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What Is Current About Nephrogenic Systemic Fibrosis V6

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Presented HKCRRT Inauguration conference (Dec 8, 08)

Presented HKCRRT Inauguration conference (Dec 8, 08)


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  • Multiple risk factors have been identified for CINincluding preexisting renal insufficiency, diabetes mellitus,congestive heart failure, volume depletion andthe dose of contrast agent administered.
  • Useof Gadolinium for vascular angiography appears to beassociated with postprocedural renal dysfunction in patients with preexisting renal insufficiency, whengiven in high doses. Therefore use of Gd in lieu of isomolar iodinated contrast media is not recommended.
  • Now let’s go back to GBCA. GBCA are very safe within clinically recommended doses. Adverse reactions towards GBCA are classified as nonallergic and idiosyncratic.
  • There are 6 GBCAapproved to be used in North America, namely, Omniscan, Magnavist, Multihance, Optimark, and Prohance. Vasovist is a new comer.
  • Classification of GBCA are mainly based on tissue biodistribution and molecular structures.
  • The majority of GBCA are extracellular, while some are intracellular, tissue-specific, and blood pool / intravascular, e.g. Vasovist.
  • Or classified based on molecular structure e.g. macrocyclic or linear, ionic or non-ionic, non-protein-binding or protein-binding.
  • Or classified based on molecular structure e.g. macrocyclic or linear, ionic or non-ionic, non-protein-binding or protein-binding.
  • Or classified based on molecular structure e.g. macrocyclic or linear, ionic or non-ionic, non-protein-binding or protein-binding.
  • In North America, the most commonly used GBCAis Omniscan. It is linear and nonionic.
  • The 2nd commonest GBCAis Magnavist. This agent has extraordinary safe records, but also associated with a few NSF cases.
  • ContracturesCachexiaDeath, in a proportion of patients
  • Etiology / pathogenesis is unknown. The pathology closely resembles wound healing.
  • The most important risk factor of NSF is Renal impairment, including patients on dialysis. About 3 – 5% of dialysis patients developed NSF after exposure to GBCA. Infant age under 1 year are also at risk because of immature renal function.
  • Please note that NSF has not been reported in patients with GFRgreater than 60 ml/min. The role of other possible cofactors is not proven.
  • Less stable GBCA have higher risk of NSF. NSF has occurred following the administration of OmniScan, Magnavist, and OptiMARK.
  • Higher doses or recommended doses repeated over a short time are also associated with NSF. Slower clearance rate causes increased toxicity of gadolinium., therefore rapid elimination of GBCA is important.
  • For hemodialysis patient, prompt hemodialysis following GBCAcan enhance the contrast agent's elimination. However, it is unknown if hemodialysis prevents NSF. Also, the risk to mild to moderate renal insufficiency or normal renal function is also unknown.
  • Treatment. There are no known cure or effective treatment for NSF. Symptoms may improve with improved renal function by means of renal transplantation or medical therapy.
  • Transmetallation is the process thatfree Gd3+ ions are released from chelate. Other metals are exchanged In place of Gd in chelate.
  • The chelator must be highly selective for Gd ion, tightly bound to prevent gd3+ releaseinto the circulation This process happens in all GBCA except ProHance and Dotarem.
  • Transcript

    • 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