Welcome to IM Department Meeting!

Gadolinium Based Contrast Exposure and Risk of Nephrogenic Systemic Fibrosis

Tonight’s Facilitators:Barbara Doerr, DOWilliam Myers, DOStaci Smith, DOMichelle Cacek, DO

Nephrogenic Systemic Fibrosis (NSF)o originally named nephrogenic fibrosing

dermopathy (NFD)o manifestations initially thought to be

confined to the skino systemic fibrosis on autopsy (NSF)

oskeletal 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 ptso 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 yearo about 2.4 % for each time a CKD pt is

exposed to gadoliniumo balancing benefit and risko 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 dxo litigation opportunities

September 12, 2007

Boxed Warningo 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 agento metal with powerful magnetic properties o contrast for MR imaging or MR angiographyo chelates are excreted exclusively by the

kidney

Gadolinium Half Lifeo 1.3 hrs if healthyo 10 hrs at GFR of 20 - 40 mL/mino 34 hrs if ESRDo 1.9 - 2.6 hrs if HD follows administration

Gadolinium Based Contrast Agentso Omniscan

o launched in the U.S. in 1993 by GEo Magnevisto MultiHanceo OptiMARKo ProHance

Risk factors for NSFo renal impairmento hypercoagulable stateo thrombotic eventso recent vascular studyo transplant failure

Signs and Symptoms of NSFo burning skino itchy skino swelling o tight and hard skin o red or dark skin

patcheso contractures

o stiffness in joints o trouble moving

extremities o pain deep in the boneso muscle weaknesso “woody” feel of skino yellow scleral plaques

NSF Upper Extremityo thick, hardened

skin

o brawny hyperpigmentation

o distinct papules

o subcutaneous nodules

NSF Upper Extremityo soft-tissue swelling o flexion contractures of hand

o slightly raised and erythematous nodular plaqueso linear, confluent regions of fibrosis

NSF

Differential Diagnosis

o scleroderma / systemic sclerosis o eosinophilic fasciitis o eosinophilia–myalgia syndrome

Differential Diagnosiso Unlike scleroderma

o NSF spares the face o lacks the serologic markers of

sclerodermao symmetrical lesions

oprefers trunk and extremities

Punch Biopsy : Skin

widening of subcutaneous septae w/ thick collagen bundles

Histological Findings and Pathogenesis

o thick collagen bundles with surrounding clefts

o mucin depositiono increased fibrocytes and elastic fiberso increased factor XIIIa and mononucleated

cells

Topic Development: PICOo P

Patient Populationo I

Intervention or Exposureo C

Comparison Interventiono O

Outcome

Question ???o What degree of kidney disease should

we not use gadolinium based contrast agents ?

Articleo 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 754-759.

Evidence Based Medicineo 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 2000o renal dysfunction pts

o regardless of causeo not just HD pts, PD pts as well

o other associations:o vascular sxo vascular thrombosiso scleral plaques

The Patient: NSF: Report of a New Case

o 39 yo AAM o ESRD on HD d/t HTN for 8 yrso multiple medical problems

oantiphospholipid ab syndromeo no other rheumatologic history o 3 yrs before hospital admission

ostiff fingers and armsothickening skin on calves and thighsorapid progression to contractures

The Patient- NSF: Report of a New Caseo pt’s lab data -p 755o fibrosis around

translumbar HD catho pt expired after 45

min of ACLS

o autopsy resultso extensive fibrosiso plaque like changes

across chest, extremities

o contractureso thickened pleurao dense collagenous

bandso fibrotic cardiac tissue

NSF: Report of a New Case

o taut, waxy appearanceo 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 sectiono 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 diseaseo systemic manifestations

omuscle, pleura, diaphragm, myo and pericardium

o initiating factors in NSFo tissue injuryo hypercoagulable state

Discussion - NSF: Report of a New Case

o NSF involves aberrant fibrocyte recruitmento decrease EPO due to fibrogenic properties

o NO consistent treatment proven effective

Articleo 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 ptsoboth 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

odiscussed with Dermatologyo stratified by gadolinium exposure

o0, 1, or greater than 1o 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 dialysiso 592 pts or 4% had CKD 3 – 4o 6,636 total pts received gad from 2004-

2006o skin bx w/ immunoperoxidase staining for

CD 34

NSF After Gadolinium Exposure

o Results:o 849 total ptso 261 had 354 MRI scans

ow/ gadolinium (Omniscan)o1 time exposure in 191 ptso2 exposures in 53o3 exposures in 13o4 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 Dialysiso overall NSF rate 0.5% (4 of 261)o 1.5% risk of NSF after one gad exposureo 98.5% did not develop NSFo odds ratio 6.67 w/ one exposure

o44.5 odds ratio with multiple exposureso skin lesions appeared within 2-3 moo strong statistical association with NSF

and gadolinium exposure

NSF After Gadolinium Exposure

o Results : CKD 3 – 4 ptso no patients discovered to have NSFo 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 lowo increased exposure leads to increased risko higher Ca, Phos, and Epo may be associated

with increased NSF incidenceo NO need for gad restriction in CKD 3- 4o monitor skin for 4-6 mo if gad is usedo consider dialysis immediately after exposureo kidney transplant therapy in future

Concluding Pointso A

o Academic Detailingo R

o Reminderso E

o Enticementso A

o Audit

Concluding Points: Academic Detailso Academic Detailing:

o Medical knowledgeoNSF

o Patient careo Communicationo OMM/OPP o Systems based practice

oPhysician interacts with healthcare systemo Practice based learning

oPhysicians maintain knowledge and skills to provide ongoing pt care

Osteopathic Considerationso myofascial release

o indirect techniqueso whole body approach

Osteopathy in Actiono 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.como CDC

o www.cdc.govo FDA

o 1-800-FDA-1088o www.FDA.gov

Systems Based Practice o acute NSF: 58089o chronic NSF: 5829o include CKD staging: 585.-o principal procedure

o MRI imaging: 8897

Systems Based Practiceo 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 futureo screening baseline kidney fxn / sizeo acute kidney injury vs CKDo CrCl –when not to use gadoliniumo follow-up labs after gadolinium useo when to dialyze ESRD pts if GBCA used

Enticements/ Systems Based Practiceo MRI imaging: DRG 8897o MRI brain w/ contrast: $3,692o MRI brain w/o contrast: $2,255o MRI thoracic/lumbar spine w/ contrast :

$2,465o MRI thoracic/lumbar w/o contrast: $2,144

Audito How can we measure outcomes and

progress?

o Practice habits changed in the future?

Conclusions : Take Home Points

o interest of pt safetyo balance benefits and risks of GBCA’s

o screen all pts with labs and historyo GBCA’s should NOT be used if CrCl

<30o careful consideration if CrCl <60

o alternative imaging methods

Conclusions: Take Home Pointso monitor for skin manifestations after GBCAo follow labs after administration o do not exceed recommended dose

o 0.1-0.2 mmol/kgo allow time for elimination before

readministration

Please Join Us Next Montho IM Journal Club

o presented by Dr. Bryano laryngeal reflux and proton pump

inhibitors

Referenceso 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.