Clinical Review

Man, 48, With Excruciating Leg Pain

Clinician Reviews. 2008 August;18(8):30-32

References

1. US Food and Drug Administration. Public health advisory: gadolinium-containing contrast agents for magnetic resonance imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed July 24, 2008.

2. Cowper SE, Su L, Bhawan J, et al. Nephrogenic fibrosing dermopathy. Am J Dermatopathol. 2001;23(5):383-393.

3. US Food and Drug Administration. Information for healthcare professionals: gadolinium-based contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). Last updated June 4, 2008. www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705.htm. Accessed July 24, 2008.

4. International Center for Nephrogenic Fibrosing Dermopathy Research. www.icnfdr.org. Accessed July 24, 2008.

5. DeHoratius DM, Cowper SE. Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial. 2006;19(3):191-194.

6. Galan A, Cowper SE, Bucala R. Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol. 2006;18(6):614-617.

7. Swaminathan S, Ahmed I, McCarthy JT, et al. Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med. 2006;145(3):234-235.

8. Miskulin D, Gul A, Rudnick MR, Cowper SE. Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced renal failure. www.uptodate.com/patients/content/topic.do?topicKey=dialysis/48700. Accessed July 24, 2008.

9. Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108.

10. 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(9):2359-2362.

11. Centers for Disease Control and Prevention. Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents—St. Louis, Missouri, 2002-2006. MMWR Morb Mortal Wkly Rep. 2007;56(7):137-141.

12. Khurana A, Runge VM, Narayanan M, et al. Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (Omniscan). Invest Radiol. 2007;42(2):139-145.

13. Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology. 2007;243(1):148-157.

14. Morcos SK. Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition? Br J Radiol. 2007;80(950):73-76.

15. GE Healthcare. Omniscan safety update. http://md.gehealthcare.com/omniscan/safety/index.html. Accessed July 24, 2008.

16. Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. 2007;56(1):27-30.

17. High WA, Ayers RA, Chandler J, et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 2007;56(1):21-26.

18. Thomsen H; European Society of Urogenital Radiology. European Society of Urogenital Radiology guidelines on contrast media application. Curr Opin Urol. 2007;17(1):70-76.

19. Bongartz G. Imaging in the time of NFD/NSF: do we have to change our routines concerning renal insufficiency? MAGMA. 2007;20(2):57-62.

20. Kanal E, Barkovich AJ, Bell C, et al; ACR Blue Ribbon Panel on MR Safety. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol. 2007;188(6):1447-1474.

21. GE Healthcare Paper on Nephrogenic Systemic Fibrosis (March 2007). http://md.gehealthcare.com/omniscan/GE% 20Healthcare%20Paper%20On%20Nephrogenic%20 Systemic%20Fibrosis.pdf. Accessed July 24, 2008.

22. Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol. 2007;2(2):264-267.

23. Okada S, Katagiri K, Kumazaki T, Yokoyama H. Safety of gadolinium contrast agent in hemodialysis patients. Acta Radiol. 2001;42(3):339-341.

24. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology. 2007;242(3):647-649.

25. Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis. 2005;46(4):763-765.

The American College of Radiology guidelines published in 2007²⁰ stated that patients with any level of renal disease should not receive gadodiamide.

In March 2007, GE Healthcare published a paper on NSF, reiterating the safety of gadodiamide while acknowledging that 120 more cases had been reported to them ("usually associated with exposure at high doses").²¹ The FDA upholds an alert regarding use of all gadolinium-based contrast agents for patients with acute or chronic severe renal insufficiency,³ while stopping short of a ban on gadodiamide in such patients.

How Common Is NSF?
In a 2007 study conducted at the University of Wisconsin, Sadowski et al¹³ reported 13 cases of gadolinium-induced NSF, 11 involving patients with a GFR below 30 mL/min/1.73 m² but two with a GFR between 30 and 60 mL/min/1.73 m² (ie, with renal insufficiency, although the authors noted that renal insufficiency was acute in these two patients). The incidence of NSF was 4.6% among hospitalized patients with a GFR be-low 60 mL/min/1.73 m² who underwent gadolinium-enhanced MRI at the university hospital's radiology department. A reexamination of the charts of the patients with a GFR between 30 and 60 mL/min/1.73 m² revealed that these patients had levels below 30 mL/min/1.73 m² when their gadolinium exposure took place.

In an outpatient population–based calculation performed by Deo et al,²² a 2.4% chance of NSF was determined for each gadolinium exposure. Incidence of NSF was calculated at 4.3 cases per 1,000 patient-years in this population, making NSF as common as contrast-induced nephropathy. Nearly 5% of patients with NSF have an exceedingly rapid and fulminant disease course that may result in death. NSF, of itself, is not a cause of death but may contribute to death by restricting effective ventilation or by restricting mobility to the point of causing an accidental fall that may be further exacerbated by fractures and clotting complications. NSF survivors may experience disabling systemic symptoms. Full recovery occurs only in patients who recover renal function, either naturally or by kidney transplantation.⁴

Why Is NSF More Common With Gadodiamide?
As of June 2008, five gadolinium-based contrast agents were FDA approved for use with MRI (none with MRA)³: gadobenate (MultiHance^®), gadodiamide (Omniscan), gadopentetate (Magnevist^®), gadoteridol (ProHance^®), and gadoversetamide (Opti-MARK^®). More than 90% of NSF cases are associated with gadodiamide. Because this agent is the least stable thermodynamically, it may be more likely than the others to transmetallate.¹⁴ All gadolinium chelates are excreted by the kidney, and the decreased renal clearances associated with renal impairment may expose patients to prolonged gadolinium transmetallation, allowing the agent to accumulate in bone and other tissue.

Gadoterate (Dotarem^®), a cyclic gadolinium-based agent that is available in Europe but not the US, is considered more stable than other agents. It has been suggested that such agents may be safer choices for patients with decreased renal function.^14,19

Strategies to Prevent NSF
In the US and Europe, only a physician who has consulted with a radiologist can write an order for gadolinium use in a patient with a GFR below 30 mL/min/1.73 m².^18,20 European guidelines do not allow use of gadodiamide in such patients.

Although the actual population-based occurrence of NSF is low, the nature of the disease calls for an effort to limit vulnerable patients' exposure to gadolinium (see box). Outside of withholding imaging procedures, the only currently known strategies to reduce the incidence of NSF are to use a more stable, nonchelating gadolinium¹⁴ and to remove the gadolinium as soon as possible.^3,24

It has been recommended that patients with renal disease who are presently undergoing dialysis be dialyzed within two to three hours of gadolinium exposure, then again within 24 and 48 hours, provided it is clinically safe.^20,24 This has been shown to remove 99% of the gadolinium.²³

Since peritoneal dialysis clears gadolinium poorly, hemodialysis is recommended for peritoneal dialysis patients after gadolinium exposure, following the regimen outlined above.²⁰

No consensus has been reached regarding the patient with a GFR between 30 and 60 mL/min/1.73 m², nor for the patient with a lower GFR and no access for dialysis to be administered. Placement of a catheter for two days' dialysis incurs both surgical and renal risks for these patients.⁸

Patient Outcome
The only known cure for NSF is kidney transplantation, which is associated with a complete cure rate of 40%.^4,25 Nevertheless, while this manuscript was in preparation, the patient presented in this case study underwent kidney transplantation. On day 8 postsurgery, he was no longer taking oxycodone, his skin condition was clearing up, and he was feeling considerably better. His health care providers hope for further regression from his disease.