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Saudi J Kidney Dis Transpl 2018;29(1):1-9

© 2018 Saudi Center for Organ Transplantation Saudi Journal
of Kidney Diseases
and Transplantation

Review Article

Contrast-Induced Nephropathy: Pathophysiology, Risk Factors, and

Prevention
Mohammad A. Hossain1, Eric Costanzo1, James Cosentino1, Chirag Patel1, Huzaif Qaisar1, Vikas
Singh1, Taimoor Khan1, Jennifer S. Cheng1, Arif Asif1, Tushar J. Vachharajani2
1
Department of Medicine, Jersey Shore University Medical Center, Seton Hall-Hackensack
Meridian School of Medicine, Neptune, New Jersey, 2Department of Medicine, Nephrology
Section, Salisbury Veterans Affairs Health Care System, Salisbury, North Carolina, USA

ABSTRACT. Contrast-induced acute kidney injury is a common iatrogenic complication

associated with increased health resource utilization and adverse outcomes, including short- and
long-term mortality and accelerated progression of preexisting renal insufficiency. The incidence
of contrast-induced nephropathy (CIN) has been reported to range from 0% to 24%. This wide
range reported by the studies is due to differences in definition, background risk factors, type and
dose of contrast medium used, and the frequency of other coexisting potential causes of acute
renal failure. CIN is usually transient, with serum creatinine levels peaking at 2–3 days after
administration of contrast medium and returning to baseline within 7–10 days after
administration. Multiple studies have been conducted using variety of therapeutic interventions in
an attempt to prevent CIN. Of these, careful selection of patients, using newer radiocontrast
agents, maintenance of hydration status, and avoiding nephrotoxic agents pre- and post-procedure
are the most effective interventions to protect against CIN. This review focuses on the basic
concepts of CIN and summarizes our recent understanding of its pathophysiology. In addition,
this article provides practical recommendations with respect to CIN prevention and management.

Introduction health-care resource utilization by extending

Contrast-induced nephropathy (CIN) is an
increasingly common cause of iatrogenic acute
kidney injury (AKI) associated with increased
Correspondence:
Dr. Tushar J. Vachharajani,
Department of Medicine,
Nephrology Section, Salisbury Veterans
Affairs Health Care System, Salisbury,
North Carolina, USA.
E-mail: Tushar.vachharajani@va.gov
the hospital stay, increasing the short- and
long-term mortality, and accelerated progres-
sion of underlying chronic kidney disease
(CKD).1,2 It is an important reversible and
transient cause of hospital-acquired renal
failure, the incidence of which varies between
0% and 24% depending on patient’s risk
factors, the amount and type of agent admi-
nistered, and the types of radiological proce-
dures performed.3 In simple terms, CIN is
defined as impairment of renal function
(measured as either a 25% increase in serum
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2 Hossain MA, Costanzo E, Cosentino J, et al
creatinine from baseline or a 0.5 mg/dL
increase in absolute serum creatinine value)
within 48–72 h of administration of contrast
material.4,5 CIN is potentially preventable;
high-risk patients can often be identified ahead
of time, and most procedures requiring con-
trast material are performed on a nonemergent
basis with ample time to institute prophylactic
measures. Recent studies have confirmed that
the use of low or iso-osmolar agents, with
lowest effective dose possible, and the admi-
nistration of preprocedure intravenous (i.v.)
isotonic crystalloid solution mitigated the risk
of CIN in high-risk patients. The proposed
pathophysiologic mechanisms of CIN are
complex including intrarenal vasoconstriction
with resultant medullary hypoxia, generation
of reactive oxygen species, and direct renal
tubular toxicity. This article will review the
recent evidence concerning the incidence CIN,
its pathogenesis, and risk factors that increase
the likelihood of developing CIN.6-8 In addi-
tion, this report provides vital information on
prevention and management of CIN.
Pathophysiology
The pathophysiology of CIN is complex and
poorly understood. Multiple mechanisms act in
concert to induce CIN. Intrarenal vasocons-
triction, generation of reactive oxygen species,
and direct tubular damage are the predominant
factors that lead to CIN.6,7 However, relative
contribution of each mechanism alone is not
known.6,7
Several groups have documented immediate
vasoconstriction and reduction in renal blood
flow occurring after administration of contrast
medium.6-12 Multiple studies in animal models
have shown that intra-arterial infusion of ionic
contrast medium caused transient initial
increase in blood flow followed by an intense
and prolonged constriction of renal vascu-
lature.6,7 Although the mechanism for this
vasoconstriction is not completely known,
these investigators demonstrated the impor-
tance of calcium influx in the vasoconstrictive
phase following contrast exposure.8 Recent
information has demonstrated that the flow to
the outer medulla is reduced by 40% following
contrast material administration and is asso-
ciated with a 60% reduction in oxygen
delivery. These changes result in ischemic
injury, which contributes to the histo-
pathologic findings seen in CIN models.9,10
Multiple agents are implicated in producing
renal vasoconstriction. For instance, there is
significant evidence for the role of endothelin
in the pathogenesis of CIN. A seminal study
demonstrated a significant elevation in plasma
endothelin level within 5 min of contrast
material administration.11 Importantly, the
study revealed that no significant change in
plasma endothelin levels was detected until the
volume of the contrast material exceeded 150
mL. Adenosine has also been found to induce
local renal vasoconstriction.11 In addition to
the presence of vasoconstrictors, there is
concomitant impairment of vasodilatation in
patients with CIN.10 Nitric oxide (NO) is a
potent vasodilator produced from L-arginine in
the presence of the enzyme NO synthase.
High-osmolar contrast agents reduce NO pro-
duction, and this reduction was proportional to
osmolality of the solution.10,12 However,
concerns regarding NO inhibition following
contrast administration and its negative impact
on renal function have been raised by Sancak
et al.13,14
A compromised medullary blood supply
brought on by contrast administration creates a
mismatch between the metabolic demands of
thick ascending limbs of the loop of Henle and
its own blood supply resulting in the produc-
tion of superoxide (a potent reactive oxygen
species) leading to oxidative tubular damage.15
Preexisting chronic renal failure, increased
age, and diabetes decrease the ability to
accommodate oxidative stress and lead to
increased risk of CIN.15
Contrast administration induces osmotic
diuresis in euvolemic patients with normal
kidney function.16 Exposure of renal tissue to
high osmotic radiocontrast agents results in
characteristic histopathologic changes called
“osmotic nephrosis.”16 The most frequent
histopathologic features of “osmotic nephrosis”
include intense focal or diffuse proximal
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Contrast-induced nephropathy
tubular vacuolization as well as full-blown
tubular necrosis. Iodinated contrast media
reduce the viability of cultured renal cells and
induce apoptosis.16 Other toxic effects include
cellular energy failure, disturbance of cellular
calcium, and alterations in tubular cell
polarity.16 Investigators have demonstrated
contrast material retention within renal cortex
as well as medulla and its association with
CIN.16-19 A recent study revealed that renal
cortical contrast retention at 24 h, as deter-
mined by computerized tomography scan, had
a better predictive value for the development
of CIN than did the 24-h serum creatinine
level. This was seen more intensely in patients
with preexisting renal damage as well as older
individuals.15
Taken together, renal vasoconstriction coupled
with impaired vasodilatation is important
mechanism that can result in CIN. In this
context, ischemic damage to the kidney can be
seen with the administration of contrast mate-
rial. Contrast agents can be retained by the
kidney and are capable of causing tubular toxi-
city and generating reactive oxygen species
that can further augment renal injury.18,20
Risk Factors
For optimal management, it is critically
important for providers to be able to stratify
patients according to their risk for CIN.
Preexisting CKD with concomitant diabetes
mellitus poses the highest risk for CIN. Other
factors that increase the risk for CIN include
advanced age, cardiovascular disease, pre-
procedure hemodynamic instability, and con-
comitant use of certain drugs. Table 1 summa-
rizes some common risk factors.20-30 A quick
review of the risk factors could be very helpful
in evaluating patients who would be at risk for
the development of CIN.
Preexisting impairment of renal function
Preexisting CKD is of paramount importance
and places patients at a high risk for the deve-
lopment of CIN. In a series of 1144 patients,
Davidson et al19 investigated patients under-
going cardiac catheterization and documented a
3
Table 1. Important risk factors that increase the
risk of development of contrast-induced
nephropathy
 Diabetes with chronic kidney disease (at
least stage III)
 Preexisting chronic kidney disease (at least
stage III)
 Advanced age
 Intravascular volume depletion
 High volume of contrast and high-osmolarity
agents
 Concomitant use of common medications
- Diuretics
- Angiotensin-converting enzyme inhibitors
- Nonsteroidal anti-inflammatory drugs
- Aminoglycosides
- Calcineurin inhibitors
low risk of CIN (increment of creatinine levels
of at least 0.5 mg/dL) in patients with normal
renal function compared to those with pre-
existing CKD (creatinine level exceeding 1.2
mg/dL). These investigators found that the risk
for CIN increased significantly (20%) when
serum creatinine exceeded 2.0 mg/dL.
Diabetes mellitus with preexisting chronic
kidney disease
Diabetics with CKD are reported to have a
four-fold increase in the risk for development
of CIN when compared with patients without
diabetic nephropathy.20 Diabetes mellitus with
associated renal insufficiency has been iden-
tified as an independent risk factor for contrast
nephropathy, with as many as 56% of those
who develop the condition progressing to
irreversible renal failure. Diabetics with
advanced CKD (serum creatinine >3.5 mg/dL)
are at a particularly higher risk for the deve-
lopment of CIN.20,21
Age
In many studies, higher prevalence of CIN
was observed in patients with increased age,
possibly reflecting the decline in renal function
with age. Advanced age is associated with
increased vascular stiffness with declined
endothelial function resulting in reduced vaso-
dilator responses as well as a reduced capacity
for vascular repair with pluripotent stem cells.
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4 Hossain MA, Costanzo E, Cosentino J, et al
All these factors together increase the risk of
CIN in the elderly patient and reduce the
potential for prompt recovery.22
Reduction of effective intravascular volume
Reduction of effective intravascular volume
(due to congestive heart failure, liver cirrhosis,
or abnormal fluid losses), prolonged hypo-
tension (especially when induced by intensive
antihypertensive treatment combined with
angiotensin-converting enzyme (ACE) inhi-
bitors, and diuretics, most notably furose-
mide), and dehydration have been reported as
contributing to prerenal reduction in renal
perfusion, thus enhancing the ischemic insult
of contrast media.22-25
Contrast volume and timing of contrast
administration
High doses and repeated injections of con-
trast material administered within 72 h
augment the risk of AKI due to contrast
material. The first-generation contrast agents
are rarely used today and are ionic and
hyperosmolar compared with plasma and
impart a higher risk of nephrotoxicity.27 In
contrast, low osmolar (iohexol, ioversol, and
iopamidol) or iso-osmolar (iodixanol) agents
are associated with a much lower risk of
causing CIN. Iodixanol is a nonionic dimeric
iso-osmolar contrast medium and offers an
even lower risk of nephrotoxicity than low-
osmolar contrast agents.26,28
Concomitant use of medications
Diuretics lead to volume depletion and cause
intrarenal vasoconstriction. In this context,
they increase the risk of contrast nephropathy.
There are other agents that can cause direct
nephrotoxicity. These include cyclosporine A,
aminoglycosides, amphotericin, and cisplatin.
Nonsteroidal anti-inflammatory drugs
(NSAIDs) inhibit the local vasodilatory effects
of prostaglandins and increase the risk of
CIN.29,30 Likewise, ACE inhibitors and
angiotensin receptor blockers (ARB) can
potentially increase the likelihood of contrast
nephropathy. In a large study (n = 5299),
patients taking an ACE inhibitor/ARB were
more likely to have contrast-induced AKI
(odds ratio: 1.43, 95% confidence interval:
1.06–1.94).31 Thus, it is prudent to review the
list of medications before contrast administra-
tion. If possible, nephrotoxic drugs should be
withheld at the time of contrast administration.
Management of Contrast Nephropathy
To date, there is no definitive treatment of
AKI following radiocontrast administration.
However, prevention still remains the corner
stone of this entity and as such demands a
careful analysis of the risk factors and imple-
mentation of preventive strategies noted
below.
Maintenance of volume status
Avoidance of intravascular volume depletion
is the single most important strategy to reduce
the risk of contrast-induced renal injury. In this
context, maintenance of adequate hydration is
of paramount importance. Often patients are
receiving NSAIDs. Such agents should be
stopped 24–48 h before the procedure. Recom-
mended regimens for volume replacement for
hospitalized patients undergoing contrast ad-
ministration include normal saline adminis-
tered at 1 mL/kg/h for 6–12 h preprocedure,
intraprocedure, and continued for 6–12 h post-
procedure.32,33 In patients with compensated
congestive heart failure, fluids should be
administered based on physician discretion
and with frequent lung examination. Normal
saline produces better volume expansion and
has been shown to have superiority over
hypotonic solutions such as 0.45% saline.34-36
While diuretics are not recommended, a recent
study demonstrated that loop diuretics may
decrease the incidence of CIN.37
Conflicting data continue to surround the use
of sodium bicarbonate versus normal saline.
Thus far, the largest randomized clinical study
failed to show any benefit of sodium bicar-
bonate over normal saline.38,39 As such, normal
saline is the best available solution to reduce
the risk of contrast nephropathy.
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Contrast-induced nephropathy 5

N-acetylcysteine tially no cost, oral hydration is an attractive

The sulfhydryl group of N-acetylcysteine is and viable option compared to i.v. fluid
an excellent antioxidant and scavenger of free replacement. A recent meta-analysis of rando-
oxygen radicals. However, it has failed to mized clinical trials demonstrated that oral
show conclusive evidence of protecting against hydration with water was as effective as
the development of CIN.40,41 Because of its hydration using i.v. saline.43 Statins, oral
low cost, lack of adverse effects, and potential sodium citrate, atrial natriuretic peptide, ascor-
beneficial effect, this agent is frequently a part bic acid, theophylline, and nifedipine have all
of the protective strategies of multiple medical been studied and failed to show any benefit
centers against contrast nephropathy. Never- against CIN.41,42,44
theless, based on the lack of conclusive evi-
dence, we do not recommend this agent.40,41 Logistical barrier to contrast-induced
nephropathy prevention
Prophylactic hemofiltration and hemodialysis While i.v. hydration has been reported to be
Clinicians often ask for dialysis therapy soon the single most important element in halting
after the administration of contrast material. CIN, from a purely opinion-based point of
However, there is no conclusive evidence that view, there are several barriers that create a
prophylactic dialysis prevents renal injury due problem for the implementation of this
to contrast administration.42 At present, we do strategy in clinical practice (Table 2). Often,
not recommend prophylactic dialysis therapy. procedures are scheduled in an emergency and
Dialysis itself is not devoid of complications at times with coexisting confounding factors
and requires an invasive procedure of a large (congestive heart failure, etc.,) limiting the use
bore catheter insertion. of i.v. hydration. In addition, the lack of space
in radiology suites to provide i.v. hydration
Oral hydration and other measures adds to the complexity in implanting strategies
Due to the ease of administration and essen- to prevent CIN. The infusion centers provide an
Table 2. Potential barriers of preventing contrast-induced nephropathy in clinical practice from various
perspectives. These barriers may be overcome by systematic analysis of this problem and best
coordination of care.
Perspective Complicating factors
 Lack of optimal clinical information on the patient
 Decision and implementation of intravenous fluid administration
Radiologist for outpatients
 Multiple imaging procedures and emergency add-on procedures
 Limited communication with clinician
 High patient census
 Limited coordination with the radiology department
Clinician
 Limited procedure-related information
 Length of stay
 Need for admission/observation status to provide hydration
 Length of stay
Hospital/hospitalist
 Outpatient procedure
 Space to provide hydration before the procedure
 Distance from radiology department
 Busy schedule with intravenous iron therapy, chemotherapy,
Infusion centers
immunoglobulin, blood transfusions, etc.
 Insurance coverage
 Lack of preprocedure billing code for hydration
Billing service
 Denial of admission/insurance coverage and cost incurred
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6 Hossain MA, Costanzo E, Cosentino J, et al

alternative for i.v. hydration; however, these
centers are often overbooked with other
critically important therapeutic infusions (i.v.
iron, blood transfusions, chemotherapy, etc.,).
It is worth mentioning that there is always an
opportunity for improved coordination of care
between clinicians and radiologists. For ins-
tance, a preprocedure practice of disallowing
oral fluid intake for 12-h before any contrast
imaging study can potentially lead to sub-
clinical volume depletion and thereby increase
the risk of CIN. Implementing strategies to
improve coordination will have a positive
impact on minimizing the risk of CIN.
Rightfully so, there are practical and logis-
tical complexities at multiple levels (Figure 1).
From the radiology perspective, the question is
who would write the order for i.v. fluids and
who would administer and monitor? There are
several imaging studies performed on a daily
basis in hospitals worldwide. The required
space and personnel to administer i.v. hydration
would stress the limited existing resources.
From the clinician’s standpoint, at times, the
exact time of the study is not known. Hence,
i.v. hydration orders are difficult to implement.
Throughout the world, clinicians in the
hospital frequently carry a busy ward service
making it difficult to keep up with the changes
in imaging study times. Importantly, some of
the imaging services are performed on an
outpatient basis. In this context, from a hos-
pital standpoint, a 12-h hydration cannot be
performed unless the patient is brought to the
hospital at least 12 h before the procedure.
Such an approach introduces short-term ad-
mission and use of limited resources. Finally,
from the billing standpoint, preprocedure

Figure 1. Factors affecting coordination of care for patients undergoing contrast imaging.
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Contrast-induced nephropathy
billing of such a patient further complicates
the situation.
While challenging, a closer look at the factors
highlighted above might bring ideas that
would have a positive impact on ameliorating
CIN. At a minimum, oral hydration is some-
thing that could be encouraged before a
contrast imaging study.
Summary
Contrast material continues to be a common
cause of AKI. Patients with preexisting renal
dysfunction, diabetes, advanced age, and intra-
vascular volume depletion are at a particularly
high risk for developing contrast-induced renal
injury. There is no definitive treatment of CIN.
In this context, identification of high-risk
patients and institution of preventive measures
are of critical importance. i.v normal saline is
the best available solution for the prevention
of CIN. However, oral hydration is equally
effective. N-acetylcysteine has failed to show
conclusive benefit against CIN. Finally, pro-
phylactic dialysis therapy cannot be recom-
mended to protect against the development of
CIN. If contrast administration is absolutely
contraindicated, then carbon dioxide angio-
graphy should be considered.
Conflict of interest: None declared.
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