Department of Diagnostic Sciences

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

NSF publications / Pubmed

232

2008: 10 months

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Cases

In the peer-reviewed literature (biopsy proven)

Broome EJR 2008

190

As of February 1st 2008

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Cases

Biopsy-proven cases in the peer-reviewed literature

Gadodiamide Gadopentetate dimeglumine Gadovertisamide Unspecified Confounded No Gd-CA 157 (83%) 8 3 18 4 5

Broome EJR 2008

As of February 1st 2008

Not examined for Gd in the skin!!!!

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1st Meta-analysis

Agarwal et al. NDT 2008

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.

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Cases

Europe

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

104
As of March 11 2008

2300 cases in Europe?

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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 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.

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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

Prevalence in clinically inspected CKD 5 patients

Overall All degrees (0-4) One exposure 9/75 patients Two exposures 8/22 patients

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18 %
(CI: 11-27) 12 % (CI: 6-21)
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

Abraham et al Brit J Dermatol 2008

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 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

Siebert et al Invest Radiol 2007 & JMRI 2008

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 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
NSF
Herlev Hospital - unpublished

High risk agent

Low risk agent

30 340

0 >200

No NSF

Observation period: > 3 months

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2002-2007
Injections in inflammatory nephrology patients

High risk agent

Intermediate risk agent

NSF
Univ Wisconsin Home page

6 125

0 101

No NSF

Observation period: > 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 < 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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