Update on NSF

1
Update on NSF

• Henrik S. Thomsen
• Department of Diagnostic Sciences
• Faculty of Health Sciences
• University of Copenhagen
• DENMARK

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NSF

• A horrible adverse reaction

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Have you met a patient with NSF?
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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)

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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

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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

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NSF publications / Pubmed
232
2008 10 months
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Cases

• In the peer-reviewed literature (biopsy proven)
  190

Broome EJR 2008
As of February 1st 2008
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Cases

• Biopsy-proven cases in the peer-reviewed
  literature
• Gadodiamide 157
  (83)
• Gadopentetate dimeglumine 8
• Gadovertisamide 3
• Unspecified
  18
• Confounded
  4
• No Gd-CA
  5

Broome EJR 2008
Not examined for Gd in the skin!!!!
As of February 1st 2008
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1st Meta-analysis

• According to Hills 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.

Agarwal et al. NDT 2008
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Cases

• Europe
• 104

• Underreporting?
• Is it likely that Denmark (30) Switzerland (18)
  have 50 of the cases but only 2 of the
  population?

2300 cases in Europe?
As of March 11 2008
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European experience

• 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.

Report to the Danish Parliament 2008
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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
• Belgium 3 cases
• United Kingdom 14 cases

60 cases --- 58 of the 106 reported cases?
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European fact

• We have a reporting problem in Europe.

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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.

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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

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Prevalence in clinically inspected CKD 5 patients
Overall All degrees (0-4) 18 (CI 11-27)
One exposure 9/75 patients 12 (CI 6-21)
Two exposures 8/22 patients 36 (CI 18-59)
Rydahl et al. Invest Radiol 2007
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Cumulative risk dose

• Is something left over?

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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?

Abraham et al Brit J Dermatol 2008
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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 cant be excluded.

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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

White et al. Invest Radiol 2006
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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.

Siebert et al Invest Radiol 2007 JMRI 2008
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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 cant be excluded based on the current
  knowledge.
• RESEARCH IS URGENTLY NEEDED!!!

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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

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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 High risk agent Low risk agent
NSF 30 0
No NSF 340 gt200
Herlev Hospital - unpublished
Observation period gt 3 months
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2002-2007
Injections in inflammatory nephrology patients High risk agent Intermediate risk agent
NSF 6 0
No NSF 125 101
Univ Wisconsin Home page
Observation period gt 3 months
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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.

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IN EUROPE

• Gadodiamide Magnevist Optimark
• CONTRAINDICATED in
• patients with CKD 4 and 5 (GFR lt 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

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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 dont have an appropriate overview of the
  problem, including pathophysiology.
• EMEA has chosen a different approach than FDA
  NSF is not a class phenomenon.
• We cant 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.

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