1) Dr. Swapnil Hiremath presented at the CAMRT joint Congress from May 28-30, 2015 in Montreal, Quebec on contrast nephropathy. 2) He discussed risk factors for contrast nephropathy including diabetes, dehydration, and severe chronic kidney disease. He also reviewed evidence for interventions to prevent contrast nephropathy such as N-acetyl cysteine, bicarbonate-based hydration, safer contrast media, and dialysis after contrast exposure. 3) Based on meta-analyses and randomized controlled trials, N-acetyl cysteine, bicarbonate hydration, and iso-osmolar contrast media may be most effective at reducing the risk of

1. May 28 – 30, 2015, Montréal, Québec
Contrast Nephropathy
Swapnil Hiremath, MD, MPH
@hswapnil
Nephrologist
The Ottawa Hospital
University of Ottawa
Ottawa Hospital Research Institute

2. May 28 – 30, 2015, Montréal, Québec
Disclosure Statement: With a Conflict of Interest
Financial:
• Study funding: GE Healthcare is funding an economic analysis to study the
impact of osmolality of contrast medium and acute kidney injury
• I own no stock or securities nor do I serve or have served as a consultant
for any drug or device manufacturer
Others:
• I am the PI of an ongoing trial examining oral hydration (vs IV) to prevent
contrast nephropathy
• I am a co-author of the Canadian Association of Radiology (CAR)
guidelines

3. CAMRT joint Congress May 2015
Objectives
At the end of this talk, the listener will
• Identify patients who are at high risk of contrast
nephropathy
• Know what to order to minimize risk of
contrast nephropathy

4. CAMRT joint Congress May 2015
What is Contrast
Nephropathy*?
*Now known as
Contrast-induced
Acute Kidney Injury
Following Contrast
exposure:
Arterial (cardiac cath,
arteriograms)
Venous (CT Scans)

5. CAMRT joint Congress May 2015
What is Contrast
Nephropathy*?
• Acute Kidney Injury,
defined as:
• Rise in creatinine of
25%
• Rise in creatinine of
44 micromol/L
• A much smaller
proportion: Dialysis
or Death
*Now known as
Contrast-induced
Acute Kidney Injury
Following Contrast
exposure:
Arterial (cardiac cath,
arteriograms)
Venous (CT Scans)

6. CAMRT joint Congress May 2015
Case

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Case
• 59 year old gentleman, DM2
• Worsening angina
• Cr 170 at baseline (eGFR 38)

8. CAMRT joint Congress May 2015
Case
• 59 year old gentleman, DM2
• Worsening angina
• Cr 170 at baseline (eGFR 38)

9. CAMRT joint Congress May 2015
Case
• 59 year old gentleman, DM2
• Worsening angina
• Cr 170 at baseline (eGFR 38)

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Pathophysiology
from: cJASN Jan 2008

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Pathophysiology
from: cJASN Jan 2008

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Pathophysiology
• Courtesy Prof Persson, Berlin

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Which patients are at risk?

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Which patients are at risk?
• Arterial contrast (Cardiac Catheterization,
Angiograms) >>Venous Contrast (Contrast
enhanced CT scans)

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Which patients are at risk?
• Arterial contrast (Cardiac Catheterization,
Angiograms) >>Venous Contrast (Contrast
enhanced CT scans)
• Diabetes, Dehydration

16. CAMRT joint Congress May 2015
Which patients are at risk?
• Arterial contrast (Cardiac Catheterization,
Angiograms) >>Venous Contrast (Contrast
enhanced CT scans)
• Diabetes, Dehydration
• Severe Chronic Kidney Disease (eGFR <
30, stage 4 and 5 CKD)

17. CAMRT joint Congress May 2015
How should we prevent Contrast - AKI?
Literature Roundup
>8000 publications
14 + 57 + 22 + 18
=113 RCTs
(4 interventions)
3412 with RCT
filter
42 Meta-
analyses

18. CAMRT joint Congress May 2015
How should we prevent Contrast - AKI?
Literature Roundup
>8000 publications
14 + 57 + 22 + 18
=113 RCTs
(4 interventions)
3412 with RCT
filter
42 Meta-
analyses
+ 82 studies
currently recruiting
(per
Clinicaltrials.gov)

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N-Acetyl Cysteine
(mucomyst)

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N-Acetyl Cysteine:
Mixed Evidence?
Gonzales et al, BMC Medicine, 2007

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N-Acetyl Cysteine:
Mixed Evidence?
Gonzales et al, BMC Medicine, 2007

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N-Acetyl Cysteine:
Mixed Evidence?
Gonzales et al, BMC Medicine, 2007

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N-Acetyl Cysteine:
Definitive Evidence

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N-Acetyl Cysteine:
Definitive Evidence

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N-Acetyl Cysteine:
Definitive Evidence
ACT study, Berwanger et al,
Circulation, 2011
N = 2272

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N-Acetyl Cysteine:
Definitive Evidence
ACT study, Berwanger et al,
Circulation, 2011
N = 2272

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Volume Expansion: Bicarb

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Volume Expansion: Bicarb

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Volume Expansion: Bicarb
Merten et al, JAMA
2004
N = 119

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Volume Expansion: Bicarb
or Saline?

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Volume Expansion: Bicarb
or Saline?

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Volume Expansion: Bicarb
or Saline?

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Volume Expansion: Bicarb
or Saline?

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Oral hydration?
Source: Hiremath et al, PLoS One, 2013
Small number of studies
Ongoing trial at Ottawa

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Safer Contrast Media

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Safer Contrast MediaIonicity Relative
Osmolality
Osmolality
(mOsm/kg H20)
Examples
Ionic monomers High osmolality 1500 – 1900 Diatrizoate, Iothalamate,
Metrizoate,
Iodamide, Ioxithalamate
Ionic dimers Low osmolality 600 Ioxaglate
Nonionic monomers Low osmolality 500 – 700 Iopamidol,
Iohexol,
Iomeprol,
Iopentol,
Iopromide,
Ioversol,
Ioxitol,
Metrizamide
Nonionic dimers Iso-osmolal 290-320 Iodixanol,
Iotrolan

37. CAMRT joint Congress May 2015
Safer Contrast MediaIonicity Relative
Osmolality
Osmolality
(mOsm/kg H20)
Examples
Ionic monomers High osmolality 1500 – 1900 Diatrizoate, Iothalamate,
Metrizoate,
Iodamide, Ioxithalamate
Ionic dimers Low osmolality 600 Ioxaglate
Nonionic monomers Low osmolality 500 – 700 Iopamidol,
Iohexol,
Iomeprol,
Iopentol,
Iopromide,
Ioversol,
Ioxitol,
Metrizamide
Nonionic dimers Iso-osmolal 290-320 Iodixanol,
Iotrolan

38. CAMRT joint Congress May 2015
Safer Contrast MediaIonicity Relative
Osmolality
Osmolality
(mOsm/kg H20)
Examples
Ionic monomers High osmolality 1500 – 1900 Diatrizoate, Iothalamate,
Metrizoate,
Iodamide, Ioxithalamate
Ionic dimers Low osmolality 600 Ioxaglate
Nonionic monomers Low osmolality 500 – 700 Iopamidol,
Iohexol,
Iomeprol,
Iopentol,
Iopromide,
Ioversol,
Ioxitol,
Metrizamide
Nonionic dimers Iso-osmolal 290-320 Iodixanol,
Iotrolan

39. CAMRT joint Congress May 2015
Safer Contrast MediaIonicity Relative
Osmolality
Osmolality
(mOsm/kg H20)
Examples
Ionic monomers High osmolality 1500 – 1900 Diatrizoate, Iothalamate,
Metrizoate,
Iodamide, Ioxithalamate
Ionic dimers Low osmolality 600 Ioxaglate
Nonionic monomers Low osmolality 500 – 700 Iopamidol,
Iohexol,
Iomeprol,
Iopentol,
Iopromide,
Ioversol,
Ioxitol,
Metrizamide
Nonionic dimers Iso-osmolal 290-320 Iodixanol,
Iotrolan

40. CAMRT joint Congress May 2015
Safer Contrast MediaIonicity Relative
Osmolality
Osmolality
(mOsm/kg H20)
Examples
Ionic monomers High osmolality 1500 – 1900 Diatrizoate, Iothalamate,
Metrizoate,
Iodamide, Ioxithalamate
Ionic dimers Low osmolality 600 Ioxaglate
Nonionic monomers Low osmolality 500 – 700 Iopamidol,
Iohexol,
Iomeprol,
Iopentol,
Iopromide,
Ioversol,
Ioxitol,
Metrizamide
Nonionic dimers Iso-osmolal 290-320 Iodixanol,
Iotrolan

41. CAMRT joint Congress May 2015
Safer Contrast Media
• Low Osmolar >>safer then High Osmolar (Barrett
et al, Radiology 1993)
Ionicity Relative
Osmolality
Osmolality
(mOsm/kg H20)
Examples
Ionic monomers High osmolality 1500 – 1900 Diatrizoate, Iothalamate,
Metrizoate,
Iodamide, Ioxithalamate
Ionic dimers Low osmolality 600 Ioxaglate
Nonionic monomers Low osmolality 500 – 700 Iopamidol,
Iohexol,
Iomeprol,
Iopentol,
Iopromide,
Ioversol,
Ioxitol,
Metrizamide
Nonionic dimers Iso-osmolal 290-320 Iodixanol,
Iotrolan

42. CAMRT joint Congress May 2015
Safer Contrast Media
• Low Osmolar >>safer then High Osmolar (Barrett
et al, Radiology 1993)
• Iso-osmolar versus Low osmolar?
Ionicity Relative
Osmolality
Osmolality
(mOsm/kg H20)
Examples
Ionic monomers High osmolality 1500 – 1900 Diatrizoate, Iothalamate,
Metrizoate,
Iodamide, Ioxithalamate
Ionic dimers Low osmolality 600 Ioxaglate
Nonionic monomers Low osmolality 500 – 700 Iopamidol,
Iohexol,
Iomeprol,
Iopentol,
Iopromide,
Ioversol,
Ioxitol,
Metrizamide
Nonionic dimers Iso-osmolal 290-320 Iodixanol,
Iotrolan

43. CAMRT joint Congress May 2015
Use Safer Contrast media

44. CAMRT joint Congress May 2015
Use Safer Contrast media

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Use Safer Contrast media
Aspelin et al, New Engl J Med,
2003
N = 129

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Is Iodixanol truly
superior?

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Is Iodixanol truly
superior?

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Is Iodixanol truly
superior?
CARE study, Solomon et al,
Circulation, 2007
N = 414

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Is Iodixanol truly
superior?

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Is Iodixanol truly
superior?

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Meta-Analysis: LOCM
vs IsoCM

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Meta-Analysis: LOCM
vs IsoCM

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Meta-Analysis: LOCM
vs IsoCM

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Meta-Analysis: LOCM
vs IsoCM

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Iodixanol vs
Iohexol

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Iodixanol vs
Other LOCMs

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What about Dialysis to
remove contrast?

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What about Dialysis to
remove contrast?
Cruz et al,AJKD,
2007

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What about Dialysis to
remove contrast?
Cruz et al,AJKD,
2007

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What about Dialysis to
remove contrast?
Marenzi et al, New Engl J Med,
2003
N = 114
Cruz et al,AJKD,
2007

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What about Dialysis to
remove contrast?

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What about Dialysis to
remove contrast?

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What about Dialysis to
remove contrast?
Reinecke et al, Clin Res
Cardiol, 2007

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Comparison of Effect Sizes

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Comparison of Effect Sizes
Intervention First Study
Best
Study
N-Acetyl Cysteine 0.1 1.01
Bicarb-based Hydration 0.125 0.94
Dialysis after Contrast 0.1 0.90
Iso-osmolar vs low-
osmolar Contrast
0.09 1.13

66. CAMRT joint Congress May 2015
Comparison of Effect Sizes
Intervention First Study
Best
Study
N-Acetyl Cysteine 0.1 1.01
Bicarb-based Hydration 0.125 0.94
Dialysis after Contrast 0.1 0.90
Iso-osmolar vs low-
osmolar Contrast
0.09 1.13

67. CAMRT joint Congress May 2015
Comparison of Effect Sizes
Intervention First Study
Best
Study
N-Acetyl Cysteine 0.1 1.01
Bicarb-based Hydration 0.125 0.94
Dialysis after Contrast 0.1 0.90
Iso-osmolar vs low-
osmolar Contrast
0.09 1.13

68. CAMRT joint Congress May 2015
Comparison of Effect Sizes
Intervention
First
Study
Best
Study
N-Acetyl
Cysteine
0.1
NEJM
1.01
CirculationN-Acetyl
Cysteine
0.1
N = 83
1.01
N =2400
Bicarb-based
Hydration
0.125
JAMA
0.94
JAMABicarb-based
Hydration
0.125
N =119
0.94
N = 353
Dialysis after
Contrast
0.1
NEJM
0.90
CRCDialysis after
Contrast
0.1
N = 114
0.90
N = 424
Iso-osmolar
Contrast
0.09
NEJM
1.13
JACCIso-osmolar
Contrast
0.09
N = 129
1.13
N = 418

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Contrast media
DoesVenous Contrast
cause Acute Kidney
Injury?

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Contrast media Acute Kidney Injury
DoesVenous Contrast
cause Acute Kidney
Injury?

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Contrast media Acute Kidney Injury
DoesVenous Contrast
cause Acute Kidney
Injury?

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Contrast media Acute Kidney Injury
Sepsis
Cardiogenic Shock
DoesVenous Contrast
cause Acute Kidney
Injury?

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Contrast media Acute Kidney Injury
Sepsis
Cardiogenic Shock
DoesVenous Contrast
cause Acute Kidney
Injury?

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Contrast-
induced
Contrast media Acute Kidney Injury
Sepsis
Cardiogenic Shock
DoesVenous Contrast
cause Acute Kidney
Injury?

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Contrast-
associated
Contrast media Acute Kidney Injury
Sepsis
Cardiogenic Shock
DoesVenous Contrast
cause Acute Kidney
Injury?

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DoesVenous Contrast
Cause AKI?
Source: Radiology, 2014

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DoesVenous Contrast
Cause AKI?
Source: Radiology, 2014

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Others
• If hydration helps, so will stopping diuretics
• Potentially nephrotoxic medications: NSAIDs,
others
• RAS Blockade? (ACE inhibitors,Angiotensin
receptor blockers, renin inhibitors,
spironolactone)
• Statins

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Metformin and Contrast?

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Metformin and Contrast?
• Metformin is NOT nephrotoxic;
phenformin, its predecessor was banned
for causing lactic acidosis. Case reports
exist with metformin as well

81. CAMRT joint Congress May 2015
Metformin and Contrast?
• Metformin is NOT nephrotoxic;
phenformin, its predecessor was banned
for causing lactic acidosis. Case reports
exist with metformin as well
• So, if a patient is on metformin AND

82. CAMRT joint Congress May 2015
Metformin and Contrast?
• Metformin is NOT nephrotoxic;
phenformin, its predecessor was banned
for causing lactic acidosis. Case reports
exist with metformin as well
• So, if a patient is on metformin AND
• Is given contrast AND

83. CAMRT joint Congress May 2015
Metformin and Contrast?
• Metformin is NOT nephrotoxic;
phenformin, its predecessor was banned
for causing lactic acidosis. Case reports
exist with metformin as well
• So, if a patient is on metformin AND
• Is given contrast AND
• Develops severe AKI (GFR <20) AND

84. CAMRT joint Congress May 2015
Metformin and Contrast?
• Metformin is NOT nephrotoxic;
phenformin, its predecessor was banned
for causing lactic acidosis. Case reports
exist with metformin as well
• So, if a patient is on metformin AND
• Is given contrast AND
• Develops severe AKI (GFR <20) AND
• Metformin is not stopped THEN

85. CAMRT joint Congress May 2015
Metformin and Contrast?
• Metformin is NOT nephrotoxic;
phenformin, its predecessor was banned
for causing lactic acidosis. Case reports
exist with metformin as well
• So, if a patient is on metformin AND
• Is given contrast AND
• Develops severe AKI (GFR <20) AND
• Metformin is not stopped THEN
• There is a possibility of lactic acidosis

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Metformin and Contrast?
‘ The legacy of phenformin, anecdotes,
scattered case reports, product inserts
and medicolegal anxieties are more at
the heart of this issue than scientific
fact’ - Gerald Pond, Radiology, 2001

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Summary

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Summary
• Contrast procedures have become safer with
time

89. CAMRT joint Congress May 2015
Summary
• Contrast procedures have become safer with
time
• IV (eg CT scans) contrast is considerably less
harmful than IA contrast (eg cardiac cath)

90. CAMRT joint Congress May 2015
Summary
• Contrast procedures have become safer with
time
• IV (eg CT scans) contrast is considerably less
harmful than IA contrast (eg cardiac cath)
• CKD stage 4 & 5 (GFR < 30) might still be at risk
of AKI with CT Scans

91. CAMRT joint Congress May 2015
Summary
• Contrast procedures have become safer with
time
• IV (eg CT scans) contrast is considerably less
harmful than IA contrast (eg cardiac cath)
• CKD stage 4 & 5 (GFR < 30) might still be at risk
of AKI with CT Scans
• Most prophylactic measures (bicarb, NAC,
dialysis) don’t work; except for volume expansion

92. CAMRT joint Congress May 2015
Thank you
• Email:
shiremath@toh.on.ca
• Twitter: @hswapnil
• https://about.me/
swapnil.hiremath