Introduction:
Epidemiology:
Each year, there are millions of procedures done in the United States
that utilize iodinated contrast agents. The main risk of iodinated
contrast is kidney injury which could lead to morbidity and
mortality (1–6).
Contrast-induced nephropathy (CIN), also known as contrast-induced acute
kidney injury (CI-AKI), is one of the most common causes of impairment
of renal function in the United
States (7–10) and
is the third common cause of hospital-acquired renal
insufficiency (11).
Different studies have used various definitions for contrast-induced
nephropathy including an increase in serum creatinine ≥0.5 mg/dl or
≥25% from baseline creatinine within 24 to 72 hours after contrast
medium
administration (3,6,12–16).
The mortality rate is increased among patients who developed CIN during
and after hospitalization, especially among those who required
dialysis (6,17,18).
Therefore, any preventive measures that can reduce CIN risk can be
lifesaving with a reduction in mortality and morbidity in patients
undergoing iodinated contrast exposure.
Brief Summary of CIN preventive measures:
● Hydration and fluid optimization
Several methods have been proposed to prevent CIN in clinical settings.
However, none of them has been proved to be consistently effective
except for hydration and reduction in the amount of contrast exposure.
Hydration is the most common prophylactic technique to reduce CIN
occurrence in a way that all high-risk patients undergoing contrast
exposure should receive appropriate hydration if possible before the
procedure in high-risk patients and after the procedure in all patients
if feasible without contraindication to
hydration (14,19–23).
It has been shown that intravenous fluid administration with isotonic
saline is more effective compared to the half saline
infusion (14,22).
However, the optimal fluid volume and infusion rate is controversial.
Current guidelines recommend intravenous administration of 1-1.5 ml/kg/h
of normal saline six hours before and after contrast
injection (24).
With respect to proper fluid administration, left ventricular
end-diastolic pressure (LVEDP) can be assessed and adjusted accordingly.
This theory was assessed in the POSEIDON trial. Their findings suggested
patients who received adjusted fluid based on LVEDP had a significantly
lower risk of CIN after cardiac catheterization (relative risk: 0.41,
95% confidence interval (CI): 0.22 – 0.79, P= 0.005). However, three
cases of shortness of breath, probably in the context of pulmonary
edema, were reported in both intervention and control
groups (25).
Also, Maioliet et al. used bioimpedance vector analysis (BIVA) for the
assessment of body fluid status. After randomization of low BIVA
patients to normal or double volume normal saline administration, they
found no significant difference in CIN occurrence defined by standard
criteria (increase serum creatinine by ≥ 0.3 mg/dl within 48 hours)
between those groups (10.8% vs. 4.7%, P= 0.08,
respectively) (26).
● Avoidance of nephrotoxic agents
Another factor that can raise CIN risk might be related to nephrotoxic
drugs. Although there are not enough trials to strongly prove the
benefit of nephrotoxic drugs discontinuation before contrast exposure,
it is generally recommended to hold potentially nephrotoxic drugs
including nonsteroidal anti-inflammatory drugs, aminoglycosides,
vancomycin, sulfonamides, penicillins, amphotericin, loop diuretics, and
metformin in high-risk patients. The latter drug has been associated
with metabolic acidosis which might predispose kidneys to the
development of CIN but this concept has not been
proven (27,28).
● N-Acetylcysteine administration
N-Acetylcysteine (N-AC) was initially reported by Tepel et al. to be
protective against contrast-induced nephropathy in a small trial (29).
However, numerous trials and meta-analyses have completely failed to
show any benefit and therefore its use is not
recommended (29–31).
Contrast media typed based on osmolality is thought to be important for
CIN pathogenesis and has been categorized into three different types
based on the osmolality (high osmolar, low osmolar, and
iso-osmolar) (32).
Initially, several studies have shown that iso-osmolar contrast media
have the lowest risk of CIN incidence in comparison to low-osmolar
contrast
agents (33–36),
but numerous other trials failed to show any significant differences in
the occurrence of contrast-induced
nephropathy (37–40).
● Dialysis and hemofiltration
In terms of dialysis and hemofiltration which directly removes the
contrast from the systemic circulation, there is no clinical evidence
suggesting prophylactic use of dialysis can prevent
CIN (41).
No benefit has been reported for post-procedural dialysis
either (42).
Marenzi et al. reported the use of hemofiltration might be beneficial in
the prevention of
CIN (43).
However, it remains unclear whether it was related to increased
clearance through dialysis or due to alkalinizing agents used during
filtration.
● Treatment of hypoperfusion
Due to the negative effect of renal hypoperfusion, regardless of its
etiology, with contrast administration resulting in increased CIN risk,
utilization of short time assisted devices increasing cardiac output
might reduce this risk. Flaherty and colleagues performed a randomized
clinical trial and found usage of a Microaxial percutaneous assist
device (Impella) was associated with a lower likelihood of acute kidney
injury among high risk percutaneous coronary intervention (PCI) patients
with reduced left ventricular ejection fraction ≤ 35% (odds ratio (OR):
0.13, 95% CI: 0.09 – 0.31, P<
0.001) (44).
These findings might be associated with resultant reduced CIN risk.
However, larger studies are warranted.
● Balanced hydration system
Another proposed mechanism in CIN prevention has been attributed to a
balanced hydration procedure. This process has been suggested based on
the theory that as urine output becomes higher, the contrast
concentration in kidneys would become lower ultimately resulting in
decreasing CIN risk. Briguori et al. implemented Renal Insufficiency
After Contrast Media Administration Trial II (REMEDIAL II) trial to
assess the feasibility of the RenalGuard system (PLC Medical Systems,
Inc, Franklin, MA) in the prevention of CIN. Briefly, the mentioned
system consists of closed-loop fluid management that consistently
monitors and evaluates hydration status and urine output. 294 candidates
for coronary or peripheral angiography/angioplasty with an estimated
glomerular filtration rate (eGFR) of ≤ 30 ml/min/1.73
m2 and/or risk score of at least 11 were selected and
randomly allocated to control (sodium bicarbonate and N-AC
administration) or RenalGuard (hydration with saline and N-AC under
RenalGuard system control with furosemide administration) group. The
intervention group received an initial bolus for 30 minutes and
furosemide (0.25 mg/kg) would be prescribed to increase urine output to
≥ 300 ml/h. They found CIN was significantly decreased in the RenalGuard
arm compared to controls (11% (16 out of 146 subjects) vs. 20.5% (30
out of 146 subjects), OR: 0.47, 95% CI: 0.24 – 0.92). Different
administration routes of N-AC (oral agent for controls and intravenous
route for intervention group) resulting in probable variable
bioavailability of the drug as well as their reported data applicable to
a subset of chronic kidney disease (CKD) patients might be considered
for extension of the
outcomes (45).
Likewise, the Induced Diuresis With Matched Hydration Compared to
Standard Hydration for Contrast-Induced Nephropathy Prevention (MYTHOS)
trial using the RenalGuard system was performed for CKD patients who
underwent coronary procedures. 170 subjects with eGFR< 60
ml/min/1.73 m2 were randomly assigned to standard
intravenous saline hydration as a control group (n= 83) or furosemide
with matched hydration as an intervention group (n= 87). The
intervention arm received 250 ml of normal saline as well as 0.5 mg/kg
of furosemide to reach a urine output of more than 300 ml/h. Patients in
the intervention group experienced CIN less frequently rather than
controls (4.6% vs. 18%, P= 0.005). Single-center and not-blinded study
design, as well as pre-determined hydration protocol in the intervention
group, were some limitations related to the mentioned
project (46).
Also, a cooling renal method based on the theory of decreasing oxidative
injury in lower temperatures in the context of contrast injection has
been announced. However, it did not show any promising outcome in terms
of CIN prevention. For instance, Stone and colleagues performed a
randomized trial and allocated 128 cardiac catheterization candidates
with CKD (estimated creatinine clearance: 20-50 ml/min) to control (n=
70) and intervention (n= 58) groups. In addition to hydration, the
latter group underwent systemic hypothermia at 33-34 °C starting before
contrast injection toward three hours post-procedure followed by
rewarming to 36 °C with a rate of 1 °C per hour afterward. CIN was
observed in 18.6% and 22.4% of normothermia and hypothermia groups,
respectively. However, there was no significant association neither in
unadjusted nor in adjusted models (OR: 1.27, 95% CI: 0.53 – 3.00, P=
0.59 and OR: 0.83, 95% CI: 0.18 – 3.78, P= 0.81,
respectively) (47).
● Ischemic preconditioning
The hypothesis of ischemic preconditioning, as multiple short cycles of
ischemia and reperfusion in one organ, could be effective on another
organ, on reduction of CIN has been tested in a randomized clinical
trial on 100 subjects which revealed four 5-minute inflation-deflation
cycles of blood pressure cuff to 50 mmHg above each patient systolic
blood pressure before coronary angiography (CA) had been associated with
a decreased likelihood of CIN compared to controls (OR: 0.21, 95% CI:
0.07 – 0.57, P=
0.002) (48).
Although this procedure can be applied in all clinical settings, further
studies with a larger sample size are required.
One small study showed infusion of sodium bicarbonate might be more
effective in the prevention of CIN rather than isotonic
saline (49).
However, subsequent larger trials failed to prove this
association (25,26).
Therefore, sodium bicarbonate is not recommended to be used for this
purpose by the Consensus Working
Panel (22).
Other pharmacologic agents include ascorbic acid, diuretics, mannitol,
calcium channel blockers, fenoldopam, dopamine, atrial natriuretic
peptide, L-arginine, theophylline, and statins have been reported in the
literature in terms of CIN prevention with controversial
results (50–62).
The role of contrast volume
● Contrast volume as a
risk for CIN
Contrast volume has been shown to be an independent risk factor for
CIN (63–65).
It has been previously proved the amount of contrast correlates with the
incidence of
CIN (66).
After a data analysis of 53780 vascular interventions, Lee et al.
indicated CIN was correlated with CKD stage in a way that the incidence
of AKI in the context of contrast administration raised with each CKD
stage (CKD stage 1: 0.39%, CKD stage 2: 0.45%, CKD stage 3: 1.5%, CKD
stage 4: 4.3% and CKD stage 5: 7.5%). They suggested the risk of
post-contrast AKI could be reduced by using safe thresholds of contrast
volume (67).
Rihal et al.’s study reported the volume of contrast media administered
during the PCI was correlated with acute renal
failure (6).
Kooiman and colleagues analyzed data from 82,120 PCI procedures and
found patients who received high contrast, as defined by division of
contrast volume over calculated creatinine clearance resulting in more
than 3, had increased CIN odds in both univariate and multivariate
regression models (OR: 1.61, 95% CI: 1.46 – 1.79, P< 0.001
and OR: 1.77, 95% CI: 1.58 – 1.98, P< 0.001,
respectively) (68).
Likewise, another observational study on 561 patients suffering from
myocardial infarction who underwent PCI revealed CIN was significantly
higher among those with a contrast ratio (measured by administered
contrast volume divided by calculated maximum contrast agent dose) of
more than 1 in comparison to the ratio of less than one (34.6% vs. 3%,
P<
0.001) (65).
Kane et al. reported the rate of CIN
in patients with CKD undergoing CA could be reduced by ultra-low
contrast
volumes (69).
However, even small amounts of contrast can deteriorate renal function,
especially among high-risk
patients (70).
A small study on 30 patients with eGFR< 45
ml/min/1.73m2 underwent CA/PCI with ultra-low volume
contrast media showed utilization of this kind of agent was safe with no
reported increased serum creatinine 48 hours
post-procedure (71).
However, a single study design and small sample size are potential
limitations needed to be considered. 123 subjects with at least stage 3
of CKD experienced CA/PCI was selected by Kelly and colleagues. They
used a novel ultra-low contrast delivery technique with an automated
contrast injector for their procedures and reported a CIN rate of 3.3%.
Quite a small sample size, as well as retrospective study design and
performance in a single-center, should be considered for the
generalization of their
findings (72).
Although the CIN rate was lower among CKD patients who underwent PCI
with ultra-low contrast (n= 8) compared with the conventional group (n=
103) in another retrospective study, the difference was not
statistically significant (0 vs. 15.5%, P= 0.28). Asymmetric sample
distribution between groups and their small cohort size might limit
their
outcomes (73).
Mariani et al. proposed the theory of zero contrast volume and performed
MOZART (Minimizing cOntrast utiliZation With IVUS Guidance in coRonary
angioplasTy) trial to assess whether intravascular ultrasound (IVUS)
could decrease contrast exposure compared to the routine method. 83 PCI
candidate patients were selected and randomly assigned to routine
angiography (n= 42) or IVUS method (n= 41) with matched clinical and
laboratory data. The median contrast volume was significantly lower in
IVUS rather than in the routine angiography group (20 ml, interquartile
range (IQR): 12.5 – 30 ml vs. 64.5 ml, IQR: 42.8 – 97 ml, P<
0.001). Also, the ratio of contrast volume to creatinine clearance was
remarkably lower in the IVUS group (0.4, IQR: 0.2 – 0.6 vs. 1.0, IQR:
0.6 – 1.9, P<
0.001) (74).
Although they found a promising outcome, the higher cost of IVUS might
be a limiting factor for usage in clinical settings. On the other hand,
it has been suggested that contrast volume reduction before contrast
exposure may lower the risk of
CIN (75).
● Methods for reducing contrast volume administration
In terms of reducing contrast volume administration, few studies are
available. Mehran et al. performed a randomized clinical trial to assess
the efficiency of contrast reduction in patients with underlying renal
diseases who underwent CA. 578 patients in stage III (eGFR between 30
and 60 ml/min) and IV (eGFR between 20 and 30 ml/min) of CKD with at
least two further criteria of New York heart association (NYHA)
functional class of III or IV of heart failure, diabetes mellitus
(treated with either insulin or oral agents), anemia, hypertension,
albuminuria or age of at least 75 years were randomly assigned to
hydration (n= 286) or hydration plus AVERT system group (n= 292). The
latter system is a contrast modulation system designed to adjust the
pressure of contrast injection toward the patient. The relative
reduction in contrast volume was 15.5% (hydration group: 101.3 ± 71.1
ml vs. hydration plus AVERT group: 85.6 ± 50.5 ml, P= 0.02). The
distribution of AKI induced by contrast did not differ significantly
(26.6% vs. 27%, P= 0.70,
respectively) (76).
Likewise, Gurm and colleagues performed an observational study on 114
patients with eGFR of 20 – 60 ml/min/1.73m2 to assess
the feasibility of contrast volume reduction during CA or PCI using
DyeVertTM Plus Contrast Reduction System (DyeVert Plus
System, Osprey Medical). Data analysis of 105 successfully recruited
patients revealed the contrast volume saving of 40.1 ± 8.8% per each
performed procedure. AKI induced by contrast agent was observed in three
(2.6%) of
patients (77).
The small sample size and observational design of the study should be
considered for the generalization of reported data.
● Automated contrast injection devices
Although data analysis of 60,884 candidates who underwent PCI revealed
contrast agent usage was lower in centers that used automated contrast
injectors compared to those centers not used this method (199 ± 84 ml
vs. 204 ± 82 ml, P< 0.0001), no difference had been found in
terms of CIN occurrence (3.11% vs. 3.42%, P=
0.15) (78).
On the other hand, Minsinger and colleagues performed a meta-analysis
and found automated contrast injectors decreased contrast volume up to
45 ml per subject (95% CI: 0.78 – 0.93, P< 0.001), and it
was associated with a 15% reduction in CIN compared to manual injection
methods (OR: 0.85, 95% CI: 0.78 – 0.93, P<
0.001) (79).