update on nsf

Department of Diagnostic Sciences

Update on NSF

Henrik S. ThomsenDepartment of Diagnostic SciencesFaculty of Health SciencesUniversity of CopenhagenDENMARK


NSFA horrible adverse reaction

Have you met a patient with NSF?



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)


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


Risk management

The magnitude of the problem is unclear



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


Cases

In the peer-reviewed literature (biopsy proven)

190As of February 1st 2008B

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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

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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.


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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?

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.


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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


60 cases ---58% of the 106 reported cases?

European experience

European fact

We have a reporting problem in Europe.


Other figures

FDA ~600 casesInternational center ~300Lawyers ~500 cases


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.


European experience


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)


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Cumulative risk doseIs something left over?


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?


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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.


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


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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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It is well known that heavy metals accumulate in the bone in man.



Will we face a major health problem in the future?

It can’t be excluded based on the current knowledge.

RESEARCH IS URGENTLY NEEDED!!!



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


Pathophysiology of NSFContentious subject

Does it matter?

Is it not the clinical facts that matter?


2002-2008

Injections in “nephrology” patients

High risk agent

Low risk agent

NSF 30 0

No NSF 340 >200

Observation period: > 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

Observation period: > 3 monthsUniv

Wis

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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.



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


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.


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.


Conclusion

update on nsf

Documents

published cases

swiss cases

diseasesevere cases

development of nsf

skin changes

broome ejr

literature results

high riskoptimark