Teaching Module IV

Nephrogenic Systemic Fibrosis (NSF)

Astana, November 5, 2010

Delayed adverse reactions to GBCA Nephrogenic Systemic Fibrosis

This slide deck was prepared by: Gertraud Heinz-Peer, MD Dept. of Radiology, Medical University of Vienna, Austria gertraud.heinz@meduniwien.ac.at

November 5th, 2010

Learning objectives
General considerations on GBCA

Delayed adverse reactions to GBCA

Update knowledge on NSF

Physicochemical properties of GBCA

Guidelines and recommendations

Gadolinium-based contrast agents (GBCA)

Expanded intrinsic tissue contrast

Improved signal-to-noise ratio (SNR)

Improved contrast-to-noise ratio (CNR)

Increased sensitivity, specificity, and accuracy of MRI

Gadolinium-based contrast agents (GBCA)

Supposed to be very safe in general

No deterioration of renal function in early studies

Preferably CE-MRI studies performed in patients with renal dysfunction

Bold off-label applications in MRA and myocardial viability studies

GBCA in clinical use

Gd chelate (trade name)
Gadopentetate dimeglumine (Magnevist) Gadodiamide (Omniscan) Gadoterate meglumine (Dotarem) Gadoteridol (Prohance) Gadobutrol (Gadovist) Gadobenate dimeglumine (MultiHance)

Body regions approved

CNS, whole body CNS, whole body CNS, whole body CNS, whole body CNS, liver, kidney, MRA CNS, liver

Approval
EU, USA, Jap EU, USA, Jap EU EU, USA, Jap EU EU, USA

Gadoversetamide (OptiMARK)
Gadoxetic acid disodium (Primovist) Gadofosveset (Vasovist)

CNS, liver
Liver Vessels (abd., limbs)

EU, USA
EU, USA EU

MR contrast agents
Generally most MR contrast agents are safe

but
they are not a 100% safe

MR contrast agents safety considerations

Anaphylactoid/anaphylactic reactions (requiring immediate intervention)

Side effects
Nephrogenic systemic fibrosis (NSF)

Nephrotoxicity

Nephrogenic Systemic Fibrosis (NSF)

NSF affects patients with advanced or acute renal insufficiency

Severe fibrosis scleroderma like skin lesions

Flexion contractures of joints

Fibrosis may also affect liver, lung, heart, muscles

Clinical presentation of NSF

Progressive skin disease Erythematous papules, brownish plaques

Symmetric distribution
Peau dorange Thickening of cutis woody texture

Pains
Pruritus

Burning sensation (neuropathic pain)

NSF

Histopathologic findings in NSF

Gold Standard = deep skin biopsy

Cells resembling fibroblasts

CD 34 and procollagen I positive TGF-1 expression

Dendritic cells
CD68, F XIIIa positive Thickened, chaotic collagen bundles Mucin deposits in the skin

Prognosis of NSF
Natural history - not well understood

Sometimes gradual improvement in mobility

Complete spontaneous healing in patients with ongoing kidney disease has not yet been reported 5% or less have an exceedingly rapid and fulminate disease course that may result in death

Pathophysiology of NSF
Circulating fibrocytes

Leave the circulation

Endothelial damage

Fibrocytes differentiate into cells that resemble normal dermal fibroblasts

Circulating cells deposit in other organs multi-system fibrosis

NSF and GBCA

Strong evidence of GBCA to trigger NSF

Mostly affected patients with severe renal insufficiency (grade 4 and 5) i.e. eGFR < 30 mL/min per 1.73 m2 or ARF
Higher cumulative doses Proinflammatory or profibrotic conditions Linear GBCA risk compared to macrocyclic agents

NSF and GBCA

Pathophysiology not well known stability?
GBCA with linear molecular structure

GBCA with macrocyclic molecular structure

Stability of GBCA
In vitro and in vivo studies

Linear GBCA are less stable compared to macrocyclic agents

NSF and GBCA

Possible mechanism
Transmetallation may play a role in the pathophysiology of NSF

Peripherally deposited Gd might be a target for circulating fibrocytes

GBCA - Transmetallation
Leads to release of free Gd3+ which is extremely toxic. Gd replaced by endogenous metals such as zinc or copper Transmetallation is more likely with linear chelates and when GBCA remains in the body for a long period Transmetallation is more likely in acidotic condition

GBCA - Stability
Thermodynamic stability (Ktherm) describes affinity of Gd for the ligand at pH 14 Conditional stability (Kcon) describes equilibrium considering all protonated forms of the ligand at pH 7.4 Variable amounts of free ligands or calcium complexes in some agents to ensure chelation of any free Gd3+

GBCA Stability
Kinetic stability describes speed of dissociation

Assessed by measuring dissociation half-life under acidic conditions

GBCA - Transmetallation
More likely to occur with unstable molecules as indicated by:

Low Ktherm value

Low Kcon value Low kinetic stability Presence of large amount of excess chelate

Linear molecules are less stable compared to macrocyclic agents

Non-ionic linear molecules are thermodynamically less stable than ionic ones

Kimura et al., Radiation Medicine 2005; 23:322-326

GBCA - Stability
Molecular structure
Non-ionic molecules are thermodynamically less stable in comparison to ionic chelates [Kcon] Gadoversetamide (Optimark) Gadodiamide (Omniscan) non-ionic (15.0) non-ionic (14.9)

Gadoteridol (ProHance)
Gadobutrol (Gadovist) Gd-DTPA (Magnevist) Gadobenate (MultiHance)

non-ionic (17.1)
non-ionic (15.5) ionic ionic (18.1) (18.4)

Gd-DOTA (Dotarem)

ionic

(18.8)

GBCA - Stability
[Ktherm]

Gadoversetamide (Optimark)
Gadodiamide (Omniscan) Gd-DTPA (Magnevist) Gadobutrol (Gadovist)

16.6
16.9 22.1 21.8

Gadobenate (MultiHance)
Gadoteridol (ProHance) Gd-DOTA (Dotarem)

22.6
23.8 25.8

GBCA - Stability
Excess chelates

Gadoversetamide (Optimark)
Gadodiamide (Omniscan) Gd-DTPA (Magnevist) Gadoteridol (ProHance)

28.40
12.00 00.40 00.23

Gadobutrol (Gadovist)
Gadobenate (MultiHance) Gd-DOTA (Dotarem)

00.00
00.00 00.00

GBCA - Stability
Molecular structure
Macrocyclic agents are kinetically much more stable than linear chelates

Gadoversetamide (Optimark)
Gadodiamide (Omniscan) Gd-DTPA (Magnevist) Gadobenate (MultiHance)

Linear
Linear Linear Linear

Gadobutrol (Gadovist)
Gadoteridol (ProHance) Gd-DOTA (Dotarem)

Cyclic
Cyclic Cyclic

Extracellular Gd-CM Gadoversetamide (OptiMark) Gadodiamide (Omniscan) Gadobutrol (Gadovist) Gadoteridol (ProHance) Gadopentetate (Magnevist) Gadobenate (MultiHance) Gadoterate (Dotarem)

Type

Thermodynamic stability constant 16.6

Condition stability

Dissociation Excess half-life at pH chelate (mg/ml) 1.0

28.4 Not available

Non-ionic linear Non-ionic linear Non-ionic cyclic Non-ionic cyclic

15

16.9

14.9

12

35 sec

21.8 23.8

15.5 17.1

Not available 0.23

18h* 4h*

Ionic linear
Ionic linear Ionic cyclic

22.1
22.6 25.8

18.1
18.4 18.8

0.4
None None

10 min
Not available 85h*

* pH=1.2, 37C Port Br J Radiol 2008; 81: 258-259

In-vitro stability measurements in native human serum

Differences within the group of non-ionic and the ionic linear class, but no differences within the macrocyclic class For the macrocyclic agents, Gadovist, Dotarem and Prohance, no (< 0.1%) release was observed within 15 days
Frenzel et al. Invest. Radiol. 2008

In-vitro stability measurements in human serum + phosphate

Addition of phosphate enhances release of Gd from linear agents, but class differences prevail For the macrocyclic agents, Gadovist, Dotarem and ProHance, no (< 0.1%) release was observed within 15 days. Phosphate had no effect on stability. No difference between Gadovist, Dotarem, and ProHance
Frenzel et al. Invest. Radiol. 2008

Epidemiology of NSF published case reports

Up to October 2009 in peer-reviewed literature Estimated # of appl. (Dec. 09)*

Omniscan
Magnevist OptiMark Unspecified Gd-CM

48 mio.
100 mio. 9 mio.

347 patients
89 patients 5 patients 151 patients

Gadovist

4 mio.

one patient

* Company data presented at FDA Advisory Board Dec. 09, Gadovist data from BSP

How to reduce the risk of NSF

Patients with GFR <30 ml/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 the dialysis session shortly after the MRI examination Patients on peritoneal dialysis should be asked to do several rapid exchanges after the examination

Current guidelines
FDA

EMA
ESUR

FDA
Package insert with black box warning on the risk of NSF

Risk groups for NSF: acute and chronic kidney disease grades 4 and 5 and every grade of ARF
Check for renal dysfunction before administration of GBCA (medical history, laboratory tests) No off-label use

FDA (September 2010)

Omniscan, OptiMark and Magnevist no longer allowed in CKD grade 4 and 5 Other GBCA may be carefully used in these patients

FDA

It may be prudent to institute prompt dialysis in patients with advanced kidney dysfunction who receive GBCA. Although there are no data to determine the utility of dialysis to prevent or treat NSF in patients with decreased kidney function, average excretory rates of gadolinium are 78%, 96%, and 99% in the first to third haemodialysis sessions, respectively.

EMA
Package insert with black box warning on the risk of NSF

Omniscan, OptiMark and Magnevist no longer allowed in CKD grade 4 and 5

Other GBCA may be carefully used in these patients

Check for renal dysfunction before administration of GBCA (medical history, laboratory tests)

ESUR guidelines on NSF

Patients at risk of NSF

Patients with CKD (GFR < 30 ml/min)

Patients on dialysis

Patients suffering from acute renal failure

Patients with reduced renal function who have had or are awaiting liver transplantation

ESUR guidelines on NSF

Do not use in patients at risk of NSF

Omniscan
Magnevist

OptiMark

ESUR guidelines on NSF

In high-risk patients

Use a GD-CM with high stability

Give the lowest dose possible to achieve a diagnostic examination

Allow at least one week before giving more Gd-CM

Note: Do not deny at risk patients clinically important MR examinations

Ethical issue

Dont go into panic because of NSF

NSF - a complication that could be avoided

At the centre which reported the largest series of cases with NSF: Since they have stopped gadodiamide in March 06 and switched to a macrocyclic MRI-CM, they have not seen a single new case of NSF.

Thomsen et al., ACTA Radiologica 2007; 48:593-596

No cases of NSF were identified in dialysis patients who received ProHance Reilly RF, Clin J Am Soc Nephrol 2008

A recent study documented that no cases of NSF were seen in 135 patients with advanced renal impairment (GFR < 30 ml/min) who received the ionic macrocyclic agent Dotarem between July 05 to July 06

Janus et al., The FINEST study, Eur J Radiol 2009

Thank you!