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Update on NSF. Henrik S. Thomsen Department of Diagnostic Sciences Faculty of Health Sciences University of Copenhagen DENMARK. NSF. A horrible adverse reaction. Have you met a patient with NSF?. A very hot topic. - PowerPoint PPT Presentation
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Department of Diagnostic Sciences
Update on NSF
Henrik S. ThomsenDepartment of Diagnostic SciencesFaculty of Health SciencesUniversity of CopenhagenDENMARK
Department of Diagnostic Sciences
NSFA horrible adverse reaction
Have you met a patient with NSF?
Department of Diagnostic Sciences
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.
Difficult Diagnosis
HistoryClinical inspection of the skinHistology(Gd in the tissue)
Department 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
Departement 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
Department of Diagnostic Sciences
Risk management
The magnitude of the problem is unclear
Department of Diagnostic Sciences
Department of Diagnostic Sciences
Many registries
Yale university (NSF registry)Medwatch (FDA)Medicines Agencies in EuropeThe VendorsESURACR Contrast Media CommitteeThe published literature Results in confusion and uncertainty
NSF publications / Pubmed
2008: 10 months
232
Department of Diagnostic Sciences
Cases
In the peer-reviewed literature (biopsy proven)
190As of February 1st 2008B
room
e E
JR 2
00
8
Department of Diagnostic Sciences
Cases
Biopsy-proven cases in the peer-reviewed literature
Gadodiamide 157 (83%)Gadopentetate dimeglumine 8Gadovertisamide 3Unspecified 18 Confounded 4No Gd-CA 5
As of February 1st 2008Bro
om
e E
JR 2
00
8
Not examined for Gd in the skin!!!!
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.
Department of Diagnostic Sciences
Agarw
al e
t al. N
DT 2
008
Department of Diagnostic Sciences
Cases
Europe
104
Underreporting?
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?
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
Report
to t
he D
anis
h P
arl
iam
ent
20
08
European experience
There is an uneven distribution of original reports/ case reports in the peer-reviewed literature:
Denmark – 29 casesAustria – 5 casesFrance – 1 caseSpain - 9 casesThe Netherlands – 1 caseBelgium – 3 casesUnited Kingdom – 14 cases
Department of Diagnostic Sciences
60 cases ---58% of the 106 reported cases?
European experience
European fact
We have a reporting problem in Europe.
Department of Diagnostic Sciences
Other figures
FDA ~600 casesInternational center ~300Lawyers ~500 cases
Departement of Diagnostic Sciences
Some hospitals are now reporting that they have reviewed their nephrology patients.
For exampleUniversity 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
European experience
Department of Diagnostic Sciences
NoticeMost studies are derive from search on
databases e.g.Dialysis registriesDermatopathology filesRheumatology filesDermatology filesRadiology Information Systems
Underestimate in many instances
Prevalence in clinically inspected CKD 5 patients
OverallAll degrees (0-4)
18 % (CI: 11-27)
One exposure9/75 patients
12 % (CI: 6-21)
Two exposures8/22 patients
36 % (CI: 18-59)
Department of Diagnostic Sciences
Rydahl et
al. Invest
Radio
l 2
00
7
Cumulative risk doseIs something left over?
Department of Diagnostic Sciences
Cumulative risk doseIn 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?
Department of Diagnostic Sciences
Abra
ham
et
al B
rit
J D
erm
ato
l 2
008
Cumulative risk doseThere 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
Gd accumulates in bones of humans with normal renal function.
~4 times more after non-ionic linear chelates than non-ionic cyclic chelates
Department of Diagnostic Sciences
Whit
e e
t al. Invest
Radio
l 2
00
6
Gd accumulates in skin and bone of rodents with normal renal function.
The amount of accumulated Gd varies between the various agents.
Department of Diagnostic Sciences
Sie
bert
et
al In
vest
Radio
l 2
00
7 &
JM
RI 2
00
8
Cumulative risk dose
It is well known that heavy metals accumulate in the bone in man.
Department of Diagnostic Sciences
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!!!
Department of Diagnostic Sciences
Cumulative risk dose
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 NSFContentious subject
Does it matter?
Is it not the clinical facts that matter?
Departement of Diagnostic Sciences
2002-2008
Injections in “nephrology” patients
High risk agent
Low risk agent
NSF 30 0
No NSF 340 >200
Observation period: > 3 months
Department of Diagnostic Sciences
Herl
ev H
osp
ital -
unpublis
hed
2002-2007
Injections in “inflammatory nephrology” patients
High risk agent
Intermediate risk agent
NSF 6 0
No NSF 125 101
Observation period: > 3 monthsUniv
Wis
consi
n H
om
e p
ag
eDepartment of Diagnostic Sciences
Possible co-factorsErythropoietinInflammationInhibitors of angiotensin converting enzymeInduced antibodies against phospholipidsDialyzate fluidHepatorenal renal syndromeRecent surgeryThrombotic eventsMetabolic 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
Department of Diagnostic Sciences
IN EUROPEGadodiamide + 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.
Department of Diagnostic Sciences
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.
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
Conclusion
Department of Diagnostic Sciences