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
• 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
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)
• 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
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
LinearLinear 16.816.8
Magnevist, Magnevist, GdDTPAGdDTPA
LinearLinear 22.222.2
MultiHanceMultiHanceGdBOPTAGdBOPTA
LinearLinear 22.622.6
GadovistGadovistGdDO3A-butrolGdDO3A-butrol
MacrocyclicMacrocyclic 21.021.0
ProHance, ProHance, GdHPDO3AGdHPDO3A
MacrocyclicMacrocyclic 23.823.8
DotaremDotaremGdDOTAGdDOTA
MacrocyclicMacrocyclic 25.625.6
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
MacrocyclicMacrocyclic 23.823.8 6.4x106.4x10-5-5
DotaremDotaremGdDOTAGdDOTA
MacrocyclicMacrocyclic 25.625.6 8.4x108.4x10-7-7
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
Discussion w/ referrer
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
Algorithm for Gd-Enhanced MRIAlgorithm for Gd-Enhanced MRI
OK to proceed
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
Outpatient / EU
START
Point of servicePoint of service queryquery
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.
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
Discussion w/ referrer
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
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 > 60
Discussion w/ referrer
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
eGFR within 4 weeks
Inpatient Outpatient / EU
START
“YES” to any
Algorithm for Gd-Enhanced MRIAlgorithm for Gd-Enhanced MRI
eGFR w/in 3 daysIf worsening trend, day of exam
eGFR < 30On HD
eGFR < 30On PD
Obtain central venous access
HD x 2 w/in 2 hrs and 24 hrs
Discussion w/ referrer
Discussion w/ referrer
Proceeding Proceeding
Informed consent
ProHance™ or MultiHance™:
No > 0.1 mmol/kg
*Except for run-offs, which are permitted up to 0.2 mmol/kg after risk:benefit discussion w/ referrer.
Gd-MRI in last 7 days?
YES
NO
Consider delay to allow 7 days
between Gd doses
Proceeding
Inpatient
START
DIALYSISDIALYSISDIALYSISDIALYSIS
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
ReferencesReferences1.1. 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.
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.
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
• 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)• ~ 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
• 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
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
Response to Choyke questions
“NO” to all
Outpatient / EU
Point of servicePoint of service queryquery
Point of servicePoint of service queryquery
“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
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 > 60
Discussion w/ referrer
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
eGFR within 4 weeks
Inpatient Outpatient / EU
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)
• 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• Documented cases with Omniscan >>Magnevist, OptiMARK• 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)
• 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• Documented cases with Omniscan >>Magnevist, OptiMARK• Risk different across agents (e.g., due to excess chelate)?
• Cases typically develop in days to few months after Gd exposure
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