CONTRAST INDUCED NEPHROPATHY

IN CARDIAC PATIENTS: UPDATE ON

PREVENTION AND TREATMENT

Zorica Dimitrijevic, Clinic for Nephrology, Nis

• Rapid growth in interventional and image-
guided medical procedures in the cath lab

• More than 7 million interventional cardiology

and radiology procedures performed annually
worldwide
• The extensive administration of contrast agents
during these procedures has become a highly
focused issue globally.

• Contrast-Induced Nephropathy (CIN or Contrast-

Induced Acute Kidney Injury - CI-AKI) is an
iatrogenic disease that may occur when
radiographic contrast media are injected
intravenously or intra-arterially
 Impact
• Radiographic contrast media is the third most
common cause of hospital acquired kidney injury ,
accounting for 11% of cases

• In-hospital mortality rate of CIN as high as 14%1

• In patients with multiple risk factors, incidence of CIN

can rise to 50% or greater2

1 Nash et al. Am J Kidney Dis 2002

2 McCullough PA et al. Am J Cardiol 2006
 The Consequences of C-I-N

CIN may result in any or all of the following:

– Delay in discharge of patient
– Permanent kidney damage
– Dialysis
– Increased patient mortality

Dangas G, et al. Am J Cardiol. 2005;95:13-19.

 Acute CIN is Associated with Long Term
Morbidity and Mortality 5-yr death
P < 0.001
N=78
No CIN
CIN

1-yr major 1-yr All AE

AE P = 0.02
P = 0.04 N=294
% 1-yr death N=294
1-yr death
P < 0.001 P < 0.0001
N=5,397 N=7,586

Lindsay Rihal Solomon Solomon Goldenberg

2004 2002 2009 2009 2009
 Contrast-Induced Acute Kidney Injury (AKI)
Definition
• New onset or exacerbation of renal dysfunction
after contrast administration:
increase by >25%
or from baseline
absolute  of > 44 µmol/ L serum creatinine

and in the absence of other etiology

• Always try to exclude other causes such as athero-embolism,
ischemia, other nephrotoxins….
 Time course of CI-AKI:
CI-AKI or CIN
• Cr peaks in 3-5days and
normalizes in 7-10 days(70%)

• In 30%, 3 weeks to return

Contrast baseline or progress to CKD

• CIN may range in severity

from asymptomatic,
nonoliguric transient renal
dysfunction to oliguric
severe renal failure that
necessitates permanent
dialysis.
 Frequency of Contrast-Induced
Nephropathy
14.5%* N=1826 consecutive patients undergoing PCI
16%
14%
12% Rise > 25% Cr
Incidence rate

10% Rise > 50% Cr

8% Doubling
6% Rise > 1 mg/dl
4% Post Cr > 5 or dialysis
2%
0%
Definition of Renal Outcome

*Validated at 16.5% in 8,628 consecutive series at Washington Hospital Center,

Iakovou, et al. ACC 2002

McCullough PA, Am J Med 1997;103:386-375.

 Incidence
• CIN has decreased over the past decade from ~15% to
~7% recently
Nash et al. 4622 patients, 7.2% CIN
• Thought to be due to
– Greater awareness of the problem
– Better risk prevention measures
– Improved iodinated contrast media

Total number of cases did not decline due to increasing

number of procedures requiring contrast
CKD progression: biology versus “iatrogenesis”?

NSAID for
NSAID for
Gout
Gout
Gentamicin for
Gentamicin for
UTI
UTI
FR
GGFR

Contrast for
Contrast for
coronary cath
coronary cath

CHF with diuresis

CHF with diuresis
leading to AKI
leading to AKI
and low BP
and low BP

ESRD
ESRD

time
time
Fink, et al, AJKD, 2009
CKD progression: biology versus “iatrogenesis”?

NSAID for
NSAID for
Gout
Gout
Gentamicin for
Gentamicin for
UTI
UTI
FR
GGFR

Contrast for
Contrast for
coronary cath
coronary cath

CHF with diuresis

CHF with diuresis
leading to AKI
leading to AKI
and low BP
and low BP

ESRD
ESRD

time
time
Fink, et al, AJKD, 2009
 Risk Factors for CIN

Patient-related Risk Factors Procedure-related Risk Factors

• CKD • Multiple contrast media injection
• Diabetes mellitus with } additive risk within 72 hrs
CKD
• Intra-arterial injection site
• Age >70
• High volume of contrast media
• Volume depletion
• High osmolality of contrast media
• Hypotension • High viscosity of contrast media ?
• Class IV CHF
• Albuminuria with preserved eGFR
• Other nephrotoxins(NSAID…)

Diabetes alone not strong risk factor

 Scheme to Define CIN Risk Score
Risk Factors Integer Score
Hypotension 5

IABP 5

CHF 5

Age >75 years 4 Risk Risk Risk of

Score of CIN Dialysis
Anemia 3
≤5 7.5% 0.04%
Diabetes 3

Contrast media volume 1 for each 100 cc3 Calculate 6 to 10 14.0% 0.12%

11 to
4 26.1% 1.09%
Serum creatinine > 1.5mg/dl 16
OR
2 for 40 – 60 ≥ 16 57.3% 12.6%
eGFR <60ml/min/1.73 m 2
4 for 20 – 40
6 for < 20
eGFR < 60ml/min/1.73 m2 =
186 x (SCr)-1.154 x (Age)-0.203
X (0.742 if female) x (1.210
if African American)

Mehran et al. JACC 2004;44:1393-1399.

 Contrast induced AKI - pathophysiology

• How contrast agents cause AKI ?

 Pathophysiology of CIN
Radiocontrast Administration

Intrarenal Rheologic Osmotic Generation Direct

Vasoconstriction Effects Load of ROS Cytotoxicity

Medullary Hypoxia

CIN
 Uniqueness of Contrast induced AKI

• Universally iatrogenic
• Risk factors well characterised
• Time of insult largely predictable

Make it amenable to prevention!!!

 Preventive strategies
Because no effective
treatment exists for CIN,
prevention remains the
key strategy.

After the high-risk

patient population has
been identified and risk
factors addressed, the
next step in preventing
CIN is the use of
different prophylactic
therapies.
Intervention Trial Design Result
Hydration RCT Reduced incidence of CIN
Furosemide RCT Increased incidence of CIN
Mannitol RCT Increased incidence of CIN
Atrial Natriuretic Peptide RCT No benefit
Endothelin Antagonist RCT No benefit
Dopamine RCT No benefit
Adenosine Antagonist RCT Potential benefit
Calcium Channel Blocker Prospective Not adequately studied
Reduced incidence of CIN after low
n-Acetycysteine RCT
volume I.V. contrast

Reduced incidence of CIN vs. high

Low Osmolar Contrast RCT
osmolar contrast
Pre-emptive Dialysis Prospective No benefit
Fenoldopam RCT No benefit
Ioxaglate vs. Iodixanol RCT Ongoing Studies; Results Pending
RCT == Randomized
RCT Randomized Clinical
Clinical Trial
Trial
 Preventive strategies for CIN

Ineffective Unclear benefit Effective

• CCB • NAC • IVF
• Loop diuretics* • Theophylline • Low
• Mannitol* • Aminophylline contrast
• Dopamine* • Ascorbic acid volume
• Fenoldopam* • Statins
• ANP • Hemofiltration
• Hemodialysis*

* Possibly harmful
 How to prevent CIN

• Assesment of the individual risk for CIN

• Minimisation the risk
• Volume expansion
• Pharmacological prevention?
 How to Assess Renal Function?

Abbreviated Modification of Diet in Renal Disease equations

(MDRD) equation:
eGFR, ml/min/1.73 m2= 186 x (Serum Creatinine [mg/dL]) -1.154 x (Age-
0.203x (0.742 if female) x (1.210 if African American)

Cockcroft-Gault equation:
                                    (140- age)  x  Body Weight [kg]*
  Creatinine Clearance, ml/min   =                                             
Serum Creatinine mg/dL]  x  72
* Multiple by 0.8 in female
Kidney Disease Outcome Quality Initiative
(K/DOQI) Classification of Renal Function
“Chronic Kidney Disease” (CKD)
Kidney Function
Glomerular Filtration Rate (mL/min/1.73m2) ≈
Creatinine Clearance (mL/min)

Stage I Stage II Stage III Stage IV Stage V

CKD Risk
Factors/ Mild  Moderate Severe  Kidney
Damage with Kidney  Kidney Kidney Failure
Preserved Function Function Function ESRD
GFR

130 120 110 100 90 80 70 60 50 40 30 20 15 10 0

National Kidney Foundation. Am J Kidney Dis. 2002;2(Suppl 1):S46–S75.

Screening of the population at risk for CIN

• S creat. in all patient – eGFR

• Simple risk factor questions:
- known CKD?
- diabetes?
- C-V disease?
- list of medications?
- contrast media within the last 3 days?
• In patient with increased risk:

IS CONTRAST MEDIA ABSOLITELY NEEDED?

 How to prevent CIN

• Assesment of the individual risk for CIN

• Minimisation the risk
• Volume expansion
• Pharmacological prevention?
 Minimisation the risk

• Discontinue concurrent nephrotoxic agents

(NSAID, diuretics) and metformin (48h)

• Avoid repeated contrast injection within 72 hours

• Use the lowest volume of contrast

• Apply a prevention protocol

 How to prevent CIN

• Assesment of the individual risk for CIN

• Minimisation the risk
• Volume expansion
• Pharmacological prevention?
 HYDRATION-Goal: Produce both volume
expansion and a large volume of dilute urine

• Various protocols in the literature

• Should be suited to the clinical situation
 IV Fluids

• IVF protects against CIN in two ways

 Intravascular space expansion blunts the vasoconstrictive

effect of contrast in the medulla by suppressing
vasopressin, RAAS and increasing prostaglandins which,
in turns, increases medullary perfusion.

 Attenuates direct toxic effect of contrast on tubules by

decreasing concentration and viscosity.

Before coronary angiography, the volume status of patients can be assessed

through the inferior vena cava index, mean atrial pressure, noninvasive
pulmonary-capillary wedge pressure or bioimpedance spectroscopy
“Despite recognition of volume depletion as an important risk factor
for AKI, there are no RCT that have directly evaluated the role of
fluids vs placebo in the prevention of AKI” (KDIGO)

There is however a large consensus as to recommend volume

expansion in at-risk patient.

BUT:

*Oral or IV fluids?
* Na-chloride or bicarbonates?
 Peri-Procedural Fluid Administration
Protocols
• Inpatients: IV 0.9% saline at 1-1.5 ml/kg (100 ml/hr) 3 to 12
hours before and continuing 6 to 12 hours after CM.

• Outpatients: IV 0.9% saline at 100 ml/hr 1-6 hours prior to CM

and 6 hour after. Liberal oral fluids immediately following CM.

Salty foods the day before the examination to encourage volume

expansion.

0.9% NaCl increase delivery of sodium to the distal nephron,

leading to reduced activation of the RAS via the macula densa.
 IV fluids
• More recently isotonic normal saline vs sodium
bicarbonate has been the focus of investigation

• Bicarbonate therapy alkalinizes the renal tubular fluid

and, thus, prevents free radical injury through Harber-
Weiss reaction, which is activated in an acidic
environment.

• It also scavenges reactive oxygen species (ROS)

• 10 clinical trials in the past 5 years (largest trial 502

patients)
 There was a protective effect of sodium bicarbonate
on the risk of CI-AKI, especially in patients who underwent
coronary procedures and those with CKD, without effect on
need for RRT or mortality.
Due to the borderline statistical significance, the
relative low quality of the individual studies, heterogeneity
and publication bias, only a limited recommendation can be
made in favour of the use of sodium bicarbonate.
Bicarbonate Therapy:

• Bicarbonate protocols most often include

infusion of sodium bicarbonate at the rate of 3
mL/kg/hour an hour before the procedure,
continued at 1 mL/kg/hour for 6 hours after.

• Some investigators have used 1 mL/kg/hour for

24 hours, starting 12 hours before the
procedure.
 What is optimal hydration?

• Volume?
• Duration ?

• There is no clear evidence from the literature to guide the

choice of the optimal rate and duration of fluid infusion in
CI-AKI prevention, but most studies suggest that the fluids
should be started at least 1 h before and continued for 3–6
hours after CM administration.

• A ‘‘good’’ urine output (>150 ml/h) in the 6 hours after the

procedure has been associated with reduced rates of AKI
 Prevention of CIN
•• 78
78 Pts
Pts with
with CKD
CKD (Cr(Cr 1.6-4.2
1.6-4.2 mg/dl)
mg/dl)
•• IV
IV Fluids:
Fluids: 1/2
1/2 NS
NS @ @ 1ml/kg/hr
1ml/kg/hr for
for 12
12 hr
hr before
before &
& after
after contrast
contrast
•• Mannitol:
Mannitol: 5050 gg 11 hr
hr before
before contrast
contrast
•• Furosemide:
Furosemide: 80 80 mgmg IV
IV 30
30 min
min before
before contrast
contrast

60% Non-DM 43%

50% DM
40% 38%
36%
% CIN

30%
20% 14% 17%
10% 7%

0%
Saline Saline + Mannitol Saline + Furosemide

Solomon, et al. NEJM

Solomon, NEJM 1994; 331:
331: 1416-1420
POSEIDON
 Aim
To investigate different rates
of fluid administration
guided by the left ventricular
end-diastolic pressure
Results
Total mean (SD) volume of NS administered was
1727 ml in LVEDP group vs 812 ml in control group
 Conclusion
• LVEDP guided iv saline
Overall incidence of CI AKI was 11.4% :
administration is well
6.7 % in LVEDP group vs tolerated and could
16.3% in control group (p = 0.005) substantially reduce
chances of CI AKI and
subsequent adverse
outcomes

• More aggressive
volume expansion is
not suitable for all
patients.

• LVEDP measurement
is invasive and not
always available
 Contrast Media Classification
Osmolality High Low Low Iso
(mOsm/kg) (>1500) (600) (600-1000) (280)

Ionicity Ionic Ionic Non-ionic Non-ionic

benzen rings Monomer Dimer Monomer Dimer

Iohexol (Omnipaque)
Diatrizoate meglumine Ioxaglate Iopamidol (Isovue) Iodixanol
Name (Hypaque, Cistografin, (Hexabrix) Ioversol (Optiray) (Visipaque)
MD-76) Iopromide (Ultravist)
Ioxilan (Oxilan)

Viscosity 14 15 26
10-20
at 37ºC
Left ventricular &-----: 30-45 mL
aortic angiography
PCI-----------------------:150-200 mL
CECT scan--------------:uses 100-150 mL
IVU-----------------------:100-mL bolus of a 50%–60%
 Contrast media

• Contrast volume is • CIN consensus panel: >100

independent predictor for CIN. ml of contrast is associated
The worse the CKD is, the with higher incidence of CIN
lower amount of contrast can
cause CIN.
• Intra-arterial administration
• The relatively safe cutoff point is associated with higher
of contrast amount varies rate of CIN
from 70 ml up to 220ml.
• LOCM is more beneficial
• However, doses as low as 20 over HOCM
to 30 ml are capable of
inducing CIN.
 Meta analysis
High vs. Low Osmolar Contrast Media

• 39 Trials - 5146 patients 1.2

• CIN in 7% of all patients
1 1.0
• CIN in 30% of CKD patients

Relative Risk of CIN

0.8
• No significant benefits of 0.61
0.6
low osmolar media
compared to high osmolar 0.4
media in low risk patients.
• High risk patients low 0.2

osmolar media reduced

0
the risk of CIN by 39%. High Osm Low Osm

Barrett, et
Barrett, et al.
al. Radiology
Radiology 1993;
1993; 188:
188: 171-178
171-178
 Preventive strategies for CIN

Ineffective Unclear benefit Effective

• CCB • NAC • IVF
• Loop diuretics* • Theophylline • Low
• Mannitol* • Aminophylline contrast
• Dopamine* • Ascorbic acid volume
• Fenoldopam* • Statins
• ANP • Hemofiltration
• Hemodialysis*

* Possibly harmful
 NAC for CI-AKI (n=83)

25% 21%
% CIN (Scr ↑  0.5 mg/dL @ 48h)

20%

15%
P=0.01
10%
2%
5%

0%
NAC Control

Tepel M, et al. N Engl J Med 2000; 343:180-184

 N-acetylcysteine

• Antioxidant N-acetylcysteine (NAC) might

scavenge oxygen free radicals, thus attenuate
the cytotoxic effects of CM.

• NAC may also have direct vasodilating effects

on the kidneys through an increase in the
biologic effects of nitric oxide.
 Citing these results, 2011 guidelines issued by the
American College of Cardiology/American Heart
Association/Society for Cardiovascular
Angiography and Interventions state that:

“NAC is not useful for the prevention of CI-AKI and

recommend against its administration” 
• In patients undergoing emergency diagnostic procedures, in
which a full hydration protocol is not possible, an
abbreviated hydration regimen plus oral NAC can be
recommended.

• We suggest using oral NAC, together with

i.v. isotonic crystalloids, in patients at
increased risk of CI-AKI. (2D)

• If NAC is to be used as a preventative measure, it should be

given at a dose of 600 mg orally twice daily on the day
before and day of the procedure.
 Role of extracorporeal therapies

HEMODIALYSIS:
• Contrast medium is dialyzable and rapid removal of contrast
media from circulation would limit glomerular damage

• There were initial reports that HD was beneficial in preventing

CIAKI.

• Later studies showed that in patients not previously on RRT,

HD had no preventive role even if given within 1 hr of
procedure and one study even reports a detrimental effect.
 CHF patients
• CHF poses a particular challenge.

• Patients with compensated CHF should still be

given volume, albeit at lower rates.

• Uncompensated CHF patients should undergo

hemodynamic monitoring, if possible, and
diuretics should be continued.
 Proposed guidelines for CIN prevention
• Risk score (pre-procedural) calculation for CIN (consider
online CIN-risk calculators)

• Evaluate post-procedural (48 hour) renal function in high-risk

patients

• Nephrotoxic meds (Review/Adjust) and account for recent

contrast exposure

• Adequate hydration (Start 3-4 hours before and continue 6-8

hours post-procedure)

• Limit contrast use (aim for maximum contrast volume of 3.7 x

eGFR)

Prophylactic hemofiltration/hemodialysis of no benefit

THANK YOU!