Toxicity of contrast agents

N. Grenier, Bordeaux

Iodine contrast agentsIodine atom :

- atomic n° 53- 3 atoms per benzene structure

Radicals: - dissociable (ionic) : COO-H, COO-Na ou COO-Meglumine- non dissociable (non-ionic)

Monomer

Dimer

Low osmolarity contrast agents (LOCM)Increase the number of iodine / mol Decrease the number of particles

1 molecule for 3 iodine atoms2 molecules for 6 iodine atoms

Isosmolar contrast agents(IOCM)Increase the number of iodine / mol

1 molecule for 6 iodine atoms

Nonionic dimer

Iodine contrast agents

Iodineatoms

Particles I/P Osmolality

Ionic monomers 3 2 1,5 High osmolality

Non-ionicmonomers

3 1 3 Low osmolality

Ionic dimers 6 2 3 Low osmolality

Nonionic dimers 6 1 6 Iso- osmolality

Nephrotoxicity of iodine CA• Mechanisms

– direct toxicity• cellular toxicity• tubular obstruction• « osmotic nephrosis »

– ischemia• vasoconstriction, in medulla +++• mechanisms : – alteration of intracellular [Ca], – globular aggregation, – Release of vaso-active substances

(adenosine, endotheline...)

Liss P et al. Acad Radiol 1998

Nephrotoxicity of iodine CA

• Definition :« increase of SCr within 3 days followinginjection of CA without any other cause » :- either absolute : > 44µmol/l- or relative : > 25%

Nephrotoxicity of iodine CA• Incidence :– Low incidence in patients with normal renal function (0-10%)– More frequent if renal risk factors (12-27%)– 3rd most frequant cause of renal failure in hospitals after hypotension

and surgery– Increases morbidity and mortality *

* Lévy, JAMA 96 Dangas G et al. Am J Cardiol 2005

Morbidity and Nephrotoxicity of iodine CA

• One year survival without any event

00%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7 8 9 10 11 12

Renal function deteriorationNo increase in creatinine

Time (Months)Time (Months)

Even

t-Fre

e Sur

viva

l 86%86%

62%62%

P<0.001

Gruberg et al. JACC 2000; 36: 1542-1548

Nephrotoxicity of iodine CA• Risk factors :

– pre-existing RF (130 µmol/l)– diabetes– Nephrotoxic drugs (Ab, NSAI +++)– dehydration– Cardiopathy with diuretics– myeloma– age > 70 years

Maximal risk : diabetes and RF +++

Renal risk with preexisting RF and diabetes

McCullough (2003)

Incidence of CIN• Factors of variation :

– Definition de la NCI– Type of population

• Out-patients vs in-patients• Risk factors

– Type and duration of follow-up– Hydration state– Type of CA– Doses of CA– Route of administration– …

Which incidence after IV injection?• Analysis of literature (2006) :

– Research on Medline : 3081 publications on CIN (1966-2004)

– 40 about IV injections in humans :• 9 showed no effect on renal function• 31 showed CIN

– Only 2 had a control group

– In-patients +++– No preparation

Rao QA & Newhouse JH, Radiology 2006

Which incidence after IV injection?• Studies after IV injection of LOCM-IOCM

Katzberg & Barrett, Radiology 2007

Which incidence after IV injection?• Analysis of literature (2006) :

– Controlled studies• Cramer BC et al, Arc Int Med 1985 :

– 193 with contrast (HOCM) and 233 wo contrast– ↑ SCr in 4/193 (2,1%) and 3/233 (1,3%) – NS– High risk roup : RF in 0/19 (with CA) and 2/46 (4,3%) (wo CA)

• Heller CA et al, Med J Aust 1991 :– 292 with HOCM, 187 with LOCM, 405 wo contrast– ↑ SCr in 12/292 (4%), 23/187(12%) and 16/405 (4%)

Rao QA & Newhouse JH, Radiology 2006

Spontaneous changes of SCr in patients with CKD

32,161 patients wo administration of CA.Dosage of SCr during 5 consecutive days

More than 50% of pts showed a spontaneousmodification of SCr ≥ 25%

In patients with SCr > 177 µmol/L, increase ≥ 25% → in 16 %

Newhouse JH et al. AJR 2008

Necessity of control groups !

LOCM vs IOCM with IV injectionStudy Competitor Population Design CIN (%) Result

Carraro 1998 Ultravist 300 64, SCr > 1.5Prosp, randomized, open-label, single

centerV = 3.1

LOCM = 0 No difference

Kolehmainen & Soiva2003

Xenetix 350 50, SCr > 1.5Prosp, randomized,

open-label, multi-centerV = 16

LOCM = 16 No difference

Barrett 2006IMPACT

Iopamiro/Isovue370

153, SCr > 1.5or CrCl < 60

Prosp, randomized, open-label, multi-center

V = 2.6LOCM = 0 No difference

Thomsen 2008ACTIVE

Iomeron 400 148, SCr > 1.5Prosp, randomized,

open-label, multi-centerV = 6.9

LOCM = 0(p = 0.02) LOCM better

Kuhn 2008PREDICT

Iopamiro/Isovue370

248, SCr > 25% Prosp, randomized, open-label, multi-center

V = 4.9LOCM = 5.6 No difference

Nguyen 2008Ultravist 370 117, SCr > 1.5

or eGFR < 60Prosp, randomized, open-label, single-

centerV = 5.1

LOCM = 18.5 IOCM better

↑↑ plasmatic viscosityplasmatic viscosity

↑ Resistance in vasa recta

↓Perfusion of vasa recta

Medullary hypoxiaMedullary hypoxia

↑ Viscosity in renal tubules

Tubular obstruction

↑renal interstitial pressure

tubular tubular lesions lesions

↓↓ GFR GFR

tubularreabsorption+

Viscosity and physiopathology of CIN

PB Persson et al. Kidney Int 2005

+

Viscosity and physiopathology of CIN

0

5

10

15Increase in urine

viscosity (%)

Ultravist Visipaque

Seeliger E et al. JASN 2007

Jost G, Invest Radiol 2009

Kidney injury molecule

Heme oxygenase

P < 0.05

Retention of CA on CT

Does that mean….

…. A lot of noise for nothing ?

Nephrotoxicity of iodine CA• Incidence :

– Probably much lower than expected after IV injection

• Prevention in risk patients :– Identification of risk patients – Search for alternative technique– Hydration +++

• 1-2 ml/kg/h of saline 0.9%o or bicarbonate• 4-6h before => 12h-24h after

– Stop all nephrotoxic drugs (24h)– Medications :

• theophylline ?• acetylcysteine (Mucomyst) ?

Toxicity of Gd-chelates• Nephrotoxicity :

– No nephrotoxicity demonstrated at recommendeddoses

– More nephrotoxic than iodine CA at equimolardose

• Nephrogenic systemic fibrosis– In patients with severely impaired renal function

NSF - History

Juluru, Radiographics 2009

• The world's first NSF case was identified in 1997 in California, USA • The condition was first reported in the literature in 2000 by Cowper et al• Initially, the disease was thought to affect only the skin and was given the

name Nephrogenic Fibrosing Dermopathy• The original name was replaced by “Nephrogenic Systemic Fibrosis” when it

became clear that the disease affects multiple organs and several tissues

History

January 20065 patients

July 200613 patients

NSF - Clinical findings

Cowper, Eur J Radiol 08

NSF - Clinical findings

Cowper, Eur J Radiol 08

Superficial pink plaques : early sign

Indurated brown plaques : deeper lesions

In progressive NSF, the skin becomes fibrotic with a shiny appearanceand subcutaneous tissue is diminished.

NSF - Clinical findings

Cowper, Eur J Radiol 08

Contractures in lower distal extremity

Contractures in upper distal extremity

Prominent yellow scleral plaque

Clinical findings : outcome

• Severely affected patients are unable to walk

• NSF may cause severe morbidity and even mortality in some patients

• Improvement in a small percentage of patients following recovery of renal function

Mendoza FA. Semin Arthtitis Rheum 2003Jimenez S. Arthritis Rheum 2004

Swartz RD. Am J Med 2003

NSF - Clinical findings• Differential Diagnosis :

Thomsen, Eur J Radiol 08

HistologyCD34

Cowper, Eur J Radiol 08

FibrocytesH&E CD34 Protocollagène I

Histology

Cowper, Eur J Radiol 08

Thickening of subcutaneaous septas

Immature collagen matrix

Fibrocytes

increased spindle cells, thick, pink collagen bundles, andintervening myxoid material (light pink)

Histology• Differential Diagnosis :

Thomsen, Eur J Radiol 08

NSF and renal function• Facts :

– Patients with normal or moderate renal failure never develop NSF– The risk of developing NSF increases with severity of renal failure– Majority of risk patients do NOT develop NSF– No age, ethnic or gender preference

• Risk factors :– Patients with CKD (GFR < 30ml/min)– Patients on dialysis– Patients suffering from acute renal failure– Patients with hepato-renal syndrome – Patients requiring liver transplantation

Gd-chelates• Biodistribution of approved agents

– These agents are eliminated mainly by the kidney with an exclusive glomerular filtration (same than iodine CA)

?

Aime S et al, JMRI 2009

Gd-chelates

• Pharmacokinetics of approved agents :– Their blood half-life is around 2h when

function is normal– This half-life can reach 30h to 120h in

case of severe renal failure– Renal failure increases the exposition of

tissues to Gd-chelates– Dialysis after injection increase the

clearance of these agents

Full doseNormal RF

1/3 doseNormal RF

Full doseImpairedl RF

Aime S et al, JMRI 2009

Physiopathology• Possible co-factors of development of NSF :

– Repeated and increasing exposition to the CA– High blood concentration of phosphate and ionized calcium– Hypoalbuminemia – Liver insufficiency, particularly before liver transplantation– Concomitant pro-inflammatory state– Metabolic acidosis– Treatment with high doses of erythropoietin

Marckman, Eur J Radiol 08

Hypotheses

Prevalence Difficult to know :- around 3% and 7% in risk patients- depends on the series- depends on the type of CA

PrevalenceReported cases :

– Around 500 reported cases but all are not proved– In publications : 186 « non confounded » cases in 2008• 134 with Omniscan• 18 with Magnevist• 2 with Optimark• 1 with Prohance

– Other cases are « confounded »

Confounded cases• Ex: Dotarem

Gd-chelates

Stability of Gd-chelates

Morcos, Br J Radiol 2007

Physiopathology• Transmetallation

Tweedle MF Invest. Radiol. 1992; 27:S2-S6

Opt Mag

2000

1500

1000

500

0

nmol/Gd/g skin

Omnisc

an

Dotarem

Gadovist

Gd concentration in skin biopsies 5 days after the last injection of Gd-CM

( 2.5 mmol/kg IV, 5 times/week X 4 weeks)

Multihance

Sieber M et al, Invest Radiol 2008; 43: 65-75 and Eur Radiol 2008; 18: 2164-2173

Physiopathology

Abraham, Eur J Radiol 08

Skin biopsy showing free gadolinium

H&S ME

Spectroscopie

Open Questions • It is unknown whether Gd deposition results in non-NSF subjects as

well, and if so, whether such deposition correlates with impaired renal function.

• In the cases of Gd deposition in NSF patients, it is likely that the Gd is no longer associated with its chelator, but this has still not been definitively shown.

• Is the form of Gd the same in skin deposits compared to internalorgans?

• If dechelation occurs, then where does it occur and how is the Gd transported to other organs?

How to reduce the Risk of NSF ?• Patients with GFR<30ml/min including those on dialysis should not

receive non-ionic linear chelates or Magnevist• The most stable Gd-CM should be used in these patients (macrocyclic Gd-CA)• The lowest possible dose• Allow at least one week before giving more Gd-CM• Patients on haemodialysis can be scheduled to have a dialysis

session shortly after the MRI examination• Patients on peritoneal dialysis should be asked to do several rapid exchanges after the examination

Recommendations

Juluru, Radiographics 2009

« black blood »

« white blood » (TOF)

« We suggest that in patients with poor renal function, especially those on dialysis, the choice of contrastenhanced CT or MRI should be based on the expected diagnostic benefits. However, the current evidence shows that stable GBCAs are safer than ICAs in this patient population. »

CIN vs NSF

Conclusions• Iodine CA :

– Nephrotoxicity of CA is probably overestimated with IV injections

– However, detection of risk patients and prevention must stay the rule

• NSF :– It is a complication linked to unstable agents which have to be waved in risk patients

– However, use of Gd injections should be rationalized in these risk patients

ESUR Guidelines on Contrast Media

ESUR

Contrast Media Safety Committee

www.esur.org

Acknowledgments to Pr Sam K Morcos, Sheffield, UK for help