Welcome to IM Department Meeting!

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Welcome to IM Department Meeting!

• Gadolinium Based Contrast Exposure and Risk of
  Nephrogenic Systemic Fibrosis

Tonights Facilitators Barbara Doerr, DO William
Myers, DO Staci Smith, DO Michelle Cacek, DO
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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

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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

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Whats 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

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Whats the issue with NSF?

• avoidance of GBCAs
• limited radiological studies
• roadblocks to specific dx
• litigation opportunities

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September 12, 2007
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Boxed Warning

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

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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

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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

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Gadolinium Based Contrast Agents

• Omniscan
• launched in the U.S. in 1993 by GE
• Magnevist
• MultiHance
• OptiMARK
• ProHance

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Risk factors for NSF

• renal impairment
• hypercoagulable state
• thrombotic events
• recent vascular study
• transplant failure

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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

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NSF Upper Extremity

• thick, hardened skin
• brawny hyperpigmentation
• distinct papules
• subcutaneous nodules

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NSF Upper Extremity

• soft-tissue swelling
• flexion contractures of hand

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NSF

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

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Differential Diagnosis

• scleroderma / systemic sclerosis
• eosinophilic fasciitis
• eosinophiliamyalgia syndrome

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Differential Diagnosis

• Unlike scleroderma
• NSF spares the face
• lacks the serologic markers of scleroderma
• symmetrical lesions
• prefers trunk and extremities

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Punch Biopsy Skin
widening of subcutaneous septae w/ thick collagen
bundles
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Histological Findings and Pathogenesis

• thick collagen bundles with surrounding clefts
• mucin deposition
• increased fibrocytes and elastic fibers
• increased factor XIIIa and mononucleated cells

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Topic Development PICO

• P
• Patient Population
• I
• Intervention or Exposure
• C
• Comparison Intervention
• O
• Outcome

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Question ???

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

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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.

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Evidence Based Medicine

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

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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

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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

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The Patient- NSF Report of a New Case

• pts 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

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NSF Report of a New Case

• taut, waxy appearance
• cobblestone pattern
• fig 1B

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NSF Report of a New Case

• chest wall w/thick dermis
• dense white fibrous bands in septa

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

• diaphragm section
• fibrous bands
• fibroblast like cells

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

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Discussion - NSF Report of a New Case

• NSF involves aberrant fibrocyte recruitment
• decrease EPO due to fibrogenic properties
• NO consistent treatment proven effective

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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.

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Evidence Based Medicine

• Nephrogenic Systemic Fibrosis After Exposure to
  Gadolinium in Patients with Renal Failure

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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

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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

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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

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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

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NSF After Gadolinium Exposure
Gadolinium Exposure NSF Incidence
Never 0
One time 1.1
Greater than one time 2.9
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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

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NSF After Gadolinium Exposure

• Results CKD 3 4 pts
• no patients discovered to have NSF
• incidence estimated at lt0.2
• possibly due to only 4 have CKD 3-4

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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

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Concluding Points

• A
• Academic Detailing
• R
• Reminders
• E
• Enticements
• A
• Audit

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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

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Osteopathic Considerations

• myofascial release
• indirect techniques
• whole body approach

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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 _at_juno.com
• CDC
• www.cdc.gov
• FDA
• 1-800-FDA-1088
• www.FDA.gov

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Systems Based Practice

• acute NSF 58089
• chronic NSF 5829
• include CKD staging 585.-
• principal procedure
• MRI imaging 8897

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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

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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

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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

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Audit

• How can we measure outcomes and progress?
• Practice habits changed in the future?

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Conclusions Take Home Points

• interest of pt safety
• balance benefits and risks of GBCAs
• screen all pts with labs and history
• GBCAs should NOT be used if CrCl lt30
• careful consideration if CrCl lt60
• alternative imaging methods

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Conclusions Take Home Points

• monitor for skin manifestations after GBCA
• follow labs after administration
• do not exceed recommended dose
• 0.1-0.2 mmol/kg
• allow time for elimination before readministration

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Please Join Us Next Month

• IM Journal Club
• presented by Dr. Bryan
• laryngeal reflux and proton pump inhibitors

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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.

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Happy Halloween !!

• Trick or treat

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References

• www.cdc.gov
• www.fda.gov
• Gadodiamide-Associated Nephrogenic Systemic
  Fibrosis Why Radiologists Should Be Concerned .
  Dale R. Broome et al. AJR 2007 188586-592.
• Adverse Reactions to Gadolinium Contrast Media A
  Review of 36 Cases. Murphy,et al. AJR, Oct
  1996847-849.