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Update on NSF

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.

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Update on NSF

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  1. Department of Diagnostic Sciences Update on NSF Henrik S. Thomsen Department of Diagnostic Sciences Faculty of Health Sciences University of Copenhagen DENMARK

  2. Department of Diagnostic Sciences NSF • A horrible adverse reaction

  3. Department of Diagnostic Sciences Have you met a patient with NSF?

  4. 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.

  5. Department of Diagnostic Sciences Difficult Diagnosis • History • Clinical inspection of the skin • Histology • (Gd in the tissue)

  6. 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

  7. 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

  8. Department of Diagnostic Sciences Risk management • The magnitude of the problem is unclear

  9. Department of Diagnostic Sciences 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

  10. NSF publications / Pubmed 232 2008: 10 months

  11. Department of Diagnostic Sciences Cases • In the peer-reviewed literature (biopsy proven) 190 Broome EJR 2008 As of February 1st 2008

  12. Department of Diagnostic Sciences 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

  13. Department of Diagnostic Sciences 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. Agarwal et al. NDT 2008

  14. Department of Diagnostic Sciences Europe 104 Underreporting? Is it likely that Denmark (30) & Switzerland (18) have 50% of the cases but only 2% of the population? Cases 2300 cases in Europe? As of March 11 2008

  15. Department of Diagnostic Sciences 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

  16. 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 • Belgium – 3 cases • United Kingdom – 14 cases 60 cases --- 58% of the 106 reported cases?

  17. Department of Diagnostic Sciences European fact • We have a reporting problem in Europe.

  18. Departement of Diagnostic Sciences Other figures • FDA ~600 cases • International center ~300 • Lawyers ~500 cases

  19. Department of Diagnostic Sciences 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.

  20. 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

  21. Department of Diagnostic Sciences Prevalence in clinically inspected CKD 5 patients Rydahl et al. Invest Radiol 2007

  22. Department of Diagnostic Sciences Cumulative risk dose • Is something left over?

  23. Department of Diagnostic Sciences 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

  24. Department of Diagnostic Sciences 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.

  25. 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 White et al. Invest Radiol 2006

  26. Department of Diagnostic Sciences 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

  27. Department of Diagnostic Sciences Cumulative risk dose • It is well known that heavy metals accumulate in the bone in man.

  28. 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!!!

  29. 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

  30. Departement of Diagnostic Sciences Pathophysiology of NSF • Contentious subject • Does it matter? • Is it not the clinical facts that matter?

  31. Department of Diagnostic Sciences 2002-2008 Herlev Hospital - unpublished Observation period: > 3 months

  32. Department of Diagnostic Sciences 2002-2007 Univ Wisconsin Home page Observation period: > 3 months

  33. 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.

  34. 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

  35. 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.

  36. 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.

  37. Department of Diagnostic Sciences 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.

  38. Department of Diagnostic Sciences

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