Presented HKCRRT Inauguration conference (Dec 8, 08)

1. Holly Chun
M.Phil., B(app)Sc., MRTMR,
MRTR, P.D.D.R.

2. Holly Chun
M.Phil., B(app)Sc., MRTMR, MRTR, P.D.D.R.
University Health Network
Toronto
Canada

3. What Is Current About
Nephrogenic Systemic Fibrosis &
Gadolinium Based Contrast
Agents
Holly Chun
M.Phil., B(app)Sc., MRTMR, MRTR, P.D.D.R.
University Health Network
Toronto
Canada

4. Introduction
• Before Nephrogenic Systemic Fibrosis
(NSF)
– Adverse effects related to gadolinium-
based contrast agents (GBCA)
• Minor
• Unimportant

5. Wide Applications of GBCA
• Since 1980s
• GBCA
– All indications of magnetic resonance imaging
(MRI)
– All body systems
– Magnetic resonance angiogram (MRA)
– 30% MRI
Kuo. J Am Coll Radiol 2008;5:29-35.

6. GBCA and Renal Functions
• GBCA substitute I-CM
– When iodinated contrast media
contraindicated
– Patients with compromised renal functions
– Little risk of contrast-induced nephropathy
(CIN)
1. Kay. Cleveland clinic journal of medicine 2008; Vol 75. No. 2
2. Weinreb. J Am Coll Radiol 2008;5:53-56

7. Since NSF
• GBCA no longer safe for everyone!

8. Presentation
1. Gadolinium based contrast agent
(GBCA)
2. Nephrogenic systemic fibrosis (NSF)
3. GBCA + NSF
4. Polices  prevent NSF

9. 1. Gadolinium Based
Contrast Agent (GBCA)

10. GBCA
• Gadolinium based contrast agent
– GBCA
• Gadolinium based contrast medium
– Gd-CM

11. Contrast-induced
Nephropathy
• CIN
– Contrast-induced nephropathy
• Risk factors
– Preexisting renal insufficiency
– Diabetes mellitus
– Congestive heart failure
– Dose of contrast agent
Boyden. Gurm. Catheterization and cardiovascular interventions
2008;71:687–693

12. Gadolinium and CIN
• Post procedural renal dysfunction
– Pre-existing renal insufficiency
– Dose ≥ 0.4 mmol/kg
• Gd in lieu of isomolar iodinated
contrast media
– Not suggested
Boyden. Gurm. Catheterization and cardiovascular interventions
2008;71:687–693

13. GBCA Safety
• Safe
– Clinically recommended doses
• Reactions
– Nonallergic
– Idiosyncratic
Ersoy. Rybicki. Journal of magnetic resonance imaging 2007; 26:1190–
1197

14. Adverse Events to GBCA
Extremely low overall incidence
(0.17% - 0.07%)
• Nonallergic • Idiosyncratic
– Headache – Hives
– Fatigue – Diffuse erythema
– Nausea and/or – Periorbital edema
vomiting – Respiratory
distress
Ersoy. Rybicki. Journal of magnetic resonance imaging 2007; 26:1190–
1197

15. Gadolinium Based MRI
Contrasting Agents
• Currently approved in North America:
• OmniScan - Gadadiamide
• Magnavist - Gadopentetate Dimeglumine
• OptiMARK - Gadoversetamide
• Multihance -Gadobenate Dimeglumine
• Prohance - Gadoteridol
• Vasovist – Gadofosveset Trisodium
Ersoy. Rybicki. Journal of magnetic resonance imaging 2007; 26:1190–
1197

16. Classification of GBCA
Based on
• Tissue biodistribution
• Molecular structures
Ersoy. Rybicki. Journal of magnetic resonance imaging 2007; 26:1190–
1197

17. Classification of GBCA
• Based on tissue biodistribution
– Extracellular – majority
– Intracellular
– Tissue-specific
– Blood pool/intravascular, e.g. Vasovist
Ersoy. Rybicki. Journal of magnetic resonance imaging 2007; 26:1190–
1197

18. Classification of GBCA
• Based on molecular structure
Macrocyclic Linear
Ionic Non-ionic
Non-protein-binding Protein-binding
1. Dharnidharka. Wesson. Fennell. Pediatr nephrol 2007; 22:1395
2. Kuo. J Am Coll Radiol 2008;5:29-35.

19. Classification of GBCA
• Based on molecular structure
Macrocyclic Linear
Ionic Non-ionic
Non-protein-binding Protein-binding
1. Dharnidharka. Wesson. Fennell. Pediatr nephrol 2007; 22:1395
2. Kuo. J Am Coll Radiol 2008;5:29-35.

20. Classification of GBCA
• Based on molecular structure
Macrocyclic Linear
Ionic Non-ionic
Non-protein-binding Protein-binding
1. Dharnidharka. Wesson. Fennell. Pediatr nephrol 2007; 22:1395
2. Kuo. J Am Coll Radiol 2008;5:29-35.

21. OmniScan
• Linear
• Nonionic
• Gadadiamide
• Gd-DTPA-BMA
• 0.5 mol/L

22. Magnavist
• Linear
• Ionic
• Gadopentetate Dimeglumine
• Gd- DTPA
• 0.5 mol/L

23. OptiMARK
• Linear
• Nonionic
• Gadoversetamide
• Gd-DTPA-BMEA
• 0.5 mol/L

24. Prohance
• Macrocyclic
• Nonionic
• Gadoteridol
• Gd-HPDO3A
• 0.5 mol/L

25. Multihance
• Linear
• Ionic
• Gadobenate Dimeglumine
• Gd-BOPTA

26. Gadovist
• Macrocyclic
• Nonionic
• Gadobutrol
• Gd-BT-DO3A

27. Vasovist
• Blood pool agent
• Reversibly binds to the human blood
protein albumin
• Linear
• Ionic
• Gadofosveset trisodium
• Gd-DTPA
• 0.25 mol/L
http://www.epixpharma.com/products/vasovist.asp

28. Dotarem
• Macrocyclic
• Ionic
• 2.5 mmol/L
• Gadoterate
meglumine
• Gd-DOTA
http://www.mr-tip.com/serv1.php?type=db1&dbs=Dotarem

29. 2. Nephrogenic Systemic
Fibrosis (NSF)

30. Nephrogenic Systemic
Fibrosis (NSF)
• First described in 1997
• 2006
– Suggested to be related to Gadolinium
based contrast agent (GBCA)
Thomsen. Eur Radiol 2007;17: 2692–2696

31. Nephrogenic Systemic
Fibrosis (NSF)
• Delayed reactions
– Same day
– 2 – 3 months post injection
– Up to 18 months
1. Ersoy. Rybicki. Journal of magnetic resonance imaging 2007;
26:1190–1197
2. Thomsen. Eur Radiol 2007;17: 2692–2696
3. Dharnidharka. Wesson. Fennell. Pediatr nephrol 2007; 22:1395

32. Signs and Symptoms of
NSF
• Skin
– Burning / itching
– Reddened /
darkened patches
– Skin swelling
– Hardening and/or
tightening
1. Todd. Kagan. Chibnik. Kay. Arthritis & rheumatism 2007; Vol. 56,
No. 10. pp 3433–3441
2. http://www.fda.gov/Cder/Drug/InfoSheets/HCP/gcca_200705.htm
(Jun, 2008)

33. Signs and Symptoms of
NSF
• Face spared
• Eyes
– Yellow raised spots on the whites of the
eyes
1. Kay. Cleveland clinic journal of medicine 2008. Vol 75. No. 2
2. http://www.fda.gov/Cder/Drug/InfoSheets/HCP/gcca_200705.htm
(Jun, 2008)

34. Signs and Symptoms of
NSF
• Bones, joints and
muscles
– Joint stiffness
– Limited range of
motion
1. Todd. Kagan. Chibnik. Kay. Arthritis & rheumatism 2007; Vol. 56,
No. 10. 3433–3441
2. http://www.fda.gov/Cder/Drug/InfoSheets/HCP/gcca_200705.htm
(Jun, 2008)

35. Signs and Symptoms of
NSF
• Pain deep in hip bone
/ ribs
– And/or muscle
weakness
http://www.fda.gov/Cder/Drug/InfoSheets/HCP/gcca_200705.htm (Jun,
2008)

36. Signs and Symptoms of
NSF
• Visceral involvement
• Fibrosis of internal organs
– Diaphragm
– Heart
– Liver
– Lungs
1. Todd. Kagan. Chibnik. Kay. Arthritis & rheumatism 2007; Vol. 56,
No. 10: 3433–3441
2. Thomsen. Eur Radiol 2007;17: 2692–2696

37. Signs and Symptoms of
NSF
• Contractures
• Cachexia
• Death
Thomsen. Eur Radiol 2007;17: 2692–2696

38. NSF
• Etiology / pathogenesis
– Unknown
• Pathology
– Closely resembles wound healing
1. Dharnidharka. Wesson. Fennell. Pediatr nephrol 2007; 22:1395
2. Grobner. Prischl. Kidney international 2007; 72: 260–264
3. Boyd. Zic. Abraham. J Am acad dermatol 2007;56:27-30
4. Kuo. Kanal. Abu-Alfa. Cowper. Radiology 2007 ; Vol. 242: No. 3

39. Risk Factors of NSF
– Patient Related
• Renal impairment
– Moderate to severe
• Dialysis
– 3-5%
• Infant (< 1 year old)
– Immature renal function
1. Ersoy. Rybicki. Journal of magnetic resonance imaging 2007;
26:1190–1197
2. Boyd. Zic. Abraham. J Am acad dermatol 2007;56:27-30
3. Thomsen. Eur Radiol 2007;17: 2692–2696

40. Risk Factors of NSF
– Patient Related (Cont’d)
• GFR > 60 ml/min
– Not NSF reported
• Role of other possible cofactors
– Not proven
1. Ersoy. Rybicki. Journal of magnetic resonance imaging 2007;
26:1190–1197
2. Boyd. Zic. Abraham. J Am acad dermatol 2007;56:27-30
3. Thomsen. Eur Radiol 2007;17: 2692–2696

41. Risk Factors of NSF
- Contrast Medium Related
• Less stable GBCA
– NSF has occurred following the
administration of
• OmniScan
• Magnavist
• OptiMARK
Thomsen. Eur Radiol 2007;17: 2692–2696

42. Other Risk Factors of NSF
• Raised serum creatinine levels
– Particularly secondary to diabetic
nephropathy
• Dehydration
• Congestive heart failure
• Over 70 years
Kalb. et.al. British journal of dermatology 2008; 158: 607–610

43. Other Risk Factors of NSF
(Cont’d)
• Repeated /higher than recommended
doses of a GBCA
• Slower clearance rate ↑toxicity of Gd
• Rapid elimination important
1. Thomson. BMJ 2007; Vol 334
2. Ersoy. Rybicki. Journal of magnetic resonance imaging 2007;
26:1190–1197

44. Other Risk Factors of NSF
(Cont’d)
• Prompt hemodialysis following GBCA
– Enhance the contrast agent's elimination
– Unknown if hemodialysis prevents NSF
• Mild to moderate renal insufficiency or
normal renal function
– Risk - unknown
Thomson. BMJ 2007; Vol 334

45. Treatment
• No known cure
• No effective treatment
• Improve renal function
– Transplantation
– Medical therapy
1. Kei. Chan. Singapore Med J 2008; 49(3) : 182
2. Bucala. J Am Coll Radiol 2008;5:36-39
3. Boyden. Gurm. Catheterization and cardiovascular interventions
2008;71:687–693

46. 3. GBCA & NSF Combined

47. GBCA & NSF
• Transmetallation
• Half life

48. Transmetallation
• Transmetallation
– Process of releasing Gd3+ ions
– Binding a different cation
– Free Gd3+ released from chelate
• Exchange of other metal
– In place of Gd in chelate
1. Kuo. J Am Coll Radiol 2008;5:29-35
2. Bongartz. Magn Reson Mater Phy 2007; 20:57–62

49. Transmetallation
• The chelator must be
– Highly selective for Gd3+
– Tightly bound
– Prevent gd3+ release into the circulation
• ProHance + Dotarem
– No transmetallation
1. Ersoy. Rybicki. Journal of magnetic resonance imaging 2007;
26:1190–1197
2. Kuo. J Am Coll Radiol 2008;5:29-35.

50. Half life
• Transmetallation & Gd release from
Gd chelates
– Substantially slower than the renal clearance
rate
• Long elimination half-life
– Likely to increase the toxicity of Gd complexes
1. Kuo. J Am Coll Radiol 2008;5:29-35
2. Bongartz. Magn Reson Mater Phy 2007; 20:57–62

51. 4. Polices towards NSF
Prevention

52. Policy for GBCA
• Select type of GBCA
– Given to renal impaired patients
Weinreb. J Am Coll Radiol 2008;5:53-56

53. Policy for GBCA
• Linear agents – highest incidence of NSF
• Omniscan
– Greatest number of NSF
– No NSF in any patient with an eGFR > 30
ml/min
–  Very safe GBCA in this group
–  Continue use
Leiner 2008. ISMRM Annual Meeting

54. Policy for GBCA
• Keep dose to the lowest amount
– Compatible with diagnostic quality
– 0.1 mmol/Kg body weight
1. Weinreb. J Am Coll Radiol 2008;5:53-56
2. Leiner 2008. ISMRM Annual Meeting

55. Policy for GBCA
• Gd-MRA
– Larger doses of GBCA
• Dose
– One of the risk factors for NSF
• To lower risk
– Lower GBCA dose
– Use another agent e.g. Gadovist
Leiner 2008. ISMRM Annual Meeting

56. Policy for GBCA
• Dialysis patients
– Greatest risk of NSF
– Estimated 3-5%
• GBCA should not be given to dialysis
patients
– Unless Gd-MRI absolutely essential (benefit-
to-risk analysis)
– Nephrology consult
– Prior to giving a GBCA
Leiner 2008. ISMRM Annual Meeting

57. Policy for GBCA
• Risks for renal disease
– Advanced age
– Diabetes
– Renal transplants
– Solitary kidneys
• Use Gadovist
Leiner 2008. ISMRM Annual Meeting

58. Conclusions
1. GBCA
– Safe
– Low overall adverse events
– Mostly minor
2. NSF
– Late adverse reaction
– Only in moderate – severe renal failure
1. Ersoy. Rybicki. Journal of magnetic resonance imaging 2007;
26:1190–1197

59. Conclusions
3. Free Gd hypothesized to cause NSF
4. All Gd compounds
5. Caution
– Any degree of renal dysfunction
1. Kuo. J Am Coll Radiol 2008;5:29-35
2. Bongartz. Magn Reson Mater Phy 2007; 20:57–62

60. Conclusions
6. Informed consent
– NSF
– Other adverse reactions
7. NSF Reported
– National Medicines Agencies
– International Registries
1. Weinreb. J Am Coll Radiol 2008;5:53-56
2. Grobner. Prischl. Kidney international 2007; 72: 260–264

61. Conclusions
8. Rename NSF  GASF
– Gadolinium-associated system fibrosis
Kay. Cleveland clinic journal of medicine 2008. Vol 75. No. 2

62. Thank you for your attention!
6-Dec-08
Last updated
23-Sep-10