CONTRAST INDUCED NEPHROPATHY

Definition:
 Any internally administered substance that has
a different opacity from soft tissue on
radiography or computed tomography; includes
barium, used to opacify parts of the
gastrointestinal tract; water-soluble iodinated
compounds, used to opacify blood vessels or
the genitourinary tract is called a Radiocontrast
agent or Radiocontrast medium (RCM).
2

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 Iodine Contrast Agents: Diatriazoate, Iodipamide
Iothalamite, Metrizoate, Iohexol, Iopamidol, Iomersol,
Iomeprol,Iopromide, Iptrolan, Ipodate, Iodixanol, etc.
Types of Radiocontrast agents:

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 Iodinated contrast agents are usually tri iodo
benzoic acid derivatives of sodium or meglumine
salts.
 Either salt used alone has a serious risk of
ventricular fibrillations, thus used as mixture.
PARAMETER SODIUM MEGLUMINE
Solubility Less Better
Tolerance Less Better
BBB Effect Crosses Not
Vascular effects More Less
Viscosity Low High
Opacification Better Less
Bronchospasm No Yes

Non iodinated contrast agents:
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 Barium Sulphate (Used in X- ray and GIT imaging)
Gadolinium contrast agents (used in MRI scan)
 Gadoterate (Dotarem)
 Gadodiamide (Omniscan)
 Gadobenate (MultiHance)
 Gadopentetate (Magnevist)
 Gadoteridol (ProHance)
 Gadofosveset (Ablavar, formerly Vasovist)
 Gadoversetamide (OptiMARK)
 Gadoxetate (Eovist)
 Gadobutrol Gadavist)

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 Mangafodipir(Teslascan) – MRI withdrawn from
market in 2012.
 Rubidium-82 chloride (Myocardial perfusion
imaging)
 Technetium (99mTc) fanolesomab (NeutroSpec) –
formerly used in diagnosis of appendicitis,
suspended from the market in 2005 owing to life
threatening adverse effects.

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 Used in Ultrasound:
 Microspheres of human albumin(ALBUNEX), galactose,
phospholipids.
 Poly Lactic co glycolic acid (PLGA) particles
comprising of liquid perfluorocarbon and a metal have
been suggested for use in ultrasound.
 Optison™ (GE Healthcare Systems) is FDA-approved
protein-shelled microbubble contrast agent which
contains a perfluoropropane (perflutren) gas core.

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Alzheimer’s disease and amyloid beta PET
imaging:
 Florbetaben (18F) [NEURACEQ]
 Florbetapir (18F)
 Flutemetamol (18F)

ADVERSE REACTIONS OF
RCM:
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• Nausea, vomiting Altered taste, Sweating, Cough,
Itching, Rash, hives Warmth (heat) ,Pallor, Nasal
stuffiness Headache Flushing Swelling eyes, face
Dizziness Chills Anxiety Shaking
MILD
• Tachycardia/bradycardia ,Hypotension
Bronchospasm, wheezing,
Hypertension,Dyspnea Laryngeal edema
,Pronounced cutaneous reaction, Pulmonary
edema.
MODERATE
• Hypersensitivity and anaphylactoid reactions,
Laryngeal edema, Profound hypotension
Unresponsiveness (severe or progressive)
Convulsions Cardiopulmonary arrest ,
arrhythmias
SEVERE

Based on mechanism:
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1. Chemotoxic reactions: which include organ
specific reactions like nephrotoxicity,
cardiovascular toxicity, neurotoxicity, vasovagal
reactions and also associated with thyroid
function abnormalitie, rarely thyrotoxicosis.
2. Anaphylactoid/Hypersensitivity reactions:
Immediate hypersensitivity reactions – develop
within 5 minutes to one hour of contrast
administration.
Delayed hypersensitivity reactions – develop
from one hour to several days after contrast
administration.

Treatment of Contrast Reactions:
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 Post-contrast acute kidney injury (PC-AKI) is a
general term used to describe a sudden
deterioration in renal function that occurs within 48
hours following the intravascular administration of
iodinated contrast medium.
 PC-AKI may occur regardless of whether the
contrast medium was the cause of the deterioration.
PC-AKI is a correlative diagnosis.
 Contrast-induced nephropathy (CIN) is a specific
term used to describe a sudden deterioration in
renal function that is caused by the intravascular
administration of iodinated contrast medium;
therefore, CIN is a subgroup of PC-AKI . CIN is a
causative diagnosis.

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 Contrast induced nephropathy is a sudden
deterioration is renal function within 48 to 72 hours
of contrast administration in patients without other
attributable factors for renal insufficiency.
 It is a condition with impairment in renal function
defined as an increase in SCr by more than 25%
within three days following intravenous
administration in the absence of an alternative
etiology.
 Incidence: The frequency of CIN has decreased in
the past decade from a general incidence of 15 to
7% [2013].
 The overall incidence of PC-AKI in studies of
cardiac angiography is higher than it is in studies
of patients who receive IV iodinated contrast
medium.

DIAGNOSIS:
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 There are no standard criteria for the diagnosis of PC-
AKI or CIN.
 One of the most commonly used criteria has been an
absolute increase of 0.5 mg/dL over a baseline serum
creatinine.
 The diagnosis of AKI is made according to the AKIN
(Acute Kidney injury network) criteria if one of the
following occurs within 48 hours after a nephrotoxic
event (e.g., intravascular iodinated contrast medium
exposure)
1) Absolute serum creatinine increase ≥0.3 mg/dL (>26.4
µmol/L).
2) A percentage increase in serum creatinine ≥50% (≥1.5-
fold above baseline).
3) Urine output reduced to ≤0.5 mL/kg/hour for at least 6
hours.

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 Serum creatinine is limited as a measure of renal
function in that it is impacted by gender, age, and
muscle mass and nutritional status.
 An alternative method for evaluating renal function
is estimating creatinine clearance using the
Cockcroft-Gault formula or GFR which is estimated
by the Modification of Diet in Renal Disease (MDRD)
formula.
 The Cockcroft-Gault equation:
[(140-age) X Actual Body Weight (kg) / (Serum Cr X
72)] multiply the result by 0.85 for females
 GFR (mL/min/1 .73m2) = 175 x (SCr)-1.154 x (Age)-
0.203 x (0.742 if female) x (1.212 if African American)

SCREENING:
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1. Age > 65 years
2. Diabetes treated with insulin or other prescribed
3. Receiving chemotherapy or aminoglycoside within the
past one month.
4. Diagnosis of a collagen vascular disease
5. Diagnosis of a paraproteinemia syndrome
6. History of a kidney transplant, renal tumor, renal
surgery, or single kidney
7. History of end stage liver disease
8. History of severe congestive heart failure
9. Metformin or metformin-containing drug combinations
Following risk factors require a serum creatinine
measurement
within 1 month of the proposed dose of contrast:

Risk assessment and prophylactic
strategies are based on eGFR rather than
the absolute level of SCr :
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 eGFR ≥ 60 mL/min: very low risk for CIN. These
patients require no specific prophylaxis or follow
up.
 eGFR 45- 59 mL/min: low risk for CIN. In the
absence of additional risk factors patients receiving
IV CM require
no specific prophylaxis or follow up. For patients
receiving IA CM preventative measures are
recommended.

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 eGFR < 45 mL/min: moderate risk of CIN,
preventive measures are recommended. IV
hydration recommended
for patients receiving intra-arterial contrast. For
intravenous administration, either oral or IV
hydration could be used; IV hydration being
preferred if eGFR < 30 mL/min.
 Patients with unstable renal function, an acute
illness and/or acute renal failure: GFR calculation
in these
patients is unreliable. They are thought to be at
particular risk, full preventative measures,
including intravenous
hydration and follow up are recommended.

The American College of Radiology
provides the following
recommendations for holding
Metformin:
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 Category 1 : For patients with eGFR ≥ 45
mL/min without liver dysfunction, alcohol
abuse, cardiac failure, myocardial or peripheral
muscle ischemia, sepsis or severe infection:
Do not hold metformin or check creatinine
after contrast administration.

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 Category 2: For patients with eGFR ≥ 45 mL/min
with liver dysfunction, alcohol abuse, cardiac
failure, myocardial or peripheral muscle ischemia,
sepsis or severe infection:
Hold metformin for 48 hours. The procedure for
assessing renal function and time to restart
metformin will be determined by the radiologist and
practitioner and communicated to the patient.
 Category 3: For patients with impaired renal
function, eGFR < 45 mL/min:
Hold metformin at the time of contrast
administration and follow renal function until
metformin can be re-instituted safely.

PREVENTION AND MANAGEMENT
OF CIN
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1. Avoid dehydration.
2. Alternative imaging not requiring CM should be
considered if the alternate imaging can adequately
address the diagnostic questions.
3. CM volume and frequency of administration
should be minimized while still maintaining
satisfactory image quality. Avoid repeat CM
injection within 72 hours.

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4. High osmolar CM should be avoided, as iso-
osmolar and low-osmolar CM have been proven
safer.
5. Nephrotoxic medications should be discontinued
48 hours prior to contrast administration.
6. Metformin should be discontinued on the day of
the proposed CM administration, withheld for the
subsequent 48 hours and recommenced after
renal function has been re-evaluated and found
to have returned to baseline.

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1. Choice of Iodinated Contrast Media: A meta-
analysis of literature concerning high osmolar
(HOCM) and low osmolar contrast media (LOCM)
by Barreett and Carlisle concluded that LOCM are
less nephrotoxic than HOCM in patients with
underlying renal insufficiency.
A 2009 meta-analysis using data pooled from 25
trials found no difference in the rate of PC-AKI
between iodixanol (iso-osmolar IOCM) and low
osmolality agents after intravenous
administration.
DIFFERENT STRATEGIES:

28
2. Volume Expansion / Hydration: The ideal
infusion rate and volume is unknown, but
isotonic fluids are preferred (Lactated Ringer’s
or 0.9% normal saline).
One possible protocol would be 0.9% saline at
100 mL/hr, beginning 6 to 12 hours before and
continuing 4 to 12 hours after, but this is only
practical in the inpatient setting.

29
 Solomon et al studied adult patients with
chronic
kidney disease who underwent cardiac
angiography. The reported incidence of PC-AKI
was decreased by
periprocedural IV volume expansion (0.45% or
0.9% saline, 100 mL/h, 12 hours before to 12
hours after
intravascular contrast medium administration).
 In another study, IV volume expansion with
0.9% saline was superior to IV volume
expansion with 0.45% saline in PC-AKI risk
reduction.

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 Current data does not support the routine use of
isotonic sodium bicarbonate infusions for the
prevention of CIN.
 Bicarbonate infusions should not be administered
to patients with pulmonary edema, uncontrolled
hypertension (SBP>160 or DBP >100, or patient at
high risk for severe fluid overload.
 Some studies and meta-analyses of patients
undergoing cardiac angiography have shown
intravenous volume expansion with sodium
bicarbonate to be superior to 0.9% saline in
reducing the risk of PC-AKI but the results are not
considered definitive.

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 N-acetylcysteine (NAC) is a thiol compound with
antioxidant and vasodilatory properties. A possible
mechanism of benefit in CIN involves minimizing
both vasoconstriction and oxygen free radical
generation after radio contrast administration.
 Dose: Preferred oral dose is 1200mg twice daily on
the day before and on the day of procedure to
patients at risk of CIN.
 Patients requiring emergent coronary angiography
or procedures, in whom preventive therapy with oral
NAC cannot be given the day before, has been
treated with IV acetylcysteine.

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 Effiacy of NAC to reduce the incidence of CIN is
controversial.
 There is evidence that it reduces serum creatinine in
normal volunteers without changing cystatin-C which
raises the possibility that NAC might be simply
lowering serum creatinine without actually preventing
renal injury.
 NAC should not be considered a substitute for
appropriate pre-procedural patient screening and
adequate volume expansion.

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DIURETICS:
 Solomon et al reported no benefiial effects from
the osmotic diuretic mannitol when it was added
to IV saline solution in patients with or without
diabetes mellitus.
 There was an exacerbation of renal dysfunction
when the loop diuretic furosemide was used in
addition to IV saline solution.
 Neither mannitol nor furosemide is recommended
for CIN risk reduction.

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3. Contrast volume and frequency: Minimize
amount of contrast administered (< 2 ml/kg or
max of 150 mL)
 Lowest rates of CIN were seen in patients
receiving less than 100 to 140 mL.
 CM volumes in excess of 5mL/kg strongly
predict nephropathy requiring dialysis.
 A significantly increased risk of CIN has also
been demonstrated among patients who
received a second dose of CM within 48 hours

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4. RENAL DIALYSIS:
 CM can be easily removed with hemodialysis,
however there is no evidence that this removal
reduces the risk of CIN.
 Since the CM would reach the kidneys within one
or two cardiac cycles and subsequent removal of
CM is unlikely to stop the cascade of renal injury,
which would have already begun.
 Patients receiving dialysis are also at theoretical
risk from the osmotic load imposed by
intravascular iodinated contrast medium because
they cannot readily clear the excess intravascular
volume which may result in pulmonary edema
and anasarca.

36
 In patients at risk for fluid overload, low
osmolality or iso-osmolality contrast media
should be employed with dosing as low as
necessary to achieve a diagnostic result.
 Most low-osmolality iodinated contrast media are
not protein-bound, have relatively low molecular
weights, and are readily cleared by dialysis.
 Unless an unusually large volume of contrast
medium is administered, or there is substantial
underlying cardiac dysfunction, there is no need
for urgent dialysis after intravascular iodinated
contrast medium administration.

Alternative to Iodinated Contrast:
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 Any appropriate non iodinated contrast agents may be
used as alternative to iodinated contrast.
 For example, Gadolinium agents are recommended as
alternatives to iodinated contrast agents especially for
coronary angiography.
 Gadolinium-based contrast media (GBCM) have been
approved for parenteral use since the late 1980s.
 GBCM are extremely well tolerated by the vast majority
of patients in whom they are injected.


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 Adverse effects: Most reactions are mild and
physiologic, including coldness, warmth, or pain at the
injection site; nausea, vomiting; headache;
paresthesias; and dizziness.
 GBCM administered to patients with acute kidney injury
or severe chronic kidney disease can result in a
syndrome of nephrogenic systemic fibrosis (NSF).
 Nephrogenic systemic firosis (NSF) is a firosing
disease, primarily involving the skin and subcutaneous
tissues but also known to involve other organs, such as
the lungs, esophagus, heart, and skeletal muscles.
Initial symptoms typically include skin thickening
and/or pruritis.

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 NOVA(Noninvasive Optimal Vessel Analysis), a
noninvasive MRI study that is noncontrast-based
invented by Dr. Fady Charbel, head of the
department of neurosurgery at the University of
Illinois at Chicago, approved by FDA in 2001.
 NOVA is a flow analysis system that works with
magnetic resonance imaging to produce a 3-D
model of the vasculature and quantify vessel blood
flow. It is used to diagnose conditions such as
stroke and aneurysms.

REFERENCES:
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1. ACR Manual on Contrast media Version 10.1,
2015. Page 33-45, 79,83.
2. Owen RJ, Hiremath S, Myers A, Fraser-Hill M,
Barrett B. Canadian association of radiologists.
Consensus guidelines for the prevention of
contrast induced nephropathy. June 17 2011
3. Vijay SK, Tiwari BC, Singh AK. Contrast
induced nephropathy: Pathophysiology and
prevention. Heart India 2013;1:39-45.

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4. David J. Spinosa, MD John A. Kaufmann, MD
Gary D. Hartwell, DSc – Gadolinium chelates
in angiography and interventional radiology,
Radiology 2002; 223:319–325
5. Molecular Imaging: Principles and Practice,
Mark A. Borden, Shenping Qin, and Katherine
W. Ferrara Ultrasound Contrast Agents Pg
425,429.
6. VasSol NOVA vassolinic.com
7. Jessica B. Robbins, Myron A. Pozniak,
Contrast Media Tutorial, radiolody.wisc.edu
2010.

CONTRAST INDUCED NEPHROPATHY

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CONTRAST INDUCED NEPHROPATHY