In Practice

The Controversy of Contrast-Induced

Nephropathy With Intravenous Contrast:
What Is the Risk?
Michael R. Rudnick, Amanda K. Leonberg-Yoo, Harold I. Litt, Raphael M. Cohen,
Susan Hilton, and Peter P. Reese

Contrast-induced nephropathy (CIN) has long been observed in both experimental and clinical studies. Complete author and article
However, recent observational studies have questioned the prevalence and severity of CIN following information provided before
references.
intravenous contrast exposure. Initial studies of acute kidney injury following intravenous contrast were
limited by the absence of control groups or contained control groups that did not adjust for additional Am J Kidney Dis. 75(1):
acute kidney injury risk factors, including prevalent chronic kidney disease, as well as accepted pro- 105-113. Published online
August 28, 2019.
phylactic strategies. More contemporary use of propensity score–adjusted models have attempted to
minimize the risk for selection bias, although bias cannot be completely eliminated without a pro- doi: 10.1053/
spective randomized trial. Based on existing data, we recommend the following CIN risk classification: j.ajkd.2019.05.022
patients with estimated glomerular filtration rates (eGFRs) ≥ 45 mL/min/1.73 m2 are at negligible risk © 2019 by the National
for CIN, while patients with eGFRs < 30 mL/min/1.73 m2 are at high risk for CIN. Patients with eGFRs Kidney Foundation, Inc.
between 30 and 44 mL/min/1.73 m2 are at an intermediate risk for CIN unless diabetes mellitus is
present, which would further increase the risk. In all patients at any increased risk for CIN, the risk for
CIN needs to be balanced by the risk of not performing an intravenous contrast-enhanced study.

Note from Editors: This article was commis-

sioned to celebrate the selection of Iodinated
Contrast as a finalist in NephMadness 2018.
NephMadness is an educational project styled
as a tournament in which key concepts in
nephrology “compete” to determine which de-
serves to be crowned the most notable recent
advance in the field.
Clinical Vignette
A 60-year-old man presented to the emer-
gency department with sudden onset of
right anterior chest pain. The pain was sharp
in nature, exacerbated with breathing, and
there were no symptoms of fever, hemop-
tysis, or shortness of breath. The patient also
provided a history of right calf pain for the
past 3 days. Medical history includes hy-
pertension and diabetes mellitus (DM) each
of 10 years’ duration, and chronic kidney
disease (CKD; baseline serum creatinine
[Scr], 1.9 mg/dL). Physical examination
revealed a mildly obese man with blood
pressure of 160/100 mm Hg, pulse rate of
95 beats/min, regular respirations with rate
of 16 breaths/min, temperature of 98.8 F,
and pulse oximetry while breathing room
air of 91% oxygen saturation. The rest of
the examination findings were normal
with the exception of a tender nonswollen
right calf. Laboratory results were normal
except for Scr level of 1.8 mg/dL. Estimated
glomerular filtration rate (eGFR) was FEATURE EDITOR:
39 mL/min/1.73 m2 (using the CKD-EPI Holly Kramer
equation). A urinalysis dipstick demon-
strated protein (1+) but no other abnor- ADVISORY BOARD:
malities. A chest x-ray was normal and Linda Fried
lower-extremity duplex ultrasonography Ana Ricardo
Roger Rodby
was negative. Pulmonary embolism was Robert Toto
suspected and a discussion occurred about
the risk for contrast-induced nephropathy In Practice is a
(CIN) with computed tomography angiog- focused review
raphy (CTA). providing in-depth
guidance on a clinical
topic that nephrolo-
Introduction gists commonly
encounter. Using
Contrast media (CM) was first reported to clinical vignettes,
cause acute kidney injury (AKI) in 1954 when these articles illus-
Bartels et al1 reported a patient with multiple trate a complex prob-
myeloma who developed anuria following lem for which optimal
intravenous pyelography. This report was diagnostic and/or
therapeutic ap-
followed by additional case series of AKI after proaches are
intravascular CM with excretory urography, uncertain.
computed tomography (CT), and non-
coronary angiography.2 In the 1980s, larger
series of AKI following CM administration
during coronary angiography began to appear,
with CKD and DM being established as risk
factors for this complication.3 The entity of
CIN was coined, most commonly in associa-
tion with coronary angiography despite 90%
of all intravascular CM being given intrave-
nously during CT. Until recently it has been
accepted that in high-risk patients, CM given
either intra-arterially or intravenously was
capable of causing AKI. In addition, there is

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extensive experimental literature demonstrating contrast
nephrotoxicity, supporting the possibility that CM is
nephrotoxic in humans.4-8
During the past 10 to 15 years, an increasing number of
publications have called into question whether CIN
following intravenous CM administration has been over-
stated, exists at all, and is clinically relevant.2,9-11 These
opinions arose from controlled studies demonstrating
similar AKI rates in patients who underwent contrast-
enhanced CT (CECT) compared with those who under-
went unenhanced CT. It is important to determine the true
risk for nephrotoxicity following intravenous CM expo-
sure. If the risk for CIN is overstated, CM exposure may be
needlessly avoided in patients who could clinically benefit
from the improved diagnostic accuracy of CECT.12 How-
ever, if the risk for CIN is underestimated, patients may be
unnecessarily exposed to a nephrotoxic agent capable of
causing AKI that may have both short- and long-term
clinical implications.
The purpose of this review is to critically examine
publications about AKI following intravenous CM expo-
sure in an effort to better define the true incidence of AKI
due to CM administered intravenously and its clinical
relevance.
Randomized Studies Demonstrating Differences
in AKI After Contrast Exposure
Support for the position that intravenous CM can be
nephrotoxic comes from prospective randomized
controlled trials (RCTs) demonstrating different AKI rates
between groups who received different CM or who were
or were not exposed to a prophylactic intervention. Risk
factors for AKI other than type of CM or prophylactic
intervention should be balanced in RCTs, so differences in
AKI incidence should be due to contrast nephrotoxicity.
RCTs have demonstrated that high-osmolal CM have a
greater risk for AKI than low-osmolal CM (LOCM), indi-
cating that high-osmolal CM are nephrotoxic.13-15 How-
ever, this does not prove that LOCM are nephrotoxic
because it is possible that the AKI observed in patients
exposed to LOCM is due to factors other than CM.14,15 For
a study of a prophylactic intervention to provide support
that CM are nephrotoxic, the intervention would need to
show a consistent benefit, with no effect itself on the
pathogenesis of AKI.
Volume expansion is a prophylactic intervention that
could meet these criteria.16 Several RCTs comparing
intravenous fluids with no fluids, normal saline with
half-normal saline solution, and different rates of saline
solution infusion have shown reductions in AKI
post–contrast exposure.17-20 In these studies, the differ-
ence in AKI between the intervention and control groups
could be due to contrast nephrotoxicity, although the
ability of intravenous fluids to cause hemodilution of Scr
level and correct hypotension makes this interpretation
less certain.
106
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In Practice
Comparison of CIN With Intra-arterial and
Intravenous Contrast Administration
Those who propose that CIN from intravenous CM is
overstated argue that this conclusion has been inappro-
priately extrapolated from studies investigating AKI
following intra-arterial CM exposure.9 Given differences in
baseline patient comorbid conditions and the procedural
risks of coronary angiography, it is intuitive to expect a
higher AKI rate following CM exposure with coronary
angiography compared to CECT.21,22 Numerous studies of
patients undergoing coronary angiography have demon-
strated AKI rates of w13%, which exceeds the average AKI
rates of 5% to 6% associated with intravenous CM expo-
sure.13,23-25
One conclusion of these results, although controver-
sial, is that intra-arterial delivery of CM is more neph-
rotoxic compared to intravenous administration.26-28
Statements that intra-arterial CM administration presents
a higher concentration of CM to the kidney are only true
when intra-arterial contrast is given in the aorta above
or at the level of the renal arteries and possibly with
high-dose left ventriculography (first-pass renal expo-
sure).29,30 With infrarenal aortic or coronary artery
administration, CM will drain into the venous system
before being delivered to the kidney (second-pass renal
exposure).30
It has also been suggested that CM volume administered
during coronary angiography is higher compared with the
intravenous CM volume used for CECT, thus accounting
for the higher rate of AKI with intra-arterial administra-
tion. When contrast dose is expressed as the ratio of grams
of iodine to GFR (g-I/GFR) to normalize for the exposure
of CM seen by the kidneys, higher ratios correlate with
nephrotoxicity.25 During coronary angiography, mean g-
I/GFR dose in patients without and with AKI are 0.7 to 1.0
and 1.0 to 1.8, respectively. CECT studies demonstrate a
mean g-I/GFR dose of 0.9.25 Thus, at similar high doses,
the risk for AKI following intravenous and intra-arterial
administration may be the same.
Studies comparing AKI following intra-arterial and
intravenous exposure in the same patients eliminate patient
differences in risk factors for AKI because each patient
serves as his or her own internal control. This approach
should capture nephrotoxic differences between intra-
arterial and intravenous contrast exposure. In the few
studies that have examined patients exposed to both intra-
arterial and intravenous CM, the rates of AKI were
similar.31-33 However, differences in contrast volume be-
tween intra-arterial and intravenous CM studies are a
limitation of this conclusion. In summary, reported dif-
ferences in contrast nephrotoxicity between intravenous
and intra-arterial contrast exposure do not appear to be
due to a greater inherent nephrotoxicity with intra-arterial
CM exposure but rather are likely due to differences in
population comorbid conditions, procedural risks, and
contrast volumes.
AJKD Vol 75 | Iss 1 | January 2020
In Practice
CECT Studies of CIN Without Control Groups
Initial studies of AKI following intravenous CM were
conducted, with rare exception, without control groups
(patients who underwent similar radiologic procedures
without CM administration).34-37 These reports identified
CKD as an independent risk factor for CIN, and that DM
was an additional risk factor when coupled with CKD.
Many of these studies focused on hospitalized patients due
to the necessity of obtaining 24- to 72-hour postscan Scr
data. The focus on hospitalized patients had the unin-
tended consequence of creating ascertainment bias toward
a sicker population with multiple comorbid conditions
that may have been responsible for the observed AKI risk,
independent of CM exposure.35
Among uncontrolled studies of AKI following intrave-
nous CM exposure, the AKI rate was 5.1%, with a wide
range (0%-21%) across individual studies.23,34,35,38 In
patients with moderate to severe CKD, the AKI rate
following intravenous CM exposure varied from 0% to
42%, with most having rates >5%.23 The wide range of
AKI following intravenous CM exposure in these uncon-
trolled studies is due to differences in clinical settings, the
prevalence of noncontrast AKI risk factors, number of
high-risk patients, definitions of AKI, timing of post-
contrast Scr determinations, presence of prophylactic
strategies, and type and dose of CM used.23,35,36,38 It is
difficult to determine the true rate of AKI following
intravenous CM exposure using these uncontrolled studies.
CECT Studies of CIN With Nonrandomized
Control Groups
The importance of controls in CM exposure studies was
largely ignored until the publication of 2 landmark
observational studies.39,40 Newhouse et al39 performed a
retrospective analysis of 32,161 hospitalized patients with
serial Scr values on 5 consecutive days and with no CM
exposure to determine the frequency of Scr level changes
over time.39 During the 5-day period, a change in Scr level
of at least 25% or 0.4 mg/dL was observed in a significant
proportion of patients with both normal and abnormal
baseline Scr values. This is relevant because CIN is usually
defined as an increase in Scr level ≥ 0.5 mg/dL or a 25%
increase from baseline value, assessed at 48 hours after
contrast exposure.41 The authors concluded that previous
studies of intravenous CIN using change in Scr level as the
sole criterion for defining CIN should be re-evaluated
because attributing these changes as AKI due to CM
exposure is a post hoc, ergo propter hoc (after this,
therefore because of this) logical fallacy. Thus, an increase
in Scr level following CM exposure does not prove the Scr
level increase was due to CIN.35
Bruce et al40 performed a large retrospective study in
11,588 patients comparing AKI incidence in patients who
underwent CECT and unenhanced CT and found that the
incidence of AKI in contrast-exposed patients was similar to
nonexposed patients. The inclusion of a control arm in this
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study strongly suggested that AKI observed following CM
exposure cannot automatically be assumed to be due to CIN.
Following these 2 studies, multiple observational
controlled studies of AKI following intravenous CM
exposure were performed. For the most part, these studies
demonstrated an equivalent rate of AKI between CECT and
unenhanced CT groups, leading the authors to conclude
that AKI after intravenous CM exposure is overstated or
nonexistent (Table S1). A recent systematic review and
meta-analysis of 28 observational controlled studies
demonstrated that CECT compared with unenhanced CT
was not significantly associated with AKI (odds ratio [OR],
0.94; 95% confidence interval [CI], 0.83-1.07).42
Wilhelm-Leen et al43 performed an analysis of more than
5 million inpatient admissions to estimate AKI in patients
exposed to CM compared with patients with similar
baseline comorbid conditions and severity of illness but
without exposure to CM.43 When adjusted for comorbid
conditions, the risk for AKI with CM exposure was 7.4%
lower than with no CM exposure. Because CM is not
nephroprotective, these findings indicate the presence of
selection bias; patients perceived to be at highest risk for
CIN may have selectively not been exposed to CECT. All
these controlled studies have major limitations, including a
higher prevalence of CKD in the control patients, limited
numbers of high-risk patients, and lack of adjustment for
confounding variables.44-47
CECT Controlled Studies of CIN With Propensity
Score Adjustments
Given the imbalance in confounding covariates and se-
lection bias between CM and control populations, the ideal
approach to determine CIN following intravenous contrast
would be an RCT in patients undergoing CT with or
without CM enhancement, which would ensure balanced
comorbid conditions between groups and nonbiased
randomization. For ethical and logistical reasons, it is
unlikely that such RCTs will be performed. Recognizing
these limitations, several investigators performed studies
using propensity score matching methods, summarized in
Table 1.
Davenport et al48 performed a retrospective study with
1:1 propensity score matching of AKI risk in patients who
had undergone CECT or unenhanced CT. AKI was defined
using either AKI Network (Scr ≥ 0.3 mg/dL or 50%) or
traditional (Scr ≥ 0.5 mg/dL or 25%) criteria. In patients
with baseline Scr levels < 1.5 mg/dL (w90% of all pa-
tients), AKI rates for the CECT and unenhanced CT groups
were similar (Table 1). In patients with baseline Scr lev-
els ≥ 1.5 mg/dL, the incidence of AKI in the CECT group
was higher than in the unenhanced CT groups. Davenport
et al49 also examined AKI risk with CECT using stratified
eGFR as a more accurate reflection of baseline kidney
function, with similar results observed. The majority
(79%) had baseline eGFR ≥ 60 mL/min/1.73 m2, while
only 0.66% had a baseline eGFR < 30 mL/min/1.73 m2.
107
 In Practice

Table 1. Incidence of CIN and Adverse Outcomes Following Intravenous Contrast Exposure in Studies With Propensity Score
Matching for AKI Risk

No. Propensity AKI No. (%) with AKI Distribution by AKI Ratea
Author Analyzed Definition +C −C Kidney Function +C −C
Davenport48 10,121 (+C); T; A T: 1,221 (12.1%) T: 1,259 (12.4%) Scr < 1.5: 94.3% T: 11.8% T: 12.6%
(2013)b 10,121 (−C) A: 835 (8.3%) A: 867 (8.6%) A: 7.1% A: 7.3%
Scr ≥ 1.5: 18.4% T: 14.9%c T: 11.3%
A: 22% A: 19.2%
Scr ≥ 1.6: 13.7% T: 16.9%c T: 11.7%
A: 26.3%c A: 19.7%
Scr ≥ 2.0: 4.8% T: 31.2%c T: 14.5%
A: 43.3%c A: 22.5%
Davenport49 8,826 (+C); A 619 (7.0%) 606 (6.9%) eGFR ≥ 60: 79% 5.4% 5.5%
(2013)b 8,826 (−C) eGFR 45-59: 14% 10.5% 10.8%
eGFR 30-44: 6.2% 16.7%d 14.2%
eGFR < 30: 0.66% 36.4%c 19.4%
McDonald50 10,686 (+C); T 515 (4.8%) 544 (5.1%) Scr < 1.5: 68% 3.0% 3.0%
(2013) 10,686 (−C) Scr 1.5-2.0: 23% 9.0% 9.0%
Scr > 2.0: 9% 10.0% 11.0%
McDonald51 6,254 (+C); T 313 (5%) 325 (5.2%) eGFR ≥ 90: 13.1% 1.2% 1.3%
(2014)e 6,254 (−C) eGFR 60-89: 30.9% 2.1% 2.0%
eGFR 30-59: 44.1% 5.8% 6.2%
eGFR < 30: 11.9% 14% 14%
McDonald52 1,639 (+C); T; A T: 123 (7.5%) T: 132 (8.1%) eGFR 30-59: 74.4% T: 5.0% T: 5.8%
(2015)e 1,639 (−C) A: 215 (13.1%) A: 266 (16.2%) A: 10.0% A: 15.0%
eGFR < 30: 25.6% T: 15.0% T: 15.0%
A: 21.0% A: 20.0%
McDonald53 1,402f (+C); T; A T: 87 (6.2%) T: 131 (8.6%) eGFR ≥ 60: 34% T: 3.8% T: 4.6%
(2017)e 1,524 (−C) A: 179 (12.8%) A: 237 (15.6%) A: 7.8% A: 10.0%
eGFR 30-59: 60.7% T: 7.2% T: 7.9%
A: 15.0% A: 18.0%
eGFR < 30: 9.4% T: 11.0% T: 21.0%
A: 17.0% A: 25.0%
McDonald54 1,508 (+C); T; A T: 254 (16.8%) T: 240 (15.9%) eGFR > 45: 81.1% T: 14.0% T: 14.0%
(2017)e 1,508 (−C) A: 526 (34.9%) A: 546 (34.9%) A: 31.0% A: 34.0%
eGFR ≤ 45: 18.9% T: 29.0% T: 25.0%
A: 50.0% A: 45.0%
Hinson55 7,201 (+C); T; A T: 766 (10.6%) T: 786 (10.9%) eGFR ≥ 60: 87.5% T: 10.9% T: 10.5%
(2017)g 7,201 (−C) A: 488 (6.8%) A: 466 (63.5%) A: 6.1% A: 5.7%
eGFR 45-59: 7.9% T: 10.3% T: 8.0%
A: 12.3% A: 9.2%
eGFR 30-44: 3.3% T: 5.0% T: 9.5%
A: 9.1% A: 12.0%
eGFR < 30: 1.1% T: 7.3% T: 5.1%
A: 10.9% A: 14.1%
Abbreviations and definitions: A, Acute Kidney Injury Network definition of AKI (increase from baseline Scr ≥ 0.3 mg/dL or 50% increase in Scr); AKI, acute kidney
injury; +C, contrast-enhanced computed tomography; −C, unenhanced computed tomography; CECT, contrast-enhanced computed tomography; CIN, contrast-induced
nephropathy; CKD, chronic kidney disease; CT, computed tomography; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); Scr, serum creatinine (in mg/dL); T,
traditional definition of AKI (increase from baseline Scr ≥ 0.5 mg/dL or 25%).
a
Stratified: percent cohort.
b
Similar study cohort used in both studies.
c
P < 0.05 between the CECT and unenhanced CT groups.
d
Odds ratio, 1.4 (95% confidence interval, 0.997-1.97).
e
Overlap between original McDonald et al 2013 cohort.50
f
Propensity score matching was done 1:1 for all CKD stages except in patients with CKD stages 4 to 5 who underwent a 1:3 (iodixanol:no contrast) matching.
g
Propensity data for −C provided by author.

The rates of AKI between CECT and unenhanced CT pa-
tients were similar in the groups with eGFR ≥ 60 mL/min/
1.73 m2 but were significantly higher in patients with
eGFR < 30 mL/min/1.73 m2 exposed to CECT (Table 1).
Among patients with eGFRs of 30 to 44 mL/min/1.73 m2,
there were nominally greater odds of AKI following CECT
exposure, compared to unenhanced CT imaging (OR,
1.40; 95% CI, 1.00-1.97), although the difference was not
statistically significant.
McDonald et al50 also performed a retrospective study
with 1:1 propensity score matching of AKI risk among
patients who had undergone CECT or unenhanced CT. The
risk for AKI for the CECT and unenhanced CT patients were
similar for all cohorts when risk was stratified by baseline
Scr level: 3% in each group for low risk (<1.5 mg/dL); 9%
in each group for medium risk (1.5-2.0 mg/dL); and
10% versus 11%, respectively, for high risk (>2.0 mg/dL).
In a smaller subset of patients who underwent both

108 AJKD Vol 75 | Iss 1 | January 2020

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In Practice
unenhanced CT and CECT, the risk for AKI for the CECT
and unenhanced CT groups were also similar: 4.5% and
4.9%, respectively. Using baseline eGFR as a predictor for
risk for AKI, the same authors found no difference in AKI
rates between CECT and unenhanced CT patients
(Table 1).51 The findings of the McDonald et al studies are
different from the Davenport et al48,49 studies, which
found statistically increased rates of AKI in CECT patients
compared with unenhanced CT patients with
eGFR < 30 mL/min/1.73 m2 or Scr level ≥ 1.5 mg/dL and
borderline statistical significance with eGFR of 30 to
44 mL/min/1.73 m2. McDonald et al suggest that the
discrepancy may be explained by different propensity
methodologies and/or sample size of patients with
eGFR < 30 mL/min/1.73 m2.
These same investigators have performed additional
propensity score analyses in specific cohorts with high AKI
risk.52-54 The results of these studies did not show an
increased risk for AKI after CM exposure, even after risk
stratification by eGFR (Table 1). Among a cohort exposed
to iso-osmolal contrast media (IOCM) only, there was a
trend toward greater AKI in the unenhanced CT compared
with CECT in individuals with eGFRs < 60 mL/min/
1.73 m2, suggesting residual selection bias despite pro-
pensity score matching.53 In an intensive care unit setting,
patients with eGFRs < 45 mL/min/1.73 m2 exposed to
CECT had increased odds of emergent dialysis as compared
with those exposed to unenhanced CT (OR, 2.72; 95% CI,
1.14-6.46).54 Finally, Hinson et al55 performed a pro-
pensity score analysis in a single-center emergency
department setting that showed similar AKI in CECT and
unenhanced CT patients irrespective of AKI definition or
eGFR stratification. Baseline Scr level in the entire cohort
was 1.0 mg/dL and only 3.3% and 1.0% of patients had
eGFRs of 30 to 44 or <30 mL/min/1.73 m2, respectively.
Mortality, Dialysis, and CKD With CIN
AKI is associated with risks for CKD development, pro-
gression, and all-cause mortality.56-60 These observational
studies are supported by experimental studies of AKI that
provide plausible biological mechanisms for clinically
relevant outcomes.61-64 In a population that has developed
CIN, there is a debate of whether this is associated with a
clinically relevant longer-term adverse outcome. Several
studies have demonstrated increased in-hospital and long-
term mortality, CKD progression, and kidney failure in
patients who developed AKI following contrast angiog-
raphy, compared with those without AKI following cor-
onary angiography.65-68 Of course, observational studies
do not prove a causal relationship between CIN and
adverse clinical outcomes because the association could be
due to confounding comorbid conditions that predispose
to both CIN and adverse clinical outcomes.65 The effect of
non-CM confounding comorbid conditions on adverse
clinical outcomes may be more relevant with intra-arterial
than intravenous studies of CIN.
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Examining data from RCTs evaluating prophylactic in-
terventions or different CM on postcontrast AKI may
provide information about the clinical relevance of AKI
following contrast exposure. Some RCTs of prophylactic
strategies have found an increase in adverse clinical out-
comes in conjunction with a higher frequency of CIN but
are confounded by the potential effect on mortality by the
prophylactic strategy itself. The CARE study was an RCT
comparing an IOCM versus a LOCM with end points of
CIN rate and adverse clinical outcomes.69 This study
demonstrated a lower rate of CIN in the LOCM group
compared to the IOCM group. Long-term follow-up
showed a lower rate of major adverse events (death,
stroke, myocardial infarction, or kidney failure) among
those who received LOCM as compared to IOCM, sup-
porting the possibility that CIN directly can contribute to
these clinical outcomes.70
If CM is nephrotoxic, adverse clinical outcomes from
AKI following intra-arterial CM exposure would be rele-
vant to AKI from intravenous CM exposure. Adverse events
of AKI following intravenous CM exposure have been less
frequently studied compared to coronary angiography and
have demonstrated conflicting findings. A few studies have
shown increased risk for in-hospital, 30-day, and 1-year
mortality in individuals who developed AKI following
intravenous CM administration.71-74 However the validity
of these results is questionable because in one particular
study, 12% of patients with AKI required renal replace-
ment therapy and 29% were oliguric, which is atypical of
CIN.71 Other studies contradict these associations, showing
no difference in adverse long-term outcomes of eGFR
decline, 30-day mortality, or need for emergent dialysis
following CECT exposure.75-78 When evaluating risk for
kidney failure in patients with CKD exposed to CECT and
unenhanced CT, Hsieh et al78 found no difference among
the exposure groups, although in individuals with more
frequent CECT per year, there was an increased risk for
kidney failure compared with patients with more frequent
unenhanced CT exposure.78 Application of this conclusion
is questionable because underlying comorbid conditions
requiring more frequent CECT studies may have also been
responsible for the increased risk.
Summary and Recommendations
It is important to determine with as much precision as
possible the true risk for nephrotoxicity from intravenous
CM exposure. If the risk is overestimated, patients who
could clinically benefit from CECT would be deprived of
that benefit and there would be needless application of
resources to prevent against this complication. If the risk is
underestimated, patients could be exposed to a nephro-
toxic insult with the potential for adverse clinical out-
comes, including progression of CKD.
Initial studies of AKI following intravenous CM were
uncontrolled and reported a wide range of AKI rates in a
variety of clinical settings. On average, the incidence of
109

AKI following intravenous CM exposure was determined
to be 5% to 6%, leading many to conclude that AKI risk
with intravenous CM was lower than AKI risk reported
after coronary angiography and thus intravenous CM
administration may be less nephrotoxic than intra-arterial
CM administration. However, differences in AKI rates
following intravenous and intra-arterial CM administration
are more likely a function of comorbidity and procedural
differences between the 2 patient populations. The litera-
ture of CIN also contains numerous studies comparing a
CM-exposed group with a nonexposed and non-
randomized control group that consistently demonstrated
equivalent rates of AKI in both groups. However, these
studies had numerous methodologic limitations that limit
this conclusion. These controlled studies were all obser-
vational, thus subject to selection bias, whereby physicians
may avoid CM exposure in patients believed to be at
highest risk for CIN due to other comorbid conditions.11
The presence of these unmeasured risk factors in the
unenhanced CT controls was undoubtedly the cause of AKI
observed in these control groups. However, if these pre-
disposing AKI risk factors were present to a lesser degree in
the CECT patients, this would have the biased the effect of
CM in the AKI toward no difference when compared with
unenhanced CT control groups.2,79
Despite these limitations, these studies led to 2 con-
clusions that are valid. First, previously reported rates of
AKI from intravenous CM are in general overstated. Sec-
ond, the occurrence of AKI following intravenous CM
should not be automatically inferred as being due to CIN.
We agree with the American College of Radiology
recommendation that the term postcontrast AKI instead of
CIN should be used when the cause of AKI post–CM
exposure is unclear.
Recognizing the limitations of these nonrandomized
controlled studies, propensity score studies were per-
formed in an attempt to remove the imbalance of AKI-
predisposing comorbid conditions between the CM and
control groups 80 All of the propensity scores have
demonstrated an equivalent rate of AKI after CM in patients
with normal or mildly decreased kidney function, which
was not surprising given the known absence of CIN in
these populations. However, in these propensity score
studies, the risk for CIN following CM exposure in patients
with moderate to severe CKD has been conflicting. Pro-
pensity score methods are used in an attempt to minimize
selection bias by balancing measurable confounders;
however, unmeasured confounders may still influence
outcomes.81 The robust numbers and sophisticated
matching techniques of these propensity score studies have
led many to conclude that the risk for CIN is negligibly
low or nonexistant and is clinically insignificant. Because
observational studies lack randomization, the patients
exposed to a treatment, in this case CM, are almost
certainly different from those who are not exposed to the
treatment. The propensity score studies of intravenous
CIN have one or more known confounders that are not
110
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In Practice
included in the propensity score, including prophylactic
strategies and adjustment for peri-scan medications known
to affect Scr levels. Another major limitation of existing
propensity score studies is the low number of patients with
severely decreased eGFRs who have the highest risk for
CIN (Table 1). Furthermore, in none of these studies was a
separate propensity score analysis performed for patients
stratified by eGFR and DM together. Other limitations of
these propensity score studies include binary measurement
of confounding covariates, inclusion of patients with un-
stable baseline Scr values, and analysis of only inpatients
with adequate Scr data, which predisposes to ascertain-
ment bias. 82
So how should physicians interpret the risk for AKI
from intravenous CM exposure? Existing evidence points
to a negligible risk for CIN following intravenous CM
exposure in patients with eGFRs ≥ 60 mL/min/1.73 m2 or
mildly decreased kidney function (eGFRs of 45-59 mL/
min/1.73 m2). It also seems clear that patients with
eGFRs < 30 mL/min/1.73 m2 are at greatest risk for CIN
following intravenous CM exposure, despite mixed find-
ings of the propensity score studies (Table 1). This leaves
open the question on how to risk classify patients with
eGFRs of 30 to 44 mL/min/1.73 m2. Fortunately, this
group of patients constitutes only a minority of patients
who undergo CT.83 Although guidelines by the European
Society of Urogenital Radiology Contrast Medium Safety
Committee and American College of Radiology suggest
that this group is not at increased risk for CIN, in our
opinion, there remains lingering concerns about this
conclusion.12,30 Our concern for CIN is further heightened
when patients with CKD in this eGFR range also have DM.
We suggest that risk classification for AKI following
intravenous CM exposure should not be based solely on a
single eGFR determination. This is especially true for pa-
tients with eGFRs of 30 to 45 mL/min/1.73 m2 and in
some patients with eGFRs < 30 mL/min/1.73 m2. We
recommend ensuring that the patient has a stable Scr level
before CM exposure. Second, physicians should take into
consideration each patient’s unique risk factors for CIN
following intravenous CM exposure and weigh this against
the clinical benefit of performing CECT. Third, we
encourage increased discussions between radiologists and
physicians ordering CT on the added clinical value of CM
enhancement. In patients at risk for CIN, noniodinated
contrast studies including contrast-enhanced ultrasound or
magnetic resonance imaging with newer gadolinium-
based contrast agents may provide adequate diagnostic
information without a risk for nephrotoxicity.
If CM exposure is unavoidable in patients at high risk
for CIN, we recommend prophylactic saline solution hy-
dration and techniques to minimize contrast volume.
Spacing of CM exposures remains a reasonable but un-
proven precaution. Although controlled studies of AKI
following intra-arterial CM exposure have not been done
for obvious reasons, our recommendations would also
apply to risk for AKI with intra-arterial CM exposure.
AJKD Vol 75 | Iss 1 | January 2020
In Practice
Finally, we recommend that additional adequately pow-
ered propensity score studies should be conducted in pa-
tients with eGFRs < 45 mL/min/1.73 m2 with and
without DM to further clarify the true risk for CIN in these
presumed at-risk patients.
Review of the Clinical Vignette
The patient was suspected of having a pulmonary embo-
lism and a decision was made to proceed with CTA with
intravenous CM. Because the patient was considered high
risk for CIN, he received normal saline solution (240 mL
over 1 hour) before contrast exposure, which was
continued at 100 mL/h for 6 hours after the procedure.
CTA identified a segmental pulmonary embolism. The
following day, Scr level was 2.5 mg/dL with urine output
of 1,100 mL and then started to decline, returning to an
Scr level of 1.9 mg/dL by the third day.
Supplementary Material
Supplementary File (PDF)
Table S1: Incidence of CIN and adverse outcomes following IV
contrast exposure (controlled studies).
Article Information
Authors’ Full Names and Academic Degrees: Michael R. Rudnick,
MD, Amanda K. Leonberg-Yoo, MD, MS, Harold I. Litt, MD, Raphael
M. Cohen, MD, Susan Hilton, MD, and Peter P. Reese, MD, MSCE.
Authors’ Affiliations: Divisions of Nephrology (MRR, AKL-Y, RMC,
PPR) and Radiology (HIL, SH), Perelman School of Medicine at
the University of Pennsylvania, Philadelphia, PA.
Address for Correspondence: Michael R. Rudnick, MD, Perelman
School of Medicine at the University of Pennsylvania, 51 N 39th
St, Medical Office Bldg, Ste 240, Philadelphia, PA 19104. E-mail:
michael.rudnick@uphs.upenn.edu
Support: There was no additional support provided for the work
described in this article.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Other Disclosures: Dr Reese serves as an AJKD Associate Editor;
he was entirely recused from the manuscript consideration process.
Peer Review: Received November 12, 2018, in response to an
invitation from the journal. Evaluated by 2 external peer reviewers
and a member of the Feature Advisory Board, with direct editorial
input from the Feature Editor and a Deputy Editor. Accepted in
revised form May 7, 2019.
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