Welcome to IM Department Meeting!

1. Welcome to IM Department Meeting! Gadolinium Based Contrast Exposure and Risk of Nephrogenic Systemic Fibrosis Tonight’s Facilitators: Barbara Doerr, DO William Myers, DO Staci Smith, DO Michelle Cacek, DO

2. Nephrogenic Systemic Fibrosis (NSF) • originally named nephrogenic fibrosing dermopathy (NFD) • manifestations initially thought to be confined to the skin • systemic fibrosis on autopsy (NSF) • skeletal muscles ,diaphragm ,pleura ,dura mater, pericardium & myocardium

3. Nephrogenic Systemic Fibrosis (NSF) • predominately in pts with acute kidney injury or severely impaired renal function • CrCl less than 30 • no predilection for age, race, gender ,or location • typically middle aged pts • reported in 8 yo children, as well as elderly

4. What’s the risk? • risk of NSF estimated at 4.3 cases per 1,000dialysis patients per year • about 2.4 % for each time a CKD pt is exposed to gadolinium • balancing benefit and risk • majority of pts who receive Gd do not develop NSF

5. What’s the issue with NSF? • avoidance of GBCA’s • limited radiological studies • roadblocks to specific dx • litigation opportunities

6. September 12, 2007

7. Boxed Warning • Gadolinium based contrast agents increase risk of NSF in pts with: • acute and chronic renal failure (GFR < 30) • acute renal insuffciency of any severity due to hepatorenal syndrome or in perioperative liver transplant period

8. What is Gadolinium? • nonionic, hyperosmolar (650 mosmol/kg) contrast agent • metal with powerful magnetic properties • contrast for MR imaging or MR angiography • chelates are excreted exclusively by the kidney

9. Gadolinium Half Life • 1.3 hrs if healthy • 10 hrs at GFR of 20 - 40 mL/min • 34 hrs if ESRD • 1.9 - 2.6 hrs if HD follows administration

10. Gadolinium Based Contrast Agents • Omniscan • launched in the U.S. in 1993 by GE • Magnevist • MultiHance • OptiMARK • ProHance

11. Risk factors for NSF • renal impairment • hypercoagulable state • thrombotic events • recent vascular study • transplant failure

12. burning skin itchy skin swelling tight and hard skin red or dark skin patches contractures stiffness in joints trouble moving extremities pain deep in the bones muscle weakness “woody” feel of skin yellow scleral plaques Signs and Symptoms of NSF

13. NSF Upper Extremity • thick, hardened skin • brawny hyperpigmentation • distinct papules • subcutaneous nodules

14. NSF Upper Extremity • soft-tissue swelling • flexion contractures of hand

15. NSF • slightly raised and erythematous nodular plaques • linear, confluent regions of fibrosis

16. Differential Diagnosis • scleroderma / systemic sclerosis • eosinophilic fasciitis • eosinophilia–myalgia syndrome

17. Differential Diagnosis • Unlike scleroderma • NSF spares the face • lacks the serologic markers of scleroderma • symmetricallesions • prefers trunk and extremities

18. Punch Biopsy : Skin widening of subcutaneous septae w/ thick collagen bundles

19. Histological Findings andPathogenesis • thick collagen bundles with surrounding clefts • mucin deposition • increased fibrocytes and elastic fibers • increased factor XIIIa and mononucleated cells

20. Topic Development: PICO • P Patient Population • I Intervention or Exposure • C Comparison Intervention • O Outcome

21. Question ??? • What degree of kidney disease should we not use gadolinium based contrast agents ?

22. Article • Nephrogenic Fibrosing Dermopathy/ Nephrogenic Systemic Fibrosis: Report of a New Case with Literature Review • Daram, et al. AJKD, Vol 46, No 4, 2005, pp 754-759.

23. Evidence Based Medicine • Nephrogenic Fibrosing Dermopathy /Nephrogenic Systemic Fibrosis: Report of a New Case with Literature Review • Daram ,et al. • AJKD 2005

24. Introduction- NSF: Report of a New Case • first cases of NSF recognized in 2000 • renal dysfunction pts • regardless of cause • not just HD pts, PD pts as well • other associations: • vascular sx • vascular thrombosis • scleral plaques

25. The Patient: NSF: Report of a New Case • 39 yo AAM • ESRD on HD d/t HTN for 8 yrs • multiple medical problems • antiphospholipid ab syndrome • no other rheumatologic history • 3 yrs before hospital admission • stiff fingers and arms • thickening skin on calves and thighs • rapid progression to contractures

26. pt’s lab data -p 755 fibrosis around translumbar HD cath pt expired after 45 min of ACLS autopsy results extensive fibrosis plaque like changes across chest, extremities contractures thickened pleura dense collagenous bands fibrotic cardiac tissue The Patient- NSF: Report of a New Case

27. NSF: Report of a New Case • taut, waxy appearance • cobblestone pattern • fig 1B

28. NSF: Report of a New Case • chest wall w/thick dermis • dense white fibrous bands in septa

29. NSF: Report of a New Case haphazardly arranged collagen bundles w/ clefts

30. NSF: Report of a New Case • diaphragm section • fibrous bands • fibroblast like cells

31. NSF: Report of a New Case dendritic projections on CD34 cells CD45 RO cells

32. Discussion- NSF: Report of a New Case • NFD is not merely a cutaneous disease • systemic manifestations • muscle, pleura, diaphragm, myo and pericardium • initiating factors in NSF • tissue injury • hypercoagulable state

33. Discussion - NSF: Report of a New Case • NSF involves aberrant fibrocyte recruitment • decrease EPO due to fibrogenic properties • NO consistent treatment proven effective

34. Article • Nephrogenic Systemic Fibrosis After Exposure to Gadolinium in Patients with Renal Failure • Othersen, J. et al, Nephrology Dialysis Transplantation, Sept 21, 2007, p 1-7.

35. Evidence Based Medicine • Nephrogenic Systemic Fibrosis After Exposure to Gadolinium in Patients with Renal Failure

36. NSF After Gadolinium Exposure • Purpose: • analyze NSF incidence • association of NSF with gadolinium exposure in CKD pts • both pre-dialysis and dialysis pts • determine if increased gadolinium exposure increases NSF

37. NSF After Gadolinium Exposure • Methods: • 849 total pts in 5 yr time span (2001-2006) • Nephrology at Medical University of SC • discussed with Dermatology • stratified by gadolinium exposure • 0, 1, or greater than 1 • statistical association between NSF rate and gad exposure • statistical association of increasing gad exposure and NSF occurrence

38. NSF After Gadolinium Exposure • Methods: • CKD pts NOT on dialysis • 592 pts or 4% had CKD 3 – 4 • 6,636 total pts received gad from 2004-2006 • skin bx w/ immunoperoxidase staining for CD 34

39. NSF After Gadolinium Exposure • Results: • 849 total pts • 261 had 354 MRI scans • w/ gadolinium (Omniscan) • 1 time exposure in 191 pts • 2 exposures in 53 • 3 exposures in 13 • 4 exposures in 5

40. NSF After Gadolinium Exposure

41. NSF After Gadolinium Exposure • Results: Pts on Dialysis • overall NSF rate 0.5% (4 of 261) • 1.5% risk of NSF after one gad exposure • 98.5% did not develop NSF • odds ratio 6.67 w/ one exposure • 44.5 odds ratio with multiple exposures • skin lesions appeared within 2-3 mo • strong statistical association with NSF and gadolinium exposure

42. NSF After Gadolinium Exposure • Results : CKD 3 – 4 pts • no patients discovered to have NSF • incidence estimated at <0.2% • possibly due to only 4% have CKD 3-4

43. NSF After Gadolinium Exposure • Conclusions: • NSF incidence is very low • increased exposure leads to increased risk • higher Ca, Phos, and Epo may be associated with increased NSF incidence • NO need for gad restriction in CKD 3- 4 • monitor skin for 4-6 mo if gad is used • consider dialysis immediately after exposure • kidney transplant therapy in future

44. Concluding Points • A • Academic Detailing • R • Reminders • E • Enticements • A • Audit

45. Concluding Points: Academic Details • Academic Detailing: • Medical knowledge • NSF • Patient care • Communication • OMM/OPP • Systems based practice • Physician interacts with healthcare system • Practice based learning • Physicians maintain knowledge and skills to provide ongoing pt care

46. Osteopathic Considerations • myofascial release • indirect techniques • whole body approach

47. Osteopathy in Action • NSF registry • collects info about NSF pts from all over the world • General Clinical Research Center at Yale University • e-mail : registermc @juno.com • CDC • www.cdc.gov • FDA • 1-800-FDA-1088 • www.FDA.gov

48. Systems Based Practice • acute NSF: 58089 • chronic NSF: 5829 • include CKD staging: 585.- • principal procedure • MRI imaging: 8897

49. Cerebral a. occlusion w/ cerebral infarction DRG: 43491 $5,246.24 Medicare Cerebral a. occlusion w/ cerebral infarction plus acute NSF DRG: 43491, 58089 $7,877.25 Medicare Systems Based Practice

50. Reminders • Carepath in future • screening baseline kidney fxn / size • acute kidney injury vs CKD • CrCl –when not to use gadolinium • follow-up labs after gadolinium use • when to dialyze ESRD pts if GBCA used