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Nephrogenic Systemic Fibrosis

History, Diagnosis & The Registry

Shawn E. Cowper, MD

Associate Professor of Dermatology and Pathology

Yale University New Haven, CT


Pink Plaques


Reticulated Lesions


Severe Contractures


Deep Involvement


Registry population characteristics


Renal status at NSF onset, Registry

Dialysis (79%)

Hemodialysis (52%)

Peritoneal Dialysis (16%)

End Stage Renal Disease (11%)

Non-Dialysis (17%)

Acute Kidney Injury (10%)

Renal Insufficiency (8%) Stage IV CKD (1.5%)

Stage V CKD (3%)


JAAD, January 2003


Archives of Dermatology, July 2003

• Known history of anti-thrombin III and Factor II deficiency

• Patient elected to

discontinue dialysis due to intolerable morbidity

• Findings included fibrosis of proximal esophagus, diaphragm, and psoas muscle


Tissue localized fibrocytes in NSF


Current Opinion in Rheumatology,

October 2003


Thrombosis and Surgery


Nephrology Dialysis Transplantation, January 2006


Strength of Association,

Presence and Magnitude

J Am Acad Dermatol. 2007 Jan;56(1):21-6. Epub2006 Nov 9


Temporal: NSF latency



GBCA dose/exposure, Registry cases


Animal and ex-vivo tests

J. Pathol. Vol.214, 5 Pages: 584-593 Courtesy Bayer-Schering Pharma


Nephrogenic Systemic Fibrosis



Major Criterion

Patterned Plaques

Red to violaceous, hyperpigmented, thin plaques showing polygonal to reticular morphologies on the upper extremities



Major Criterion

Joint contractures

Often with edema of the fingers and wrists, toes and ankles [absence of signs of scleroderma]. Loss of range of motion of



Major Criterion


Deep induration showing a pattern of bumpiness over the upper arms and/or thighs



Major Criterion

Marked Induration/Peau d’orange

Unpinchable, firm, shiny, often hyperpigmented bound down skin over extremities. Peau d’orange dimpling



Minor Criterion

Puckering/Linear Banding

Focal areas/linear bands of bound-down skin on an upper extremity or proximal lower extremity (thigh)



Minor Criterion

Superficial NSF

Hyperpigmented, pink or flesh colored macules coalescing into patches or thin plaques on the upper extremities (common) or trunk (rare). May have



Minor Criterion

Dermal Papules



Minor Criterion

Scleral Plaques Patient < 45 years old


Clinical Scoring

• Major Criteria

– Patterned Plaques

– Joint Contractures

– Cobblestoning

– Marked Induration/Peau d’orange (upper extremity or above knee)

• Minor Criteria

– Puckering/Linear Banding

– Superficial (Plaque/Patch)

– Dermal Papules

– Scleral plaques (pt <45 yo)

• Scoring

– > 1 Major Criterion Highly Consistent = 4

– 1 Major Criterion Consistent = 3

– > 1 Minor Criterion Suggestive = 2

– 0-1 Criterion Inconsistent = 1


Nephrogenic Systemic Fibrosis


Pathology Scoring

• Increased Cellularity (+1)

• CD34+ Tram-tracks (+1)

• Thick and thin collagen fibers (+1)

• Elastic preservation (-1 if elastic absent)

• Septal involvement (+1)

• Lollipop Sign (+3)

• Highly Consistent (Score = 4 or 5)

• Consistent (Score = 3)

• Suggestive (Score = 2)

• Inconsistent (Score = 1)


Nephrogenic Systemic Fibrosis


US Distribution of Registry cases


Patient impact, Registry data


NSF onset dates, Registry cases



Calendar Year


Temporal association with NSF onset


International Center for NSF Research Supported by a grant from the General Clinical Research Center at Yale

http://www.icnsfr.org Yale University

Carol Hribko (Registry Coordinator) Ali Abu-Alfa, MD (Nephrology) Richard Bucala, MD PhD (Rheumatology)

Richard Edelson, MD (Dermatology) Michael Girardi, MD (Dermatology) Avery LaChance (Research Assistant)

Mark Perazella, MD (Nephrology) Jeffrey Weinreb, MD (Radiology)

Additional thanks…

Philip Boyer, MD PhD (U Colorado) Dirk Elston, MD (GeisingerMC, PA)

Whitney High, MD (U Colorado) Emanuel Kanal, MD (U Pittsburgh)

Ira Krefting, MD (US FDA) Phillip Kuo, MD PhD (U Arizona)

Philip E. Leboit, MD (UCSF) Sameh Morcos(Sheffield, UK) PritiPatel, MD (CDC&P, Atlanta)

Georges Saab, MD (U Missouri) Lyndon Su, MD (U Michigan) Jonathan Kay, MD (U Massachusetts) Charles Bennett, MD PhD (Northwestern U)

And the many patients, family, physicians, attorneys and friends who have been instrumental in bringing this work together!


Use of GBCAs in Clinical Practice


Provide background concerning use of

GBCAs in day to day practice and the

possible implications of any limitations of their



Clinical Utility

Current Practice

Impact on Patients



Use of GBCAs in Clinical Practice

Clinical Utility

– Improve

• detection (sensitivity)

• characterization (specificity)

– Disruption of “blood-brain barrier”

• staging (margins, number)

• confidence level

• reliability & exam time (eg. MRA)

Without GBCA


None are FDA approved for use in the;



Musculoskeletal System

Intra-articular or intra-arterial

Only one is approved for CE-MRA (AIOD only)

>1,000,000 GBCA-MRA procedures are performed

each year using GBCAs not approved for MRA

All not approved for higher doses, faster

injection rates, or pediatric patients


MRI Scans in the US

0 5000 10000 15000 20000 25000 30000 35000 40000 1999 2001 2003 2005 2007 Scans (000's) G BCA (000's) 25% 25% 26% 26% 27% 28% 28% 28% 28% 29%

% Scans with GBCA


GBCA Utilization

39% Brain/Brain Stem 20% Spinal Canal & Contents 13% Angiography (MRA) 4% Face/Orbit/Neck 5% Abdomen (complete) 3% Pelvis 3% Other 10% Extremities 2% Breast



Magnetic Resonance Angiography


MRI of Blood Vessels

Magnetic Resonance Imaging




2009 1994


“High dose” CE-MRA




GBCA-MRA Procedures and GBCA Volume

0 200 400 600 800 1000 1200 1400 1999 2001 2003 2005 2007 CE-M RA (000's) Volume (cc's) 23 22 23 24 25 26 28 27 25 24

Average GBCA Volume Per CE-MRA Procedure (ml/procedure)


Prior to link with NSF, GBCAs were commonly

(and often preferentially) used in patients with renal

insufficiency because they are less likely to harm

the kidneys than iodinated contrast agents used for


Contrast-induced Nephropathy


Rofsky NM, et al. Radiology 1991;180:85–89. Haustein J, et al. Invest Radiol 1992;27:153–156.

Niendorf HP, et al. Invest Radiol 1994;29(suppl 2):S179–S182. Prince MR, et al. Radiology 1996;6:162–166.

Thomsen HS. Eur Radiol 2004;14:1654–1656. Thomsen HS. AJR 2003;181:1463–1471.

Elmståhl B, et al. Acad Radiol 2004;11:1219–1228. Gemery J, et al. AJR 1998;171:1277–1278.


Adverse Events

• The majority of AEs resulting from both iodinated agent and GBCA exposure are mild

• More common with iodinated agents

– 0.15–0.7% with iodinated agents

– 0.03%–0.2% with GBCAs


Among 456,930 contrast doses, AEs occurred in 0.15% with low-osmolar iodinated agent vs 0.04% with GBCA

In a pediatric population, 0.18% incidence of acute allergic-like reaction to low- osmolality nonionic iodinated contrast compared with 0.04% with GBCAs

Among 78,353 GBCA injections, acute allergic-like reactions occurred in 0.07%, of which 19% were moderate and 7% severe

Murphy KP, et al. Acad Radiol 1999;6:656–664. Li A, et al. Br J Radiol 2006;79:368–337.

Jordan RM, Mintz RD. AJR 1995;164:743–744. Mortelé KJ, et al. AJR 2005;184:31–34.

Hunt CH, et al. AJR 2009;193:1124-1127. Cochran ST, et al. AJR 2001;176:1385–1388 .

Dillman JR, et al. AJR 2008;190:187–190. Dillman JR, et al. AJR 2007;188:1643–1647. Murphy KJ, et al. AJR 1996;167:847–849.

ACR. Manual on Contrast Media. Version 6, 2008.




Nonanaphylactoid Reaction Anaphylactoid Reaction Contrast Extravasation 2005 CIN


Choice of GBCA

Prior to link with NSF, most radiologists believed

that all brands of extracellular GBCAs were very

similar in mechanism of action, efficacy and risk

of adverse events

– Even if they knew about differences in chemical

structure, measure of stability, viscosity,ionicity, etc…..

Purchasing decisions were based primarily on

pricing, GPO contracts, and personal



June 8, 2006


May 27, 2007

FDA Boxed Warning




• US Professional Organizations

– American College of Radiology

• Guidance Document for Safe MR Practices

• Manual on Contrast Media

– National Kidney Foundation

• Laminated Reference Tool


– Individual Medical Centers and MRI Facilities

• Outside the US

– Europe (EMEA, ESUR)

– Canadian Association of Radiologists

– Japan

– Australia

Outside of US, all indicate that

the risk for NSF varies between types of GBCAs

All recommend screening for renal dysfunction


Use of GBCAs in Clinical Practice

Current Practices: How have they changed since


– Fewer patients with dialysis and known CKD referred for GBCA-MRI

– Some reluctance to use GBCAs (anecdotal)

• Some MRI facilities no long administer GBCAs

• Some MRI facilities will not administer GBCAs to patients with CKD 3 or any risk factors for CKD (eg. diabetes, hypertension)

• Some patients are being “turfed” to other facilities (especially hospitals)

– Alternative imaging tests (e.g. non-contrast MRI/MRA, low dose contrast-CT)

• Reassessment of the risk of clinically relevant CIN from intravenous iodinated contrast agents





Adverse Events with Contrast Enhanced Imaging




Nonanaphylactoid Reaction Anaphylactoid Reaction Contrast Extravasation CIN NSF 2009


• 40 yo obese f with ADPCKD and eGFR < 30

• Ultrasound showed a 2 cm echogenic mass in the right kidney

• Request imaging to evaluate for renal cell carcinoma

Volume expansion with saline (hydration)

• Premedication with N-acetlycysteine before and after and isotonic sodium bicarbonate (3cc/kg/hr for 1 hr prior)

• Non-C CT

•If fat present in mass, stop (benign AML)

•If no fat, perform low dose CE-CT with low-osmolality or iso-osmolality iodinated agent

• CE-MRI with macrocyclic or low dose high relaxivity GBCA

• Diffusion-weighted MRI (no GBCA)


• 25 yo m with suspected intramedullary spinal cord tumor

• eGFR 28 ml/min/1.73m2

• Request imaging to determine type and extent of mass

GBCA-enhanced MRI

MRI better that CT

• Non-contrast MRI not sufficient

Use lowest diagnostic dose of macrocyclic or

low dose high relaxivity GBCA

Sometimes GBCA-MRI is the best exam, even

in patients with compromised renal function !


Use of GBCAs in Clinical Practice

Current Practices: How have they changed

since NSF?

– Screening for CKD/risk factors for CKD is much more common

• Enterprise-wide EMR

• Require referring MD to provide eGFR or submit CKD risk factor form prior to scheduling GBCA-MRI

• Patient questionnaire prior to exam

– Ranges from one question (“Do you have a

problem with your kidneys) to series of questions about risk factors for CKD

• Point-of-service eGFR (based on serum creatinine) in every patient.

Screening results in increased time, costs, and



Use of GBCAs in Clinical Practice

Current Practices: How have they changed

since NSF?

– Change in GBCA Usage

• Decreased use of linear non-ionic GBCA(s)

• “High dose” (>FDA approved dose) MRI/MRA less common

• “Low dose” (< FDA approved dose) MRI more common

• Patients with compromised renal function less likely to get repeat doses of GBCA at short time intervals


Use of GBCAs in Clinical Practice

Current Practices: How have they changed

since NSF?

More common to weigh patient and administer

dose based on patient weight


Diagnostic/Optimal Dose of GBCA

Not always known


• specific GBCA

• patient characteristics

• type of MRI exam

• MR scanner software/hardware

• magnetic field strength

Krautmacher C et al. Radiology. 2005;237:1014-1019. Desai NK, et al Top Magn Reson Imaging 2003;14:360-364 Brekenfeld C, et al. Invest Radiol 2001;36:266-275


Contrast Dose and Field Strength Effects in

Contrast Dose and Field Strength Effects in

Lesion Visualization

Lesion Visualization

• No significant difference between field strengths for lesions grNo significant difference between field strengths for lesions greater eater than 20 mm

than 20 mm

• Small lesion visualization at low field strength improves with hSmall lesion visualization at low field strength improves with higher igher contrast contrast Low field (0.2T) Single dose Low field (0.2T) Double dose Low field (0.2T) Triple dose High field (1.5T) Single dose

Visualization of metastatic disease in one patient.

Desai NK, et al.

Desai NK, et al. Top Top MagnMagn ResonReson Imaging 2003;14:360Imaging2003;14:360--364.364. Brekenfeld


Use of GBCAs in Clinical Practice

Impact on patients


• Are diagnoses being missed?

• Are patients receiving suboptimal care because of concern for NSF?


• Unknown (has not been studied)


• In effort to limit risk of NSF, some may be using

suboptimal or non-diagnostic dose in some instances (don’t know what they are missing)



GBCA-enhanced MRI plays (and will likely

continue to play) an essential role in modern

medical diagnosis

Off-label use (dose and clinical application) is


FDA policy and other education efforts have

resulted in changes in clinical practice in the

United States

– Including marked decrease of new cases of NSF



Ali Abu-Alfa: Yale University

Shawn Cowper: Yale University

Philip Kuo: Yale/University of Arizona

Emanual Kanal: University of Pittsburgh

Kenneth Maravilla: University of Washington

Lawrence Tanenbaum: Mount Sinai