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Journal of the Chinese Medical Association 76 (2013) 673e681
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Review Article

Current concepts of contrast-induced nephropathy: A brief review

Chao-Fu Chang a,b, Chih-Ching Lin b,c,*
a
Division of Nephrology, Department of Medicine, Taipei City HospitaldHeping Branch, Taipei, Taiwan, ROC
b
National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
c
Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
Received October 10, 2012; accepted April 17, 2013

Abstract

Contrast-induced nephropathy (CIN) is a common hospital-acquired acute kidney injury. Published studies on this condition have dramat-
ically increased in recent years. This article aims to provide a brief literature review. English articles published from 1983 to 2012 were retrieved
from PubMed by searching using the term contrast-induced nephropathy. Patients with CIN were associated with increased resource utili-
zation, prolonged hospital stay, and increased long-term mortality. CIN is defined as a
0.5 mg/dL rise in serum creatinine or a 25% increase,
assessed within 48e72 hours after administration of contrast medium (CM). All patients receiving CM should be evaluated for their CIN risk,
especially preexisting kidney disease. The CM should be prewarmed to 37  C and injected at the lowest possible dose. Repeat injection within 72
hours should be avoided. Either iso-osmolar CM or low-osmolar CM, except ioxaglate or iohexol, can be used in all patients. Iso-osmolar CM
iodixanol may be a better choice for high-risk patients with chronic kidney disease requiring intra-arterial administration. Nephrotoxic drugs
should be stopped 2 days prior to when the patient undergoes a procedure. All patients receiving CM should be at an optimal volume status.
Parenteral isotonic saline without any diuretic should be started 12 hours prior to CM at a rate of 1 mL/kg/h and continued for 24 hours if there is
no contraindication. In patients who require shorter volume supplement periods or are at a higher risk, bicarbonate infusion (154 mEq/L, 3 mL/
kg/h for 1 hour bolus prior to CM, followed by 1 mL/kg/h for 6 hours) may be used as an alternative to isotonic saline. Oral N-acetylcysteine
(600 mg bid, starting on the day prior to the procedure) together with parenteral hydration is suggested for patients at risk. Hemodialysis/
hemofiltration is only considered in chronic kidney disease stage 4/5 patients when an access is available. The other medications or techniques
for reducing CIN risk are still unclear. CIN is a potentially preventable clinical condition. A careful review of published reports gives us a deeper
understanding of CIN and a greater chance of decreasing its risk.
Copyright 2013 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.

Keywords: contrast-induced acute kidney injury; contrast-induced nephropathy; contrast media; coronary angiography; N-acetylcysteine

1. Introduction computerized tomography (CT) imaging examinations, or

Contrast-induced nephropathy (CIN), also called contrast-
induced acute kidney injury, is the third most common cause
of hospital-acquired acute kidney injury (AKI) after impaired
renal perfusion and use of nephrotoxic medications.1,2 CIN
can result from intravenous or intra-arterial injections of
iodine-based contrast media (CM) during enhanced X-ray and
* Corresponding author. Dr. Chih-Ching Lin, Division of Nephrology,
Department of Medicine, Taipei Veterans General Hospital, 201, Section 2,
Shih-Pai Road, Taipei 112, Taiwan, ROC.
E-mail address: lincc2@vghtpe.gov.tw (C.-C. Lin).
coronary artery interventions. It accounts for 11e12% of all
cases of in-hospital AKI and is also associated with an overall
in-hospital mortality rate of 6%.2,3 Among all procedures
utilizing CM for diagnostic or therapeutic purposes, coronary
angiography and percutaneous coronary intervention (PCI) are
associated with the highest rates of CIN.2,4 An early study
reported an incidence rate of CIN of about 14.5% in patients
after coronary interventions, with an in-hospital mortality rate
of 7.1% in those not undergoing dialysis, and 35.7% in those
requiring dialysis.5 The incidence of CIN can be much higher
if the patients have underlying conditions such as chronic
kidney disease (CKD), diabetes, or old age.6,7 Patients with

1726-4901/$ - see front matter Copyright 2013 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.
http://dx.doi.org/10.1016/j.jcma.2013.08.011
674 C.-F. Chang, C.-C. Lin / Journal of the Chinese Medical Association 76 (2013) 673e681
CIN are also associated with increased health resource utili-
zation, prolonged hospital stay, increased long-term mortality,
and accelerated progression of CKD.8e10
It is possible that the incidence of CIN will increase in the
future because of the continuing increase not only in the prev-
alence of both CKD and diabetes, but also in the number of
elderly patients. Although the rates of coronary and conven-
tional angiography have been relatively stable in recent years,
the number of contrast-enhanced CT scans has risen.11
Furthermore, patients with advanced CKD are at risk of neph-
rogenic systemic fibrosis using gadolinium-based CM in mag-
netic resonance imaging examinations.12 Therefore, treatment
of patients with CKD may be changed to an iodine-based CM,
thereby increasing the number of patients at risk of CIN.13
The number of published studies on CIN has dramatically
increased in the past few years. Because CIN is a potentially
preventable clinical condition, the more CIN is understood, the
greater the likelihood of reducing the risk. The aim of this report
is to provide a brief review and summary of the studies relating to
CIN, especially in terms of definition, risk factors, characteristics
of the CM, pathogenesis, prevention strategies, and medications.
2. Definition and diagnosis
CIN is defined as the acute deterioration of renal function
after parenteral CM exposure in the absence of other causes.
Levels of serum creatinine (Scr) usually begin to rise within
24e48 hours of CM exposure, peaking at 2e3 days and
returning to baseline values within 2 weeks.14 In the related
literature, CIN is usually defined as a rise in Scr of
0.5 mg/
dL (44 mmol/L) or a 25% increase from baseline assessed
within 48 hours after a radiological procedure.4,15,16 The So-
ciety of Urogenital Radiology uses the same definition,
although differing in terms of Scr changes that occur within
3 days after intravascular administration of contrast without an
alternative etiology.7 This definition has also been shown to
consistently predict major cardiovascular events and mortality
after PCI.4,10 The Kidney Disease: Improving Global Out-
comes (KDIGO) guidelines of 2012 suggest that a more spe-
cific definition of Scr concentration (increased >2) and urine
output (<0.5 mL/kg/h for >12 hours) be used for the diag-
nosis of CIN, as is the case for the other forms of AKI.17
However, this definition has not yet been accepted worldwide.
A recent prospective study on the early diagnosis of CIN
showed that a 5% elevation of Scr at 12 hours after CM
exposure was highly predictive of CIN [sensitivity 75%,
specificity 72%, odds ratio (OR) 7.37, CI 3.34e16.23,
p < 0.001].18 Some studies have shown that serum cystatin C
level and neutrophil-gelatinase-associated lipocalin (NGAL)
are more specific and sensitive for the prediction of acute and
early deterioration of renal function than Scr.19,20 Because
cystatin C is not affected by renal tubular secretion or phar-
macological treatments, serum levels of cystatin C more
accurately reflect the glomerular filtration rate (GFR) than Scr,
and may detect AKI 1e2 days earlier than Scr.20 However, Scr
is still a better marker for detecting temporal changes of renal
function in patients with CKD.21 As for NGAL, it has been
shown to be useful for the earlier diagnosis of CIN, being
significantly higher at 2 hours (serum NGAL) or 4 hours
(urinary NGAL) after a PCI procedure.22 However, whereas
the early detection and intervention using NGAL may improve
renal outcomes of CIN,23 disadvantages including a lack of
urine samples in patients with severe oliguria or changes in
urinary concentration during volume depletion have been
observed; another limitation is that NGAL cannot distinguish
AKI from CKD.24
3. Risk factors
All patients receiving CM should be evaluated for the risk of
CIN, and high-risk patients should consider pharmacological
prophylaxis with therapies that are supported by clinical evi-
dence.25 The reported risk factors are summarized in Table 1.
Although many risk factors have been described for CIN, pre-
existing renal disease is the most important. In patients with
CKD, the incidence of CIN can be relatively high and range from
14.8% to 55%, depending on the underlying conditions.16,26 By
contrast, in patients with a GFR >60 mL/min, the risk of CIN is
only 2%.26 Renal function should be assessed reliably by using
the CockcrofteGault formula for creatinine clearance (CrCl) or
the Modification of Diet on Renal Disease formula to estimate
GFR (eGFR), instead of focusing solely on Scr.27 Prediabetes
and hyperuricemia have recently been identified as risk factors
for CIN, and the metabolic syndrome has been shown to increase
the risk of CIN (OR 4.26, CI 1.19e15.25, p < 0.026).28,29
Increased systemic oxidative stress, enhanced
renineangiotensinealdosterone system activity, and higher
levels of endothelin-1 also contribute to an elevated risk of CIN.
Prediabetes (serum glucose
124 mg/dL) has been reported to
increase the incidence of CIN by 2.1-fold compared to patients
with normal fasting glucose (11.4% vs. 5.5%, p 0.032).30 And
although it has been suggested that tubular obstruction by uric
acid plays a role in the pathogenesis of CIN, hyperuricemia has
not been shown to be an independent risk factor for CIN.
Although patients with hyperuricemia in a recent study had a
higher risk of CIN (OR 4.71, p 0.019), a high incidence of
multivessel coronary involvement in hyperuricemia was linked
to this association (OR 3.59; CI 1.12e11.48, p 0.032).
Furthermore, results from studies on the influence of
angiotensin-converting enzyme inhibitor (ACEI) or angiotensin
II receptor blocker (ARB) on the incidence of CIN are conflict-
ing.29,31,32 Because ACEI and ARB are commonly used in pa-
tients undergoing PCI, large randomized controlled trials are
required to investigate their roles in the risk for CIN.
In addition to GFR, many risk factors for CIN can be detected
by history-taking and physical examinations. For outpatient
radiological studies where Scr data are unavailable, Choykes
questionnaire or a dipstick test for urine protein can be used to
identify high-risk patients.18,33 For patients undergoing PCI,
Mehrans model, which includes preprocedural and periproce-
dural risk factors, is a simple method capable of predicting the
risk of CIN.34 Mehrans model of risk factor scoring includes
congestive heart failure, hypotension, use of intra-aortic balloon
pumps, age >75 years, anemia, diabetes, contrast volume, and
 C.-F. Chang, C.-C. Lin / Journal of the Chinese Medical Association 76 (2013) 673e681
Table 1
Risk factors for contrast induced nephropathy.
Patient-related risk factors
Preexisting kidney disease
Diabetes with chronic kidney disease
Age > 75 y
Dehydrationa
Hypoalbuminemia (<35 g/L)a
Poor heart function or hemodynamic instabilitya
Preprocedure intra-aortic balloon pump
Anemia or postprocedure drop in hematocrit
Hypotension
Advanced heart failure
Left ventricular ejection fracture <40%
Acute myocardial infarction or increased CK-MB
Need for cardiac surgery after contrast exposure
Urgent or emergent procedure
Peripheral vascular disease
Concurrent nephrotoxic medicationa
NSAIDs, aminoglycoside, amphotericin B, high-dose diuretics,
antiviral drugs such as acyclovir and foscarnet, cyclosporine A
New risk factorsa
Metabolic syndrome
Prediabetic condition
Hyperuricemia
ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; CK-MB creatine phosphokinase
MB isoenzyme; CM contrast media; NSAIDs nonsteroidal anti-inflammatory drugs.
a
Potential modifiable risk factors.
GFR, and an increased score is strongly associated with CIN
[ranging from 8.4% (low-risk score) to 55.9% (high-risk score)].
Moreover, Browns model, which includes preprocedural risk
factors, has been validated for the prediction of serious renal
dysfunction or the need for dialysis after PCI.35 Preprocedure
Scr (37%), congestive heart failure (24%), and diabetes (15%)
were found to account for 76% of the predictive ability of
Browns model, with the remaining 24% being attributable to
urgent and emergent priority (10%), preprocedural intra-aortic
balloon pump use (8%), age
80 years (5%), and female sex
(1%). Although many risk factors have been identified, different
studies have produced conflicting results.29 Clinical practi-
tioners should pay attention to potentially modifiable risk fac-
tors. Whenever possible, the risk of CIN can be reduced by
stopping the use of nephrotoxic drugs, improving heart function
or hemodynamic status prior to examinations, using nonionic
low-osmolar or iso-osmolar CM, avoiding repeat CM injections,
and using a smaller volume of CM.
4. Type and volume of CM in CIN
4.1. Types of CM
CM are traditionally classified according to their osmolality:
high-osmolar CM (HOCM), >1500 mOsm/kg (i.e., 5e8 times
plasma); low-osmolar CM (LOCM), 550e850 mOsm/kg (i.e.,
2e3 times plasma); and iso-osmolar CM (IOCM), 290 mOsm/
kg (i.e., isotonic to plasma).36 However, products containing
different concentrations of iodine can change their osmolality
and viscosity properties, which are important for the develop-
ment of CIN. The characteristics of commonly used CM are
675
Procedure-related risk factors
Type of CMa
High-osmolar CM
Ionic vs. non-ionic CM
High-viscosity CM
High volume of CMa
Multiple CM injections within 72 ha
Intra-arterial vs. intravenous injection
Conflicting (doubtful) risk factors
Female
Multiple myoloma
Cirrhosis
Use of ACEI or ARBa
Renal transplant
Diabetes with normal renal function
Low-osmolar CM in high-risk patientsa
listed in Table 2. Compared with HOCMs, LOCMs have a lower
risk of CIN in both patients with existing renal failure (OR 0.5,
CI 0.36e0.68) and in those without prior renal failure
(OR 0.75, CI 0.52e1.1).37 The risk of CIN with two
LOCMs, iohexol and ioxaglate, has been found to be higher than
other LOCMs (e.g., iopamidol, iopramide, ioversol) and the
IOCM iodixanol in many studies.27,38 Some randomized
controlled trials have reported that iodixanol is not associated
with a lower incidence of CIN compared with LOCMs.27,39
Other studies, by contrast, have shown that iodixanol is asso-
ciated with lower rates of CIN compared with LOCMs, espe-
cially with intra-arterial administration or in patients with CKD
or CKD diabetes.40,41 Although the lower osmolality of
IOCMs may decrease the incident adverse effects, the higher
viscosity of IOCMs may block this protective benefit in com-
parison with LOCMs. To date, no consensus has been reached on
the relative importance of osmolality and viscosity.42 The cur-
rent guidelines of the American College of Cardiology/Amer-
ican Heart Association recommend the use of either IOCMs or
LOCMs other than iohexol and ioxaglate in patients with CKD
undergoing angiography.43
4.2. Volume of CM
It is well documented that a higher volume of CM is asso-
ciated with a higher risk of CIN.9 Even relatively low doses of
CM (<100 mL) can result in permanent renal failure and the
need for dialysis in patients with CKD,44 and each 100-mL
increment in contrast volume has been shown to result in a
30% increase in the odds of CIN.45 An early study reported that
the limit of the dose of radiographic contrast in patients with
676 C.-F. Chang, C.-C. Lin / Journal of the Chinese Medical Association 76 (2013) 673e681

Table 2
Characteristics of some contrast media.
Type Generic name Trade namea Iodine Osmolality Viscosity cPs Viscosity cPs
(mg/mL) (mOsm/kg) at 20e25 C at 37 C
High-osmolar CM (HOCM)
Ionic monomer Diatrizoate Hypaque, Urografin 300e370 1500e2000 3.3e16.4 1.4e19.5
Ionic monomer Metrizoate Isopaque 280e370 2100 5e9 2.8e5
Ionic monomer Iothalamate Conray 141e325 600e1843 2e9 1.5e5
Low-osmolar CM (LOCM)
Ionic dimer Ioxaglate Hexabrix 280e320 600 12e15.7 6e7.5
Nonionic monomer Iohexol Omnipaque 140e350 322e844 2.3e20.4 1.5e10.4
Nonionic monomer Metrizamide Amipaque 170e300 300e484 d d
Nonionic monomer Loxilan Oxilan, Ioxitol 300e350 610e721 9.4e16.3 5.1e8.1
Nonionic monomer Ioversol Optiray 240e350 502e792 4.6e14.3 3.0e9.0
Nonionic monomer Iomeprol Iomeron 150e400 301e726 1.9e27.5 1.3e12.6
Nonionic monomer Iopentol Imagopaque 150e350 310e810 2.7e26.6 1.7e12.0
Nonionic monomer Iopromide Ultravist 150e370 328e774 2.3e22 1.5e10
Nonionic monomer Iopamidol Lopamiro, Isovue 150e370 342e796 2.3e20.9 1.5e9.4
Iso-osmolar CM (IOCM)
Nonionic dimer Iodixanol Visipaque 270e320 290 12.7e26.6 6.3e11.8
Nonionic dimer Iotrolan Isovist, Iotrovist 240e300 270e320 6.8e16.4 3.9e8.1
Nonionic dimer Ioseminol Iosimenol 280e 273e 10.9 6.3
a
Characteristic of products may vary when containing different concentrations of iodine. Some products may not be indicated for intravascular usage. Generic
names of products are not completely listed. For detailed information, please see the product labels.

CKD (Scr
1.8 mg/mL) can be calculated using the following
formula: 5 mL  body weight in kilograms (maximum 300 mL)
O Scr (mg/mL).46 Recent studies have modified the method of
renal function assessment and found that the independent pre-
dictors of CIN are V/eGFR
2.39 or V/CrCl
3.7 in different
populations.46,47 These findings, however, should be interpreted
with care, as adverse effects may vary with the concentration
and amount of the contrast agent and the technique used. In
addition, elevated osmolality, volume, concentration, viscosity,
and rate of administration of the solution may increase the
incidence and severity of the adverse effects.48 We suggest that
the CM be prewarmed to 37 C to decrease viscosity and injected
with the lowest possible dose to obtain acceptable images.
5. Pathophysiology
The pathogenesis of CIN is still not completely under-
stood,49 although it is clear that the root concept is medullary
hypoxia-induced renal tubular damage. Whereas an interaction
of various mechanisms has been shown to cause CIN,14,42 a
reduction in renal perfusion and toxic effects on the tubular
cells caused by direct and indirect effects of the CM on the
kidneys are generally recognized as important mechanisms
(Table 3).14,42,50,51
5.1. Reduction in renal perfusion
5.1.1. Rheologic alterations result in medullary hypoxia
The viscosity of blood at 37 C is normally 3e4  cPs. The
blood flow through the vasa vecta, a major blood supply of the
vulnerable deep outer renal medulla, is inversely correlated
with viscosity but not osmolality. The viscosity of nonionic
monomeric LOCMs at an iodine concentration of 300 mg/L is
slightly higher than that of blood.14 By contrast, the viscosity
of nonionic dimeric IOCMs at 37 C is much higher than that
of blood. The CM can increase renal tubular viscosity when it
is filtered across the glomerulus, thereby resulting in tubular
obstruction and elevation of the interstitial pressure. In addi-
tion, high plasma viscosity also raises the blood resistance of
the vasa vecta, thus decreasing medullary blood perfusion.
Although these mechanisms result in renal medullary hypoxia
and renal tubular damage (CIN), the viscosity of the fluid is
not the only important factor. A higher osmolality of the CM
can also diminish erythrocyte deformability, increase stiffness,
and make its pass through the vasa recta more difficult.52
5.1.2. Imbalance between oxygen demand and supply
results in medullary hypoxia
An imbalance between oxygen demand and supply also
plays a role in radiocontrast-induced outer medullary hypoxic
damage.53 The physiological pO2 in the renal medulla can be
as low as 20 mmHg to maintain the countercurrent mechanism
Table 3
Possible mechanisms of contrast-induced nephropathy.
Medullary hypoxia resulting in renal tubular necrosis
Rheologic alterationdviscosity
Osmotic loaddincreased demand
Vasoactive mediator imbalance
Decreased vasodilators
Increased vasoconstrictors
Systemic hemodynamic instability
Direct tubular cytotoxicity
Apoptosis through mitochondrial pathway
Generation of ROS
Increased adenosine from endothelial cells
Medullary hypoxia
ROS block nitric oxide vasodilatation effect
ROS result in vasoconstriction
ROS reactive oxygen species.
 C.-F. Chang, C.-C. Lin / Journal of the Chinese Medical Association 76 (2013) 673e681
for controlling urine excretion.54 An early animal study
observed that CM caused an initial increase in blood flow
followed by 3 hours of renal vasoconstriction.55 In humans,
total renal blood flow has been reported to be reduced by 50%
up to 4 hours after an injection of CM in cardiac in-
terventions.56,57 Whereas HOCMs can markedly reduce the
medullary pO2 to about one-third, IOCMs can impair the
medullary pO2 to a greater extent than LOCMs.58 Despite the
decrease in pO2, GFR and renal medullary blood flow have
been shown to be initially increased after CM exposure.53,59,60
This suggests that an increase in oxygen demand plays a role
in radiocontrast-induced outer medullary hypoxic damage
after CM exposure. In addition, osmotic diuresis after CM
administration can also result in large amounts of NaCl having
to be taken up in distal segments, thus increasing the oxygen
demand in these areas.
Complicated mechanisms work together to regulate renal
blood flow and tubular function.14,50,51 Local vasoconstrictors
include endothelin-A receptor, adenosine-A1 receptor, angio-
tensin II, vasopressin, prostaglandin E2 (PGE2) EP1, and
PGE2 EP3. They are balanced by local vasodilators, such as
nitric oxide, adenosine-A2 receptor, dopamine, urodilatin,
endothelin-B receptor, PGE2 EP2, and PGE2 EP4. CM can
induce vascular endothelial cells to release various factors that
may increase vasoconstriction and decrease vasodilatation in
the renal medulla and consequently cause hypoxia. Medullary
hypoxia can also be aggravated by systemic effects such as a
reduction in transient cardiac output, suboptimal pulmonary
perfusioneventilation, and increased hemoglobin oxygen
affinity, all of which may contribute to intrarenal
hypoxia.14,53,61e63
5.2. Renal tubular damage
5.2.1. Apoptosis
It is not known to what extent CIN is due to direct cyto-
toxicity. The current understanding and knowledge of this area
come mostly from studies on cells and animals. The CM, and
especially ionic CM, are toxic to mesangial cells, tubular cells,
and endothelial cells.64,65 The CM can decrease proximal
tubular mitochondrial activity, increase production of adeno-
sine and hypoxanthine, and impair proliferation of the
cells.66,67 Regarding cellular appearance, CM can result in the
concentration-dependent toxic effect of increased vacuoliza-
tion.68 LOCMs and IOCMs can induce dose- and time-
dependent renal cell apoptosis through a mitochondrial
pathway, with an increase in caspase-3 and caspase-9 but not
caspase-8 and caspase-10.69
5.2.2. Reactive oxygen species
Reactive oxygen species (ROS) are mainly generated by the
adenosine of endothelial cells and by hypoxia of the renal
medullary during CM administration.51 During oxidative
stress, ROS are generated endogenously in the mitochondria.
The most common ROS include oxygen radical superoxide
(O2 ), hydrogen peroxide (H2O2), and the hydroxyl radical
(OH), with O 2 and OH
being more reactive and permeable
677
across cell membranes. These ROS are extracellular signaling
molecules and may play roles in the effects of vasoconstriction
such as angiotensin II, thromboxane A2, endothelin-1, aden-
osine, and norepinephrine.42 For example, O 2 can rapidly
scavenge nitric oxide (NO) and blunt NO activity in renal
vasodilatation. N-Acetylcysteine (NAC) acts through the in-
hibition of the mitochondrial pathway for apoptosis.70 NAC
also scavenges ROS, induces synthesis of glutathione, and
possibly inhibits the angiotensin-converting enzyme.71
Although NAC that is given in addition to a hydration proto-
col has been recommended for the prevention of CIN in pa-
tients with mild-to-moderate renal insufficiency, this
suggestion has not been universally accepted.71,72
6. Prevention
6.1. Evaluation of the risk of CIN and alternative
imaging methods
Because the risk of CIN can be evaluated and prevention is
possible, patients at high risk should receive, where possible,
alternative imaging methods without CM, as well as suitable
procedural and prevention strategies (Table 4). The use of
gadolinium (Gd)-based CM is not recommended to avoid
nephrotoxicity in patients with renal impairment.73 The Eu-
ropean Medicines Agency declared a contraindication for the
use of gadodiamide in patients with a GFR of <30 mL/min per
1.73 m2, and issued a warning for its use in patients with a
GFR between 30 mL/min and 60 mL/min per 1.73 m2. The
United States Food and Drug Administration added a warning
about the risk of nephrogenic systemic fibrosis following
exposure to Gd-containing contrast agents in patients with a
GFR of <30 mL/min per 1.73 m2 and AKI due to hepatorenal
syndrome or during the perioperative liver transplantation
period. When Gd-containing contrast is required to obtain
optimal images, the use of low dosages of more stable
macrocyclic agents is safer and preferred.74 In patients under
maintenance hemodialysis, it is recommended that performing
hemodialysis after CM exposure and for the following 2 days
be considered.74
6.2. Drug review
Prior to CM exposure, use of nephrotoxic drugs including
nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, ami-
noglycoside, and cyclosporine A should be stopped for at least 2
days. Diabetic patients with preexisting renal impairment
should stop metformin for 48 hours because lactic acidosis may
occur once CIN develops. However, patients with normal renal
function taking metformin are not at risk of CIN and should be
assessed according to their overall clinical condition.75
6.3. Nonpharmacological prevention strategies
The CM should be prewarmed to 37 C and injected at the
lowest possible dose for acceptable images. We also suggest
using IOCMs or LOCMs except for ioxaglate or iohexol in all
678 C.-F. Chang, C.-C. Lin / Journal of the Chinese Medical Association 76 (2013) 673e681
Table 4
Strategies to prevent contrast-induced nephropathy in high-risk patients.
Evaluation of the risk for CIN and benefit of examination in all patients
Consider alternative imaging methods in patients at high risk of CIN
Drug review
Nonpharmacological prevention strategies
Use lowest possible dose
Use IOCM or LOCM except Ioxaglate or Iohexol
Avoid repeat injection within 72 h
Pharmacological prevention strategies
IV volume expansion with isotonic NaCl or NaHCO3
Oral N-acetylcysteine with IV volume expansion
Hemodialysis or hemofiltration for CKD 4/5 with functional access
Policy to perform electronic alertness
IV intravenous; IOCM iso-osmolar contrast media; LOCM low-
osmolar contrast media.
patients. In high-risk patients with CKD or CKD diabetes
requiring intra-arterial administration, iodixanol may be a
better choice than LOCMs.40,41 Furthermore, clinicians should
avoid repeat injections within 72 hours of the first CM
administration.
A recent pilot trial demonstrated that remote ischemic
preconditioning (IPC), induced by intermittent upper-arm
ischemia prior to an invasive coronary procedure, dramati-
cally reduced the incidence of CIN in patients with CKD and
those at high risk of CIN (OR 0.21, CI 0.07e0.57,
p 0.002).76 The IPC was accomplished by performing 4
cycles of alternating 5 minutes of inflation and 5 minutes of
deflation of a standard upper-arm blood pressure cuff to the
individuals systolic blood pressure plus 50 mmHg to induce
transient and repetitive arm ischemia and reperfusion. The true
protective mechanism of IPC is unknown, although it has been
postulated that an organ releases humoral factors into the
systemic circulation, which subsequently protects the remote
organ. Although IPC can be applied easily and safely, a large
trial is required to establish its effect.
6.4. Pharmacological prevention strategies
6.4.1. Volume expansion
All patients receiving CM should have an optimal volume
status at the time of exposure,25 given that volume supple-
mentation plays an important role in the prevention of CIN.
Volume expansion can decrease the activity of the
renineangiotensinealdosterone system, reduce vasoconstric-
tive hormones such as endothelin, increase sodium diuresis,
decrease tubule-glomerular feedback, prevent tubular
obstruction and ROS production, dilute the CM in the tubular
cells, and then decrease the nephrotoxic effects on the tubular
cells.68 In patients without heart failure, parenteral isotonic
normal saline (0.9% NaCl) without any diuretics should be
started 12 hours prior to CM administration with an infusion
rate of 1 mL/kg body weight per hour and continued for 24
hours. In addition, although patients should be encouraged to
drink plenty of fluids (tea, mineral water, etc.), oral fluid
supplementation alone is inadequate to prevent CIN. The use
of sodium bicarbonate (NaHCO3) infusion may not only allow
for shorter periods of volume supplementation, but can also
further reduce the generation of injurious oxygen free radicals.
Typically, patients should receive 154 mEq/L of NaHCO3, as
a bolus of 3 mL/kg/h for 1 hour prior to CM administration,
followed by an infusion of 1 mL/kg per hour for 6 hours after
the procedure.77 Recent large meta-analysis studies demon-
strated that NaHCO3 had a greater benefit than sodium chlo-
ride (NaCl; OR 0.33e0.57, CI 0.16e0.85), but no
significant difference in the occurrence of death (OR 0.6,
CI 0.26e1.41, p 0.24) and requirement for renal
replacement therapy (OR 0.56, CI 0.22e1.41,
p 0.22).78,79 We suggest hydration with NaHCO3 prior to
CM exposure instead of NaCl for prophylaxis of CIN in pa-
tients at risk and who are not contraindicated for NaHCO3
infusion. A recent study increased the bolus concentration of
NaHCO3 to 833 mEq/L with the same infusion rate, and the
results indicated that this was more effective for urine alkali-
zation and prevention of CIN.80 However, such evidence is
inadequate at present to conclusively determine the optimal
regimen of volume supplementation, and further studies are
necessary to elucidate this issue.77e81
6.5. N-Acetylcysteine
NAC scavenges ROS, reduces the depletion of glutathione,
and increases the effects of vasodilatation, including NO. The
standard dose is 600 mg orally twice daily on the day prior to
and on the day of the procedure.82 However, the many trials
evaluating NAC for the prevention of CIN have yielded con-
flicting results.17,83e85 And even though some studies used a
modified dosage, timing, or intravenous administration, the
results were also inconsistent. The largest meta-analysis found
that either oral or IV NAC could significantly lower the risk of
CIN (OR 0.62, CI 0.44e0.88) when compared with NaCl
hydration.83 Some studies also found that NAC could prevent
CIN in a dose-dependent manner.84,85 Considering that oral
NAC has a very low toxicity and low cost, it has been sug-
gested that oral NAC at a standard dose together with paren-
teral hydration be used for patients at risk of CIN.17,86 In
patients at very high risk of contrast-induced AKI, a combi-
nation prophylactic administration of NaHCO3 plus NAC or a
real-time matched fluid replacement device are treatments still
under investigation.87
6.5.1. Other medications
Further pharmacological prevention may be appropriate for
patients who cannot tolerate parenteral hydration and are at
risk of CIN. Some drugs focus on blocking vasoconstriction,
increasing vasodilatation, and decreasing the ROS induced by
the CM, including endothelin antagonists, adenosine antago-
nists (theophylline), atrial natriuretic peptide, selective dopa-
mine A1 receptor agonist (fenoldopam), and calcium channel
blockers. However, given the dearth of evidence and uncer-
tainty of the benefits over harm, these treatments cannot be
recommended at present. Moreover, most of these drugs failed
to prevent CIN in high-risk patients, and some antioxidants,
 C.-F. Chang, C.-C. Lin / Journal of the Chinese Medical Association 76 (2013) 673e681
including ascorbic acid and statins, have also failed to show a
consistent benefit in the prevention of CIN.88
6.6. Dialysis (hemodialysis, hemofiltration, or peritoneal
dialysis)
In patients with renal failure, the renal excretion of CM is
delayed. A single session of hemodialysis can effectively
remove 60e90% of the CM from the blood.89 Because most
CMs are middle-sized molecules, the high-flux membranes
used in hemofiltration or hemodiafiltration modalities can
remove the CM more quickly. However, dialysis may also
cause deterioration of renal function through activation of
inflammatory reactions, with the release of vasoactive sub-
stances that may induce acute hypotension.88,90 A recent meta-
analysis found that dialysis did not reduce the incidence of
CIN compared with routine preventive care, and that there was
a trend toward a greater risk of CIN with hemodialysis.91
Subgroup analyses have found that hemodialysis was harm-
ful for the prevention of CIN in patients with stage 3 CKD
(OR 1.53, p 0.01), but overwhelmingly favorable over the
standard treatment in reducing the risk of CIN in patients with
stage 4 or stage 5 CKD (OR 0.19, p < 0.001).86,91 However,
further evidence is necessary because of the small sample sizes
used in these studies. Considering the risk of dialysis pro-
cedures and the greater cost, it is recommended that hemodi-
alysis or hemofiltration only be considered in patients with
CKD stage 4 or stage 5 at high risk of CIN when functioning
access is already available.88
To date, only a few studies have evaluated the effects of
CM on residual renal function in patients under maintenance
peritoneal dialysis.92 It seems that intravenous CM used in the
standard CT scan has no significant long-term effects on re-
sidual renal function in patients under maintenance peritoneal
dialysis. Nonetheless, the aforementioned prevention strate-
gies of CIN are still suggested unless contraindication exists.
Although it takes a longer time than hemodialysis, CM can
be removed effectively by peritoneal dialysis, including
intermittent peritoneal dialysis, automatic peritoneal dialysis,
and continuous ambulatory peritoneal dialysis.89 For this
reason, peritoneal dialysis should be started immediately after
CM exposure in these patients.
6.7. Other techniques to remove CM
One novel technique for the prevention of CIN is removing
the majority of the CM from coronary sinuses prior to when it
enters the systemic circulation during coronary angiog-
raphy.90,93 A blood suction catheter is inserted into the coro-
nary sinus via the right femoral vein, and venous blood from
the coronary sinus is transferred into a 500-mL contrast-
adsorbing column using an extracorporeal system. However,
even though the mean calculated iodine removal rate has been
reported at 49.4% and this new procedure has been shown
to be safe and effective in reducing risk of CIN, a high tech-
nique failure rate (57%) currently limits its clinical
application.88,90,93
679
6.8. Electronic warning systems
A recent paper has described a computerized alertness
program in hospitalized patients that may decrease the risk of
CIN (3% vs. 10%, p 0.02).94 When contrast-enhanced CT
was ordered in patients with a GFR of <60 mL/min/1.73 m,
the physician was alerted by a warning message to consider
prophylactic measures for CIN. Such systems should be used
whenever possible.
In conclusion, CIN is a common complication of hospital-
acquired AKI and is associated with higher in-hospital mor-
tality, prolonged hospital stay, increased long-term mortality,
and accelerated progression of CKD. All patients should be
evaluated for the risk factors of CIN, and the potentially
modifiable risk factors should be carefully evaluated and
minimized. For patients considered to be at high risk, clini-
cians should consider alternative imaging methods without
CM where possible, and consider more suitable procedures or
prevention strategies. The CM should be prewarmed to 37 C
and injected at the lowest possible dose for acceptable images.
IOCMs or LOCMs, except for ioxaglate or iohexol, should be
used in all patients. In high-risk patients with CKD or
CKD diabetes requiring intra-arterial administration,
iodixanol may be a better choice than LOCMs. Repeat in-
jections within 72 hours of the first CM administration should
be avoided. All of the drugs should be carefully reviewed, and
use of nephrotoxic drugs should be stopped at least 2 days
prior to the procedure. All patients receiving CM should have
an optimal volume status at the time of exposure. In patients
without heart failure, parenteral isotonic (0.9%) normal saline
without any diuretics should be started 12 hours prior to
administration of the CM. The use of bicarbonate infusion
may allow for a shorter period of volume supplementation.
Oral NAC together with parenteral hydration is suggested for
patients at risk of CIN. Hemodialysis or hemofiltration should
only be considered in patients with stage 4 or stage 5 CKD at
high risk of CIN when the functioning access is already
available. Electronic warning systems for physicians and
technicians should be used when possible. The effects of other
medications or techniques for reducing the risk of CIN remain
unclear at this time, and further studies are necessary.
Acknowledgments
This study was sponsored by a grant from the Department
of Health, Taipei City Government, Taiwan, R.O.C. (96001-
61-001-055).
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