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 1,000 dialysis 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 mL/min
34 hrs if ESRD
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
Hepatorenal syndrome, liver transplant

12. Signs and Symptoms of NSF
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

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
symmetrical lesions
prefers trunk and extremities

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

19. Histological Findings and Pathogenesis
thick collagen bundles with surrounding clefts
mucin deposition
increased fibrocytes and elastic fibers
increased factor XIIIa and mononucleated cells
THICK AND WAVY BUNDLES!!

20. Topic Development: PICO
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

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. The Patient- NSF: Report of a New Case
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

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 ( )
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
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
NSF Incidence
Never 0%
One time
1.1%
Greater than one time
2.9%

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
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 CDC FDA
collects info about NSF pts from all over the world
General Clinical Research Center at Yale University
CDC
FDA
1-800-FDA-1088

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

49. Systems Based Practice
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

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

51. Enticements/ Systems Based Practice
MRI imaging: DRG 8897
MRI brain w/ contrast: $3,692
MRI brain w/o contrast: $2,255
MRI thoracic/lumbar spine w/ contrast : $2,465
MRI thoracic/lumbar w/o contrast: $2,144

52. Audit How can we measure outcomes and progress?
Practice habits changed in the future?

53. Conclusions : Take Home Points
interest of pt safety
balance benefits and risks of GBCA’s
screen all pts with labs and history
GBCA’s should NOT be used if CrCl <30
careful consideration if CrCl <60
alternative imaging methods

54. Conclusions: Take Home Points
monitor for skin manifestations after GBCA
follow labs after administration
do not exceed recommended dose
mmol/kg
allow time for elimination before readministration

55. Please Join Us Next Month
IM Journal Club
presented by Dr. Bryan
laryngeal reflux and proton pump inhibitors

56. References
Nephrogenic Fibrosing Dermopathy /Nephrogenic Systemic Fibrosis: Report of a New Case with Literature Review.Daram ,et al. AJKD 2005.
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.

57. Happy Halloween !!
Trick or treat

58. References www.cdc.gov www.fda.gov
Gadodiamide-Associated Nephrogenic Systemic Fibrosis: Why Radiologists Should Be Concerned . Dale R. Broome et al. AJR 2007; 188:
Adverse Reactions to Gadolinium Contrast Media: A Review of 36 Cases. Murphy,et al. AJR, Oct 1996: