nsf: history, diagnosis, and the registry

Nephrogenic Systemic Fibrosis

History, Diagnosis & The Registry

Shawn E. Cowper, MD

Associate Professor of Dermatology and Pathology

Yale University

New Haven, CT

January 1997

Philip LeBoit, MD

AJDP, October 2001

Pink Plaques Superficial Dermal Involvement

Reticulated Lesions Superficial Dermal Involvement

Severe Contractures Ankles and toes locked

Deep Involvement Severe Contractures

Registry population characteristics (n=345)

Age at NSF onset, Registry cases

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%)

Post-Transplant (3%)

JAAD, January 2003

•

Scleral plaques in NFD patients

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

Involved skeletal muscle tissue from a patient with NSF

Involved cardiac (heart) muscle from a deceased NSF patient

AJDP, August 2003

Tissue localized fibrocytes in NSF (red=procollagen I/brown=CD34)

Current Opinion in Rheumatology, October 2003

Thrombosis and Surgery

What do these have in common?

Nephrology Dialysis Transplantation, January 2006

First published association of NSF with gadolinium administration

Strength of Association, Presence and Magnitude

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

2006 Nov 9

J Am Acad Dermatol. 2007 Jan;56(1):27-30. Epub

2006 Nov 15

Gadolinium particles in NSF tissue

Temporal: NSF latency

n

Weeks post Gd exposure before symptom onset

GBCA dose/exposure, Registry cases (n=78)

Animal and ex-vivo tests

J. Pathol. Vol.214, 5 Pages: 584-593

Courtesy Bayer-Schering Pharma


Clinical Scoring

NSF -

Major Criterion

Patterned Plaques

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

NSF -

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

fingers, wrists, elbows

NSF -

Major Criterion

“Cobblestoning”

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

NSF -

Major Criterion

Marked Induration/Peau d’orange

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

NSF -

Minor Criterion

Puckering/Linear Banding

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

NSF -

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 epidermal change (fine scale)

NSF -

Minor Criterion

Dermal Papules

Subtle, flesh-colored papules without epidermal changes

NSF -

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

–

Another Diagnosis

Excluded = 0


Pathological Scoring

Increased Dermal Cellularity

CD34+ (“Tram-Tracks”)

Thick and Thin Collagen Fibers

Preserved Elastic

Septal

Involvement

“Lollipop”

Sign

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)

•

Excluded (Score = 0)

Diagnostic Grid


The Registry and the Future

NSF Registry case sources

US Distribution of Registry cases (n=320)

Patient impact, Registry data (n=345)

NSF onset dates, Registry cases Cumulative

n

Calendar Year

< 304

Temporal association with NSF onset (n=78)

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 (Geisinger

MC, 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)Priti

Patel, 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• Purpose

– Provide background concerning use of GBCAs in day to day practice and the possible implications of any limitations of their use

• Outline– Clinical Utility– Current Practice– Impact on Patients

[email protected]

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

With GBCA

GBCA-enhanced MRI plays an essential role in modern medical diagnosis

• None are FDA approved for use in the;– Heart– Breast– 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

“Off-label” use of GBCAs has been common

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

Source: Arlington Medical Research (AMR)

GBCA Utilization39% 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


MRA Magnetic Resonance Angiography

= MRI of Blood VesselsMagnetic Resonance Imaging

MRI Magnetic Resonance Imaging

1993

2009

1994

Non-CE-MRA

“High dose” CE-MRA

Non-CE-MRA

MRAMagnetic Resonance Angiography

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 24Average 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 CT

Contrast-induced Nephropathy (CIN/CIAKI)

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.Nyman U, et al. Radiology 2002;223:311–318.

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 GBCAsExamples:

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.

Severe Adverse Events Are Rare

MR CT

NonanaphylactoidReaction

AnaphylactoidReaction

ContrastExtravasation

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 preferences– Magnevist and Omniscan dominated the market

June 8, 2006

There appears to be an association between GBCAs and NSF

May 27, 2007

FDA Boxed WarningMay 27, 2007

Guidelines/Recommendations• FDA• US Professional Organizations

– American College of Radiology• Guidance Document for Safe MR

Practices• Manual on Contrast Media

– National Kidney Foundation• Laminated Reference Tool

– NKF/ACR– 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

NSF?– 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

MR CT

NSFCIN

Adverse Events with Contrast Enhanced Imaging

2006

MR CT

NonanaphylactoidReaction

AnaphylactoidReaction

ContrastExtravasation

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)

Alternative Imaging Algorithm

• 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 inconvenience


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


since NSF?– More common to weigh patient and administer

dose based on patient weight – Documentation of dose and specific GBCA used

Diagnostic/Optimal Dose of GBCA

• Not always known• Depends;

• 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;14:360-364Brekenfeld C, et al. Invest Radiol 2001;36:266-275Kuhl CK et al. Radiology. 2008;247:16-35.

Contrast Dose and Field Strength Effects in Contrast Dose and Field Strength Effects in Lesion VisualizationLesion Visualization

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

•• Small lesion visualization at low field strength improves with hSmall lesion visualization at low field strength improves with higher igher contrastcontrast

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 ImagingImaging 2003;14:3602003;14:360--364.364.BrekenfeldBrekenfeld C, et al. C, et al. Invest Invest RadiolRadiol. 2001;36:266. 2001;36:266--275.275. Slide courtesy Lawrence Tanenbaum, Mt Sinai

Use of GBCAs in Clinical Practice

• Impact on patients– Questions:

• Are diagnoses being missed?• Are patients receiving suboptimal care because of

concern for NSF?

– Answer• Unknown (has not been studied)

– Concern• 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)

Summary• 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 common

• 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

• Effect on patient care?

Acknowledgements

• 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

• Staff at Yale-New Haven Hospital

nsf: history, diagnosis, and the registry

Documents

nsf research

nsf tissue

nsf red

nsf onset n

deceased nsf patient

nsf onset dates

md cdcp

nsf registry case sources