Acute kidney injury (AKI) in hospitalized patientsis associated
with mortality,andincreasing severity of the AKI correlates
with the risk of death [1-4]. Both advanced age [2,5,6]
and intravascular contrast media [7,8] have been recognized
as risk factors for the development of AKI in hospitalized patients. With the liberal use of computed tomography (CT) in
the evaluation of injuries in the emergency department (ED),
a potential concern is the impact of intravascular contrast mediain
elderly trauma patients. The two objectives of the study
were to (1) evaluate the impact of contrast exposure (CE) in
the development of early AKI and (2) whether AKI in this cohort
was associated with mortality. Our hypotheses were that elderly trauma patients who had CE had similar rates of early
AKIwhen compared to patients without CE, but that the development
of early AKI was associated with poor outcome.
Materials and Methods
After obtaining IRB approval with waiver of consent,
the records of all elderly (age≥65 years) trauma patients admitted
to a level 1 trauma center were reviewed retrospectively
over a 16- month period (January 2011 to May 2012). Acute
kidney injury was defined by meeting at least Stage 1 criteria
based on the Kidney Disease: Improving Global Outcomes
(KDIGO) Clinical Practice Guideline, namely, an increase in
serum creatinine [Scr] of more than or equal to 0.3 mg/dl or
an increase to more than or equal to 150% from baseline, and/
or less than 0.5 ml/kg per hour of urine output for more than
6 hours) . If these criteria were met within 120 hours of
admission, they were considered to have early AKI. This time
period was arbitrarily specified so as to distinguish AKI developing
shortly after admission from that developing later the
hospital course, as the latter could have been associated with
other factors during hospitalization.
Patients were excluded from analysis for the following
reasons: (1) death or discharge prior to 48 hours, (2) if they received
their first dose of contrast 48 hours after admission, (3)
pre-injury renal replacement therapy, (4) if there was only one
measured Scr, (5) missing admission weight in the medical records.
Patients with missing weights were excluded as there is a
known strong correlation between measured glomerular filtration
rate and weight . Estimated glomerular filtration rate
(eGFR) was calculated using the Modification of Diet in Renal
Disease (MDRD) formula, and stratified into three categories
based on eGFR: ≤30, >30 and ≤60, and >60 ml/min/1.73m2.
Admission Scr was analyzed both as a continuous variable and
a categorical variable (≤1.5 mg dl-1vs. >1.5 mg dl-1).
The contrast media used during this period werenonionic
low osmolar iodinated agents (iopamidol, iohexol, ioversol).
The study cohort was divided into two groups: those
with contrast exposure (+CE) and those without (-CE). Plausible
variables selected included vital signs, pre-existing diabetes
mellitus, the need for blood transfusion prior to arrival or in
the ED, and the need for intubation prior to arrival or in the
ED. For CE and each plausible variable, univariate analysis was
performed to determine association with the two outcomes,
namely, early AKI and 30-day mortality. The Student's t test,
Mann-Whitney U test, Fisher exact test or the Pearson chisquare
test were used where appropriate. To estimate the effect
of CE on AKI stratified by renal function, the Mantel-Haenszel
common odds ratio was calculated.
Multivariate analysis using stepwise logistic regression
was performed to examine the effect of CE on AKI while controlling
for other potentially confounding variables. Pairs of
variables were examined for multicollinearity with correlation
matrix plots prior to multivariate analysis.
A second logistic regression analysis was performed to
examine if there were independent predictors of 30-day mortality.
We attempted to find a parsimonious model with the
three variables of interest, namely, AKI, CE and eGFR forced
into the model.
Based on published data, we assumed an incidence of
3% of early AKI in thegroup without CE, and proposed that a
difference between the two groups of 5% would be clinically
significant. Based on a non-inferiority hypothesis, with an
alpha of 0.05 and 90% power, and assuming that 50% of the
entire cohort was exposed to contrast, 710 subjects would be
Statistical analysis was performed using Minitab 16.2.4
(www.minitab.com/support). A p-value of 0.05 was considered
During the study period, 1240 trauma patients 65 years
and older were evaluated in the emergency room. After applying
the exclusion criteria, 905 remained and formed the
basis for further analysis. Of the 905 patients, there were 422
(46.6%) patients who received contrast. The overall rate of early
AKI was 52/905 (5.7%). The rates of early AKI were similar
in the +CE versus the –CE groups (21/422 [5.0%] vs. 31/483
[6.2%], p=0.36 respectively) (Table 1). There were only two
patients in their hospital course, one from each group, who
required initiation of renal replacement therapy during their
acute hospital stay.
All patients in the +CE group received contrast within
48 hours of admission. Twenty-four (5.7%) of +CE patients
had two or more CE episodes within 48 hours after admission.
When these patients were compared to those with only one
episode of CE, the proportions of patients developing early
AKI were statistically similar (0/24 vs. 20/398, p=0.6).
Only 27 (2.8%) of patients received intra-arterial contrast.
When this group was compared to those who received
only intravenous contrast, the rates of early AKI were similar
(7.4% vs. 5.5%, p=0.7). The rates of early AKI were also statistically
similar between the +CE and –CE groups when only
patients with intravenous contrast were analyzed.
Table 1 describes differences in patient characteristics
for the +CE and –CE groups. Compared to –CE patients, +CE
patients were younger, predominantly male, had better renal
function, lower admission systolic blood pressure (SBP), higher
median weight, higher Injury Severity Score (ISS), lower
median Glasgow Coma Score (GCS) and were more likely to
be intubated in or prior to arrival to the ED. Rates of early
AKI were similar but 30-day mortality was noted to be nonsignificantly
higher in the group receiving contrast.
When patients with early AKI were compared to those
without AKI, both groups were similar in terms of age, gender
predominance, SBP, ISS, GCS, and need for intubation in or
prior to arrival in the ED. However, patients with early AKI had significantly lower mean heart rate (HR), greater median
weight, higher median Scr, and were more likely to be diabetic
(Table 2). In addition, a non-significant difference in mortality
was noted between these two groups (11.5% vs 5.3%, p=0.077).
CE was not associated with AKI (Table 2). When stratified
by admission eGFR and Scr respectively, this lack of association
remained valid (Table 3 & Table 4). Logistic regression
analysis incorporating CE as a variable revealed that only
weight (odds ratio [OR] 1.02 [95% confidence interval, C.I.
1.00-1.04]) and HR (OR 0.98, 95% C.I. 0.96-1.00) were independent
predictors of early AKI. Of note, eGFR was also not
an independent factor contributing to early AKI.
The impact of contrast volume was further evaluated.
Fifty patients (11.8% of the +CE group) had missing contrast
volume data. After excluding these patients, the median volume
of contrast used cumulatively over a 48-hour period was
100 ml (range 50-280 ml, interquartile range 100-100 ml). We
calculated the following for each of the remaining patients:
contrast volume per kg weight and contrast volume-to-creatinine clearance ratio (using the Cockcroft-Gault formula).
Analyses using receiver operating characteristic (ROC) curves
demonstrated that both contrast volume per kg weight and
contrast volume –to –creatinine clearance ratio had poor discriminatory
ability in predicting early AKI (areas under the
curve, 0.45 [95% C.I. 0.37-0.52] and 0.52 [95% C.I. 044-0.61]
Since patients with missing weights were excluded
(n=70), sensitivity analysis was done to evaluate the association
of CE with AKI with the inclusion of these patients. When
stratified by eGFR, rates of early AKI were similar in each of
the three eGFR subsets whether these patients were included
or not. The overall rates of early AKI were similar with inclusion
of these patients (CE vs. no CE, 5.5% vs 6.2%, p=0.5).
With respect to 30-day mortality, Table 5 shows the
statistically significant variables by univariate analysis. Early
AKI patients had a higher but non-statistically significant
mortality rate compared to patients without early AKI.A prediction model for mortality was constructed with AKI, eGFR
and CE forced into the model. The final regression model revealed that age, GCS, ISS, moderately reduced renal function,
need for blood transfusion prior to or in the ED, and early AKI
were independent predictors of 30-day mortality (Table 6).
Approximately 30% of patients seen in level 1 and 2
trauma center in the United States are 65 years and older .
With the widespread use of CT scanning for evaluation of injuries
as well as non-traumatic emergencies, concern about
contrast-induced nephropathy (CIN) in the elderly is justified.
Although many studies have examined the relationship
between contrast exposure and the development of acute kidney
injury, few studies have focused specifically on the elderly
trauma patients, even though age has been recognized as a risk
factor for AKI . McGillicuddy et al. , using 25% relative
rise in Scr or 0.5 mgdl-1 absolute rise as criteria for AKI,
found that 2% of elderlytrauma patients developed early AKI
and that contrast administration was not associated with AKI.
In their study, no obvious risk factors for AKI were identified
on multivariate analysis. Kim et al.  found a 29% incidence
of AKI in patients admitted to the ICU > 48 hours after
trauma, and determined that CE was not associated with AKI.
However, patients with altered renal function were excluded,
and there were only 129 elderly patients. Similarly, Ehrmann
et al.  in a prospective study of ICU patients with mixed
admission diagnoses, reported minimal influence of CE on the
development of AKI, and found the Sequential Organ Failure
Assessment Score and the number of nephrotoxic agents as
risk factors for AKI.
With respect to patients with reduced kidney function,
the association between AKI and CE is still controversial. Hipp
et al. found that a Scr of > 1.5 mg/dl was associated with nephropathy
 but Finigan et al. reported no such association with Scr . These studies had attributed AKI after receiving
contrast to contrast-induced nephropathy. Since there were no
control patients in these two studies, it is difficult to determine
to what extent contrast exposure affected the development of
AKI. Another smallerstudy of 95 trauma patients with a serum
creatinine of ≥1.3 mg/dl found similar incidences of AKI with
or without contrast . On the other hand, a recent large
study of post-CT AKI with propensity matched controls found
that when pre-CT creatinine was < 1.5 mg/dl, the administration
of contrast was not associated with AKI. However, with
a pre-CT creatinine >1.5 mg/dl, the odds of developing AKI
increased with increases in creatinine . On the contrary,
a meta-analysis of 13 nonrandomized studies  as well as
a large propensity-matched cohort study  concluded that
the risk of AKI was similar between contrast exposed patients
and patients who did not receive contrast, regardless of baseline
In our study of geriatric patients, we did not find a
significant association between CE and early AKI in patients
with reduced kidney function in our subgroup analyses.This is
perhaps due to the fact that very few patients with severely reduced
renal function received contrast. Based on our study, no
definite conclusions can be drawn for patients with an eGFR
of ≤30m/min/ 1.73m2.
Several other authors have addressed the impact of
contrast volume in the development of AKI. A contrast volume
to creatinine clearanceratio of >3.7 in one study  and
a ratio of >2.62 in another  were found to be associated
with renal dysfunction after percutaneous coronary intervention.
We found that both the contrast volume-to-creatinine clearance ratio and contrast volume per kg weight had poor
discriminatory ability with respect to early AKI. This might
be that the prior studies used intra-arterial contrast, or that
higher average contrast volumes were administered compared
with our study.
In our study, we found that weight and heart rate were
independent predictors of early AKI. To our knowledge, this
has not been reported. The reason for these findings is not apparent,
and therefore should await further corroboration from
With regard to the association of AKI with mortality,
Gomes et al found that in trauma patients developing AKI,
there was no difference in mortality after 48 hours, compared
to patients without AKI . However, McGillicuddy et al 
found an association between AKI and in-hospital mortality
(odds ratio =3.1) for trauma patients aged 55 and over. Tian et
al.  also demonstrated that a rise in serum creatinine of 0.3
mg/dl within 48 hours of hospitalization had an adjusted mortality
odds ratio of >4 compared to patients without early AKI.
These conclusions were corroborated in other patient samples
such as cancer patients , geriatric postoperative patients
[25,26] and patients with acute myocardial infarction .
There were several limitations. Firstly, there was inadequate
(and missing) data about urine output and fluid balance
in the early resuscitative phase. In addition, we did not
have adequate information about post-CE hydration, as well
as the time from the injury to the time of the blood draw. Secondly,
not all patients received daily Scr measurements for the
entire 96-hour period, and hence, "peaks" of Scr could have
been missed. The significance of these above limitations is that
we could not detect patients who may have been in AKI even
prior to contrast exposure, since in patients presenting acutely
in shock, physiologic reductions in GFRmay not have been
reflected in the admission serum creatinine. However, since
the control group may have had the same issues, and that this
study was aimed at the differential impact of CE on early AKI,
we feel that the conclusions are still valid.
Thirdly, the impact of cumulative effects of CE in elderly
trauma patients is as yet unclear, since only 6% of this
sample received ≥2 CE episodes within 48 hours.
Fourthly, for most of the patients, due to the urgent
circumstances in which they presented, we had incomplete
knowledge of their baseline renal function or other comorbidities.
Frequently, there were no prior clinical records available
at the time of evaluation. We could not therefore accurately
generate validated measures of severity of the comorbid conditions.
Furthermore, an abnormal Scr or eGFR could have been
reflective of a prerenal state at admission or chronic kidney
disease. Thus, patients could have had different responses to
contrast exposure depending on the reason for abnormal renal
function during admission.
Fifthly, there were very few patients with eGFR ≤30 ml/
min/1.73m2. Thus the study likely was underpowered to detect differences in the primary outcome in this subgroup.
Sixthly, since almost all of the patients with early AKI
recovered without renal replacement therapy, we did not focus
on patients who develop AKI later in their hospital course. It
is possible that early AKI may have been associated with subsequent
development of later AKI which could be associated
Our findings not only confirm the association between
AKI and mortality in different hospitalized patient populations,
they suggest that AKI developing early in the course of
hospitalization in geriatric trauma patients may be as important
as AKI developing after a period of prolonged hospitalization.
This study was not designed to explore factors other than
those related to the initial ED evaluation, and can only support
the conclusion that clinicians should not lightly dismiss small
increases in Scr early in the hospital course.
Among elderly trauma patients, the development of
AKI early after admission was an independent predictor of 30-
day mortality. Contrast exposure did not seem to play a role
in the development of early AKI in this cohort. However, for
patients with an eGFR of ≤30 ml/min/1.73m2, no valid conclusions
can be drawn from this study due to the small sample
size. Further studies could focus specifically on elderly patients
with severely reduced eGFR in the trauma setting, and also on
modifiable factors to reduce the risk of early AKI.
All the authors declare that there are no financial or
non-financial competing interests relating to the subject matter
in the manuscript, or with the execution of the study. There
was no funding provided for this study.
AWO conceived the project, carried out data collection,
statistical analysis, and drafted the manuscript. GJN carried
out data collection, helped with data interpretation, and
provided critical revision of the manuscript. RJM helped with
data interpretation and provided critical revision of the manuscript.
All the authors have read and approve of the manuscript.