Contrast induced nephropathy (CIN) is a common cause of hospital
acquired acute kidney injury (AKI) and associated with
adverse clinical outcomes. There is still debate regarding the exact
definition, which has greatly influenced the reported incidence
of CIN in literature. Recent studies have challenged the universal
concern regarding risk of CIN in general population. It is found to
occur more commonly after intra-arterial (IA) administration of contrast
as in interventional cardiology and vascular procedures
especially in patients with multiple comorbidities and underlying renal
impairment. Recent studies report negligible risk after
intravenous (IV) contrast administration for modern diagnostic
radiological examinations. Since it is a potentially preventable
clinical condition, it is imperative for health care professional to be
well aware of this entity. All patients undergoing iodinated
contrast exposure should be risk stratified and preventive measures
should be employed in high risk population. This paper will
review the epidemiology, controversies regarding definition,
pathophysiology, risk stratification, iodinated contrast commonly used
in practice and preventive strategies.
Keywords: Contrast Induced Nephropathy,Iodinated Contrast Media,Acute Kidney Injury,Cardiac Angiography,Contrast
Enhanced Computed Tomography
Abbrevations: CIN: Contrast Induced
Nephropathy,AKI: Acute Kidney Injury,CM: Contrast Media,ICU: Intensive
Care Unit,CECT: Contrast Enhanced Computed Tomography,PTCA: Percutaneous
Trans-Luminal Coronary Angioplasty,ACR: American
College of Radiology,AKIN: Acute Kidney Injury Network,eGFR: Glomerular
Filtration Rate,NGAL: Neutrophil Gelatinase-Associated
Lipocalin,CES: Cholesterol Embolism Syndrome,ERBP: European Renal Best
Practice,KDIGO: Kidney Disease Improving Global
Outcomes,NSAIDS: Non-Steroidal Anti-Inflammatory Drugs,HOCM: High
Osmolar Contrast Media,LOCM: Low Osmolar Isosmolar
CM,HD: hemodialysis,HF: hemofiltration,NAC: N-acetylcysteine,ESUR:
European Society of Urogenital Radiology,CAR: Canadian
Association of Radiologist,ESRD: End Stage Renal Disease,TOF: Time Of
Flight,CKD: Chronic Kidney Disease,NSF: Nephrogenic
Systemic Fibrosis,NCCT: Non contrast computed Tomography,CO2: Carbon
Dioxide
Introduction
Contrast induced nephropathy (CIN) is defined as acute renal
impairment after exposure to iodinated contrast media (CM). In
the modern era with the advancement of the diagnostic modalities,
increase in number of percutaneous coronary and peripheral
artery interventions and frequent use of contrast media, CIN
has emerged as a common cause of acute renal failure. Mostly, it
results in transient renal impairment; however in patients with
multiple comorbidities it can be associated with high morbidity
and mortality [1]. It is therefore imperative to identify patients at
risk to decrease its occurrence and diagnose it early in course
to avoid short and long term clinical adverse effects. It presents a
challenging situation that is often encountered by practitioners
in varied specialties including emergency medicine, nephrology,
cardiology, radiology and intensive care unit (ICU). Since CIN
represents a form of acute kidney injury (AKI), which is potentially
preventable, it is important that clinicians are well aware of this
entity and understands the basic pathogenesis involved. The aim of
this review article is to discuss pathogenesis of CIN, associated risk
factors, different iodinated CM used in clinical practice and their
effect on kidney, alternative diagnostic modalities and preventive
measures.
Epidemiology
CIN remains an important cause of in-hospital AKI, accounting
for approximately 11% of the total cases of AKI [1]. Literature on CIN
mainly reports it to occur following exposure to iodinated contrast
during coronary or peripheral angiography [1,2] or diagnostic
imaging, however recent data shows contrast exposure associated
with modern radiographic procedure is not associated with
significant increase in CIN incidence [3]. Exposure following cardiac
or peripheral angiography differs from that during diagnostic
imaging in that the injection is intra-arterial, requires catheter and
dose of CM is concentrated and abrupt [4,5]. In general population
without any risk factor, incidence of CIN is very low; however risk
increases as comorbidities increases [1,6,7]. Critically ill patients
with baseline renal impairment are particularly susceptible and
contrast enhanced computed tomography (CECT) might account
for 18% of AKI cases in this population [8]. Reported incidence
of CIN varies with the procedure and is reported to be 11% after
outpatient CECT [9], 4% following intravenous pyelography [10],
9% after peripheral arteriography (4), <3% following percutaneous
trans-luminal coronary angioplasty (PTCA) in patient with normal
renal function and as high as 40% in patient with underlying renal
impairment [2,11,12]. Studies have documented at least 3.1% of
patients with CIN required renal replacement therapy. In hospital
mortality is reported to be 7.1% in patients with CIN after coronary
intervention and as high as 35.7% in patients requiring dialysis,
which further increases to 81.2% at 2 year [1]. CIN is reported to be
independent predictor of poor outcome in patients with diabetes
mellitus with or without renal impairment [6].
Definition
Post- contrast acute kidney injury (PC-AKI) is often defined
as acute renal impairment occurring within 48hours of exposure
to intravascular iodinated CM. It is a correlational diagnosis and
can occur irrespective of CM being cause of renal deterioration. In
contrast, CIN comes under subgroup of PC-AKI and is a causative
diagnosis. In literature, CIN has been defined as relative change
in the baseline serum creatinine (> 25-50%) and absolute
elevation from baseline serum creatinine (>0.5-2 mg/dL) [13-
15]. Temporal relationship between exposure to CM and rise in
serum creatinine along with exclusion of other causes of AKI are
crucial for the diagnosis of CIN. Defining set criteria for diagnosis
is important as incidence of CIN in clinical practice can vary greatly
with small change in serum creatinine. An absolute increase of
serum creatinine by ≥0.5 mg/dL from baseline is still commonly
used definition of AKI [16]. Another well-known criterion for CIN
proposed by Barrett and Parfrey in early 1990s was an absolute
increase in serum creatinine levels by ≥0.5 mg/dL or a relative
increase of ≥25% in serum creatinine from baseline within 72 hours
after contrast exposure [17]. However, for purpose of standardizing
the definitions, recently American College of Radiology (ACR) has
recommended using the AKIN (Acute Kidney Injury Network)
criteria to define CIN. It employs absolute serum creatinine increase
>0.3mg/dl or ≥50% (≥1.5 times) percentage increase in serum
creatinine or ≤0.5 mL/kg/hour urine output for at least 6 hours
within 48hours of exposure to define AKI [18]. In clinical practice,
serum creatinine concentration is commonly used measure of renal
function; however it has its own limitations. There is often delay
between renal insult and rise of serum creatinine, which delays the
diagnosis. It is also affected by other factors including age, gender,
nutritional status, volume status, hyper catabolic state, muscle mass
and concomitant use of other medications, therefore it is important
to interpret results in appropriate clinical settings [19,20]. Changes
in serum creatinine concentration are not linearly related to
changes in effective glomerular filtration rate (eGFR,) because of
which small changes in eGFR can often go unnoticed. Normal serum
creatinine is actually maintained till GFR or creatinine clearance is
reduced by nearly 50% [20].
Diagnosis
Diagnosing CIN is challenging. It is important to follow systemic
approach while evaluating patient with AKI. CIN is a diagnosis of
exclusion after other causes of AKI (prerenal/intrinsic/post renal)
have been ruled out. There is temporal relationship with contrast
exposure, however this should not preclude from searching for
other reversible causes of AKI, which may coexist [13-15].
Periprocedural
hypotension, bleeding, release of athero-embolic
material and use of catheter exchanges may further complicate
renal tubular injury after angiography [21]. After exposure to
intravascular iodinated contrast, serum creatinine typically rises
within the first 24-48 hours, peaks at 3-5 days and returns close
to baseline within 1-3 weeks. In most cases, it is asymptomatic and
has no significant clinical consequences. However, in rare cases it
can lead to oliguria or anuria, irreversible renal damage and need
for renal replacement therapy. Basic work up includes clinical
assessment, urine output, urinalysis and renal imaging. Volume
depleted state can predispose patient to CIN; however CIN can
result in intrinsic renal injury with tubular necrosis in extreme
cases. Finding on urinalysis may include muddy brown granular
cast, tubular epithelial cells and minimal or no proteinuria. Urine
examination is neither sensitive nor specific to diagnose CIN,
however its usefulness is mainly to exclude underlying glomerular
disease or acute interstitial nephritis [22]. Urine studies may
show intrinsic renal injury picture with urine sodium < 10 mEq/L,
fractional excretion of sodium <1% and urine osmolality <350
mOsm/kg. Persistent nephrogram (Figure 1) may be incidentally
seen on follow up imaging because of delayed clearance of contrast
[23].
Timing of serum creatinine rise after contrast exposure in
literature has been reported to be 24-72hours. However, it is
speculated that renal damage actually begins soon after exposure
to intravascular iodinated contrast. In study by Ribichini et al. [24],
it is reported that measuring change in serum creatinine from
baseline within 12hours of contrast exposure significantly predicted
occurrence of CIN and was associated with renal damage after
30days [24]. However, relying on serum creatinine for diagnosis
of renal injury has its own limitation as discussed above, therefore
finding of specific biomarkers that could predict early diagnosis
of CIN is desirable. Recently, it has been proposed to classify these
biomarkers into two group, namely, (1) reflecting change in renal
function (e.g. cystatin C) and (2) representing renal damage {e.g.
Plasma or urine neutrophil gelatinase-associated lipocalin (NGAL),
interleukin-18} [25]. Briguori et al. [26] reported increase in levels
of cystatin C ≥ 10% at 24 h after PTCA had 100% sensitivity and
85.9% specificity for the prediction of CIN [26].
Another condition often encountered after exposure to
CM especially catheter related studies is cholesterol embolism
syndrome (CES). It can be challenging to distinguish the two
conditions clinically; however it is important as both have
different treatment approach. CES is usually a rare entity and renal
impairment typically develops gradually over 3-8weeks after the
procedure. It is a multisystem disease caused by dislodgement of
cholesterol crystals from atherosclerotic plaque and occlusion of
peripheral arterioles. Other peripheral sign that can help clinch the
diagnosis include live do reticularis, petechiae, digital gangrene,
splinter hemorrhage and Hollenhorst plaques on ophthalmological
examination. Laboratory studies may show peripheral eosinophilia,
hypocomplementemia and high erythrocyte sedimentation
rate. Spectrum of presentation is varied ranging from mild and
asymptomatic to life threatening complications. CES is associated
with significantly worse long term renal effects as compared to CIN
and is suspected when multiple oral dysfunction occurs following
coronary angiography [27].
Pathophysiology
Kidneys are particularly susceptible to ischemic injury in
setting of delicate micro vascular circulation, which is particularly
vulnerable to systemic and local hypo perfusion. Pathogenesis of
CIN is multi factorial and still not completely understood. Interplay
of factors including medullary hypoxia, oxidative stress, im balance
of renal vaso constrictive and vaso dilatory mediators, changes in
renal perfusion and direct tubular toxicity of CM has been suggested
[28-30]. Two main mechanisms responsible are direct tubular
toxicity of CM and changes in renal micro vascular hemo dynamics.
Recently, high end diastolic pulmonary arterial blood pressure
and left anterior descending artery lesion has been independently
associated with development of CIN, pointing towards role of hemo
dynamics and cardiac dynamics in its pathogenesis [31].
Effect of CM on Renal Tubules
CM is freely filtered from renal glomerulus and increases the
tubular osmolality. It has direct cytopathological effects on tubular
cells, which affects energy metabolism and impairs intracellular
transport. Histopathologically, these changes consist of tubular cell
vacuolization, necrosis and termed as osmotic nephrosis. There has
been conflicting evidence to support precipitation of intratubular
proteins triggered by CM. Actually it is proposed that CM induced
cellular injury might be the inciting event responsible for CIN
which triggers the cascade rather than hypoxia or hypoperfusion.
Osmolality, viscosity and ionic properties of CM contribute to
its nephrotoxicity. High osmolar CM have been shown to affect
erythrocyte deformability, leading of stacking of blood cells
and affecting blood flow in animal models. Another mechanism
reported is mitochondrial dysfunction and release of catalytic iron,
which serve as catalyst in oxidative reactions leading to production
of free radicles [28-30].
Effects on Renal Microvascular Hemodynamics
Animal model have suggested that intra-arterial contrast
infusion results in biphasic renal perfusion, with initial transient
vasodilation followed by sustained prolonged vasoconstriction.
Renal medullary perfusion and oxygen tension is lower than outer
renal cortex under normal physiological state and thick ascending
loop of henle in outer renal medulla has high oxygen requirement
exacerbating relative medullary hypoxia. CM further aggravates
this hypoxia by causing osmotic diuresis leading to increased
sodium transport to thick ascending limb and subsequently
increased oxygen extraction. Total medullary hypoxia is actually
combination of increased oxygen demand of tubular cells and
changes in regional renal microcirculation [32,33]. Subclinical
CIN can occur in majority of patients following contrast exposure;
however it goes undetected as healthy individuals have intact
tubular repair mechanism that prevents clinically significant renal
damage. In contrast, in patients with comorbidities like baseline
renal impairment and diabetes mellitus even average dose of
contrast can have clinical implications in setting of poor reparative
mechanism and baseline reduced functional nephrons [34].
Risk Factors
Various risk factors have been described which increases the
risk for development of CIN after exposure to iodinated CM. These
can be broadly divided into intrinsic or patient related and external
or procedural/contrast related. Among the patient related factors,
baseline renal impairment (GFR < 60 mL/min per 1.73 m2) and
diabetes mellitus are the two important independent risk factors
that are commonly coexisting in vascular patient population
[7,35]. However, recent analyses by McDonald [16] and Davenport
et al. [36] have found increased incidence of CIN in diabetes only
if renal function is compromised (GFR < 30 mL/min/1.73 m2)
[16,36]. Studies have reported significant risk for CIN if baseline
serum creatinine concentration is ≥1.3 mg/dL in men and ≥1.0
mg/dL in women, mostly equivalent to an eGFR <60 mL/min/1.73
m2 [37]. In light of recent studies, European Renal Best Practice
(ERBP) along with Kidney Disease Improving Global Outcomes
(KDIGO) guidelines suggest that the threshold at which actual risk
for CIN increases could be lowered to 45 mL/min/1.73 m2 [38].
Other established risk factors include advanced age (≥70 years),
dehydration, anemia, vascular disease, hypertension, coronary
artery disease, congestive heart failure, smoking and concomitant
use of other medications including metformin, non-steroidal
anti-inflammatory drugs (NSAIDS), diuretics or calcium channel
blockers.
It was long thought that patients with multiple myeloma have
increased risk CIN secondary to precipitation of myeloma proteins
in the renal tubules. However, recent studies propose that contrast
studies can be safely performed in myeloma patients with normal
renal function provided there is no dehydration. Also, studies have
reported acute urate nephropathy in patients with hyperuricemia,
particularly leukemic patients on chemotherapy, secondary to
uricosuric property of CM, however recent studies have failed
to show independent association between the two [21,39].
Extrinsic or contrast related factors includes type of CM, route of
administration, dose of CM and numbers of contrast exposure.
Procedure related factors may include urgent or emergent
procedure, use of intra-aortic balloon pump, delayed reperfusion
and nature of procedure [12,21,39]. Various risk scoring have
been proposed to stratify the risk for CIN. One of them reported by
Mehran et al. [6] included eight variables namely age > 75 years,
anemia, hypotension, diabetes mellitus, chronic congestive heart
failure (CHF), acute pulmonary edema, chronic kidney disease, use
of intra-aortic balloon pump and increase volumes of CM. Total
risk score ≥ 16 was associated with 57% risk of CIN with 13% of
patient requiring dialysis [40]. Another simple risk scoring, which
has shown to have clinically significant predictive value for CIN, is
ACEF score. It uses three variables, namely age, creatinine level and
ejection fraction and has been developed for patients undergoing
coronary angiography [41,42].
Iodinated CM
Type of Iodinated CM: Commonly available CMs are benzoic
acid derivatives with three iodine atoms. High osmolar CM (HOCM),
with osmolality up to eight times that of plasma were frequently
used in past and had higher incidence of CIN. To decrease the
osmolality, several approaches were considered including
production of non-ionic agents, which resist dissociation in
solution or by producing double benzoic acid rings. Low osmolar
(LOCM) and isosmolar CM (IOCM) are commonly used nowadays
and associated with low nephrotoxicity [43]. (Table1) descries the
properties of CM. The adverse effect of CM is mainly related to its
osmolality, ionicity, viscosity and iodine content. Viscosity instead
of osmolality is responsible for vascular resistance [44]. Though
IOCM has lower osmolality, because of its dimeric structure it has
more viscosity than LOCM. There are conflicting results in studies
comparing LOCM with IOCM and in most, no difference was found
with respect to renal safety [45]. KDIGO guideline recommends use
of LOCM or IOCM instead of HOCM however due to lack of data,
there is no recommendation regarding preference of IOCM over
LOCM [46]. However, CIN Consensus Working Panel recommends
use of nonionic IOCM in patients with high risk for CIN undergoing
coronary angiography, whereas IOCM or LOCM can be used for
intravenous administration of contrast [47]. The current Canadian
Association of Radiologists (CAR) consensus recommends use of
CM depending upon route of administration of contrast and renal
function; LOCM or IOCM should be used if eGFR < 45 mL/min
for intravenous exposure and GFR < 60 mL/min for intra-arterial
CM studies [48]. Many radiology department now-a-days uses
IOCM in high risk patient population, especially with severe renal
impairment with eGFR < 30 mL/min. Local hospital protocols based
on guidelines can be used to decide between IOCM and LOCM.
Table 1: Properties of contrast media (information taken from
manufacturer manual).
Dose of CM: A number of studies have shown contrast volume
to be independent risk factor for subsequent development of CIN
after coronary or peripheral angiography [39]. Both volumes
of contrast and iodine content needs to be carefully considered
taking in account renal safety and optimum imaging. Iodine
content is important determinant of image enhancement and
degree of attenuation achieved. Iodine content for most of the
commonly used contrast ranges from 300 to 370mg/ml. Low dose of CM
defined as <30-125ml or <5mg/kg, is less nephrotoxic and
associated with lower risk of CIN. However, AKI can even occur with
small (30 mL) volumes of iodinated CM, ruling out threshold effect.
Some reports suggest performing staged angiography particularly
when large volume of contrast use is anticipated, however this is
solely dependent on clinical situation [39,43]. Brown et al.[49]
proposed formula and use of “maximal allowable contrast (MAC)
dose” (contrast volume limit [ml = 5 × body weight {kg}]/ [88.4 ×
SCr {μmol/l}]), which correlated, with development of CIN [49].
Whenever possible lowest dose of contrast should be used by
incorporating MAC as a part of pre-procedure contrast ‘Time-Out’;
especially in patients with high risk factors when other alternative
modalities cannot be used.
Route of Administration: This is procedure dependent. Intraarterial
(IA) injection of iodinated contrast is associated with higher
risk of CIN compared to intravenous (IV) administration. Proposed
mechanism behind greater risk after IA exposure is amount of
contrast directly reaching kidneys if contrast is administered
directly in abdominal aorta or renal arteries. Risk is less if contrast
is given below origin of renal arteries and minimal risk after IV
administration [4,43]. Recent studies by McDonald et al. [16] and
Daveport et al. [36] using “propensity matching” as statistical tool
in order to compare incidence of CIN in patients who received IV
contrast for CECT to control group, found that occurrence of CIN
in this population is rare and if it occurs it happens in patients
with baseline severe renal impairment (eGFR<30ml/min/1.73 m2)
[16,36].
Repeat Contrast Exposure: Multiple dose exposure of
contrast within short period of time is well-documented risk
factor for CIN [40,43,50]. It is believed that at least 24 hours
interval should be considered between two contrast exposures
as it takes approximately 20 hours to eliminate contrast from the
body, provided patient has normal renal function. Guitterez et al.
[51] demonstrated renal impairment may persist for 10 days after
contrast exposure and duration of renal impairment is dependent
on baseline renal function. Therefore, repeat exposure should be
delayed in patients with chronic kidney disease to allow time for
renal recovery [51].
Alternative Imaging Modalities to Prevent CIN: In patients
with high risk for CIN, alternative imaging modalities should
be chosen after proper risk benefit discussion with the patient.
Though contrast enhanced imaging have its own advantages
particularly for the diagnosis of inflammatory/ infectious disease
and neoplastic conditions as well as diagnosis and treatment of
vascular diseases, it is important for the clinicians to be well aware
of alternative modalities like ultrasonography, carbon dioxide
(CO2) angiography and magnetic resonance imaging (MRI) with
or without gadolinium (Table 2). In patients at risk for CIN every
effort should be made to avoid iodinated contrast if possible. Non
contrast computed tomography (NCCT) is preferred for diagnosis
of intracranial hemorrhage, fracture or dislocation and interstitial
lung disease [52].
Non contrast MRI [53] including Steady-state free precession
MRI (SSFP), Phase contrast MRI, time of flight (TOF) MR angiography
should be employed in appropriate setting as described in (Table
2). Gadolinium based contrast agents can be used in patients at risk
of CIN, however it is best avoided in patients on dialysis and with
severe renal impairment especially chronic kidney disease (CKD)
Stage 4 and 5 for concerns of nephrogenic systemic fibrosis (NSF)
[54,55]. CO2 angiography is another useful modality often used in
various diagnostic and therapeutic interventions when exposure to
CM must be avoided to prevent CIN or patient is allergic to iodinated
contrast [56]. It is highly soluble, non-allergic, inexpensive and
readily available gas with low viscosity relative to blood. For some
procedures, CO2 angiography is actually superior to conventional
CT including better visualization of collateral circulation, enhanced
vascular filing in central venography, detection of AV shunting
in tumors and detection of occult GI bleeding. It can be used in
patients with chronic lung disease with caution if sufficient time is
allowed for elimination of gas from the body. However, it has some
limitations as well. It is preferably used for infradiaphragmatic
arteriography due to concerns of neurotoxicity. Other complication
limiting its use is vapor lock or air trapping which increases with
simultaneous use of nitrous oxide. Another limitation for its use is
cumbersome delivery system and risk of error of measurement of
vessel size, which is dependent on injection technique [56].
Table 2: Alternative non-iodinated contrast and non-contrast diagnostic imaging modalities.
*FAST: Focused Assessment with Sonography for Trauma.
DVT: Deep Venous thrombosis.
TOF: Time of flight.
ICM: Intravascular contrast medium.
SSFP: Steady state Free Precision.
Special Consideration With Use of Iodinated CM:
a) Met Formin Use: Metformin has not been recognized
as independent risk factor for developing CIN, however
serious complications like lactic acidosis can rarely develop
in patients on metformin, if they subsequently develop AKI
after contrast exposure. Whether it should be stopped in all
patients anticipating contrast exposure or only in patients
with underlying renal impairment and how earlier it should
be stopped is still matter of controversy. The monogram
for Glucophage (metformin) recommends that it should be
discontinued at the time of or before the procedure in all patients,
withheld for at least 48 hours subsequent to the procedure, and
restarted only after confirmation of normal renal function [57].
The European Society of Urogenital Radiology (ESUR) (Table
3) and Canadian Association of Radiologist (CAR) consensus
recommends holding metformin at the time contrast exposure
in patient with normal renal function and 48 hours before
in patients with preexisting chronic kidney disease [48,58]. However, ACR recommends withholding it for 48hrs before
exposure only in patients with marked renal impairment (eGFR
≤ 30 mL/min/1.73 m2) or undergoing intra-arterial catheter
studies and no need to discontinue or withhold if eGFR > 30
mL/min1.73 m2) [59].
Table 3: Preventive strategy to lower the risk of CIN as per EUR guideline 2011.
b) End Stage Renal Disease (ESRD): Patient with ESRD
on dialysis usually do not have functional kidneys and can
receive intravascular contrast material without further risk
of renal damage, however studies have speculated conversion
of oliguric patient to anuria. Other consideration is risk of
pulmonary edema and fluid overload after osmotic load,
though it was reported in past when HOCMs were frequently
used. However, whenever possible LOCM should be used as
they are not protein bound and have low molecular weight
and can be cleared by dialysis. Usually urgent dialysis is never
indicated after CM in this population unless there is exposure to
large volume of contrast and patient develops life threatening
pulmonary edema or cardiac arrhythmia [60].
c) Screening baseline renal function: It is actually general
practice to screen baseline renal function prior to contrast
exposure; however it can lead to diagnosis or procedural delay,
increase financial cost and patient discomfort. ACR recommends
to screen renal function (e.g., serum creatinine, eGFR) prior to
exposure to iodinated CM in only selected patients with high
risk factors including age >60 year, patient with history of renal
disease, renal cancer, renal surgery, patient on dialysis, patients
with single kidney, hypertension on medical therapy and
diabetes mellitus. Patient who do not have above-mentioned
risk factors and require routine intravascular contrast do not
require routine screening [61,62]. Choyle et al. [62] listed few
risk factors (preexisting renal dysfunction, hypertension, gout,
proteinuria and prior renal surgery) and found that if none of
these factors are present 99% of patients had serum creatinine
levels less than 1.7mg/dl and 94% of patients had normal
renal function [62]. However, ERBP guidelines recommend
measuring baseline serum creatinine in all patients before an
intervention and repeat levels 12 and 72 hours after contrast
administration in high-risk patients [38]. The decision to
repeat serum creatinine after procedure is a matter of debate.
According to ESUR, renal function after contrast exposure
should be assessed in 3 days, however some studies have
documented that in certain patient populations particularly
with diabetes mellitus and chronic kidney disease peak rise in
creatinine levels is actually delayed, which demands prolonged
renal function survey [58,63].
Prevention of CIN
There has been number of preventive measures to reduce
incidence of CIN in high- risk population, however there is no
clear consensus and current evidence remains inconclusive
[64,65]. However, it has been agreed that identification of highrisk
population is the foremost. Once this population is identified,
best attempt should be done to minimize renal injury by stopping
other nephrotoxic medications particularly NSAIDS, loop diuretics
and met formin at least 24-48hours prior to contrast exposure
particularly if IA exposure is anticipated and in patients with
baseline severe insufficiency [47,57,58]. Unfortunately, in emergent
procedures it might not be possible to stop medications or delay
the procedure, however when possible restarting the nephrotoxic
medication should be delayed for at least 48 hours after or as
deemed clinically appropriate (Figure 1).
Figure 1: 68-year-old female with drop in hemoglobin status-post cardiac catheterization one day ago. Non-Contrast enhanced
CT Abdomen demonstrating persistent nephrogram phase of enhancement from prior cardiac catheterization due to contrast
induced nephropathy. Note hyperdense collection suggestive of an acute hematoma extending adjacent to RIGHT psoas
muscle (*) lateral to the RIGHT psoas muscle continues with RIGHT iliac vessels, likely cause of drop in hemoglobin. Red
arrow depicting no intra-vascular contrast media in the current study.
Figure 2: Flowchart for Risk stratification and preventive measures.
The cornerstone of practice to prevent CIN remains volume
expansion. It is low-risk practice and carries few complications.
Randomized trials have documented effectiveness of IV hydration
with normal saline in the prevention of CIN. It should be given in
all risk categories, particularly patients with an estimated GFR
<60 ml/min/1.73 m2. It is postulated to promote diuresis, increase
intravascular volume, induce vasodilation and suppress renin
aldosterone axis. However, there is no fixed regimen and in general,
starting it well before exposure and continuing even after procedure
is the best practice. Oral volume expansion has shown some benefit,
however evidence does not support it to be as effective as IV volume
expansion. For isotonic saline administration, most studies suggest
that 0.9% saline should be started at a rate of 1-1.5 mL/kg/h
3-12 h before and 6-12 h after contrast media exposure [66,67].
IV administration of sodium bicarbonate has also been studied for
prevention of CIN; however recent data have shown conflicting
and mixed results. The theoretical benefit of sodium bicarbonate is
alkalization of tubular fluid and reduced production of free oxygen
radicals, along with volume expansion. Most studies have suggested
that it should be started at a rate of 3 mL/kg/h 1 h before and 1 mL/
kg/h for 6 h after contrast exposure. Though some studies have
documented its beneficial effects, they have been critiqued for
being single center, non-blinded and small studies [67,68].
N-acetylcysteine (NAC) also gained popularity for use to
prevent CIN. It is believed to be direct free radicals scavenger, which
improves blood flow through nitric oxide-mediated pathways. Its
antioxidant and vasodilator actions are believed to protect against
CIN. As compared to IV saline alone, low-dose NAC along with IV
saline has shown significant decrease in CIN in patients receiving
either IA or IV contrast. It is commonly employed agent in clinical
setting in patients at high risk because of high tolerability, low cost,
potential cardio protective properties, even in absence of clear
scientific evidence. KDIGO 2012 guideline recommends using oral
NAC with IV fluids in patients with high risk of CIN in setting of its
low risk profile [38,69]. Algorithm showing preventive measures
to be taken is shown in (Figure 2) Various other experimental
pharmacologic agents have been studied for CIN prophylaxis
including statin, ascorbic acid, tocopherol, dopamine, fenoldopam,
theophylline, nebivolol, atrial natriuretic peptide and prostaglandin,
however none of them have achieved clinical significant results
[70]. Also, no beneficial effect of experimental procedures such
as hemo filtration (HF) and prophylactic hemodialysis (HD) was
found against CIN [71]. Moreover, prophylactic HD was found to
be associated with increased CIN [71]. New investigational study
‘Renal guard system’ which is a fluid management device seems
promising except for concern of electrolyte abnormalities and
additional studies are needed before renal guard system can be
implemented clinically [72,73].
Clinicians should be well aware of CIN, which is potentially
serious entity. Since there is no established treatment for CIN, every
effort should be taken to prevent it from occurring by recognizing
at risk population, weighing risk-benefit ratio in all patients,
optimizing volume status prior to contrast exposure, avoiding
simultaneous use of other nephrotoxic agents, using newer
generation of CM and using lowest possible dose.
Conclusion
Clinicians should be well aware of CIN, which is potentially
serious entity. Since there is no established treatment for CIN, every
effort should be taken to prevent it from occurring by recognizing
at risk population, weighing risk-benefit ratio in all patients,
optimizing volume status prior to contrast exposure, avoiding
simultaneous use of other nephrotoxic agents, using newer
generation of CM and using lowest possible dose.
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