MRI Contrast Agents and Nephrogenic Systemic Fibrosis (NSF)*

Nephrogenic systemic fibrosis (NSF), also known as nephrogenic fibrosing dermopathy (NFD), is a rare, relatively recent diagnosis, whose natural history is not well understood.

The evidence to date is:
-NSF is a systemic fibrosing disorder with its most prominent and visible effects in the skin, but other signs and symptoms may be present (e.g., muscle hardening and/or weakness, as well as burning, itching, or severe sharp pains in areas of involvement)(1-4);

-So far, it has occurred only in patients with severe or end-stage renal failure, acute or chronic (stages 4 or 5, according to the classification of the National Kidney Foundation)(1-4);

-NSF appears to affect males and females in approximately equal numbers (1);

-NSF has been confirmed in children and the elderly, but tends to affect the middle-aged most commonly (1);

-NSF has been identified in patients from a variety of ethnic backgrounds and from North America, Europe, and Asia (1);

-here is no definitive cure. There are some anecdotal reports describing at least partial responses to various therapies such as plasmapheresis, extracorporeal photopheresis, sodium thiosulphate, and thalidomide (1, 2). The disease is progressive. NSF can be fulminant in approximately 5% of cases and can be fatal (1).

-NSF may occur after exposure to gadolinium-based contrast agents in patients with, acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73 m2), or acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period (3-16). To date, there is no evidence that other patient groups are at risk.

-Recent reports have strongly correlated the development of NSF with exposure to gadolinium-containing MRI contrast agents;

-To date, the majority of NSF cases have been reported in association with the administration of Omniscan (gadodiamide, GE Healthcare), and the second highest number of cases of NSF has been reported in association with the administration of Magnevist (gadopentetate dimeglumine, Bayer Healthcare).

-Several cases followed the administration of high doses of the product or repeated contrast-enhanced MR exams (high single or cumulative doses);

-In the vast majority of cases (approx. 90%), NSF develops in the first 6 months after the last exposure to a gadolinium chelate (80% in the first three months). Some reports suggest the development of NSF at 9 months, 12 months or even 2 years after the exposure to a gadolinium chelates. Gadolinium may be found in the skin of patients with impaired renal function up to 11 months after the administration of Omniscan (gadodiamide).

Open questions regarding MRI contrast agents and NSF include, the following:

-Does the entire gadolinium chelate molecule, the excess chelate or free gadolinium trigger NSF?

-How can gadolinium chelates, excess chelate or free gadolinium trigger NSF?

-If free gadolinium in skin may trigger the disease, is the risk of NSF lower with more stable chelates?

-Why has NSF developed in only 3-5% of patients with GFR < 30 mL/min after the administration of Omniscan? The incidence of NSF following exposure to other gadolinium chelates is unknown.

-What are the concomitant risk factors?

-Preventative measures: Any?

-Post-contrast dialysis: Does it help? If so, when?

*Special thanks to Alberto Spinazzi, M.D., Senior Vice President, Group Regulatory and Medical Affairs, Bracco Diagnostics, Inc.

REFERENCES
(1) Yerram P, Saab G, Karuparthi PR, Hayden MR, Khanna R. Nephrogenic Systemic Fibrosis: A Mysterious Disease in Patients with Renal Failure - Role of Gadolinium-Based Contrast Media in Causation and the Beneficial Effect of Intravenous Sodium Thiosulfate. Clin J Am Soc Nephrol 2007; 2: 258-263.
(2) Richmond H, Zwerner J, Kim Y, Fiorentino D. Nephrogenic Systemic Fibrosis. Relationship to Gadolinium and Response to Photopheresis. Arch Dermatol. 2007;143(8):1025-1030
(3) Grobner T (2006) Gadolinium a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21: 1104-1108.
(4) Marckmann P, Skov L, Rossen K et al. Nephrogenic systemic fibrosis: suspected etiological role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006 17: 2359-2362.
(5) Khurana A, Runge VM, Narayanan M, Greene JF., Nickel AE. Nephrogenic Systemic Fibrosis A Review of 6 Cases Temporally Related to Gadodiamide Injection (Omniscan). Invest Radiol 2007; 42: 139-145.
(6) Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. Am J Roentgenol 2007 Feb; 188(2): 586-92.
(7) Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, Djamali A. Nephrogenic Systemic Fibrosis: Risk factors and incidence estimation. Radiology 2007 April; 243(1): 148-157.
(8) Lin S-P, Brown JJ, MR Contrast Agents: Physical and Pharmacologic Basics. J Magn Reson Imag 2007; 25: 884-899.
(9) Pedersen M. Safety update on the possible causal relationship between gadolinium-containing MRI agents and nephrogenic systemic fibrosis. J Magn Reson Imag 2007; 25: 881-883.
(10) Lim YL, Lee HY, Low SCS, Chan LP, Goh NSG, Pang SM. Possible role of gadolinium in nephrogenic systemic fibrosis: report of two cases and review of the literature. Clin Exp Dermatol 2007; doi:10.1111/j.1365-2230.2007.02412.x (E-pub ahead of print).
(11) Bongartz G. Imaging in the time of NFD/NSF: do we have to change our routines concerning renal insufficiency? Magn Reson Mater Phy 2007; 20: 57-62.
(12) Pryor JG, Poggioli G, Galaria N, Gust A, Robison J, Samie F, Hanjani NM, Scott GA. Nephrogenic systemic fibrosis: A clinicopathologic study of six cases. J Am Acad Dermatol 2007; 57: 105-111.
(13) Kanal E, Barkovich AJ, Bell C, et al. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol. 2007;188:1447-1474.
(14) Jennifer OB, et al. Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant 2007; in press
(15) Todd DJ, et al. Cutaneous changes of nephrogenic systemic fibrosis. Arthritis Rheumatism 2007; 56: 3433-3441
(16) Thakral C, et al. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging 2007;2:199-205

The ACR Contrast Media Guidelines Version 7 was published on line earlier this month and is available for your review and reference at the links noted below.

The URL to link to the website is:

http://www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual.aspx

Additionally the section linked below has been revised with input and approval of the ACR Subcommittee on MR Safety:

http://www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual/NephrogenicSystemicFibrosis.aspx

“Reprinted with permission of the American College of Radiology. No other representation is authorized without express permission of the American College of Radiology.”