.1
(73%) (0–29) (9–25) (0–7) (39–61) (0.0–0.5)
SCr ≤ 1× 35 0 65 0 79 0
(30%) (0–2) (55–75) (77–81)
SCr N 1 to b1.5 57 12 44 4 75 0.2
(48%) (1–36) (35–55) (1−12) (69–80) (0.1–0.8)
SCr ≥ 1.5 to b2.0 13 29 92 38 89 3.7
(11%) (10–56) (85–97) (19–63) (85–91) (1.4–10.0)
SCr ≥ 1.5 26 88 89 58 98 8
(22%) (64–99) (81–94) (43–71) (92–99) (4.5–14.5)
SCr ≥ 2.0 13 59 97 77 93 19.8
(11%) (33–82) (92–100) (51–92) (89–96) (6.1–64.7)

All serum creatinine (SCr) values are represented as comparisons to baseline SCr; data are presented as percentages (95% confidence interval).

index has been modified for both a post-cardiac surgery and an adult
Table 3
population and has shown utility as a potential screening test [27,28].
Predictors of AKI during admission using multivariable logistic regression
In our study, children with possible sepsis who were aRA(+) were
Variable Odds Ratio (95% CI) p-value more likely to receive high volumes of crystalloid for resuscitation in
Acute renal angina 1.177 (1.077, 1.286) 0.0003 the ED and be admitted to an intensive care unit. This is likely a reflec-
Age 1.038 (0.921, 1.171) 0.5385 tion of the illness severity in children with AKI. In a recent study of chil-
Prior history of AKI 0.820 (0.600, 1.127) 0.0614 dren admitted from the ED after having a SCr measured there was a 2%
ICU admission 3.207 (0.375, 27.422) 0.2872
mortality rate in children with AKI, compared to 0.4% in the non-AKI
population [11]. These children were also more likely to receive isotonic
fluids and be admitted to an intensive care unit [11]. In our study, the
In this study, we compared the utility of the aRAI to the current ED aRAI was the only independent variable tested that was associated
standard for AKI diagnosis, elevations in SCr. We found that using the with progression to AKI. This is likely two-fold, the aRAI considers
aRAI improves precision for the prediction of inpatient AKI compared many factors, similar to an illness severity score, and therefore provides
to using elevated SCr alone. In this study, 83 patients had a SCr N1× an opportunity for a more inclusive prediction. Secondly, the study was
baseline and only 17 had inpatient AKI, therefore 80% of the time, not specifically powered for this analysis and more subjects may have
when using SCr alone, there is an inaccurate prediction of inpatient changed this result. It is hypothesized that the negative association be-
AKI. Conversely, only 32 patients in the ED were RA(+) and 16 had in- tween history of AKI and current AKI is likely secondary to this factor.
patient AKI which reduced the error rate to 50%, or the correct predic- This study used an automated sepsis alert trigger that had been em-
tion goes from 20% to 50%, a 150% increase in precision. Additionally, bedded in the electronic medical record to identify a high-risk popula-
the aRAI was found to have a NPV of 99%, similar to the NPV of tion, those with the potential for sepsis, for earlier ED care. This alert is
92–99% seen in the original RAI, making this scoring system extremely used to both heighten physician awareness of a potentially ill patient
effective at ruling out the potential for AKI during admission [12]. In and provide an opportunity for medical intervention at the earliest pos-
an ED setting where resource utilization is of the utmost importance, sible time point. The electronic medical record has been used, similarly,
this test, with high sensitivity and increased precision, would allow for to predict nephrotoxin-mediated AKI before it occurs on inpatient units,
more effective triaging of patients, both in delegation of effort and in- and has been the topic of a large consensus group within Nephrology
vestment of resources. Given the recent emphasis on reducing medical [29-31]. In developed countries one of the leading causes of AKI is sepsis
waste, this proves significant. [32]. Incorporating the aRAI in the electronic medical record has the po-
The original RAI used on the day of intensive care admission had an tential to aid in earlier recognition of children at risk for AKI. Addition-
AUC of 0.74–0.81 for predicting AKI on day 3 of admission and ally, the strong association of sepsis with AKI provides a unique
outperformed the current KDIGO criteria [12]. Since the original deriva- opportunity for the merging of a dual-use tool for prediction of sepsis
tion and validation multiple studies have demonstrated similar results and AKI in the ED setting.
including a multicenter, multinational study, where the RAI used in chil- The RA paradigm provides an opportunity to delineate a high-risk
dren on admission to the intensive care unit predicted AKI on day 3 of population on which kidney injury biomarkers may prove more useful.
hospitalization better than SCr with a relative risk of 1.61 (p b 0.0001) In prior study, the incorporation of AKI biomarkers with the RAI im-
[23,24]. The RAI has been validated both in developed and in developing proved discrimination for AKI [33]. When evaluating each of the 4 bio-
countries and has shown similar predictive results [25,26]. Additionally, markers, we found that no one biomarker had an AUC that was higher
resource-limited settings have highlighted its ease of use [25]. This than the aRAI alone, however NGAL had the best performance. Our

Table 4
aRAI and Biomarkers Alone for Prediction of Inpatient AKI.

Test cut-off value aRAI 8.0 NGAL 21.5 KIM-1 939.9 IL-18 109.4 L-FABP 8.7

Sensitivity 94 (71–100) 77 (55–93) 59 (33–82) 59 (33–82) 59 (33–82)

Specificity 84 (76–91) 61 (48–73) 61 (48–73) 53 (40–66) 58 (45–70)
PPV 50 (39–61) 34 (26–44) 29 (20–40) 25 (17–35) 27 (18–38)
NPV 99 (92–100) 91 (80–96) 85 (75–91) 83 (72–90) 84 (74–91)
AUC-ROC 0.92 0.71 0.65 0.49 0.57
(0.86–0.98) (0.57–0.84) (0.49–0.80) (0.34–0.64) (0.42–0.73)

Data are presented as the percentage (95% confidence interval).

6 H.R. Hanson et al. / American Journal of Emergency Medicine xxx (xxxx) xxx

classification tree did demonstrate that the additional of NGAL(+) pa- Acknowledgements
tients to RA(+) ED patients proved to have the highest rate of inpatient
AKI. This construct may be used as foundation for further research that The authors of this study would like to thank the Center for Acute
provides an individualized approach to the care of children at risk for Care Nephrology Biomarker Core Laboratory and statistician Huaiyu
AKI. For instance, an automated alert in the electronic medical record Zang, both at Cincinnati Children's Hospital Medicine Center, for assis-
fires indicating a patient is at risk for sepsis, the patient is found to be tance in obtaining biomarker data.
RA(+), NGAL is tested and is negative and now we have a patient
who may more safety receive contrast agents. Conversely, the patient References
is found to be RA(+) and NGAL(+) and we choose ultrasound as imag-
[1] McGregor TL, Jones DP, Wang L, et al. Acute kidney injury incidence in noncritically
ing modality over CT, when possible. ill hospitalized children, adolescents, and young adults: a retrospective observa-
This study has several limitations. First, it is an observational study tional study. Am J Kidney Dis 2016;67(3):384–90.
and as such causation cannot be assessed. The retrospective nature of [2] Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL, Investigators A. Epidemiology of
acute kidney injury in critically ill children and young adults. N Engl J Med 2017;
chart review poses risks of inaccurate data, errors in data extraction, 376(1):11–20.
and incomplete data. The authors attempted to minimize this by [3] Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL. 3-5 year longitudinal
reviewing 5% of all charts for accuracy. This study was a pilot study per- follow-up of pediatric patients after acute renal failure. Kidney Int 2006;69(1):
184–9.
formed at a single, tertiary care center and therefore the results may not [4] Sigurjonsdottir VK, Chaturvedi S, Mammen C, Sutherland SM. Pediatric acute kidney
be generalizable in all healthcare populations. Additionally, the study injury and the subsequent risk for chronic kidney disease: is there cause for alarm?
population was children with possible sepsis and the results may not Pediatr Nephrol 2018;33(11):2047–55.
[5] Goldstein SL, Kirkendall E, Nguyen H, et al. Electronic health record identification of
be generalizable to a more heterogeneous population. The aRAI was de-
nephrotoxin exposure and associated acute kidney injury. Pediatrics 2013;132(3):
veloped with modification from the original RAI and was intended as a e756–67.
first step towards developing a standardized risk stratification model [6] Karcaaltincaba M, Oguz B, Haliloglu M. Current status of contrast-induced nephrop-
however more work will be required to adjudicate and refine this athy and nephrogenic systemic fibrosis in children. Pediatr Radiol 2009;39(Suppl.
3):382–4.
model. Imputation of SCr using the Schwartz formula may not be an ac- [7] Goldstein SL. Fluid management in acute kidney injury. J Intensive Care Med 2014;
curate measure of each individuals' baseline SCr and thus may have 29(4):183–9.
skewed the results. Additionally, not all subjects had a SCr performed [8] Boer DP, de Rijke YB, Hop WC, Cransberg K, Dorresteijn EM. Reference values for
serum creatinine in children younger than 1 year of age. Pediatr Nephrol 2010;25
on each day of admission so it is possible that there was a higher rate (10):2107–13.
of AKI than this study identified due to incomplete information. [9] Ceriotti F, Boyd JC, Klein G, et al. Reference intervals for serum creatinine concentra-
This study has direct advantages for informing the use of nephro- tions: assessment of available data for global application. Clin Chem 2008;54(3):
559–66.
toxic medications, for example radiocontrast agents for imaging studies, [10] Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin
and volume used for fluid resuscitation. The use of the aRAI provides an Pract 2012;120(4):179–84.
opportunity to identify a high-risk population of children and poten- [11] Hanson HR, Babcock L, Byczkowski T, Goldstein SL. Describing pediatric acute kidney
injury in children admitted from the emergency department. Pediatr Nephrol 2018;
tially at the earliest time point in medical care. This study begins an im- 33(7):1243–9.
portant discussion on applications to further mitigate injury. This is the [12] Basu RK, Zappitelli M, Brunner L, et al. Derivation and validation of the renal angina
first step in a more individualized approach to pediatric AKI. index to improve the prediction of acute kidney injury in critically ill children. Kid-
ney Int 2014;85(3):659–67.
In conclusion, in this pilot study, the aRAI was shown to be a sensi-
[13] Goldstein SL, Chawla LS. Renal angina. Clinical journal of the American Society of Ne-
tive test that can be used in the ED and that outperforms using a change phrology: CJASN 2010;5(5):943–9.
in SCr to predict AKI 24 h after admission to the hospital. This test has [14] Basu RK, Chawla LS, Wheeler DS, Goldstein SL. Renal angina: an emerging paradigm
promise for potential application into the electronic medical record as to identify children at risk for acute kidney injury. Pediatr Nephrol 2012;27(7):
1067–78.
an automated trigger tool. In future study, this tool should be evaluated [15] Agewall S, Giannitsis E, Jernberg T, Katus H. Troponin elevation in coronary vs. non-
in a broadened, heterogenous population in the ED and the prediction coronary disease. Eur Heart J 2011;32(4):404–11.
performance of the tool with biomarker use additionally explored. [16] Stein R, Gupta B, Agarwal S, et al. Prognostic implications of normal (b0.10 ng/ml)
and borderline (0.10 to 1.49 ng/ml) troponin elevation levels in critically ill patients
without acute coronary syndrome. Am J Cardiol 2008;102(5):509–12.
Funding [17] Paul R, Melendez E, Wathen B, et al. A quality improvement collaborative for pediat-
ric sepsis: lessons learned. Pediatr Qual Saf 2018;3(1):e051.
[18] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic
This work was supported by the Arnold W. Strauss Fellow Award at data capture (REDCap)–a metadata-driven methodology and workflow process for
Cincinnati Children's Hospital Medical Center. providing translational research informatics support. J Biomed Inform 2009;42(2):
377–81.
[19] Zappitelli M, Parikh CR, Akcan-Arikan A, Washburn KK, Moffett BS, Goldstein SL. As-
Prior presentation of work
certainment and epidemiology of acute kidney injury varies with definition inter-
pretation. Clinical journal of the American Society of Nephrology: CJASN 2008;3
American Society of Nephrology Annual Conference, November (4):948–54.
[20] Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for es-
2016.
timating glomerular filtration rate in infants, children, and adolescents. Pediatr
Clin North Am 1987;34(3):571–90.
CRediT authorship contribution statement [21] Sutherland SM, Byrnes JJ, Kothari M, et al. AKI in hospitalized children: comparing
the pRIFLE, AKIN, and KDIGO definitions. Clinical journal of the American Society
of Nephrology: CJASN 2015;10(4):554–61.
Holly R. Hanson:Conceptualization, Methodology, Investigation, [22] DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more
Formal analysis, Funding acquisition, Visualization, Writing - original correlated receiver operating characteristic curves: a nonparametric approach. Bio-
draft, Project administration.Michael A. Carlisle:Investigation, Writing metrics 1988;44(3):837–45.
[23] Basu RK, Kaddourah A, Goldstein SL, Investigators AS. Assessment of a renal angina
- review & editing.Rachel S. Bensman:Investigation, Writing - review index for prediction of severe acute kidney injury in critically ill children: a
& editing.Terri Byczkowski:Formal analysis, Data curation, Writing - re- multicentre, multinational, prospective observational study. Lancet Child Adolesc
view & editing.Holly Depinet:Software, Resources, Writing - review & Health 2018;2(2):112–20.
[24] Sethi SK, Raghunathan V, Shah S, et al. Fluid overload and renal angina index at ad-
editing.Tara C. Terrell:Project administration, Investigation, Writing - mission are associated with worse outcomes in critically ill children. Front Pediatr
review & editing.Hilary Pitner:Investigation, Writing - review & 2018;6:118.
editing.Ryan Knox:Investigation, Writing - review & editing.Stuart L. [25] Kaur R, Dhooria GS, Pooni PA, et al. Utilization of the renal angina index in PICU of a
developing country for prediction of subsequent severe acute kidney injury. Pediatr
Goldstein:Supervision, Writing - review & editing.Rajit K. Basu:Super- Nephrol 2018;33(11):2185–91.
vision, Funding acquisition, Conceptualization, Methodology, Writing - [26] Menon S, Goldstein SL, Mottes T, et al. Urinary biomarker incorporation into the
original draft. renal angina index early in intensive care unit admission optimizes acute kidney
 H.R. Hanson et al. / American Journal of Emergency Medicine xxx (xxxx) xxx 7

injury prediction in critically ill children: a prospective cohort study. Nephrology, di- [31] Kirkendall ES, Spires WL, Mottes TA, Schaffzin JK, Barclay C, Goldstein SL. Develop-
alysis, transplantation: official publication of the European Dialysis and Transplant ment and performance of electronic acute kidney injury triggers to identify pediatric
Association-European Renal Association 2016;31(4):586–94. patients at risk for nephrotoxic medication-associated harm. Appl Clin Inform 2014;
[27] Matsuura R, Srisawat N, Claure-Del Granado R, et al. Use of the renal angina index in 5(2):313–33.
determining acute kidney injury. Kidney Int Rep 2018;3(3):677–83. [32] Sutherland SM, Kwiatkowski DM. Acute kidney injury in children. Adv Chronic Kid-
[28] Fierro MA, Ehieli EI, Cooter M, et al. Renal angina is a sensitive, but nonspecific iden- ney Dis 2017;24(6):380–7.
tifier of postcardiac surgery acute kidney injury. J Cardiothorac Vasc Anesth 2019;33 [33] Basu RK, Wang Y, Wong HR, Chawla LS, Wheeler DS, Goldstein SL. Incorporation of
(2):357–64. biomarkers with the renal angina index for prediction of severe AKI in critically ill
[29] Park S, Baek SH, Ahn S, et al. Impact of electronic acute kidney injury (AKI) alerts children. Clinical journal of the American Society of Nephrology: CJASN 2014;9(4):
with automated nephrologist consultation on detection and severity of AKI: a qual- 654–62.
ity improvement study. Am J Kidney Dis 2018;71(1):9–19.
[30] Sutherland SM, Chawla LS, Kane-Gill SL, et al. Utilizing electronic health records to
predict acute kidney injury risk and outcomes: workgroup statements from the 15
(th) ADQI consensus conference. Can J Kidney Health Dis 2016;3:11.