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
Nephrogenic Systemic Fibrosis (NSF)
o originally named nephrogenic fibrosing
dermopathy (NFD)
o manifestations initially thought to be
confined to the skin
o systemic fibrosis on autopsy (NSF)
o skeletal muscles ,diaphragm ,pleura ,dura mater,
pericardium & myocardium
Nephrogenic Systemic Fibrosis (NSF)
o predominately in pts with acute kidney injury
or severely impaired renal function
o CrCl less than 30
o no predilection for age, race, gender ,or
location
o typically middle aged pts
o reported in 8 yo children, as well as elderly
What’s the risk?
o risk of NSF estimated at 4.3 cases per 1,000
dialysis patients per year
o about 2.4 % for each time a CKD pt is exposed to
gadolinium
o balancing benefit and risk
o majority of pts who receive Gd do not develop
NSF
What’s the issue with NSF?
o avoidance of GBCA’s
o limited radiological studies
o roadblocks to specific dx
o litigation opportunities
September 12, 2007
Boxed Warning
o Gadolinium based contrast agents
increase risk of NSF in pts with:
o acute and chronic renal failure (GFR < 30)
o acute renal insuffciency of any severity due
to hepatorenal syndrome or in
perioperative liver transplant period
What is Gadolinium?
o nonionic, hyperosmolar (650 mosmol/kg)
contrast agent
o metal with powerful magnetic properties
o contrast for MR imaging or MR angiography
o chelates are excreted exclusively by the kidney
Gadolinium Half Life
o
o
o
o
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
Gadolinium Based Contrast Agents
o Omniscan
o launched in the U.S. in 1993 by GE
o Magnevist
o MultiHance
o OptiMARK
o ProHance
Risk factors for NSF
o renal impairment
o hypercoagulable state
o thrombotic events
o recent vascular study
o transplant failure
Signs and Symptoms of NSF
o
o
o
o
o
burning skin
itchy skin
swelling
tight and hard skin
red or dark skin
patches
o contractures
o stiffness in joints
o trouble moving
extremities
o pain deep in the bones
o muscle weakness
o “woody” feel of skin
o yellow scleral plaques
NSF Upper Extremity
o thick, hardened skin
o brawny
hyperpigmentation
o distinct papules
o subcutaneous
nodules
NSF Upper Extremity
o soft-tissue swelling
o flexion contractures of hand
NSF
o slightly raised and erythematous nodular plaques
o linear, confluent regions of fibrosis
Differential Diagnosis
o scleroderma / systemic sclerosis
o eosinophilic fasciitis
o eosinophilia–myalgia syndrome
Differential Diagnosis
o Unlike scleroderma
o NSF spares the face
o lacks the serologic markers of scleroderma
o symmetrical lesions
o prefers trunk and extremities
Punch Biopsy : Skin
widening of subcutaneous septae w/ thick collagen bundles
Histological Findings and Pathogenesis
o
o
o
o
thick collagen bundles with surrounding clefts
mucin deposition
increased fibrocytes and elastic fibers
increased factor XIIIa and mononucleated cells
Topic Development: PICO
oP
Patient Population
oI
Intervention or Exposure
oC
Comparison Intervention
oO
Outcome
Question ???
o What degree of kidney disease should
we not use gadolinium based contrast
agents ?
Article
o Nephrogenic Fibrosing Dermopathy/
Nephrogenic Systemic Fibrosis: Report of a New
Case with Literature Review
o Daram, et al. AJKD, Vol 46, No 4, 2005, pp 754759.
Evidence Based Medicine
o Nephrogenic Fibrosing
Dermopathy /Nephrogenic
Systemic Fibrosis: Report of a
New Case with Literature
Review
o Daram ,et al.
o AJKD 2005
Introduction- NSF: Report of a New Case
o first cases of NSF recognized in 2000
o renal dysfunction pts
o regardless of cause
o not just HD pts, PD pts as well
o other associations:
o vascular sx
o vascular thrombosis
o scleral plaques
The Patient: NSF: Report of a New Case
o 39 yo AAM
o ESRD on HD d/t HTN for 8 yrs
o multiple medical problems
o antiphospholipid ab syndrome
o no other rheumatologic history
o 3 yrs before hospital admission
o stiff fingers and arms
o thickening skin on calves and thighs
o rapid progression to contractures
The Patient- NSF: Report of a New Case
o pt’s lab data -p 755
o autopsy results
o extensive fibrosis
o fibrosis around
o plaque like changes
translumbar HD cath
across chest, extremities
o pt expired after 45
o contractures
min of ACLS
o thickened pleura
o dense collagenous bands
o fibrotic cardiac tissue
NSF: Report of a New Case
o taut, waxy appearance
o cobblestone pattern
o fig 1B
NSF: Report of a New Case
o chest wall w/thick
dermis
o dense white fibrous
bands in septa
NSF: Report of a New Case
haphazardly
arranged collagen
bundles w/ clefts
NSF: Report of a New Case
o diaphragm section
o fibrous bands
o fibroblast like cells
NSF: Report of a New Case
dendritic projections on CD34 cells
CD45 RO cells
Discussion- NSF: Report of a New Case
o NFD is not merely a cutaneous disease
o systemic manifestations
o muscle, pleura, diaphragm, myo and
pericardium
o initiating factors in NSF
o tissue injury
o hypercoagulable state
Discussion - NSF: Report of a New Case
o NSF involves aberrant fibrocyte recruitment
o decrease EPO due to fibrogenic properties
o NO consistent treatment proven effective
Article
o Nephrogenic Systemic Fibrosis After
Exposure to Gadolinium in Patients with
Renal Failure
o Othersen, J. et al, Nephrology Dialysis
Transplantation, Sept 21, 2007, p 1-7.
Evidence Based Medicine
o Nephrogenic Systemic
Fibrosis After Exposure to
Gadolinium in Patients
with Renal Failure
NSF After Gadolinium Exposure
o Purpose:
o analyze NSF incidence
o association of NSF with gadolinium exposure
in CKD pts
o both pre-dialysis and dialysis pts
o determine if increased gadolinium exposure
increases NSF
NSF After Gadolinium Exposure
o Methods:
o 849 total pts in 5 yr time span (2001-2006)
o Nephrology at Medical University of SC
o discussed with Dermatology
o stratified by gadolinium exposure
o 0, 1, or greater than 1
o statistical association between NSF rate and
gad exposure
o statistical association of increasing gad
exposure and NSF occurrence
NSF After Gadolinium Exposure
o Methods:
o CKD pts NOT on dialysis
o 592 pts or 4% had CKD 3 – 4
o 6,636 total pts received gad from 2004-2006
o skin bx w/ immunoperoxidase staining for
CD 34
NSF After Gadolinium Exposure
o Results:
o 849 total pts
o 261 had 354 MRI scans
o w/ gadolinium (Omniscan)
o 1 time exposure in 191 pts
o 2 exposures in 53
o 3 exposures in 13
o 4 exposures in 5
NSF After Gadolinium Exposure
Gadolinium Exposure
NSF Incidence
Never
0%
One time
1.1%
Greater than one time
2.9%
NSF After Gadolinium Exposure
o Results: Pts on Dialysis
o overall NSF rate 0.5% (4 of 261)
o 1.5% risk of NSF after one gad exposure
o 98.5% did not develop NSF
o odds ratio 6.67 w/ one exposure
o 44.5 odds ratio with multiple exposures
o skin lesions appeared within 2-3 mo
o strong statistical association with NSF and
gadolinium exposure
NSF After Gadolinium Exposure
o Results : CKD 3 – 4 pts
o no patients discovered to have NSF
o incidence estimated at <0.2%
o possibly due to only 4% have CKD 3-4
NSF After Gadolinium Exposure
o Conclusions:
o NSF incidence is very low
o increased exposure leads to increased risk
o higher Ca, Phos, and Epo may be associated
with increased NSF incidence
o NO need for gad restriction in CKD 3- 4
o monitor skin for 4-6 mo if gad is used
o consider dialysis immediately after exposure
o kidney transplant therapy in future
Concluding Points
oA
o Academic Detailing
oR
o Reminders
oE
o Enticements
oA
o Audit
Concluding Points: Academic Details
o Academic Detailing:
o Medical knowledge
o NSF
o Patient care
o Communication
o OMM/OPP
o Systems based practice
o Physician interacts with healthcare system
o Practice based learning
o Physicians maintain knowledge and skills to
provide ongoing pt care
Osteopathic Considerations
o myofascial release
o indirect techniques
o whole body approach
Osteopathy in Action
o NSF registry
o collects info about NSF pts from all over the world
o General Clinical Research Center at Yale University
o e-mail : registermc @juno.com
o CDC
o www.cdc.gov
o FDA
o 1-800-FDA-1088
o www.FDA.gov
Systems Based Practice
o acute NSF: 58089
o chronic NSF: 5829
o include CKD staging: 585.o principal procedure
o MRI imaging: 8897
Systems Based Practice
o Cerebral a. occlusion
w/ cerebral infarction
DRG: 43491
$5,246.24
Medicare
o Cerebral a. occlusion
w/ cerebral infarction
plus acute NSF
DRG: 43491, 58089
$7,877.25
Medicare
Reminders
o Carepath in future
o screening baseline kidney fxn / size
o acute kidney injury vs CKD
o CrCl –when not to use gadolinium
o follow-up labs after gadolinium use
o when to dialyze ESRD pts if GBCA used
Enticements/ Systems Based Practice
o MRI imaging: DRG 8897
o
o
o
o
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
Audit
o How can we measure outcomes and
progress?
o Practice habits changed in the future?
Conclusions : Take Home Points
o interest of pt safety
o balance benefits and risks of GBCA’s
o screen all pts with labs and history
o GBCA’s should NOT be used if CrCl <30
o careful consideration if CrCl <60
o alternative imaging methods
Conclusions: Take Home Points
o monitor for skin manifestations after GBCA
o follow labs after administration
o do not exceed recommended dose
o 0.1-0.2 mmol/kg
o allow time for elimination before
readministration
Please Join Us Next Month
o IM Journal Club
o presented by Dr. Bryan
o laryngeal reflux and proton pump inhibitors
References
o Nephrogenic Fibrosing Dermopathy
/Nephrogenic Systemic Fibrosis: Report of a
New Case with Literature Review.Daram ,et
al. AJKD 2005.
o 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.
Happy Halloween !!
Trick or treat
References
• www.cdc.gov
• www.fda.gov
• Gadodiamide-Associated Nephrogenic
Systemic Fibrosis: Why Radiologists Should Be
Concerned . Dale R. Broome et al. AJR 2007;
188:586-592.
• Adverse Reactions to Gadolinium Contrast
Media: A Review of 36 Cases. Murphy,et al.
AJR, Oct 1996:847-849.