Contrast Induced

Nephropathy
David Knesek
Eric Muller

Goals

Identify pts at risk for Contrast

Induced Nephropathy

Discuss how to decrease the risk for

those pts

Educate all of you, and us

Overview

Background

Contrasting contrast
Loyola statistics
Literature review

Definition/history
Epidemiology
Risk factors
Pathophysiology

Hydration
Mucomyst
Peri-procedural management

General guidelines

In the Beginning

1930s

Osborne images the urinary tract with iodinated

contrast material

First cases of contrast induced nephropathy seen

in 1950s with advent of early IV contrast agents
Significant increase in contrast over the last 30
years

Rise of CT, angiogram and special procedures

Definition of CIN

Definitions are variable by study but

include:
.5251 _____ mg/dl 50
Rise in creatinine
or ______ %
rise
over baseline
Must occur within 72h of contrast
administration

Must rule out other causes

Atheroembolic disease, atn, interstitial

nephritis, pre-renal

Epidemiology Overview

Incidence

CIN #3 cause of ARF (#1 surgery, #2 hypotension)

Overall risk difficult to ascertain

Highly dependent on risk stratification
Roughly ~2% of all comers now
2002-angiogram data

Circulation 2002; 105:2259

~1 million contrasted studies
~150,000 CIN
Unknown what contrast was used or baseline risk
stratification

Pathophysiology

Hemodynamic
Brief Vasodilatation followed by prolonged
vasoconstrictionDecreased RBF and
GFRSubsequent Ischemia in the PCT and thick
ascending limb of Henle
Alteration in Nitric Oxide, endothelin, adenosine

Studies in animals show no current direct relations

between these mediators and ischemia

Observed that Ionic Agents and Hyperosmol

agents increase risk of vasoconstriction
Hyperosmolar more viscous and increase chance
of vascular sludging, enhancing tubular interstitial
pressure, and further reducing medullary flow

Pathophysiology

Cytotoxic
Direct Cytotoxic Effects of Contrast Dye by the
generation of oxgen free radicals

Kidney Int 2003

Contact of CM with tubular cells causes rapid loss of cell

membrane proteins including Na/K ATPase Pump as well
as mitochondrial proteins such as cytochrome C

Increase in excretion of lysosomal enzymes and small

molecular weight proteins Nonspecific indicators of
tubular damage

Difficult to dissociate true toxicity from secondary renal

ischemia

Cool Slide

Characteristics of CIN

12- ______
Creatinine starts to rise within
24
hrs post-procedure

Complete recovery typically

5- in ______
days
7

Norm
Urine output isal_________

FeNa: high or low

Ruling out other causes

Atherembolic disease

Later rise in Cr, may be permanent

Eosinophils in urine
FeNa >1%
Low complement

ATN-high FeNa, tubular casts, typically

another precipitating cause, long recovery

Interstitial Nephritis decreased urine

output, WBCs, RBCs in UA

Risk by Renal Function

Negligible risk with normal renal

function

4-11% risk with moderate renal

insufficiency (Cr 1.5-4 mg/dl)

Kidney Int 1995; 47:254 and N Engl J Med 1989;320:143

Am J Med 1989; 86:649 and Kidney Int 1992; 41:1274

50% or more if baseline Cr > 4-5 mg/dl

AJR Am J Roentgenol 1991; 157:49 and Am J Med 1990; 89:615

Other Risk Factors

~40% increase risk with DM

Severe CAD
CHF
CRF
Intra-aortic balloon pump
Multiple contrast exposures within 72h
Multiple myeloma
Age >75y
Hypotension
Anemia
Volume of contrast

Does Creatinine Matter?

ARF associated with significant increases in

in-hospital mortality
In-hospital mortality (22% vs 1.4% without RF)
1 and 5y mortality(12% vs 4% and 45% vs 15%)

HD also significantly associated with mortality

30% in-hospital mortality
80% 2-year mortality

Rev

Cardiovasc Med 2003; 4Suppl 5:S3-9

Significant increase in length of stay and cost

Contrast Agents

1st Generation agents ionic monomers

and highly hyperosmolal (1400 to 1800
mosmol/kg)

2nd Generation agents nonionic

monomers and lower osmolality (500800 mosmol/kg)

3rd Generation agents are iso-osmolal

(~290mosmol/kg), non-ionic dimers

Properties of Contrast

Osmolality

Viscosity

New dyes are non-ionic

Repeated administrations

Iso-osmolar viscosity > low osmolar

Ionicity

300-1800mosm/L

<72h

Route of administration

Intravenous vs intra-arterial

Properties of Contrast

Loyola Statistics

Data obtained from CT, cath lab

CT scans-all types

Unable to get special procedures

27,800/48,500 with contrast

Loyola radiology dept uses omnipaque (Nonionic, Low-Osmolar)

Cath lab

744 angiograms over previous 12m

519 diagnostic, 225 interventional

Contrast Studies

High vs low osmolar

Meta-analysis of 25 RCTs (1993)

Benefits

seen only in subgroup analysis

Pre-existing

renal failure (gfr <70)

Intra-arterial injection of contrast
No

benefit seen in pts with normal renal function

High osmolar dye no longer used

More Contrast Studies

Low vs iso-osmolar

4 meta-analyses done

compared iohexol (LO) and iopamidol

(LO) vs iodixanol (IO)
Iohexol found to be inferior
No difference between other two

Loyola uses iohexol (omnipaque)

Summary of iso vs low

osmolar studies
Nephrology, Dialysis, Transplant (2005)

And yet more contrast

studies

studies showed benefit for iso-osmolar

Meta-Analysis (2727 pts)of 16 double-blind,
controlled trials comparing LOCM to Iodixanol
Significant lower rate of CIN with Iso-Osmolal

All comers

CKD (Cr > 1.5) in 502 pts

2.8% vs 8.4%, p=0.001

CKD and DM in 231 pts

1.4% vs 3.5%, p<0.001

3.5% vs 15.5%, p=0.003

Iso-osmolar group had lower iodine dose

IV Hydration
Mainstay of CIN prevention
Hydration with NS superior to
forced diuresis with lasix or mannitol
0.45% vs 0.9%

0.9% superior in pts with nl renal function

(1 study)
If Cr >1.6, no difference (1 study)

Inconclusive data regarding bolus

hydration vs standard infusion

Got Bicarb?

Theoretical tubular protective benefit through prevention

of free radical formation

Randomized prospective trial of 119 pts with and without

renal failure

JAMA 2004

Administration of NS or Bicarb as a 3ml/kg one hour prior

to contrast, followed by a 1 ml/kg infusion for six hours
afterward (baseline Cr similar for both groups)

Overall Incidence of CIN was 7.6% and was lower (1 pt vs

8 pts [1.7% vs 13.6%]) in Bicarb group

Studied stopped early do to ethical concerns and all pts

treated with Bicarbonate

Study underpowered

Second study showed similar results

Acetylcysteine
Rotten or not?

Acetycysteine is a thiol compound with

antioxidant and vasodilatory properties
Extensive 1st pass metobolism, significant
variability in bioavailability (3-20%), near
completely protein bound
Possibly alters the kidneys handling of Cr

Cr shown to decrease after administration

Study showing that cystatin C remains constant
Small molecule freely filtered
Produced by all nucleated levels
No adjustments for age, wt, ht, sex, muscle mass

Mucomyst Studies

12 meta-analyses, 29 RCTs
7 favor mucomyst, 5 equivocal
Publication bias

Negative studies more likely just abstracts

Both groups had significant heterogeneity in

their RCTs
Some evidence that IV mucomyst beneficial
before urgent procedure
Some evidence that increasing dose to
1200mg is beneficial

Theophylline

Increases cAMP, adenosine antagonist

Can give 200mg IV 30m prior to
emergent procedures
Use caution due to risk of arrythmia and
tachycardia
Small ICU study (150 pts) found this to
be superior to mucomyst
Multiple other studies with equivocal
results

Random Stuf

Prophylactic hemodialysis

Acetazolamide

Not recommended
Small study at Rush showed benefit over bicarb
in pediatric population

Melatonin
Contrast filter

JACC 2006
8 pigs had coronary sinus filter placed via
femoral vein
49% of contrast removed
All pts did well

Mehran et al. Study:

Risk Stratification
Van Praet, JACC 2004

Objective risk score of CIN after

Percutaneous Coronary Intervention
Methods

Prospective, randomized study of 8357 pts

5,571 used for development dataset

2,786 used for the validation dataset

Multivariate logistic regression used to identify

independent predictors of CIN with a p value
<.0001 in development set
Based on odds ratio: 8 variables were assigned
a weighted integer; the sum of the integers was
a total risk score for each pt

Odds Ratio
Multivariate Predictors CIN
after PCI

Mehran risk scoring and

CIN risk

Guidelines

Low risk

Drink 500ml before and 2500ml/24h after procedure

If npo, 1ml/kg/h (100cc/h) 4h prior and 24h after

Medium risk

If possible, delay procedure to correct hemodynamic

status
0.9% saline 1ml/kg/h 12h before and 12h after
If chance of volume overload, use 0.45%
If unable to get 6h of hydration, use high volume
protocol 3ml/kg/h x1h, then 1ml/kg/h x12h
Keep dye load to minimum and use low or iso-osmolar
Give mucomyst, 1200mg po x4, 2 prior, 2 after

If emergent, first dose can be IV

Guidelines contd

High risk
Get renal consult
Consider ICU admission
Use hydration protocol as above though
chance of fluid overload in this group is
typically high

Our suggestion-consider bicarb

Mucomyst or theophylline

Guidelines

Specific Recommendations:
Anti-htn

Diuretics

Withdraw prior, restart once confirmed that CIN did not

occur

Metformin

Hold 24h prior and 24h after

Nsaids

Cont through procedure

This includes ace inhibitors

Hold morning of procedure

Do not restart until renal function verified

Mannitol is bad
Follow Cr for 24-48h in med/high risk pts

Future directions

Standardize protocols for IVF and other

agents
Standardize definition
Power for hard end-points of CIN, HD, allcause mortality
Large RCTs using these standardized
protocols
Loyola specific

Consider using agent other than iohexol

Bonus
Slide

Gadolinium (Gd) non-ionic, low-osmolal (650

mosmol/kg)

Excreted exclusively from kidneys

Gadolinium

Half life of 1.3 in healthy individuals

Half life 34 hours in pts with CRF

Nephrogenic Systemic Fibrosis

215 cases as of Dec 2006

No cases seen before 1997 suggesting NSF new dz probably d/t exposure
of CRF pts to new medication, infectious agent, or toxin

Disorder only seen in CRF pts

Thickening and hardening of skin overlying trunk and extremeties
and fibrosis of internal organs including lungs, myocardium
Calcification of soft tissue, muscle, myocardium, and valves

Dx by Histology Thickened collagen, prolif of fibroblast and

elastin, and absence of inflammation

Possible association with Gadolinium

Gadolinium

Eur Radiology 2006

More than 150 pts have

developed NSF after
exposure to Gd based
contrast

No cases of NSF with

normal kidney function

90% had gadolidiamide

with certaintly
200 million pts received
Gd contrast since early
80s with 30 million
receiving gadolidiamide

FDA still evaluating

correlation between
Gd and NSF

Current
Recommendations:
No Gd if GFR < 30 or
pts on dialysis
Avoid use of
galodiamide
(Omniscan) and use
other Gd preparation
such as Gabobenate
Dimeglumine
(Multihance) if pts
must receive
gadolinium contrast