Nephrogenic Systemic Fibrosis: An Update Harvard Medical School B ETH I SRAEL D EACONESS M EDICAL C...

Nephrogenic Systemic Fibrosis: Nephrogenic Systemic Fibrosis: An UpdateAn Update

Harvard

Medical

School

BBETH ETH IISRAEL SRAEL DDEACONESSEACONESSMMEDICAL EDICAL CCENTERENTER

Neil M. Rofsky, MD

MR Contrast Agents: PrinciplesMR Contrast Agents: Principles

• Unpaired electrons alter magnetic environmentUnpaired electrons alter magnetic environment• A trait of certain metal ionsA trait of certain metal ions

• Indirectly affects the local HIndirectly affects the local H2200• Naked metal ions are toxic!Naked metal ions are toxic!• Ligands for safetyLigands for safety

• (metal + ligand = chelate)(metal + ligand = chelate)

• Unpaired electrons alter magnetic environmentUnpaired electrons alter magnetic environment• A trait of certain metal ionsA trait of certain metal ions

• Indirectly affects the local HIndirectly affects the local H2200• Naked metal ions are toxic!Naked metal ions are toxic!• Ligands for safetyLigands for safety

• (metal + ligand = chelate)(metal + ligand = chelate)

Gd3+

Gd3+

Gd-DTPA-BMA (Omniscan)

Gd-DOTA (Dotarem)

Nephrogenic Nephrogenic SystemicSystemic Fibrosis (NSF): The Basics Fibrosis (NSF): The Basics

• Originally known as Nephrogenic Fibrosing Dermopathy (NFD)Originally known as Nephrogenic Fibrosing Dermopathy (NFD)• Systemic proliferation of connective tissue (NSF)Systemic proliferation of connective tissue (NSF)• ““Over 215 cases reported worldwide..” from 1997-presentOver 215 cases reported worldwide..” from 1997-present• Strong epidemiologic association with GdStrong epidemiologic association with Gd

• Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)• Almost all renal insufficiency at exposure (most ESRD, on dialysis)Almost all renal insufficiency at exposure (most ESRD, on dialysis)• Proinflammatory events in manyProinflammatory events in many1111 (e.g., vascular surgery, sepsis, thrombosis) (e.g., vascular surgery, sepsis, thrombosis)• Some Some data suggests 3-5% incidence w/ Gd in setting of renal failuredata suggests 3-5% incidence w/ Gd in setting of renal failure1111

• So far no co-factor identified (dialysate, ACEIs, EPO, etc.)So far no co-factor identified (dialysate, ACEIs, EPO, etc.)• Theories of pathogenesis:Theories of pathogenesis:

• Liberation of Gd ion from carrier moleculeLiberation of Gd ion from carrier molecule1010

• Cutaneous deposition of free Gd ionCutaneous deposition of free Gd ion1010

• Gd target attracts circulating fibrocytes (CFs)Gd target attracts circulating fibrocytes (CFs)• CFs differentiate in the dermis to resemble dermal fibroblastsCFs differentiate in the dermis to resemble dermal fibroblasts

• Originally known as Nephrogenic Fibrosing Dermopathy (NFD)Originally known as Nephrogenic Fibrosing Dermopathy (NFD)• Systemic proliferation of connective tissue (NSF)Systemic proliferation of connective tissue (NSF)• ““Over 215 cases reported worldwide..” from 1997-presentOver 215 cases reported worldwide..” from 1997-present• Strong epidemiologic association with GdStrong epidemiologic association with Gd

• Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)• Almost all renal insufficiency at exposure (most ESRD, on dialysis)Almost all renal insufficiency at exposure (most ESRD, on dialysis)• Proinflammatory events in manyProinflammatory events in many1111 (e.g., vascular surgery, sepsis, thrombosis) (e.g., vascular surgery, sepsis, thrombosis)• Some Some data suggests 3-5% incidence w/ Gd in setting of renal failuredata suggests 3-5% incidence w/ Gd in setting of renal failure1111





Patient Safety a Decade Later…Patient Safety a Decade Later…

Danish Medicines Agency reports 25

cases of Gd-associated NSF

May 2006 Jun 2006

FDA issues Public Health

Advisory

Gd “trigger” proposed for NSF (Grobner and Markmann)

Apr 20061997

First recognized

case of “NFD”

First description of

NSF in the literature

2000 Jan 2007

Literature reports Gd in

NSF skin biopsies7

Dec 2006

FDA revises Public Health

Advisory

Press reports FDA warning

to “kidney patients”

Editorial in Radiology

Uses of High Dose Gd Uses of High Dose Gd (+/- renal insufficiency):(+/- renal insufficiency):

• MRAMRA• PeripheralPeripheral• Renal Renal

• Neuro-onc Neuro-onc (local practice patterns)(local practice patterns)

• X-ray use X-ray use (k-edge of Gd is inefficient)(k-edge of Gd is inefficient)

• CTCT• Conventional AngioConventional Angio

• MRAMRA• PeripheralPeripheral• Renal Renal

• Neuro-onc Neuro-onc (local practice patterns)(local practice patterns)

• X-ray use X-ray use (k-edge of Gd is inefficient)(k-edge of Gd is inefficient)

• CTCT• Conventional AngioConventional Angio

Nephrogenic Nephrogenic SystemicSystemic Fibrosis (NSF): Diagnosis Fibrosis (NSF): Diagnosis

• Most prominent and visible effects in the skinMost prominent and visible effects in the skin• Discoloration & texture changesDiscoloration & texture changes• Tightening, thickening, swelling Tightening, thickening, swelling →→ joint immobility joint immobility• Burning, itching, sharp painBurning, itching, sharp pain

• Skin changes can be insidious -> confused w/ peripheral edemaSkin changes can be insidious -> confused w/ peripheral edema• Resembles scleroderma and eosinophilic fasciitisResembles scleroderma and eosinophilic fasciitis

• Absent: monoclonal gammopathiesAbsent: monoclonal gammopathies99, Raynaud phenomenon and , Raynaud phenomenon and autoantibodiesautoantibodies22

• Yellowish scleral plaquesYellowish scleral plaques• Fibrotic changes can be widespread (liver, lungs, heart)Fibrotic changes can be widespread (liver, lungs, heart)• Biopsy FindingsBiopsy Findings

• Skin biopsySkin biopsy: thickened collagen bundles with surrounding clefts, mucin : thickened collagen bundles with surrounding clefts, mucin deposition, deposition, ↑↑ fibroblasts, fibroblasts, ↑↑ CD34+ dendrocytes CD34+ dendrocytes22

• Muscle biopsy: Muscle biopsy: ↑ ↑ myofibroblastsmyofibroblasts22

• Most prominent and visible effects in the skinMost prominent and visible effects in the skin• Discoloration & texture changesDiscoloration & texture changes• Tightening, thickening, swelling Tightening, thickening, swelling →→ joint immobility joint immobility• Burning, itching, sharp painBurning, itching, sharp pain

• Skin changes can be insidious -> confused w/ peripheral edemaSkin changes can be insidious -> confused w/ peripheral edema• Resembles scleroderma and eosinophilic fasciitisResembles scleroderma and eosinophilic fasciitis

• Absent: monoclonal gammopathiesAbsent: monoclonal gammopathies99, Raynaud phenomenon and , Raynaud phenomenon and autoantibodiesautoantibodies22

• Yellowish scleral plaquesYellowish scleral plaques• Fibrotic changes can be widespread (liver, lungs, heart)Fibrotic changes can be widespread (liver, lungs, heart)• Biopsy FindingsBiopsy Findings

• Skin biopsySkin biopsy: thickened collagen bundles with surrounding clefts, mucin : thickened collagen bundles with surrounding clefts, mucin deposition, deposition, ↑↑ fibroblasts, fibroblasts, ↑↑ CD34+ dendrocytes CD34+ dendrocytes22

• Muscle biopsy: Muscle biopsy: ↑ ↑ myofibroblastsmyofibroblasts22

Nephrogenic Systemic Fibrosis (NSF): Nephrogenic Systemic Fibrosis (NSF): Prognosis and TreatmentPrognosis and Treatment

• Course is chronic, progressive, variableCourse is chronic, progressive, variable• May be severely debilitatingMay be severely debilitating

• Contractures - musculoskeletalContractures - musculoskeletal• Wheelchair requirement in someWheelchair requirement in some

• Complications may be fatalComplications may be fatal• Falls, fracturesFalls, fractures• Immobility, pneumoniaImmobility, pneumonia

• No consistently successful treatmentNo consistently successful treatment• Symptoms may improve if renal function improvesSymptoms may improve if renal function improves• Limited evidence for kidney transplantation, extracorporeal Limited evidence for kidney transplantation, extracorporeal

photopheresis (ECP)photopheresis (ECP)• Also in the literature: oral steroids, plasmapheresisAlso in the literature: oral steroids, plasmapheresis

• Course is chronic, progressive, variableCourse is chronic, progressive, variable• May be severely debilitatingMay be severely debilitating

• Contractures - musculoskeletalContractures - musculoskeletal• Wheelchair requirement in someWheelchair requirement in some

• Complications may be fatalComplications may be fatal• Falls, fracturesFalls, fractures• Immobility, pneumoniaImmobility, pneumonia

• No consistently successful treatmentNo consistently successful treatment• Symptoms may improve if renal function improvesSymptoms may improve if renal function improves• Limited evidence for kidney transplantation, extracorporeal Limited evidence for kidney transplantation, extracorporeal

photopheresis (ECP)photopheresis (ECP)• Also in the literature: oral steroids, plasmapheresisAlso in the literature: oral steroids, plasmapheresis

What we know about Gd and NSFWhat we know about Gd and NSF• Causation not established; data are suspicious, but have limitations

• Retrospective studies• Info is limited (e.g., Creatinine at time of Gd exposure, contemporaneous administration)

• Markedly prolonged half-life in renal failure• All cases had renal dysfunction at time of Gd exposure

• Relationship between risk and level of dysfunction• Relationship between risk and cumulative dose?

• Theoretical risk with any Gd contrast agent• Risk different across agents (e.g., due to excess chelate)?

• Cases typically develop in days to few months after Gd exposure

• Causation not established; data are suspicious, but have limitations• Retrospective studies• Info is limited (e.g., Creatinine at time of Gd exposure, contemporaneous administration)



• Theoretical risk with any Gd contrast agent• Risk different across agents (e.g., due to excess chelate)?


Normal renal function 1.3 h

End-stage renal failure 34.3 h

Hemodialysis (HD) 2.6 h

Peritoneal dialysis (PD) 52.7 h

Half-life of gadodiamide (hours)4

Brand Name, Brand Name, Chemical NameChemical Name

Amine backbone Amine backbone structurestructure

log Klog Kstst

(Stability (Stability constant)constant)

OptiMark,OptiMark,GdDTPA-BMEAGdDTPA-BMEA

LinearLinear 16.816.8

Omniscan,Omniscan,GdDTPA-BMAGdDTPA-BMA


Magnevist, Magnevist, GdDTPAGdDTPA


MultiHanceMultiHanceGdBOPTAGdBOPTA


GadovistGadovistGdDO3A-butrolGdDO3A-butrol

MacrocyclicMacrocyclic 21.021.0

ProHance, ProHance, GdHPDO3AGdHPDO3A


DotaremDotaremGdDOTAGdDOTA


Thermodynamic Thermodynamic stabilitystabilityThermodynamic Thermodynamic stabilitystability

(Optimark)

Gd-DTPA-BMA(Omniscan)

Gd-DTPA(Magnevist)

Gd-BOPTA(MultiHANCE)

Gd-HP-DO3A (ProHANCE)Gd-BT-DO3A (Gadovist)

Gd-EOB-DTPA (Primovist)

Gd-DOTA (Dotarem)

ML ML M + L M + L ML ML M + L M + L

KKDD = [ M ] [ L ] = [ M ] [ L ]

[ ML ][ ML ]

KKDD = [ M ] [ L ] = [ M ] [ L ]

[ ML ][ ML ]

10 10 -23-23 = x = x x x 500 (mM) 500 (mM)

OR, 5 x 10 OR, 5 x 10 –21–21 = x = x22 OR, 7 x 10 OR, 7 x 10 –10 –10 = x = [Gd = x = [Gd 3+3+ ] ]

10 10 -23-23 = x = x x x 500 (mM) 500 (mM)

OR, 5 x 10 OR, 5 x 10 –21–21 = x = x22 OR, 7 x 10 OR, 7 x 10 –10 –10 = x = [Gd = x = [Gd 3+3+ ] ]

Brand Name, Brand Name, Chemical NameChemical Name

Amine backbone Amine backbone structurestructure

log Klog Kstst

(Stability (Stability constant)constant)

Dissociation rate Dissociation rate in 0.1M HCl in 0.1M HCl ( sec( sec-1-1))

OptiMark,OptiMark,GdDTPA-BMEAGdDTPA-BMEA

LinearLinear 16.816.8 >2.2x10>2.2x10-2-2

Omniscan,Omniscan,GdDTPA-BMAGdDTPA-BMA

LinearLinear 16.816.8 >2x10>2x10-2-2

Magnevist, Magnevist, GdDTPAGdDTPA

LinearLinear 22.222.2 1.2x101.2x10-3-3

MultiHanceMultiHanceGdBOPTAGdBOPTA

LinearLinear 22.622.6 -not reported--not reported-

GadovistGadovistGdDO3A-butrolGdDO3A-butrol

MacrocyclicMacrocyclic 21.021.0 2.8x102.8x10-6-6

(estimated from (estimated from data)data)

ProHance, ProHance, GdHPDO3AGdHPDO3A


DotaremDotaremGdDOTAGdDOTA


The themodynamic stability constant determines the concentrations of the Gd-chelate, free chelate, and free gadolinium at equilibrium;

The rates of formation and dissociation, dictated by Ea , determine how rapidly these compounds reach equilibrium.

ZnZnZnZn

Gd L Gd L ↕ ↕ Gd Gd + +

LL

Gd L Gd L ↕ ↕ Gd Gd + +

LL

POPO44POPO44

POPO44POPO44

PbOPbO44PbOPbO44

POPO44

POPO44

POPO44

POPO44

POPO44POPO44

Laurent S, et al.. Contrast Media Mol Imaging 2006;1:128-37.Laurent S, et al.. Contrast Media Mol Imaging 2006;1:128-37.

Relaxivity Relaxivity ’s in solution pH 7.0’s in solution pH 7.0Relaxivity Relaxivity ’s in solution pH 7.0’s in solution pH 7.0

CompoundCompound R1 at 3 days R1 at 3 daysGd-DTPAGd-DTPA ↓50% ↓50%Gd-DTPA-BMAGd-DTPA-BMA ↓90% ↓90%Gd –BOPTAGd –BOPTA ↓60% ↓60%Gd-HP-DO3Gd-HP-DO3 NO SIG NO SIG

CompoundCompound R1 at 3 days R1 at 3 daysGd-DTPAGd-DTPA ↓50% ↓50%Gd-DTPA-BMAGd-DTPA-BMA ↓90% ↓90%Gd –BOPTAGd –BOPTA ↓60% ↓60%Gd-HP-DO3Gd-HP-DO3 NO SIG NO SIG

a very strong correlation between the dissociation rates of chelates in acid and the a very strong correlation between the dissociation rates of chelates in acid and the

long-term deposition of Gd3+ in rat tissues such as liver and bone (femur).long-term deposition of Gd3+ in rat tissues such as liver and bone (femur).

Wedeking, Kumar and TweedleWedeking, Kumar and TweedleWedeking, Kumar and TweedleWedeking, Kumar and Tweedle

““Acid dissociation rate constants were the most Acid dissociation rate constants were the most accurate parameters linking in vitro and in vivo accurate parameters linking in vitro and in vivo dissociation. “dissociation. “

“Gd(HP-D03A) and Gd(DOTA)-, had the lowest “Gd(HP-D03A) and Gd(DOTA)-, had the lowest residual Gd3+ in whole animals.” residual Gd3+ in whole animals.”

“No evidence of free Gd3+ could be detected for “No evidence of free Gd3+ could be detected for Gd(HP-D03A) using the free Gd3+ target tissues Gd(HP-D03A) using the free Gd3+ target tissues (liver and femur) at long residence times.”(liver and femur) at long residence times.”

Wedeking, Kumar and Tweedle, Mag Res Imag 1992Wedeking, Kumar and Tweedle, Mag Res Imag 1992Wedeking, Kumar and Tweedle, Mag Res Imag 1992Wedeking, Kumar and Tweedle, Mag Res Imag 1992

Algorithm for Gd-Enhanced MRIAlgorithm for Gd-Enhanced MRI

eGFR w/in 3 daysIf worsening trend, day of exam

eGFR < 30No dialysis

eGFR 30-60 eGFR > 60eGFR < 30

On HDeGFR < 30

On PD

Obtain central venous access

HD x 2 w/in 2 hrs and 24 hrs

Discussion w/ referrer



Proceeding Proceeding

Informed consent

Proceeding

Limit Gd to 0.1 mmol/kg*;Consider hydration

ProHance™ or MultiHance™:

No > 0.1 mmol/kg

OK to proceed

*Except for run-offs, which are permitted up to 0.2 mmol/kg after risk:benefit discussion w/ referrer.

Response to Choyke questions

Gd-MRI in last 7 days?

YES

NO

Consider delay to allow 7 days

between Gd doses

Proceeding

“NO” to all

eGFR within 4 weeks

Inpatient Outpatient / EU

START

“YES” to any

DIALYSISDIALYSISDIALYSISDIALYSIS


OK to proceed



YES

NO


between Gd doses

Proceeding

“NO” to all

Outpatient / EU

START

Point of servicePoint of service queryquery


Minimizing the Risk of NSFMinimizing the Risk of NSF• Risk : benefit analysisRisk : benefit analysis• Reduce use of Gd in renal diseaseReduce use of Gd in renal disease

• FDA recommends avoiding for eGFR < 30 FDA recommends avoiding for eGFR < 30 • Consider non-contrast protocolsConsider non-contrast protocols• Consider alternate modality (e.g., CT, conventional angiogram)Consider alternate modality (e.g., CT, conventional angiogram)• Minimize dose if Gd is deemed imperativeMinimize dose if Gd is deemed imperative

• Consider alternative agentsConsider alternative agents• Gd-BOPTA (MultiHANCEGd-BOPTA (MultiHANCE®®))

• No reports (yet…)• Can reduce dose (has higher R1)• HOWEVER…clearance kinetics less favorable (binds protein)

• ProHANCEProHANCE• Hemodialyze patients with ESRD asap ?? * Hemodialyze patients with ESRD asap ?? *

• Gd excretory rates 78%, 96%, 99% from 1Gd excretory rates 78%, 96%, 99% from 1stst to 3 to 3rdrd HD session HD session55

• When using Gd, maximize pt condition*: When using Gd, maximize pt condition*: • Hold drugs that decrease renal function (e.g., diuretics, NSAIDs)Hold drugs that decrease renal function (e.g., diuretics, NSAIDs)• Hydrate (consider bicarb – ? role of metabolic acidosis in NSF)Hydrate (consider bicarb – ? role of metabolic acidosis in NSF)

• Informed consentInformed consent

• Risk : benefit analysisRisk : benefit analysis• Reduce use of Gd in renal diseaseReduce use of Gd in renal disease

• FDA recommends avoiding for eGFR < 30 FDA recommends avoiding for eGFR < 30 • Consider non-contrast protocolsConsider non-contrast protocols• Consider alternate modality (e.g., CT, conventional angiogram)Consider alternate modality (e.g., CT, conventional angiogram)• Minimize dose if Gd is deemed imperativeMinimize dose if Gd is deemed imperative

• Consider alternative agentsConsider alternative agents• Gd-BOPTA (MultiHANCEGd-BOPTA (MultiHANCE®®))

• No reports (yet…)• Can reduce dose (has higher R1)• HOWEVER…clearance kinetics less favorable (binds protein)

• ProHANCEProHANCE• Hemodialyze patients with ESRD asap ?? * Hemodialyze patients with ESRD asap ?? *

• Gd excretory rates 78%, 96%, 99% from 1Gd excretory rates 78%, 96%, 99% from 1stst to 3 to 3rdrd HD session HD session55

• When using Gd, maximize pt condition*: When using Gd, maximize pt condition*: • Hold drugs that decrease renal function (e.g., diuretics, NSAIDs)Hold drugs that decrease renal function (e.g., diuretics, NSAIDs)• Hydrate (consider bicarb – ? role of metabolic acidosis in NSF)Hydrate (consider bicarb – ? role of metabolic acidosis in NSF)

• Informed consentInformed consent*(not evidence based!!)

How do we screen for risk?How do we screen for risk?

• Choyke QuestionnaireChoyke Questionnaire• Serum CreatinineSerum Creatinine

• Point of Service Devices??Point of Service Devices??• http://www.abbottpointofcare.com/istat/#

• Choyke QuestionnaireChoyke Questionnaire• Serum CreatinineSerum Creatinine

• Point of Service Devices??Point of Service Devices??• http://www.abbottpointofcare.com/istat/#

The Choyke QuestionnaireThe Choyke Questionnaire

Pre-existing renal disease Pre-existing renal disease (OR 13.6)(OR 13.6)Proteinuria Proteinuria (OR 8.7) (OR 8.7) Prior kidney surgery Prior kidney surgery (OR 8.1)(OR 8.1)Hypertension Hypertension (OR 5.4)(OR 5.4)Gout Gout (OR 4.6)(OR 4.6)Diabetes Diabetes (OR 3.2)(OR 3.2)

Pre-existing renal disease Pre-existing renal disease (OR 13.6)(OR 13.6)Proteinuria Proteinuria (OR 8.7) (OR 8.7) Prior kidney surgery Prior kidney surgery (OR 8.1)(OR 8.1)Hypertension Hypertension (OR 5.4)(OR 5.4)Gout Gout (OR 4.6)(OR 4.6)Diabetes Diabetes (OR 3.2)(OR 3.2)

Completely negative responses: 450 (67%) of 673 446/450 (99%) Cr values 1.7 mg/dL 424/450 (94%) - normal Cr values

Choyke, et al. Tech Urol 1998; 4: 65.




eGFR 30-60 eGFR > 60eGFR < 30

On HDeGFR < 30

On PD







Informed consent

Proceeding



No > 0.1 mmol/kg

OK to proceed




YES

NO


between Gd doses

Proceeding

“NO” to all

eGFR within 4 weeks


START

“YES” to any





eGFR 30-60 eGFR > 60


Informed consent

Proceeding



No > 0.1 mmol/kg

OK to proceed




YES

NO


between Gd doses

Proceeding

eGFR within 4 weeks


START

“YES” to any



eGFR < 30On HD

eGFR < 30On PD






Informed consent


No > 0.1 mmol/kg



YES

NO


between Gd doses

Proceeding

Inpatient

START


For Dialysis PatientsFor Dialysis Patients

Hemo Dialysis (HD) Peritoneal Dialysis

Consider alternative study

2 sessions of HD

1st w/in 3 hrs of Gd

2nd ~ 24 hours after Gd

Consider alternative study

No functional AV Fistual

Admit for temporary

central venous access

Functional fistula present

Hydration & HCO3 ????Hydration & HCO3 ????

• Oral hydrationOral hydration• 1 Liter of H1 Liter of H220 by mouth pre- and post- injection of contrast0 by mouth pre- and post- injection of contrast

• Intravenous hydrationIntravenous hydration• Contact the ordering physician or house staff for ordersContact the ordering physician or house staff for orders

• BicarbBicarb• 150mEq of NaHCO150mEq of NaHCO33 (e.g. dilute in 1L D5W) (e.g. dilute in 1L D5W) • Pre: 1 hr prior to contrast administration Pre: 1 hr prior to contrast administration

• @ 3cc/kg/hr and for • Post: 6 hrs after contrast administration Post: 6 hrs after contrast administration

• @ 1cc/kg/hr• Modifications possible for pts with renal failure/CHF)Modifications possible for pts with renal failure/CHF)• Encourage oral fluid intake if not on fluid restrictionsEncourage oral fluid intake if not on fluid restrictions

• Oral hydrationOral hydration• 1 Liter of H1 Liter of H220 by mouth pre- and post- injection of contrast0 by mouth pre- and post- injection of contrast

• Intravenous hydrationIntravenous hydration• Contact the ordering physician or house staff for ordersContact the ordering physician or house staff for orders

• BicarbBicarb• 150mEq of NaHCO150mEq of NaHCO33 (e.g. dilute in 1L D5W) (e.g. dilute in 1L D5W) • Pre: 1 hr prior to contrast administration Pre: 1 hr prior to contrast administration

• @ 3cc/kg/hr and for • Post: 6 hrs after contrast administration Post: 6 hrs after contrast administration

• @ 1cc/kg/hr• Modifications possible for pts with renal failure/CHF)Modifications possible for pts with renal failure/CHF)• Encourage oral fluid intake if not on fluid restrictionsEncourage oral fluid intake if not on fluid restrictions

Perspective – Iodinated ContrastPerspective – Iodinated Contrast

• Risk for severe adverse reactionsRisk for severe adverse reactions• 0.147% HI-ICM0.147% HI-ICM• 0.031% NI-ICM (3/10,000)0.031% NI-ICM (3/10,000)

• Death Death • ~ 1/100,000 either high ~ 1/100,000 either high oror low osmolality. low osmolality.

• Risk for severe adverse reactionsRisk for severe adverse reactions• 0.147% HI-ICM0.147% HI-ICM• 0.031% NI-ICM (3/10,000)0.031% NI-ICM (3/10,000)

• Death Death • ~ 1/100,000 either high ~ 1/100,000 either high oror low osmolality. low osmolality.

Caro AJR 1991 Apr; 156(4): 825-32

ConclusionsConclusions

• Gd is associated with NSF in pts with Gd is associated with NSF in pts with substantialsubstantial renal insufficiency renal insufficiency

• Role of acidity seems likelyRole of acidity seems likely

• Risk:Benefit assessment is vitalRisk:Benefit assessment is vital

• What is the risk of not giving CE-MRI?What is the risk of not giving CE-MRI?

• Guidelines should be submitted for institutional approval Guidelines should be submitted for institutional approval

• Education is essentialEducation is essential

• Keep reading, keeping conversing!Keep reading, keeping conversing!

• Consider using Gadoteridol in high risk situationsConsider using Gadoteridol in high risk situations

• Gd is associated with NSF in pts with Gd is associated with NSF in pts with substantialsubstantial renal insufficiency renal insufficiency

• Role of acidity seems likelyRole of acidity seems likely

• Risk:Benefit assessment is vitalRisk:Benefit assessment is vital

• What is the risk of not giving CE-MRI?What is the risk of not giving CE-MRI?

• Guidelines should be submitted for institutional approval Guidelines should be submitted for institutional approval

• Education is essentialEducation is essential

• Keep reading, keeping conversing!Keep reading, keeping conversing!

• Consider using Gadoteridol in high risk situationsConsider using Gadoteridol in high risk situations

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nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56(1):21-26.nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56(1):21-26.8.8. Stenver DI. Investigation of the safety of MRI contrast medium Omniscan. Danish Medicines Agency. Stenver DI. Investigation of the safety of MRI contrast medium Omniscan. Danish Medicines Agency.

http://www.dkma.dk/1024/visUKLSArtikel.asp?asrtikelID=8931http://www.dkma.dk/1024/visUKLSArtikel.asp?asrtikelID=8931. Published May 29, 2006. Accessed February 6, 2007.. Published May 29, 2006. Accessed February 6, 2007.9.9. Boyd AS, Zic JA, and Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. Boyd AS, Zic JA, and Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol.

January 2007. 27-30. January 2007. 27-30. 10.10. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic systemic fibrosis: suspected causative Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic systemic fibrosis: suspected causative

role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17:2359-62.role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17:2359-62.11.11. Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic fibrosis: Risk factors Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic fibrosis: Risk factors

and incidence estimation. Radiology 2007. and incidence estimation. Radiology 2007. http://radiology.rsnajnls.org/cgi/content/full/2431062144v1http://radiology.rsnajnls.org/cgi/content/full/2431062144v1. Published January 31, . Published January 31, 2007. Accessed February 1, 2007.2007. Accessed February 1, 2007.

1.1. Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007. Available at http://www.icnfdr.org. Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007. Available at http://www.icnfdr.org. Accessed 01/17/2007.Accessed 01/17/2007.

2.2. Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15:785. Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15:785. 3.3. Grobner T: Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic Grobner T: Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic

systemic fibrosis? Nephrology Dialysis Transplantation 21(4): 1104-1108, April 2006.systemic fibrosis? Nephrology Dialysis Transplantation 21(4): 1104-1108, April 2006.4.4. Joffe P, Thomsen HS, Meusel M: Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and Joffe P, Thomsen HS, Meusel M: Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and

patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 5: 491-502, 1998.patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 5: 491-502, 1998.5.5. Okada S et al. Safety of gadolinium contrast agent in hemodialysis patient. Acta Radiologica, 2001, 42(3): 339-341.Okada S et al. Safety of gadolinium contrast agent in hemodialysis patient. Acta Radiologica, 2001, 42(3): 339-341.6.6. Rofsky N et al. Renal lesion characterization with gadolinium-enhanced MR imaging: Efficacy and safety in patients with renal Rofsky N et al. Renal lesion characterization with gadolinium-enhanced MR imaging: Efficacy and safety in patients with renal

insufficiency. Radiology, July 1991, 180: 85-89.insufficiency. Radiology, July 1991, 180: 85-89.7.7. High WA, Ayers RA, Chandler J, Zito G, and Cowper SE. Gadolinium is detectable within the tissue of patients with High WA, Ayers RA, Chandler J, Zito G, and Cowper SE. Gadolinium is detectable within the tissue of patients with

nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56(1):21-26.nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56(1):21-26.8.8. Stenver DI. Investigation of the safety of MRI contrast medium Omniscan. Danish Medicines Agency. Stenver DI. Investigation of the safety of MRI contrast medium Omniscan. Danish Medicines Agency.

http://www.dkma.dk/1024/visUKLSArtikel.asp?asrtikelID=8931http://www.dkma.dk/1024/visUKLSArtikel.asp?asrtikelID=8931. Published May 29, 2006. Accessed February 6, 2007.. Published May 29, 2006. Accessed February 6, 2007.9.9. Boyd AS, Zic JA, and Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. Boyd AS, Zic JA, and Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol.

January 2007. 27-30. January 2007. 27-30. 10.10. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic systemic fibrosis: suspected causative Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic systemic fibrosis: suspected causative

role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17:2359-62.role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17:2359-62.11.11. Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic fibrosis: Risk factors Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic fibrosis: Risk factors

and incidence estimation. Radiology 2007. and incidence estimation. Radiology 2007. http://radiology.rsnajnls.org/cgi/content/full/2431062144v1http://radiology.rsnajnls.org/cgi/content/full/2431062144v1. Published January 31, . Published January 31, 2007. Accessed February 1, 2007.2007. Accessed February 1, 2007.

http://www.dkma.dk/1024/visUKLSArtikel.asp?asrtikelID=8931

http://radiology.rsnajnls.org/cgi/content/full/2431062144v1

http://www.dkma.dk/1024/visUKLSArtikel.asp?asrtikelID=8931

http://radiology.rsnajnls.org/cgi/content/full/2431062144v1

Gadolinium ChelatesGadolinium Chelates

• MR contrast agents (metal + ligand = chelate)MR contrast agents (metal + ligand = chelate)• Gd Gd Brightening on T1-WI’s Brightening on T1-WI’s• Gd is toxic!Gd is toxic!

• Chelate ‘shields’ the free metal while preserving its Chelate ‘shields’ the free metal while preserving its relaxation effect.relaxation effect.

• MR contrast agents (metal + ligand = chelate)MR contrast agents (metal + ligand = chelate)• Gd Gd Brightening on T1-WI’s Brightening on T1-WI’s• Gd is toxic!Gd is toxic!

• Chelate ‘shields’ the free metal while preserving its Chelate ‘shields’ the free metal while preserving its relaxation effect.relaxation effect.

GdGd

Gadolinium ChelatesGadolinium Chelates• MR contrast agentsMR contrast agents• Brightening on T1-weighted imagesBrightening on T1-weighted images• Gd is toxic!Gd is toxic!

• Chelate used to ‘shield’ the free metal while Chelate used to ‘shield’ the free metal while preserving its relaxation effect.preserving its relaxation effect.

• MR contrast agentsMR contrast agents• Brightening on T1-weighted imagesBrightening on T1-weighted images• Gd is toxic!Gd is toxic!

• Chelate used to ‘shield’ the free metal while Chelate used to ‘shield’ the free metal while preserving its relaxation effect.preserving its relaxation effect.

Gd3+

Gd3+

Gd-DTPA-BMA (Omniscan)

Gd-DOTA (Dotarem)

Nephrogenic Nephrogenic SystemicSystemic Fibrosis (NSF): The Basics Fibrosis (NSF): The Basics

• Originally known as Nephrogenic Fibrosing Dermopathy (NFD)Originally known as Nephrogenic Fibrosing Dermopathy (NFD)• Systemic proliferation of connective tissue (NSF)Systemic proliferation of connective tissue (NSF)• ~ 215 cases reported worldwide from 1997-2006~ 215 cases reported worldwide from 1997-2006• Strong epidemiologic association with GdStrong epidemiologic association with Gd

• All FDA-reviewed cases had prior Gd exposureAll FDA-reviewed cases had prior Gd exposure• Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)• All had renal insufficiency at exposure (most ESRD, on dialysis)All had renal insufficiency at exposure (most ESRD, on dialysis)• Proinflammatory events in manyProinflammatory events in many1111 (e.g., vascular surgery, sepsis, thrombosis) (e.g., vascular surgery, sepsis, thrombosis)• EarlyEarly data suggests 3-5% incidence w/ Gd in setting of renal failure data suggests 3-5% incidence w/ Gd in setting of renal failure1111





• Originally known as Nephrogenic Fibrosing Dermopathy (NFD)Originally known as Nephrogenic Fibrosing Dermopathy (NFD)• Systemic proliferation of connective tissue (NSF)Systemic proliferation of connective tissue (NSF)• ~ 215 cases reported worldwide from 1997-2006~ 215 cases reported worldwide from 1997-2006• Strong epidemiologic association with GdStrong epidemiologic association with Gd

• All FDA-reviewed cases had prior Gd exposureAll FDA-reviewed cases had prior Gd exposure• Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)Appears to be a class issue (Omniscan >>> Magnevist, OptiMARK)• All had renal insufficiency at exposure (most ESRD, on dialysis)All had renal insufficiency at exposure (most ESRD, on dialysis)• Proinflammatory events in manyProinflammatory events in many1111 (e.g., vascular surgery, sepsis, thrombosis) (e.g., vascular surgery, sepsis, thrombosis)• EarlyEarly data suggests 3-5% incidence w/ Gd in setting of renal failure data suggests 3-5% incidence w/ Gd in setting of renal failure1111





DeathDeath

Stage 1Stage 1 Stage IIStage II Stage III Stage IV Stage III Stage IV Stage Stage VV

CKD risk factors/CKD risk factors/ Mild ↓ Mild ↓ Moderate ↓ Moderate ↓ Severe ↓Severe ↓ Kidney Kidney damage w/ damage w/ kidneykidney kidney kidney kidneykidney failure failurepreserved GFRpreserved GFR fxnfxn fxn fxn fxnfxn ESRD ESRD

130 120 110 100 90 80 70 60 50 40 30 20 15 10 0

Kidney Fxn

(GFR [ml/min/1.73 m2])

Expected Outcomes ↑Risk of CIN, Dialysis, Death

Modified from: Am J Kidney Dis 2002;39(suppl):S1-266.Modified from: Am J Kidney Dis 2002;39(suppl):S1-266.

↑Risk of NSF

Staging of Chronic Kidney DzStaging of Chronic Kidney DzStaging of Chronic Kidney DzStaging of Chronic Kidney Dz

Algorithm for Choyke Screen; Outpt Efficacy StudyAlgorithm for Choyke Screen; Outpt Efficacy Study


“NO” to all

Outpatient / EU



“Yes” to any

“Yes”, “Yes” “Yes”, “No” “No”, “Yes” “No”, “No”

Point of servicePoint of serviceCreat/ eGFRCreat/ eGFR

Point of servicePoint of serviceCreat/ eGFRCreat/ eGFR

Pre- servicePre- service Creat/ eGFRCreat/ eGFR

Pre- servicePre- service Creat/ eGFRCreat/ eGFR

Point of servicePoint of service Creat/ eGFRCreat/ eGFR

Point of servicePoint of service Creat/ eGFRCreat/ eGFR

St 1 St 2 St 3 St 4 St 5 St 1 St 2 St 3 St 4 St 5 F/UF/U

Creat/ eGFR;Creat/ eGFR;datedate

F/UF/UCreat/ eGFR;Creat/ eGFR;

datedateNo F/UNo F/U

Creat/ eGFRCreat/ eGFR

No F/UNo F/UCreat/ eGFRCreat/ eGFR

Exam w/oExam w/oCreatCreat

Exam w/oExam w/oCreatCreat




eGFR 30-60 eGFR > 60


Informed consent

Proceeding



No > 0.1 mmol/kg

OK to proceed




YES

NO


between Gd doses

Proceeding

eGFR within 4 weeks


START

“YES” to any

What we know about Gd and NSFWhat we know about Gd and NSF• Causation not established; data are suspicious, but have limitations

• Retrospective studies• Info is limited (e.g., Creatinine at time of Gd exposure, contemporaneous administration)



• Theoretical risk with any Gd contrast agent• Documented cases with Omniscan >>Magnevist, OptiMARK• Risk different across agents (e.g., due to excess chelate)?


• Causation not established; data are suspicious, but have limitations• Retrospective studies• Info is limited (e.g., Creatinine at time of Gd exposure, contemporaneous administration)



• Theoretical risk with any Gd contrast agent• Documented cases with Omniscan >>Magnevist, OptiMARK• Risk different across agents (e.g., due to excess chelate)?


Normal renal function 1.3 h

End-stage renal failure 34.3 h

Hemodialysis (HD) 2.6 h

Peritoneal dialysis (PD) 52.7 h

Half-life of gadodiamide (hours)4

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