Transcript Dias nummer 1 - Clinical MRI

Department of Diagnostic Sciences
Update on NSF
Henrik S. Thomsen
Department of Diagnostic Sciences
Faculty of Health Sciences
University of Copenhagen
DENMARK
Department of Diagnostic Sciences
NSF
A horrible adverse reaction
Department of Diagnostic Sciences
Have you met a patient with NSF?
Department of Diagnostic Sciences
A very hot topic
Nephrogenic Systemic Fibrosis (NSF),
previously called Nephrogenic Fibrosing
Dermopathy, was described in 1997,
but was only linked to exposure to
gadolinium based contrast media in
2006.
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Difficult Diagnosis
History
Clinical inspection of the skin
Histology
(Gd in the tissue)
Departement of Diagnostic Sciences
It is not an either or disease
Severe cases (grade 3 – 4)
• skin changes causing major disabilities
having an impact on daily life and leading to
need of aiding equipment
Non-severe cases (grade 0 – 2)
• skin changes without or with only minor
associated disability
Department of Diagnostic Sciences
Current situation in Europe
EMEA uses 3 classes – FDA 1 class.
High risk
• Optimark, Omniscan, Magnevist
Moderate risk
• Primovist, Vasovist, Multihance
Low risk
• Dotarem, Gadovist, Prohance
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Risk management
The magnitude of the problem is unclear
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Many registries
Yale university (NSF registry)
Medwatch (FDA)
Medicines Agencies in Europe
The Vendors
ESUR
ACR Contrast Media Committee
The published literature
Results in confusion and uncertainty
NSF publications / Pubmed
232
2008: 10 months
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Cases
Broome EJR 2008
In the peer-reviewed literature (biopsy proven)
190
As of February 1st 2008
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Cases
Broome EJR 2008
Biopsy-proven cases in the peer-reviewed
literature
Gadodiamide
Gadopentetate dimeglumine
Gadovertisamide
Unspecified
Confounded
No Gd-CA
As of February 1st 2008
157 (83%)
8
3
18
4
5
Not examined
for Gd in the
skin!!!!
Department of Diagnostic Sciences
Agarwal et al. NDT 2008
1st Meta-analysis
According to Hill’s criteria:
For GdCA in general and gadodiamide in
particular, there was a strong and consistent
association between exposure and development
of NSF.
A clear temporal sequence was reported.
A dose-response relationship was shown.
No published cases ascribed to gadoteridol and
gadobenate were identified.
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Cases
Europe
Underreporting?
104
Is it likely that
Denmark (30) &
Switzerland (18) have
50% of the cases but
only 2% of the
population?
As of March 11 2008
2300 cases
in Europe?
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European experience
Report to the Danish Parliament 2008
The EU database has
only 8 Swiss cases.
According to the EU
database there are 3
cases in Austria, but
Grobner reported 5
cases in his original
paper (he has 6 cases
now).
At ECR another Austrian
group reported 6 cases.
Department of Diagnostic Sciences
European experience
There is an uneven distribution of original reports/
case reports in the peer-reviewed literature:
Denmark – 29 cases
Austria – 5 cases
France – 1 case
Spain - 9 cases
The Netherlands – 1 case
60 cases --Belgium – 3 cases
58% of the
United Kingdom – 14 cases
106 reported
cases?
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European fact
We have a reporting problem in
Europe.
Departement of Diagnostic Sciences
Other figures
FDA ~600 cases
International center ~300
Lawyers ~500 cases
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European experience
Some hospitals are now reporting that they have
reviewed their nephrology patients.
For example
University of Basel has performed ~27,000
enhanced MRI examinations from 2002 through
2007.
University of Paris reviewed their 308 nephrology
patients (73 % had CKD 4 or 5).
Common for these institutions – they have not
used non-ionic linear chelates.
Department of Diagnostic Sciences
Notice
Most studies are derive from search on
databases e.g.
Dialysis registries
Dermatopathology files
Rheumatology files
Dermatology files
Radiology Information Systems
Underestimate in many instances
Department of Diagnostic Sciences
Rydahl et al. Invest Radiol 2007
Prevalence in clinically inspected
CKD 5 patients
Overall
All degrees (0-4)
18 %
One exposure
9/75 patients
(CI: 11-27)
12 %
(CI: 6-21)
Two exposures
8/22 patients
36 %
(CI: 18-59)
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Cumulative risk dose
Is something left over?
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Abraham et al Brit J Dermatol 2008
Cumulative risk dose
In biopsies (several patients had more
than one biopsy) an increasing amount
of gadolinium has been shown in the
skin up to three years after the last
exposure to Gd-CA.
Where does it come from?
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Cumulative risk dose
There are reports that NSF may develop
several months and years after
administration of Gd-CA.
Is something - for example Gd3+ left in the
body? It can’t be excluded.
Department of Diagnostic Sciences
Cumulative risk dose
White et al. Invest Radiol 2006
Gd accumulates in bones of humans with
normal renal function.
~4 times more after non-ionic linear
chelates than non-ionic cyclic chelates
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Siebert et al Invest Radiol 2007 & JMRI 2008
Cumulative risk dose
Gd accumulates in skin and bone of
rodents with normal renal function.
The amount of accumulated Gd varies
between the various agents.
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Cumulative risk dose
It is well known that heavy metals
accumulate in the bone in man.
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Cumulative risk dose
Will we face a major health problem in the
future?
It can’t be excluded based on the current
knowledge.
RESEARCH IS URGENTLY NEEDED!!!
Departement of Diagnostic Sciences
High risk patients could be
Patients who develop end-stage renal
failure later
- patients with diabetes have a 50% chance
Yearly enhanced MR –
- women with BRACA-genes
Departement of Diagnostic Sciences
Pathophysiology of NSF
Contentious subject
Does it matter?
Is it not the clinical facts that matter?
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2002-2008
Injections in
“nephrology”
patients
Herlev Hospital - unpublished
NSF
No NSF
High risk
agent
Low risk
agent
30
0
340
>200
Observation period: > 3 months
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2002-2007
Injections in
“inflammatory
nephrology”
patients
Univ Wisconsin Home page
NSF
No NSF
High risk
agent
Intermediate
risk agent
6
0
125
101
Observation period: > 3 months
Department of Diagnostic Sciences
Possible co-factors
Erythropoietin
Inflammation
Inhibitors of angiotensin converting enzyme
Induced antibodies against phospholipids
Dialyzate fluid
Hepatorenal renal syndrome
Recent surgery
Thrombotic events
Metabolic acidosis
All the proposed co-factors cannot be confirmed to
be necessary co-factors. There are probably
many co-factors which together with the
gadolinium-based contrast agent can trigger
NSF.
Department of Diagnostic Sciences
IN EUROPE
Gadodiamide + Magnevist + Optimark
CONTRAINDICATED in
• patients with CKD 4 and 5 (GFR < 30 ml/min),
including those on dialysis
• patients with reduced renal function who have had
or are awaiting liver transplantation
USE WITH CAUTION in
• patients with CKD 3 (GFR 30-60 ml/min)
• children less than 1 year old
Department of Diagnostic Sciences
IN EUROPE
All patients should be screened, in
particular patients over the age of 65,
for renal dysfunction by obtaining a
history and/or laboratory tests.
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Observation
The risk of inducing NSF must always be
weighed against the risk of denying patients
gadolinium enhanced scans which are
important for patient management.
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Conclusion
We don’t have an appropriate overview of the
problem, including pathophysiology.
EMEA has chosen a different approach than FDA:
NSF is not a class phenomenon.
We can’t for the time being exclude that NSF is
only of the tip of the gadolinium toxicity iceberg.
It seems like that we introduced NSF and that we
can erase it again.
Use in all patients an agent that leaves the
smallest amount of gadolinium.
Department of Diagnostic Sciences