contrast media-induced nephropathy: what you’re dyeing to...

Contrast Media-Induced Nephropathy:What you’re DYEing to know about!!

Stephen M. Korbet, M.D.Professor of Medicine

Cases

FP is a 78 yo WF with a long history of DM and HTN was admitted for evaluation of chest pain, nausea and vomiting. Her SCr was 1.0, Urinalysis- Normal.

CB is an 81 yo WM with a history of HTN, renal cell CA s/p right nephrectomy in 2002 and metastatic prostate CA was admitted for evaluation of low back pain.

His SCr was 1.2 mg/dl, urinalysis- Normal, and Renal US-L kidney 14.6 cm, no hydronephrosis.

In both cases a contrast CT of abdomen and pelvis was performed using 125 ml of iopamidol (Isovue)

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What is the incidence of hospital acquired acute renal failure and what

are the causes?

Hospital Acquired ARF: The Rush Experience

Nash et al. AJKD 2002

Prospective study from Feb to June 1996 (4 mo)

4,622 consecutive medical and surgical admissions

Acute renal failure during the hospitalization

ARF defined by an increase in SCr of >0.5 mg/dl

ARF developed in 332 (7%) patients



(44%)(18%)(13%)

61%



(25%)(36%)

51%



25%





Cardiac cath and coronary angioplasty 21 (49%)CT scan 14 (33%)Peripheral angiogram 3 (7%)Other 5 (12%)TOTAL 43

Type of Contrast Study Resulting in ARF


Cardiac cath and coronary angioplasty 2.8% CT scan 1.7%

Proportion of Contrast Studies Resulting in ARF(Overall, 750 Cardiac Caths and 825 CTs done in 4 mo)


Contrast media-induced nephropathy

Earl D. Osborne, MD Leonard G. Rowntree, MD

Dermatologists at the Mayo Clinic studying the use of iodine-containing compounds in the treatment of syphilis

They recognized the value of the known radiopacity and renal excretion of iodine in rendering the urinary tract opaque to x-ray

Jour. A.M.A.Feb 10, 1923

• 1930, proposed using an organic nucleus as iodine carrier• Benzoic acid is metabolized to hippuran• Hippuran is excreted by the kidneys• Lead to the development of sodium diatrozoate in 1950s

Moses Swick, MD

“father of intravenous urography”

• Sodium salt of tri-iodinated benzoic acid • Ionic with high osmolarity (>1500 mOsm/kg)• Water soluble, not protein bound, mol wt- 636• 99% excreted by glomerular filtration• Renal clearance of 50% by 30-60 minutes

New England Journal of Medicine 1968

Osmolarity(mOsm/kg)

Ionicity

Benzine rings

Name

Viscosity at 98.6F

Diatrizoate IopamidalIohexol

Iodixanol

High(>1500)

Low(600-1000)

Iso(280)

Ionic Nonionic Nonionic

Monomer Monomer Dimer

6 mPa.S 5-10 mPa.S 11 mPa.S

What is the definition and presentation of contrast media-

induced nephropathy?

Contrast media-induced nephropathy:

An increase in serum creatinine within up to 48-72 hours of a contrast procedure

Increase in serum creatinine

Absolute: 0.5 mg/dl

Relative: 25%

• Overall incidence of ARF from contrast is 3%

• The incidence is 0.6% in patients with normal renal function

Incidence of Contrast Media-Induced Nephropathy

Rudnick et al, KI 1995

In 2010, 3.3 million Cardiac Angio & 70 million CTs0.03 x 73 = 2.2 million

Usually non-oliguric

Contrast Media-induced Nephropathy


Urinalysis has minimal or no proteinuria and bland sediment with granular casts




Fractional excretion of sodium is low




Fractional excretion of sodium is low

Serum creatinine peaks by 4 to 5 days


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ContrastStudy

5 days

What are the proposed mechanisms forcontrast media-induced nephropathy?

Contrast media induces CYTOTOXIC and HEMODYNAMIC insults

Contrast Media-Induced Nephropathy

Idee et al. Invest Radiol 2004

Contrast Media

Cellular effects


Contrast Media

Cellular effects

vacuolization necrosis apoptosis effects mesangial cells inhibits protein reabsorption

Acute Renal FailureIdee et al. Invest Radiol 2004

Hardiek et al. Am J Physiol Renal Physiol 2001

Altered Mitochondrial Function in Porcine Proximal Tubule Cell Line

Low-

Iso-

Hyper-

Contrast Media

Cellular effects Hemodynamic effects



Contrast Media



Osmolality unrelated

Osmolality related


Contrast Media




Osmolality related

adenosine release


Contrast Media




Osmolality related

adenosine release

vasoconstriction


Contrast Media




Osmolality related

adenosine release

vasoconstriction

Medullary hypoxia+

Free radicals


Brevis, NEJM 1995

Liss et al. Eur J Physiol 1997

Effect of Contrast on pO2 in the Cortex

Liss et al. Eur J Physiol 1997

Effect of Contrast on pO2 in the Outer Medulla

Osmolarity(mOsm/kg)

Ionicity

Benzine rings

Name

Viscosity at 98.6F

Diatrizoate

High(>1500)

Ionic

Monomer

6 mPa.S

Osmolarity(mOsm/kg)

Ionicity

Benzine rings

Name

Viscosity at 98.6F


High(>1500)

Low(600-1000)

Ionic Nonionic

Monomer Monomer

6 mPa.S 5-10 mPa.S

Osmolarity(mOsm/kg)

Ionicity

Benzine rings

Name

Viscosity at 98.6F


Iodixanol

High(>1500)

Low(600-1000)

Iso(280)

Ionic Nonionic Nonionic

Monomer Monomer Dimer

6 mPa.S 5-10 mPa.S 11 mPa.S

Effect of Contrast on pO2 in the Outer Medulla

Liss et al. KI 1998

Iso-osmolar

Low-

Iso-osmlar compounds have greater viscosity

Contrast Media




Osmolality related

adenosine release

vasoconstriction

Medullary hypoxia+

Free radicals


Osmotic diuresis

Contrast Media




Osmolality related

adenosine release

vasoconstriction

Medullary hypoxia+

Free radicals


Osmotic diuresis

Na+ delivery

Contrast Media




Osmolality related

adenosine release

endothelin release

vasoconstriction

Medullary hypoxia+

Free radicals


Osmotic diuresis

Na+ delivery

Increased In-Vivo Plasma Endothelin Levels are Not Related to Contrast Osmolarity

Solomon: KI 1998

Hyper-

Low-

Contrast Media




Osmolality related

adenosine release

endothelin release

vasoconstriction

Medullary hypoxia+

Free radicals


Osmotic diuresis

Na+ delivery +

What is the course and outcome incontrast media-induced nephropathy?

Serum creatinine peaks by 4 to 5 days and returns to baseline over 7 to 10 days


Increases length of hospital stay

Need for dialysis (10-25%)

Failure of SCr to return to baseline (30%)

Associated with increased patient mortality (34%)

Morbidity of Contrast Media-induced Nephropathy

Solomon: KI 1998

16,248 hospitalized pts having contrast studies

Contrast induced ARF- 1.1%

ARF requiring dialysis- 12%

Mortality rate: Yes No p value

ARF 34% 7% <0.001

Dialysis 60% 31% <0.01 CMIN increased the risk of severe non-renal

causes of death (sepsis, bleeding, resp failure, delerium)

Increased Mortality Associated with Contrast Media-induced Nephropathy

Levy et al, JAMA 1996

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HD

5 days

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HD

5 days 11 days

What are the risk factors forcontrast media-induced nephropathy?

Risk Factor Odds ratioPatient RelatedSCr level (mg/dl):

1.2-1.9 2.42.0-2.9 7.4>3.0 12.8

Risk Factors for Contrast Nephropathy

Goldenberg & Matetzky CMAJ 2005


1.2-1.9 2.42.0-2.9 7.4>3.0 12.8

Diabetes mellitus 5.5



McCullough, Applications in Imaging 2003

Renal Function Predicts Risk of Contrast Nephropathy

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Calculated CrCl (mL/min)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Ren

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vent

Rat

e

1020304050

Non-diabetic

Diabetic

Dialysis

CMIN


1.2-1.9 2.42.0-2.9 7.4>3.0 12.8

Diabetes mellitus 5.5Age (per yr increase) 1.02CHF 1.5HTN 1.2Low effective circulatory volume 1.2Myocardial infarction 1.9Intra-aortic balloon pump 1.9




1.2-1.9 2.42.0-2.9 7.4>3.0 12.8

Diabetes mellitus 5.5Age (per yr increase) 1.02CHF 1.5HTN 1.2Low effective circulatory volume 1.2Myocardial infarction 1.9Intra-aortic balloon pump 1.9OtherLow vs high osmolar in CRI 0.5Volume of contrast (per 100 mL) 1.12



The increased risk in patients with DM, HTN or vascular disease may be a result of “endothelial

dysfunction” with decreased release of vasodilatory substances such as nitric oxide

Risk Factor Integer scoreRisk factorHypotension 5Intra-aortic balloon pump 5CHF 5SCr >1.5 mg/dl 4Age >75 yrs 4Anemia 3Diabetes mellitus 3Volume of contrast (per 100 mL) 1Risk categoriesLow <5Moderate 6-10High 11-15Very High >16

Risk Assessment to Predict Contrast Nephropathy

Mehran et al, J Am Coll Cardiol 2004

ARF8%14%26%57%

HD0.04%0.1%1%13%




FP CB

4 43 331 1

811

Defining Chronic Renal Insufficiency

• Serum creatinine >1.5 mg/dl

• Calculated creatinine clearance <60 ml/min

Cockcroft and Gault equation:

140-age x kg

Scr x 72= [x .85 in women]

Pt SCr CrCL

FP 1.0 54 ml/min

CB 1.2 55 ml/min

Calculated Creatinine clearances




FP CB

4 44 43 331 1

15 12

ARF8%14%26%57%

What prophylactic measure can be taken to reduce the risk of contrast

media-induced nephropathy?

• Delay exposure in hemodynamically unstable pts

• Avoid repeated exposure– 48 hrs in pts with normal renal function– 72 hrs in pts with CRI or DM– until SCr returns to baseline in ARF

• Discontinue NSAIDs for 1-2 days prior

Modification of Risk Factors to Prevent CMIN

Goldenbergf, CMAJ 2005

• Contrast media• Hydration• Pharmacologic agents• Prophylactic dialysis

Prophylaxis of Contrast Media-Induced Nephropathy


• Contrast media– Minimize the dose– Avoid repeated exposure– Use the least toxic form of contrast




Non-ionic vs Ionic Contrast Media

Kidney International 1995

(Coronary angiography)


(ARF defined by >0.5 mg/dl increase in SCr at 48-72 h)

High vs Low Osmolar Contrast Media in Cardiac Angiography

Non-ionic Low vs Iso-OsmolarContrast Media

Aspelin et al, NEJM 2003

• Randomized, double-blind, prospective study• 129 pts with DM and SCr of 1.5 to 3.5 mg/dl or

calculated CrCl of <60ml/min• Underwent coronary or aorto-femoral angiography• All pts were well hydrated

Non-ionic Low vs Iso-osmolar Contrast Media

Aspelin et al, NEJM 2003

Aspelin et al, NEJM 2003 P <0.01

290 mOsm/kg

780 mOsm/kg

3%

26%

(ARF defined by >0.5 mg/dl increase in SCr at 24-72 hrs)

DB-RC Trials of Low vs Iso-Osmolar Contrast in Pts with eGFR <60 Having Coronary Angiography

What is the risk of CIN in CKD pts (eGFR <60) undergoing intravenous contrast enhanced CT?

DB-RC Trials of Low vs Iso-Osmolar Contrast in CKD Pts Undergoing CT scans

Thomsen

DB-RC Trials of Low vs Iso-Osmolar Contrast in CKD Pts Undergoing CT scans

Intra-arterial adm delivers greater concentration and/or volume.

Thomsen

• Increases renal blood flow and GFR in volume contracted patients

• Increases medullary blood flow, enhancing regional pO2

• Reduces concentration of contrast in tubules

Proposed Beneficial Effects of Hydration

Persson et al. KI 2005

What is the most effective form of hydration ?

H2O: 1 Liter

Intra-cellularExtra-cellular

330 ml 660 ml

H2O: 1 Liter


330 ml 660 ml

0.45-NS: 1 Liter 330 ml500 ml

+170 ml670 ml

H2O: 1 Liter


330 ml 660 ml

NS: 1 Liter 1000 ml

330 ml500 ml

+170 ml670 ml

0.45-NS: 1 Liter

• Prospective, randomized trial in 53 pts• Unrestricted oral fluids vs 0.9% NS infused at 1

ml/kg/hr for 12 hrs prior to the procedure• Primary endpoint:

>0.5 mg/dl increase in SCr within 48 hrs

• Oral: 9/26 (35%) vs NS: 1/27 (3%), p <0.01

Comparison of Oral vs 0.9% Saline Hydration in Patients Undergoing Coronary Angioplasty

Trivedi et al. Nephron Clin Pract 2003

• Prospective, randomized, controlled trial: 1,383 pts• Low-osmolar contrast• N-acetylcysteine was NOT used• 0.9% vs 0.45% NS infused at 1 ml/kg/hr for 24 hrs

• Primary endpoint:– >0.5 mg/dl increase in SCr within 48 hrs

Comparison of 0.9% vs 0.45% NS Hydration in Patients Undergoing Coronary Angioplasty

Mueller et al. Arch Int Med, 2002


0.7%

2.0 %

0.4%

1.1%

Comparison of 0.9% vs 0.45% NS Hydration in Patients Undergoing Coronary Angioplasty

Multivariate Analysis for the Development of Contrast Media-Induced Nephropathy


Risk Factor Odds Ratio P value

Female sex 3.9 0.005

Baseline SCr 6.6* <0.001

NS hydration 0.3 0.037

*increase in SCr of 1 mg/dl

Sodium Bicarbonate vs Saline in the Prevention of Contrast-Media Induced Nephropathy


Merten et al. JAMA, 2004

• Alkalinization of urine inhibits free radical formation

• Reducing free radical formation will decrease CIN

• SALINE– 0.9% NS

• SODIUM BICARBONATE– 154 mEq/L sodium bicarb

– 3 ml/kg/hr for 1 hr prior– 1 ml/kg/hr for 6 hrs post


N Saline Bicarb P value

Total 119 8/59 (13.6%)

1/60 (1.7%) 0.02

Cardiac cath 97 8/48

(16.7%)1/49 (2%) 0.02


Merten et al. JAMA, 2004

Saline vs Na-Bicarb in the Prevention of CIN in CKD pts undergoing Angiography: PRCTrials

Wiedermann & Joannidis. NDT 2010

• Furosemide and/or mannitol• Calcium channel blockers• Adenosine blockers• Dopaminergic agonists (fenoldopam)• Endothelin receptor antagonists• Atrial natriuretic peptide• N-Acetylcysteine

Pharmacologic Prophylaxis of Contrast Media-Induced Nephropathy


Contrast Media




Osmolality related

adenosine release

endothelin release

vasoconstriction

Medullary hypoxia+

Free radicals


Osmotic diuresis

Na+ delivery

ET receptor antagonists

Diuretics, ANP,CCB

Dopa-1 agonist

Theophylline

N-Acetylcysteine

Contrast Media




Osmolality related

adenosine release

endothelin release

vasoconstriction

Medullary hypoxia+

Free radicals


Osmotic diuresis

Na+ delivery

ET receptor antagonists

Diuretics, ANP,CCB

Dopa-1 agonist

Theophylline

N-Acetylcysteine

XX

XX

• Stimulates the synthesis of glutathione– Reduces Oxidative stress

• At high dose promotes vasodilatation

• Decreases medullary vascular resistance

N-Acetylcysteine Prophylaxis for Contrast Media-Induced Nephropathy


N-Acetylcysteine Prophylaxis for Contrast Media-Induced Nephropathy

• All patients had stable CRI

• GFR <60 ml/min, SCr 2.4 to 2.8 mg/dl

• NAC dose:

• 400 to 600 mg PO BID

• The day before and the day of the procedure

Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT)

• 2,308 pts having coronary or peripheral angio

• 1 risk factor (>70yo, CKD, DM, CHF, low BP)

• NAC 1200 mg BID Pre & Post vs Placebo

• Hydration: NS- 1 ml/kg/hr 6-12 hr pre/post-study

• End point: >25% increase in SCr at 48-96 hrs13% placebo vs 13% NAC (p =0.97)

•End point: >0.5 mg/dl increase in SCr at 48-96 hrs4% placebo vs 4% NAC (p =0.85)

ACT Investigators. Circulation 2011

Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT)

ACT Investigators. Circulation 2011

Li et al. PLoS ONE 2012; 7:e34450

Efficacy of Short-Term High Dose Statin in Preventing CIN

• Statins:↑ nitric oxide, ↓ endothelin-1, anti-inflammatory, and anti-oxidative

• Meta-analysis of 7 PRCT comparing high-dose statin (40-80 mg) v. low-dose or no statin

• Short-term statin use lead to a 49% RR of CIN• But statin use was not protective in studies of patients

with ↓ GFR or those receiving NAC

Consensus Statements of the CIN Consesus Working Panel and KDIGO AKI Work Group

Statement 10:Prophylactic hemodialysis or hemofiltration hasnot been proven to be efficacious in reducing the risk of AKI after exposure to iodinated contrast.

CIN Consensus Working Panel, Am J Cardiology, 2006

Statement 4.5:We suggest NOT USING prophylactic HD or hemofiltration for contrast-media removal in patients at increased risk for CI-AKI.

KDIGO AKI Work Group, Kidney Int, 2012

Approach to Patients Receiving IV Contrast

Low risk

Oral Hydration

High risk

Avoid contrast

-DC NSAIDs/Metformin 24-48 hrs prior- Check SCr pre-prophylaxis-Intravenous saline/bicarb hydration-Low dose, non-ionic, low osmolar contrast-Check SCr 24-48 hrs post-procedure

Consensus Panel for CIN, KI 2007/2012

1 ml/kg/h (0.5 ml/kg/hr in CHF pts) for 6-12 hrs pre- and post-procedure

Consensus Statements of the CIN Consesus Working Panel

Statement 4:

In the setting of emergency procedures, where the benefit of very early imaging outweighs the risk of waiting, the procedure can be performed without knowledge of serum creatinine or eGFR.

CIN Consensus Working Panel, Am J Cardiology, 2006

contrast media-induced nephropathy: what you’re dyeing to...

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