[occ-env-med-l] MMWR/07-02-23, Nephrogenic Fibrosing Dermopathy from Gd-med-contrast (fwd)

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Nephrogenic Fibrosing Dermopathy from Gd-med-contrast

February 23, 2007 / 56(07);137-141

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5607a1.htm?s_cid=mm5607a1_e%0A

Nephrogenic Fibrosing Dermopathy Associated with Exposure to

Gadolinium-Containing Contrast Agents --- St. Louis, Missouri,

2002--2006

Nephrogenic fibrosing dermopathy (NFD) causes thickening and hardening

of the skin, often in the extremities, and occurs in patients with

underlying renal disease. The skin lesions can progress rapidly,

sometimes leading to joint immobility and the inability to walk (1).

In May 2006, nephrologists at hospital A in St. Louis, Missouri,

reported to CDC and the Missouri Department of Health and Senior

Services (MoDHSS) a cluster of NFD among patients treated in their

dialysis units. CDC and MoDHSS conducted an investigation to determine

the number of affected patients and identify risk factors for NFD.

Thirty-three patients with NFD were identified in St. Louis, 28 of

whom had been treated at hospital A. A matched case-control study was

conducted at the hospital. This report summarizes the preliminary

results of that study, which indicated that exposure to

gadolinium-containing contrast agents during magnetic resonance

imaging (MRI) studies was independently associated with NFD.

Clinicians should be aware of the potential for NFD, and when

possible, should avoid use of gadolinium-containing contrast agents in

patients with advanced renal disease.

A confirmed case was defined as clinical findings (i.e., skin

thickening or hardening) and skin biopsy findings consistent with NFD

in a person with renal disease in St. Louis during January

2000--August 2006. Suspected cases met either the clinical or the

biopsy criteria but not both. Hospital A staff members manually

searched a logbook of dermatology biopsies to identify diagnoses

consistent with NFD from January 2000 onward. Study investigators

searched the hospital pathology database for diagnoses of NFD and

potentially related diagnoses from the same period. Investigators

searched for additional cases that would not have been identified at

hospital A by contacting eight pathology referral centers in St. Louis

and requesting information on all patients who had NFD diagnosed since

January 2000.

Demographics, comorbid conditions, and medication data for

case-patients and controls were collected from hospital A inpatient

and outpatient medical records, which included information from

hospital A admissions (including emergency department visits),

outpatient dialysis and other clinic visits, and laboratory and

radiology studies performed in the hospital A system. The maximum

erythropoietin (epoetin alfa) dose received during the preceding 6

months and the dose received at the time of disease detection (for

case-patients) or match date (for controls) were classified as high or

low relative to the median weekly dose received by all patients in the

study. Continuous variables were compared using the Wilcoxon rank-sum

test, and categorical variables were compared using a chi-square test

or Fisher's exact test. Matched univariate odds ratios (ORs) were

calculated. After adjusting for clinically relevant variables

determined to be associated within the univariate analysis,

multivariable ORs were calculated using a conditional logistic

regression model.

The case-control study included confirmed cases from hospital A. Three

controls per case-patient were selected randomly from a group of

patients who were treated in the same hospital A dialysis clinic or

treatment center on the same day that a case was diagnosed. These

matched controls were required to have received dialysis for at least

4 weeks or to have had renal insufficiency (serum creatinine >2.5

mg/dL) for at least 6 months preceding their match date. Only

case-patients and controls with medical record information available

for at least 3 of the 6 months preceding the match date were included.

Twenty-eight cases were identified at hospital A during December

2002--August 2006, including 25 confirmed and three suspected cases

(Figure). Five additional patients from St. Louis with NFD outside of

hospital A were identified during the study period; however, minimal

information was available for these patients, and they were excluded.

Among the 19 confirmed case-patients at hospital A who met criteria

for inclusion in the case-control study, the median age was 50 years

(range: 21--67), and 10 (53%) were male. The median number of months

on dialysis was 30 (range: 0.1--192 months). The primary type of

dialysis received in the 6 months preceding disease detection was

hemodialysis for 11 (58%) of the 19 case-patients and peritoneal

dialysis for six (32%) case-patients. Two of the 19 case-patients had

acute renal failure and received dialysis only for a brief time (4

days for one patient, 45 days for the other) during the 6 months

preceding disease diagnosis. The clinical sites at which NFD was first

detected were hospital A during inpatient hospitalization for 13 (68%)

case-patients, an outpatient peritoneal dialysis clinic affilitated

with hospital A for four (21%) case-patients, and an outpatient

hemodialysis unit affiliated with hospital A for two (11%)

case-patients.

No significant differences were detected between case-patients (n =

19) and matched controls (n = 57) regarding sex, number of months

since first dialysis, primary type of dialysis received, inpatient

hospitalization days in the preceding year, and presence of diabetes

mellitus (Table 1). Significant differences were detected in median

age, history of deep venous thrombosis (DVT), history of

hypothyroidism, and presence of dependent edema. In univariate-matched

analysis, exposure to gadolinium-containing contrast agents during the

preceding 6 months or preceding year was more common among

case-patients than controls (Table 2). The presence of dependent

edema, history of DVT, and history of hypothyroidism also were

associated with NFD. Although the associations were not statistically

significant, case-patients were more likely than controls to have

received a high dose (>18,000 U/week) of erythropoietin at the time of

disease detection and a high maximum dose (>30,000 U/week) of

erythropoietin in the preceding 6 months. After adjusting for age,

presence of dependent edema, history of DVT, and history of

hypothyroidism, only exposure to gadolinium-containing contrast agents

during the preceding 6 months or preceding year remained statistically

significant.

Five case-patients had no identified gadolinium exposure within 1 year

preceding NFD diagnosis. However, of these, four had gadolinium

exposure from 16 to 68 months preceding diagnosis; the fifth patient

had no evidence of gadolinium exposure. Among case-patients (n = 14)

and controls (n = 14) with gadolinium-containing contrast exposure in

the preceding year, case-patients were more likely to have received

peritoneal dialysis as their primary type of dialysis in the preceding

6 months (36% versus 0%) and had a longer median time on dialysis (27

months versus 10 months). Thirteen patients (nine case-patients, four

controls) had multiple gadolinium-containing contrast exposures during

the preceding year. The NFD attack rate estimated for persons

undergoing outpatient chronic dialysis in the hospital A system for

the 4 years in which cases were identified was 4.6 cases per 100

peritoneal dialysis patients and 0.61 cases per 100 hemodialysis

patients.

Reported by: S Cheng, MD, L Abramova, MD, Washington Univ School of

Medicine, St. Louis; G Saab, MD, Univ of Missouri School of Medicine,

Columbia; G Turabelidze, MD, Missouri Dept of Health and Senior Svcs.

P Patel, MD, M Arduino, DrPH, T Hess, Div of Healthcare Quality

Promotion, National Center for Preparedness, Detection, and Control of

Infectious Diseases (proposed); A Kallen, MD, M Jhung, MD, EIS

officers, CDC.

Editorial Note:

NFD was first identified in 1997 as a fibrotic disorder of the skin in

patients with renal failure (1). Since then, systemic involvement has

been described in some patients with NFD, resulting in use of the term

nephrogenic systemic fibrosis (NSF); NFD and NSF have been used to

describe the same condition (3). No clear etiology has been

established for NFD, and little is known about its pathogenesis or

natural history. This report describes the largest geographic cluster

of NFD that has been identified and provides evidence that exposure to

a gadolinium-containing contrast agent is a risk factor for the

development of the disease.

Although risk factors for NFD have not been studied extensively,

possible correlations with severity of renal failure, thrombotic

episodes, edema, and vascular procedures have been reported (2,4).

Recently, medication exposures such as erythropoietin and

gadolinium-containing contrast agents have been identified as

potential risk factors for NFD (5,6). In May 2006, the Danish

Medicines Agency reported 25 cases of NFD diagnosed in Europe among

patients with recent exposure to gadolinium-containing contrast. In

response, the Food and Drug Administration (FDA) issued a public

health advisory in June 2006 regarding the use of these contrast

agents in patients with renal failure (7). As of December 25, 2006,

the FDA MedWatch system had received 90 reports of NFD possibly

related to gadolinium-containing contrast agents.

Intravenously administered contrast agents are used routinely for MRI

studies; the contrast agents contain gadolinium (a paramagnetic heavy

metal), which is bound to a chelating agent. The mechanism for

possible gadolinium-associated NFD is unknown; however, one hypothesis

is that the gadolinium ions might dissociate from the chelate and

result in a fibrotic reaction (5). Five gadolinium-based contrast

agents are available in the United States; the first was approved for

use in 1988 (7). Adverse events associated with these agents typically

are minor (e.g., nausea); severe effects such as allergic reactions or

tissue necrosis as a result of extravasation are rare. In addition,

gadolinium-containing contrast agents are believed to be less

nephrotoxic than iodinated contrast agents used for computed

tomography (CT) imaging (8). Excretion of gadolinium-containing

contrast agents primarily occurs renally; the amount of contrast

eliminated from the body after dialysis has not been well-evaluated.

Two studies suggest that 65%--78% of gadolinium-containing contrast

might be cleared after one hemodialysis session and 98% after three

sessions (9,10). Peritoneal dialysis might achieve less effective

gadolinium-contrast clearance than hemodialysis. In one study, 69% of

total gadolinium-containing contrast was excreted after 22 days in

patients undergoing continuous ambulatory peritoneal dialysis (9).

Delayed clearance might prolong the duration of gadolinium-containing

contrast exposure among patients undergoing peritoneal dialysis.

However, patients undergoing peritoneal dialysis have not been

previously reported to be at higher risk for NFD than patients

undergoing hemodialysis. The chronic peritoneal dialysis outpatients

in this investigation had higher estimated NFD attack rates than

chronic hemodialysis outpatients. No controls who had

gadolinium-containing contrast exposure underwent primarily peritoneal

dialysis.

The number of cases identified at hospital A decreased during the

second and third quarters of 2006 (Figure), and the reason for this

decrease is unclear. Because NFD was not recognized at hospital A

until late 2002, initially identified cases likely represented both

incident (new) and prevalent (existing) cases; the decline might

represent the subsequently smaller number of remaining prevalent cases

that had not been identified. Although hospital A instituted changes

such as limiting the use of gadolinium-containing contrast agents in

patients with renal failure, these changes were initiated shortly

before the investigation began and are unlikely to account completely

for the decline.

The findings in this report are subject to at least two limitations.

First, NFD is a rare condition. Even though the data in this report

represent the largest cluster of NFD cases identified to date, the

small sample size of the case-control study might have limited the

power to demonstrate statistically significant associations for

variables other than exposure to gadolinium-containing contrast

agents. Second, the date of disease diagnosis was used instead of date

of disease onset; the actual date of disease onset is unknown. To

identify exposures that preceded the actual date of disease onset,

exposures as early as 1 year before the date of diagnosis were

included. This might have resulted in the inclusion of gadolinium

exposures that were not related to the development of NFD.

When possible, use of gadolinium-containing contrast agents should be

avoided in patients with advanced renal failure, particularly in

patients who are undergoing peritoneal dialysis. Depending on the

indication for imaging, other radiologic modalities (e.g., ultrasound

and CT) might be acceptable substitutes in certain situations. If

gadolinium-containing contrast is medically necessary, prompt

hemodialysis after contrast administration to facilitate clearance of

the contrast might be reasonable for patients who have established

hemodialysis access; however, the effectiveness of this strategy in

reducing the risk for NFD development or progression is unknown. Among

patients with no other indication for chronic or acute hemodialysis,

the risks of establishing hemodialysis access should be weighed

against theoretical benefits of hemodialysis after

gadolinium-containing contrast administration. CDC and FDA are

collaborating to assess potential differences among

gadolinium-containing contrast agents, including the associated risk

for NFD and possible related factors. Additional studies are needed to

assess the ability of peritoneal dialysis and hemodialysis to clear

gadolinium-containing contrast agents and to clarify the mechanism by

which use of gadolinium or chelating agents might result in NFD.

Clinicians who treat patients with renal disease should be aware of

the risk for NFD and consider the diagnosis in patients with

characteristic skin lesions. Suspected adverse drug events should be

reported to FDA via the MedWatch program by phone (1-800-FDA-1088), by

fax (1-800-FDA-0178), or online

(http://www.fda.gov/medwatch/index.html).

Acknowledgments

The findings in this report are based, in part, on contributions by S

Cowper, MD, Yale Univ School of Medicine, New Haven, Connecticut; C

Kwoh, MD, D Berk, MD, Washington Univ School of Medicine, St. Louis,

Missouri; DG Kleinbaum, PhD, Dept of Epidemiology, Rollins School of

Public Health at Emory Univ, Atlanta; R Wang, DO, S Pappas, PhD, J

Jarrett, MS, Div of Laboratory Sciences, National Center for

Environmental Health, and J Guarner, MD, Div of Viral and Rickettsial

Diseases, National Center for Zoonotic, Vector-Borne, and Enteric

Diseases (proposed), CDC.

References

1. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE.

Scleromyxoedema-like cutaneous diseases in renal-dialysis patients.

Lancet 2000;356:1000--1.

2. Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years.

Curr Opin Rheumatol 2003;15:785--90.

3. Ting WW, Stone MS, Madison KC, Kurtz K. Nephrogenic fibrosing

dermopathy with systemic involvement. Arch Dermatol 2003;139: 903--6.

4. Jan F, Segal JM, Dyer J, LeBoit P, Siegfried E, Frieden IJ.

Nephrogenic fibrosing dermopathy: two pediatric cases. J Pediatr

2003;143: 678--81.

5. Marckmann P, Skov L, Rossen K, 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.

6. Swaminathan S, Ahmed I, McCarthy JT, et al. Nephrogenic fibrosing

dermopathy and high-dose erythropoietin therapy. Ann Intern Med

2006;145:234--5.

7. Food and Drug Administration. Public health advisory:

gadolinium-containing contrast agents for magnetic resonance imaging

(MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance.

Available at http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm.

8. Runge VM. Safety of approved MR contrast media for intravenous

injection. J Magn Reson Imaging 2000;12:205--13.

9. 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 1998;5:491--502.

10. Okada S, Katagiri K, Kumazaki T, Yokoyama H. Safety of gadolinium

contrast agent in hemodialysis patients. Acta Radiologica 2001;42:

339--41.

TABLE 1. Characteristics of nephrogenic fibrosing dermopathy

case-patients and matched controls* from hospital A — St. Louis,

Missouri, December 2002–August 2006

http://www.cdc.gov/mmwr/preview/mmwrhtml/figures/m607a1t1.gif

TABLE 2. Odds ratios (ORs) for selected characteristics among

nephrogenic fibrosing dermopathy case-patients and matched controls*

from hospital A — St. Louis, Missouri, December 2002–August 2006

http://www.cdc.gov/mmwr/preview/mmwrhtml/figures/m607a1t2.gif

FIGURE. Number of confirmed and suspected cases of nephrogenic

fibrosing dermopathy at hospital A, by date of disease detection — St.

Louis, Missouri, December 2002– August 2006

http://www.cdc.gov/mmwr/preview/mmwrhtml/figures/m607a1f.gif