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Nephrogenic Systemic Fibrosis: An Update Harvard Medical School B ETH I SRAEL D EACONESS M EDICAL C ENTER Neil M. Rofsky, MD.

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Presentation on theme: "Nephrogenic Systemic Fibrosis: An Update Harvard Medical School B ETH I SRAEL D EACONESS M EDICAL C ENTER Neil M. Rofsky, MD."— Presentation transcript:

1 Nephrogenic Systemic Fibrosis: An Update Harvard Medical School B ETH I SRAEL D EACONESS M EDICAL C ENTER Neil M. Rofsky, MD

2 MR Contrast Agents (Magnetopharmacuticals) Signal AugmentationSignal Augmentation Differential distributionDifferential distribution SafetySafety Signal AugmentationSignal Augmentation Differential distributionDifferential distribution SafetySafety

3 MR 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 H 2 0Indirectly affects the local H 2 0 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 H 2 0Indirectly affects the local H 2 0 Naked metal ions are toxic!Naked metal ions are toxic! Ligands for safetyLigands for safety (metal + ligand = chelate)(metal + ligand = chelate) Gd 3+ Gd-DTPA-BMA (Omniscan) Gd-DOTA (Dotarem)

4 Nephrogenic Systemic 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-present“Over 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 many 11 (e.g., vascular surgery, sepsis, thrombosis)Proinflammatory events in many 11 (e.g., vascular surgery, sepsis, thrombosis) Some data suggests 3-5% incidence w/ Gd in setting of renal failure 11Some data suggests 3-5% incidence w/ Gd in setting of renal failure 11 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 molecule 10Liberation of Gd ion from carrier molecule 10 Cutaneous deposition of free Gd ion 10Cutaneous deposition of free Gd ion 10 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-present“Over 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 many 11 (e.g., vascular surgery, sepsis, thrombosis)Proinflammatory events in many 11 (e.g., vascular surgery, sepsis, thrombosis) Some data suggests 3-5% incidence w/ Gd in setting of renal failure 11Some data suggests 3-5% incidence w/ Gd in setting of renal failure 11 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 molecule 10Liberation of Gd ion from carrier molecule 10 Cutaneous deposition of free Gd ion 10Cutaneous deposition of free Gd ion 10 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

5 Patient Safety a Decade Later… Danish Medicines Agency reports 25 cases of Gd- associated NSF May 2006Jun 2006 FDA issues Public Health Advisory Gd “trigger” proposed for NSF (Grobner and Markmann) Apr First recognized case of “NFD” First description of NSF in the literature 2000Jan 2007 Literature reports Gd in NSF skin biopsies 7 Dec 2006 FDA revises Public Health Advisory Press reports FDA warning to “kidney patients” Editorial in Radiology

6 Gadolinium Agents in Review GenericBrandMfr FDA Approval Market Share (Doses) Gadopentetate dimeglumine MagnevistBerlex1988 (70 mil) ~50% GadodiamideOmniscanGE % 35% GadoversetamideOptiMARK Tyco / Mallinckrodt % 5% GadoteridolProHanceBracco % 10% Gadobenate dimeglumine MultiHanceBracco2004 } NSF: A Class Issue??

7 Uses of High Dose Gd (+/- renal insufficiency): MRAMRA PeripheralPeripheral RenalRenal Neuro-onc (local practice patterns)Neuro-onc (local practice patterns) X-ray use (k-edge of Gd is inefficient)X-ray use (k-edge of Gd is inefficient) CTCT Conventional AngioConventional Angio MRAMRA PeripheralPeripheral RenalRenal Neuro-onc (local practice patterns)Neuro-onc (local practice patterns) X-ray use (k-edge of Gd is inefficient)X-ray use (k-edge of Gd is inefficient) CTCT Conventional AngioConventional Angio

8 Nephrogenic Systemic 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 → joint immobilityTightening, thickening, swelling → 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 gammopathies 9, Raynaud phenomenon and autoantibodies 2Absent: monoclonal gammopathies 9, Raynaud phenomenon and autoantibodies 2 Yellowish scleral plaquesYellowish scleral plaques Fibrotic changes can be widespread (liver, lungs, heart)Fibrotic changes can be widespread (liver, lungs, heart) Biopsy Findings Biopsy Findings Skin biopsy : thickened collagen bundles with surrounding clefts, mucin deposition, ↑ fibroblasts, ↑ CD34+ dendrocytes 2 Skin biopsy : thickened collagen bundles with surrounding clefts, mucin deposition, ↑ fibroblasts, ↑ CD34+ dendrocytes 2 Muscle biopsy: ↑ myofibroblasts 2Muscle biopsy: ↑ myofibroblasts 2 Most prominent and visible effects in the skinMost prominent and visible effects in the skin Discoloration & texture changesDiscoloration & texture changes Tightening, thickening, swelling → joint immobilityTightening, thickening, swelling → 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 gammopathies 9, Raynaud phenomenon and autoantibodies 2Absent: monoclonal gammopathies 9, Raynaud phenomenon and autoantibodies 2 Yellowish scleral plaquesYellowish scleral plaques Fibrotic changes can be widespread (liver, lungs, heart)Fibrotic changes can be widespread (liver, lungs, heart) Biopsy Findings Biopsy Findings Skin biopsy : thickened collagen bundles with surrounding clefts, mucin deposition, ↑ fibroblasts, ↑ CD34+ dendrocytes 2 Skin biopsy : thickened collagen bundles with surrounding clefts, mucin deposition, ↑ fibroblasts, ↑ CD34+ dendrocytes 2 Muscle biopsy: ↑ myofibroblasts 2Muscle biopsy: ↑ myofibroblasts 2

9 Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website] Available at Accessed 02/01/2007. Nephrogenic Systemic Fibrosis (NSF): Clinical Appearance Reddened or darkened areasReddened or darkened areas Texture changesTexture changes “woody” or peau d’orange“woody” or peau d’orange Reddened or darkened areasReddened or darkened areas Texture changesTexture changes “woody” or peau d’orange“woody” or peau d’orange

10 Nephrogenic Systemic Fibrosis (NSF): Prognosis 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 photopheresis (ECP)Limited evidence for kidney transplantation, extracorporeal 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 photopheresis (ECP)Limited evidence for kidney transplantation, extracorporeal photopheresis (ECP) Also in the literature: oral steroids, plasmapheresisAlso in the literature: oral steroids, plasmapheresis

11 What 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 function1.3 h End-stage renal failure34.3 h Hemodialysis (HD)2.6 h Peritoneal dialysis (PD)52.7 h Half-life of gadodiamide (hours) 4

12 Brand Name, Chemical Name Amine backbone structure log K st (Stability constant) OptiMark,GdDTPA-BMEALinear16.8 Omniscan,GdDTPA-BMALinear16.8 Magnevist,GdDTPALinear22.2 MultiHanceGdBOPTALinear22.6 GadovistGdDO3A-butrolMacrocyclic21.0 ProHance,GdHPDO3AMacrocyclic23.8 DotaremGdDOTAMacrocyclic25.6 ThermodynamicstabilityThermodynamicstability

13 (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)

14 ML  M + L ML  M + L K D = [ M ] [ L ] [ ML ] [ ML ] K D = [ M ] [ L ] [ ML ] [ ML ] = x  x = x  x 500 (mM) 500 (mM) OR, 5 x 10 –21 = x 2 OR, 5 x 10 –21 = x 2 OR, 7 x 10 –10 = x = [Gd 3+ ] OR, 7 x 10 –10 = x = [Gd 3+ ] = x  x = x  x 500 (mM) 500 (mM) OR, 5 x 10 –21 = x 2 OR, 5 x 10 –21 = x 2 OR, 7 x 10 –10 = x = [Gd 3+ ] OR, 7 x 10 –10 = x = [Gd 3+ ]

15 Brand Name, Chemical Name Amine backbone structure log K st (Stability constant) Dissociation rate in 0.1M HCl ( sec -1 ) OptiMark,GdDTPA-BMEALinear16.8 >2.2x10 -2 Omniscan,GdDTPA-BMALinear16.8 >2x10 -2 Magnevist,GdDTPALinear x10 -3 MultiHanceGdBOPTALinear22.6 -not reported- GadovistGdDO3A-butrolMacrocyclic x10 -6 (estimated from data) ProHance,GdHPDO3AMacrocyclic x10 -5 DotaremGdDOTAMacrocyclic x10 -7

16 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.

17 ZnZn Gd L ↕ Gd Gd +L Gd L ↕ Gd Gd +L PO 4 PbO 4 PO 4 Laurent S, et al.. Contrast Media Mol Imaging 2006;1: Relaxivity  ’s in solution pH 7.0 Compound  R1 at 3 days Gd-DTPA ↓50% Gd-DTPA-BMA ↓90% Gd –BOPTA ↓60% Gd-HP-DO3 NO SIG  Compound  R1 at 3 days Gd-DTPA ↓50% Gd-DTPA-BMA ↓90% Gd –BOPTA ↓60% Gd-HP-DO3 NO SIG 

18 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). Wedeking, Kumar and Tweedle

19 “ Acid dissociation rate constants were the most accurate parameters linking in vitro and in vivo dissociation. “ “Gd(HP-D03A) and Gd(DOTA)-, had the lowest residual Gd3+ in whole animals.” “No evidence of free Gd3+ could be detected for Gd(HP-D03A) using the free Gd3+ target tissues (liver and femur) at long residence times.” “ Acid dissociation rate constants were the most accurate parameters linking in vitro and in vivo dissociation. “ “Gd(HP-D03A) and Gd(DOTA)-, had the lowest residual Gd3+ in whole animals.” “No evidence of free Gd3+ could be detected for Gd(HP-D03A) using the free Gd3+ target tissues (liver and femur) at long residence times.” Wedeking, Kumar and Tweedle, Mag Res Imag 1992

20 Algorithm for Gd-Enhanced MRI eGFR w/in 3 days If worsening trend, day of exam eGFR < 30 No dialysis eGFR 30-60eGFR > 60 eGFR < 30 On HD eGFR < 30 On PD Obtain central venous access HD x 2 w/in 2 hrs and 24 hrs Discussion w/ referrer 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 DIALYSISDIALYSIS

21 Algorithm 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 service query query Point of service query query

22 Minimizing 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 < 30FDA 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 (MultiHANCE®)Gd-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 1 st to 3 rd HD session 5Gd excretory rates 78%, 96%, 99% from 1 st to 3 rd HD session 5 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 < 30FDA 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 (MultiHANCE®)Gd-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 1 st to 3 rd HD session 5Gd excretory rates 78%, 96%, 99% from 1 st to 3 rd HD session 5 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!!)

23 How do we screen for risk? Choyke QuestionnaireChoyke Questionnaire Serum CreatinineSerum Creatinine Point of Service Devices??Point of Service Devices?? Choyke QuestionnaireChoyke Questionnaire Serum CreatinineSerum Creatinine Point of Service Devices??Point of Service Devices??

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

25 Algorithm for Gd-Enhanced MRI eGFR w/in 3 days If worsening trend, day of exam eGFR < 30 No dialysis eGFR 30-60eGFR > 60 eGFR < 30 On HD eGFR < 30 On PD Obtain central venous access HD x 2 w/in 2 hrs and 24 hrs Discussion w/ referrer 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 DIALYSISDIALYSIS

26 Algorithm for Gd-Enhanced MRI eGFR w/in 3 days If worsening trend, day of exam eGFR < 30 No dialysis eGFR 30-60eGFR > 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

27 Algorithm for Gd-Enhanced MRI eGFR w/in 3 days If worsening trend, day of exam eGFR < 30 On HD eGFR < 30 On PD Obtain central venous access HD x 2 w/in 2 hrs and 24 hrs Discussion w/ referrer 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 DIALYSISDIALYSIS

28 For Dialysis Patients

29 Hydration & HCO3 ???? Oral hydration Oral hydration 1 Liter of H 2 0 by mouth pre- and post- injection of contrast1 Liter of H 2 0 by mouth pre- and post- injection of contrast Intravenous hydration Intravenous hydration Contact the ordering physician or house staff for ordersContact the ordering physician or house staff for orders Bicarb Bicarb 150mEq of NaHCO 3 (e.g. dilute in 1L D5W)150mEq of NaHCO 3 (e.g. dilute in 1L D5W) Pre: 1 hr prior to contrast administrationPre: 1 hr prior to contrast 3cc/kg/hr and for Post: 6 hrs after contrast administrationPost: 6 hrs after contrast 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 hydration Oral hydration 1 Liter of H 2 0 by mouth pre- and post- injection of contrast1 Liter of H 2 0 by mouth pre- and post- injection of contrast Intravenous hydration Intravenous hydration Contact the ordering physician or house staff for ordersContact the ordering physician or house staff for orders Bicarb Bicarb 150mEq of NaHCO 3 (e.g. dilute in 1L D5W)150mEq of NaHCO 3 (e.g. dilute in 1L D5W) Pre: 1 hr prior to contrast administrationPre: 1 hr prior to contrast 3cc/kg/hr and for Post: 6 hrs after contrast administrationPost: 6 hrs after contrast 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

30 Perspective – 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) DeathDeath ~ 1/100,000 either high or low osmolality.~ 1/100,000 either high or 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) DeathDeath ~ 1/100,000 either high or low osmolality.~ 1/100,000 either high or low osmolality. Caro AJR 1991 Apr; 156(4):

31 Conclusions Gd is associated with NSF in pts with substantial renal insufficiencyGd is associated with NSF in pts with substantial 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 approvalGuidelines 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 substantial renal insufficiencyGd is associated with NSF in pts with substantial 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 approvalGuidelines 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

32 References 1.Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website] Available at Accessed 01/17/ Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15: Grobner T: Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation 21(4): , April 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: , Okada S et al. Safety of gadolinium contrast agent in hemodialysis patient. Acta Radiologica, 2001, 42(3): Rofsky N et al. Renal lesion characterization with gadolinium-enhanced MR imaging: Efficacy and safety in patients with renal insufficiency. Radiology, July 1991, 180: 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): Stenver DI. Investigation of the safety of MRI contrast medium Omniscan. Danish Medicines Agency. Published May 29, Accessed February 6, Boyd AS, Zic JA, and Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. January 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: Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic fibrosis: Risk factors and incidence estimation. Radiology Published January 31, Accessed February 1, Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website] Available at Accessed 01/17/ Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15: Grobner T: Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation 21(4): , April 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: , Okada S et al. Safety of gadolinium contrast agent in hemodialysis patient. Acta Radiologica, 2001, 42(3): Rofsky N et al. Renal lesion characterization with gadolinium-enhanced MR imaging: Efficacy and safety in patients with renal insufficiency. Radiology, July 1991, 180: 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): Stenver DI. Investigation of the safety of MRI contrast medium Omniscan. Danish Medicines Agency. Published May 29, Accessed February 6, Boyd AS, Zic JA, and Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. January 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: Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic fibrosis: Risk factors and incidence estimation. Radiology Published January 31, Accessed February 1,

33

34 For Non-Dialysis Patients (Conservative) *diuretics, NSAIDs, and ACE inhibitors (the latter when used with a diuretic) **Intravenous hydration with sodium bicarbonate for 1hr prior and 6hrs post Gd. Creatinine / eGFR value OR Choyke Questionnaire

35 “ Acid dissociation rate constants were the most accurate parameters linking in vitro and in vivo dissociation. “ “The most stable and least dissociation labile macrocycles, Gd(HP-D03A) and Gd(DOTA)-, had the lowest residual Gd3+ in whole animals.” “No evidence of free Gd3+ could be detected for Gd(HP-D03A) using the free Gd3+ target tissues (liver and femur) at long residence times.” “ Acid dissociation rate constants were the most accurate parameters linking in vitro and in vivo dissociation. “ “The most stable and least dissociation labile macrocycles, Gd(HP-D03A) and Gd(DOTA)-, had the lowest residual Gd3+ in whole animals.” “No evidence of free Gd3+ could be detected for Gd(HP-D03A) using the free Gd3+ target tissues (liver and femur) at long residence times.”

36 Gadolinium Chelates MR contrast agents (metal + ligand = chelate)MR contrast agents (metal + ligand = chelate) Gd  Brightening on T1-WI’sGd  Brightening on T1-WI’s Gd is toxic!Gd is toxic! Chelate ‘shields’ the free metal while preserving its relaxation effect.Chelate ‘shields’ the free metal while preserving its relaxation effect. MR contrast agents (metal + ligand = chelate)MR contrast agents (metal + ligand = chelate) Gd  Brightening on T1-WI’sGd  Brightening on T1-WI’s Gd is toxic!Gd is toxic! Chelate ‘shields’ the free metal while preserving its relaxation effect.Chelate ‘shields’ the free metal while preserving its relaxation effect. Gd

37 Gadolinium 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 preserving its relaxation effect.Chelate used to ‘shield’ the free metal while 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 preserving its relaxation effect.Chelate used to ‘shield’ the free metal while preserving its relaxation effect. Gd 3+ Gd-DTPA-BMA (Omniscan) Gd-DOTA (Dotarem)

38 Nephrogenic Systemic 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 ~ 215 cases reported worldwide from 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 many 11 (e.g., vascular surgery, sepsis, thrombosis)Proinflammatory events in many 11 (e.g., vascular surgery, sepsis, thrombosis) Early data suggests 3-5% incidence w/ Gd in setting of renal failure 11Early data suggests 3-5% incidence w/ Gd in setting of renal failure 11 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 molecule 10Liberation of Gd ion from carrier molecule 10 Cutaneous deposition of free Gd ion 10Cutaneous deposition of free Gd ion 10 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 ~ 215 cases reported worldwide from 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 many 11 (e.g., vascular surgery, sepsis, thrombosis)Proinflammatory events in many 11 (e.g., vascular surgery, sepsis, thrombosis) Early data suggests 3-5% incidence w/ Gd in setting of renal failure 11Early data suggests 3-5% incidence w/ Gd in setting of renal failure 11 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 molecule 10Liberation of Gd ion from carrier molecule 10 Cutaneous deposition of free Gd ion 10Cutaneous deposition of free Gd ion 10 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

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40  G=  S  G=-RT(LogK eq ) k=Ae -Ea/RT

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43 Death Stage 1Stage II Stage III Stage IV Stage V CKD risk factors/Mild ↓ Moderate ↓Severe ↓ Kidney damage w/ kidney kidneykidney failure preserved GFRfxn fxnfxn ESRD Kidney Fxn (GFR [ml/min/1.73 m 2 ]) Expected Outcomes ↑Risk of CIN, Dialysis, Death Modified from: Am J Kidney Dis 2002;39(suppl):S ↑Risk of NSF Staging of Chronic Kidney Dz

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45 Algorithm for Choyke Screen; Outpt Efficacy Study Response to Choyke questions “NO” to all Outpatient / EU Point of service query query Point of service query query “Yes” to any “Yes”, “Yes”“Yes”, “No”“No”, “Yes”“No”, “No” Point of service Creat/ eGFR Point of service Creat/ eGFR Pre- service Creat/ eGFR Creat/ eGFR Pre- service Creat/ eGFR Creat/ eGFR Point of service Creat/ eGFR Creat/ eGFR Point of service Creat/ eGFR Creat/ eGFR St 1 St 2 St 3 St 4 St 5 F/U Creat/ eGFR; dateF/U date No F/U Creat/ eGFR No F/U Creat/ eGFR Exam w/o Creat Creat

46 Algorithm for Gd-Enhanced MRI eGFR w/in 3 days If worsening trend, day of exam eGFR < 30 No dialysis eGFR 30-60eGFR > 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

47 What 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 function1.3 h End-stage renal failure34.3 h Hemodialysis (HD)2.6 h Peritoneal dialysis (PD)52.7 h Half-life of gadodiamide (hours) 4


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