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Gadolinium-based Contrast Media and the Development of Nephrogenic Systemic Fibrosis in Patients with Renal Insufficiency
Review Article
Gadolinium-based Contrast Media and the Development of Nephrogenic Systemic Fibrosis in Patients with Renal Insufficiency Rush H. Chewning, BA, and Kieran J. Murphy, MD
Gadolinium-based contrast media are important tools in diagnostic and interventional radiology that are particularly useful in patients with renal insufficiency. Recent reports in which exposure to gadolinium compounds has been linked to the development of nephrogenic systemic fibrosis in this patient population, however, are quite concerning. It is of great importance that radiologists be aware of this serious disease and exercise caution when considering the use of gadolinium-based contrast media in patients with moderate (glomerular filtration rate, <60 mL/min/1.73 m2) to severe (glomerular filtration rate, <15 mL/min/1.73 m2) renal disease. J Vasc Interv Radiol 2007; 18:331–334 Abbreviations:
FDA ⫽ Food and Drug Administration, NSF ⫽ nephrogenic systemic fibrosis
ALTHOUGH free gadolinium is extremely toxic, chelation of gadolinium with large organic molecules such as diethylenetriaminepentaacetic acid results in the formation of highly stable complexes that are safe for use in humans (1). In 1988, the U.S. Food and Drug Administration (FDA) approved gadolinium-based contrast media for use in magnetic resonance (MR) imaging. Gadolinium agents rapidly gained wide acceptance owing to their utility in aiding diagnosis as well as their excellent safety profile. Since 1993, gadolinium chelates have been used off-label as intraarterial contrast media for imaging studies and interventional procedures, particularly in patients with renal insufficiency or severe allergies to iodinated
From the Division of Interventional Neuroradiology (K.J.M.), Johns Hopkins University School of Medicine (R.H.C.), Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. Received January 24, 2007; final revision received January 26, 2007; accepted January 27, 2007. Address correspondence to K.J.M.; E-mail: [email protected] None of the authors has identified a conflict of interest. © SIR, 2007 DOI: 10.1016/j.jvir.2007.01.025
contrast media (2,3). Early usage was limited primarily to digital subtraction angiography and contrast medium– enhanced MR angiography, in which doses of gadolinium agents were often two to three times the recommended dose of 0.1 mmol/kg. Recently, gadolinium chelates have also been used in even higher doses in computed tomographic angiography (4). Initially, gadolinium chelates were widely believed to be well tolerated and nonnephrotoxic, even when used in patients with underlying renal disease (3,5). However, several adverse effects have been reported, ranging from nausea and vomiting to anaphylactoid reactions and even death (6,7). Within the past few years, several studies and case reports have further challenged the notion that gadolinium agents are largely benign (8 –10). Of particular concern are recent reports linking the use of gadolinium compounds in patients with renal insufficiency to nephrogenic systemic fibrosis (NSF) (11,12). NSF was first identified in 1997 and reported in the literature in 2000 (13). Since that time, more than 200 cases of NSF have been reported worldwide, including 90 patients reported to the FDA (14). Because of the lack of
awareness of the disease or perhaps variability in its severity, many cases may have been overlooked, not reported, or not labeled as NSF (15,16). Originally named nephrogenic fibrosing dermopathy because it was thought to involve only the skin, NSF is a systemic disease that involves the skin, lungs, skeletal muscles, heart, and other organs. Fibrosis and calcification of the diaphragm and renal tubules, fibrosis of the myocardium and lungs, thickening of tendons, and an increased frequency of thrombotic events have all been reported (17,18). Manifestations of the disease resemble those of scleroderma, with patients exhibiting thickening and discoloration of the skin, particularly in the extremities. This thickening can progress to the point of limiting joint movement, often resulting in contractures. In addition, patients with NSF can develop pruritus, muscle weakness, and diffuse pain (19). In some patients, NSF has contributed to death by means of ventilatory restriction or mobility impairment leading to falls (20). To date, NSF has only been evident in patients with moderate (glomerular filtration rate, ⬍60 mL/min/1.73 m2) to severe (glomerular filtration rate, ⬍15 mL/min/1.73 m2) renal disease
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(21). Although the cause of NSF is not currently known, evidence linking the disease to exposure to gadolinium compounds is mounting. Grobner (12) reported in January 2006 that five of nine patients with renal insufficiency who underwent MR angiography with a gadolinium chelate developed NSF; the odds ratio of developing NSF when exposed to gadolinium was 32.5. Marckmann et al (13) presented a review in September 2006 of 13 patients with NSF, all of whom had been exposed to a gadolinium-based contrast medium 2–75 days before the development of the disease. Strengthening the correlation between gadolinium compounds and NSF are two recent reports of the histologic discovery of gadolinium deposition in tissues of patients with NSF. High et al (22) detected gadolinium in the skin and soft tissue of four patients with NSF. These patients had received a gadolinium-based contrast medium 4 –11 months before tissue samples were taken. Boyd et al (23) reported finding gadolinium deposits in the blood vessels of a patient who had developed NSF approximately 6 months after exposure to a gadolinium compound. Gadolinium chelates used in contrast media have been shown to undergo transmetallation both in vitro and in vivo. Transmetallation refers to the process of one ion replacing another by displacing it from its ligand. In humans, endogenous cations such as zinc, calcium, copper, and iron can be involved in this process (24). Transmetallation results in the release of toxic free gadolinium ions. According to the FDA, all known cases of NSF linked to gadolinium exposure have involved three agents: gadodiamide (Omniscan, GE Healthcare, Princeton, NJ), gadopentetate dimeglumine (Magnevist, Berlex Imaging, Montville, NJ), and gadoversetamide (OptiMARK, Mallinckrodt, St. Louis, Mo) (15). The other two agents approved by the FDA, gadoteridol (ProHance, Bracco Diagnostics, Princeton, NJ) and gadobenate dimeglumine (MultiHance, Bracco Diagnostics) have not been implicated. Of note, the former three are open-chain compounds, whereas the latter two are cyclic compounds. Openchain compounds have been demonstrated to be less stable and more susceptible to transmetallation than cyclic compounds. Gadodiamide, the agent
involved in most cases of NSF to date, is the least stable open-chain gadolinium compound and the one most susceptible to transmetallation (25). In fact, gadodiamide is formulated with an excess of chelate to minimize the potential for in vivo transmetallation. In patients with renal insufficiency, the biochemical environment may favor the occurrence of transmetallation. Acid-base disturbances, electrolyte imbalances, chronic inflammation, and iatrogenic agents involved in the care of patients with renal insufficiency have all been hypothesized to play a role (12,26). Decreased renal clearance of gadolinium among patients with renal insufficiency may also increase transmetallation. In patients with normal kidney function, gadolinium compounds have halflives of approximately 1.5 hours. In patients with renal insufficiency, halflives can be more than 20 times longer (27). Extended time in the body gives these gadolinium chelates more time to undergo transmetallation and, thus, produce greater amounts of free gadolinium ions. Free gadolinium ions can remain in the body for weeks to months, allowing more time for toxic effects (28). The very population in whom gadolinium is indicated for imaging procedures, those with renal insufficiency, might actually be the group most at risk as a result of gadolinium exposure. Currently, NSF is rare. However, it is a serious disease that conveys substantial morbidity and mortality. To our knowledge, there is currently no consistently effective treatment for NSF (21). Of particular concern is the fact that NSF affects a population that is already carrying the burden of chronic disease. Highlighting this is the fact that many of the cases reported by Marckmann et al (13) occurred in patients undergoing evaluation of iliac vessels with contrastenhanced MR angiography by using double- or triple-dose gadolinium agents in preparation for renal transplantation. Although gadolinium chelates have not been proved to cause NSF, and there may be confounding variables, gadolinium-related toxicity appears to be responsible for the development of this disease. We believe the relationship between NSF and the use of gadolinium compounds as contrast media in patients with renal insufficiency
March 2007
JVIR
warrants extreme caution. As such, we agree with current FDA recommendations in proposing that the use of gadolinium-based contrast media in patients with moderate (glomerular filtration rate, ⬍60 mL/min/1.73 m2) to severe (glomerular filtration rate, ⬍15 mL/min/1.73 m2) renal disease be strongly reconsidered. Should the use of these agents be deemed necessary in these patients, the lowest possible dose should be used. Patients receiving hemodialysis should be undergo dialysis as soon as possible after exposure (29). In addition, we would urge that intrathecal, intraarticular, and intraperitoneal injection of gadoliniumbased agents—and all other off-label uses— be discontinued until proper safety guidelines are established. References 1. Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol 1984; 142:619 – 624. 2. Kinno, Y, Odagiri K, Andoh K, et al. Gadopentetate dimeglumine as an alternative contrast agent for use in angiography. AJR Am J Roentgenol 1993; 16:1293–1294. 3. Spinosa DJ, Kaufmann JA, Hartwell GD. Gadolinium chelates in angiography and interventional radiology: a useful alternative to iodinated contrast media for angiography. Radiology 2002; 223:319 –325. 4. Rosioreanu AR, Alberico RA, Litwin A, Hon M, Grossman ZD, Katz DS. Gadolinium-enhanced computed tomographic angiography: current status. Curr Probl Diagn Radiol 2005; 34:207–219. 5. Spinosa DJ, Matsumoto AH, Hagspiel KD, Angle JF, Hartwell GD. Gadolinium-based contrast agents in angiography and interventional radiology. AJR Am J Roentgenol 1999; 173:1403–1409. 6. Murphy KJ, Brungerg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. AJR Am J Roentgenol 1996; 167:847– 849. 7. Jordan RM, Mintz RD. Fatal reaction to gadopentetate dimeglumine. AJR Am J Roentgenol 1995; 164:743–744. 8. Nyman U, Elmstahl B, Leander P, Nilsson M, Golman K, Almen T. Are gadolinium-based media really safer than iodinated media for digital subtraction angiography in patients with azotemia? Radiology 2002; 223:311–318. 9. Thomsen HS. Gadolinium-based contrast media may be nephrotoxic even at approved doses. Eur Radiol 2004; 14:1654– 1656.
Volume 18
Number 3
10. Ergun I, Keven K, Uruc I, et al. The safety of gadolinium in patients with stage 3 and 4 renal failure. Nephrol Dial Transplant 2006; 21:697–700. 11. Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21:1104 –1108. 12. 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 –2362. 13. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356: 1000–1001. 14. U.S. Food and Drug Administration. Public Health Advisory: update on magnetic resonance imaging (mri) contrast agents containing gadolinium and nephrogenic fibrosing dermopathy. Department of Health and Human Services. Available at http://www.fda.gov. Accessed January 21, 2007. 15. Murphy KJ, Hansen R, Prince MR. Cutaneous nodules, pain, and thrombophlebitis as an adverse reaction to gadolinium contrast media. AJR Am J Roentgenol 1997; 169:318 –319. 16. Murphy KJ, Szopinski KT, Cohan RH, Mermillod B, Ellis JH. Occurrence of adverse reactions to gadolinium-based
Chewning and Murphy
17.
18.
19. 20.
21.
22.
23.
contrast material and management of patients at increased risk: a survey of the American Society of Neuroradiology fellowship directors. Acad Radiol 1999; 6:656 – 664. Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazques S, Jiminez SA. Description of twelve cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006; 35:238 –249. Ting WW, Stone MA, Madison KC, Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003; 139:903–906 Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15:785–790. Cowper SE. Nephrogenic fibrosing dermopathy [NFD/NSF Website]. 2001–2007. Available at http://www.icnfdr.org. Accessed January 23, 2007. Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis 2005; 46: 763–765. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissues of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007; 56:21–26. Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007; 56:27–30.
•
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24. Idee J, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 2006; 20:563–576. 25. Puttagunta NR, Gibby WA, Puttagunta VL. Comparative transmetallation kinetics and thermodynamic stability of gadolinium-DTPA bis-glucosamide and other magnetic resonance imaging contrast media. Invest Radiol 1996; 31:619– 624. 26. Dharnidharka VR, Wesson SK, Fennell RS. Gadolinium and nephrogenic fibrosing dermopathy in pediatric patients. Available at http:// www.springerlink.com/content/1432198X. Accessed January 23, 2007. 27. 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. 28. Bartolini ME, Pekar J, Chettle DR, et al. An investigation of the toxicity of gadolinium-based MRI contrast agents using neutron activation analysis. Magn Reson Imaging 2003; 21:541–544. 29. Okada S, Katagiri K, Kumazaki T, Yokoyama H. Safety of gadolinium contrast agent in hemodialysis patients. Acta Radiol 2001; 42:339–341.
Gadolinium-based Contrast Media and the Development of Nephrogenic Systemic Fibrosis in Patients with Renal Insufficiency Rush H. Chewning, BA, and Kieran J. Murphy, MD
Gadolinium-based contrast media are important tools in diagnostic and interventional radiology that are particularly useful in patients with renal insufficiency. Recent reports in which exposure to gadolinium compounds has been linked to the development of nephrogenic systemic fibrosis in this patient population, however, are quite concerning. It is of great importance that radiologists be aware of this serious disease and exercise caution when considering the use of gadolinium-based contrast media in patients with moderate (glomerular filtration rate, <60 mL/min/1.73 m2) to severe (glomerular filtration rate, <15 mL/min/1.73 m2) renal disease. J Vasc Interv Radiol 2007; 18:331–334 Abbreviations:
FDA ⫽ Food and Drug Administration, NSF ⫽ nephrogenic systemic fibrosis
ALTHOUGH free gadolinium is extremely toxic, chelation of gadolinium with large organic molecules such as diethylenetriaminepentaacetic acid results in the formation of highly stable complexes that are safe for use in humans (1). In 1988, the U.S. Food and Drug Administration (FDA) approved gadolinium-based contrast media for use in magnetic resonance (MR) imaging. Gadolinium agents rapidly gained wide acceptance owing to their utility in aiding diagnosis as well as their excellent safety profile. Since 1993, gadolinium chelates have been used off-label as intraarterial contrast media for imaging studies and interventional procedures, particularly in patients with renal insufficiency or severe allergies to iodinated
From the Division of Interventional Neuroradiology (K.J.M.), Johns Hopkins University School of Medicine (R.H.C.), Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. Received January 24, 2007; final revision received January 26, 2007; accepted January 27, 2007. Address correspondence to K.J.M.; E-mail: [email protected] None of the authors has identified a conflict of interest. © SIR, 2007 DOI: 10.1016/j.jvir.2007.01.025
contrast media (2,3). Early usage was limited primarily to digital subtraction angiography and contrast medium– enhanced MR angiography, in which doses of gadolinium agents were often two to three times the recommended dose of 0.1 mmol/kg. Recently, gadolinium chelates have also been used in even higher doses in computed tomographic angiography (4). Initially, gadolinium chelates were widely believed to be well tolerated and nonnephrotoxic, even when used in patients with underlying renal disease (3,5). However, several adverse effects have been reported, ranging from nausea and vomiting to anaphylactoid reactions and even death (6,7). Within the past few years, several studies and case reports have further challenged the notion that gadolinium agents are largely benign (8 –10). Of particular concern are recent reports linking the use of gadolinium compounds in patients with renal insufficiency to nephrogenic systemic fibrosis (NSF) (11,12). NSF was first identified in 1997 and reported in the literature in 2000 (13). Since that time, more than 200 cases of NSF have been reported worldwide, including 90 patients reported to the FDA (14). Because of the lack of
awareness of the disease or perhaps variability in its severity, many cases may have been overlooked, not reported, or not labeled as NSF (15,16). Originally named nephrogenic fibrosing dermopathy because it was thought to involve only the skin, NSF is a systemic disease that involves the skin, lungs, skeletal muscles, heart, and other organs. Fibrosis and calcification of the diaphragm and renal tubules, fibrosis of the myocardium and lungs, thickening of tendons, and an increased frequency of thrombotic events have all been reported (17,18). Manifestations of the disease resemble those of scleroderma, with patients exhibiting thickening and discoloration of the skin, particularly in the extremities. This thickening can progress to the point of limiting joint movement, often resulting in contractures. In addition, patients with NSF can develop pruritus, muscle weakness, and diffuse pain (19). In some patients, NSF has contributed to death by means of ventilatory restriction or mobility impairment leading to falls (20). To date, NSF has only been evident in patients with moderate (glomerular filtration rate, ⬍60 mL/min/1.73 m2) to severe (glomerular filtration rate, ⬍15 mL/min/1.73 m2) renal disease
331
332
•
Gadolinium-based Contrast Media and Nephrogenic Systemic Fibrosis
(21). Although the cause of NSF is not currently known, evidence linking the disease to exposure to gadolinium compounds is mounting. Grobner (12) reported in January 2006 that five of nine patients with renal insufficiency who underwent MR angiography with a gadolinium chelate developed NSF; the odds ratio of developing NSF when exposed to gadolinium was 32.5. Marckmann et al (13) presented a review in September 2006 of 13 patients with NSF, all of whom had been exposed to a gadolinium-based contrast medium 2–75 days before the development of the disease. Strengthening the correlation between gadolinium compounds and NSF are two recent reports of the histologic discovery of gadolinium deposition in tissues of patients with NSF. High et al (22) detected gadolinium in the skin and soft tissue of four patients with NSF. These patients had received a gadolinium-based contrast medium 4 –11 months before tissue samples were taken. Boyd et al (23) reported finding gadolinium deposits in the blood vessels of a patient who had developed NSF approximately 6 months after exposure to a gadolinium compound. Gadolinium chelates used in contrast media have been shown to undergo transmetallation both in vitro and in vivo. Transmetallation refers to the process of one ion replacing another by displacing it from its ligand. In humans, endogenous cations such as zinc, calcium, copper, and iron can be involved in this process (24). Transmetallation results in the release of toxic free gadolinium ions. According to the FDA, all known cases of NSF linked to gadolinium exposure have involved three agents: gadodiamide (Omniscan, GE Healthcare, Princeton, NJ), gadopentetate dimeglumine (Magnevist, Berlex Imaging, Montville, NJ), and gadoversetamide (OptiMARK, Mallinckrodt, St. Louis, Mo) (15). The other two agents approved by the FDA, gadoteridol (ProHance, Bracco Diagnostics, Princeton, NJ) and gadobenate dimeglumine (MultiHance, Bracco Diagnostics) have not been implicated. Of note, the former three are open-chain compounds, whereas the latter two are cyclic compounds. Openchain compounds have been demonstrated to be less stable and more susceptible to transmetallation than cyclic compounds. Gadodiamide, the agent
involved in most cases of NSF to date, is the least stable open-chain gadolinium compound and the one most susceptible to transmetallation (25). In fact, gadodiamide is formulated with an excess of chelate to minimize the potential for in vivo transmetallation. In patients with renal insufficiency, the biochemical environment may favor the occurrence of transmetallation. Acid-base disturbances, electrolyte imbalances, chronic inflammation, and iatrogenic agents involved in the care of patients with renal insufficiency have all been hypothesized to play a role (12,26). Decreased renal clearance of gadolinium among patients with renal insufficiency may also increase transmetallation. In patients with normal kidney function, gadolinium compounds have halflives of approximately 1.5 hours. In patients with renal insufficiency, halflives can be more than 20 times longer (27). Extended time in the body gives these gadolinium chelates more time to undergo transmetallation and, thus, produce greater amounts of free gadolinium ions. Free gadolinium ions can remain in the body for weeks to months, allowing more time for toxic effects (28). The very population in whom gadolinium is indicated for imaging procedures, those with renal insufficiency, might actually be the group most at risk as a result of gadolinium exposure. Currently, NSF is rare. However, it is a serious disease that conveys substantial morbidity and mortality. To our knowledge, there is currently no consistently effective treatment for NSF (21). Of particular concern is the fact that NSF affects a population that is already carrying the burden of chronic disease. Highlighting this is the fact that many of the cases reported by Marckmann et al (13) occurred in patients undergoing evaluation of iliac vessels with contrastenhanced MR angiography by using double- or triple-dose gadolinium agents in preparation for renal transplantation. Although gadolinium chelates have not been proved to cause NSF, and there may be confounding variables, gadolinium-related toxicity appears to be responsible for the development of this disease. We believe the relationship between NSF and the use of gadolinium compounds as contrast media in patients with renal insufficiency
March 2007
JVIR
warrants extreme caution. As such, we agree with current FDA recommendations in proposing that the use of gadolinium-based contrast media in patients with moderate (glomerular filtration rate, ⬍60 mL/min/1.73 m2) to severe (glomerular filtration rate, ⬍15 mL/min/1.73 m2) renal disease be strongly reconsidered. Should the use of these agents be deemed necessary in these patients, the lowest possible dose should be used. Patients receiving hemodialysis should be undergo dialysis as soon as possible after exposure (29). In addition, we would urge that intrathecal, intraarticular, and intraperitoneal injection of gadoliniumbased agents—and all other off-label uses— be discontinued until proper safety guidelines are established. References 1. Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol 1984; 142:619 – 624. 2. Kinno, Y, Odagiri K, Andoh K, et al. Gadopentetate dimeglumine as an alternative contrast agent for use in angiography. AJR Am J Roentgenol 1993; 16:1293–1294. 3. Spinosa DJ, Kaufmann JA, Hartwell GD. Gadolinium chelates in angiography and interventional radiology: a useful alternative to iodinated contrast media for angiography. Radiology 2002; 223:319 –325. 4. Rosioreanu AR, Alberico RA, Litwin A, Hon M, Grossman ZD, Katz DS. Gadolinium-enhanced computed tomographic angiography: current status. Curr Probl Diagn Radiol 2005; 34:207–219. 5. Spinosa DJ, Matsumoto AH, Hagspiel KD, Angle JF, Hartwell GD. Gadolinium-based contrast agents in angiography and interventional radiology. AJR Am J Roentgenol 1999; 173:1403–1409. 6. Murphy KJ, Brungerg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. AJR Am J Roentgenol 1996; 167:847– 849. 7. Jordan RM, Mintz RD. Fatal reaction to gadopentetate dimeglumine. AJR Am J Roentgenol 1995; 164:743–744. 8. Nyman U, Elmstahl B, Leander P, Nilsson M, Golman K, Almen T. Are gadolinium-based media really safer than iodinated media for digital subtraction angiography in patients with azotemia? Radiology 2002; 223:311–318. 9. Thomsen HS. Gadolinium-based contrast media may be nephrotoxic even at approved doses. Eur Radiol 2004; 14:1654– 1656.
Volume 18
Number 3
10. Ergun I, Keven K, Uruc I, et al. The safety of gadolinium in patients with stage 3 and 4 renal failure. Nephrol Dial Transplant 2006; 21:697–700. 11. Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21:1104 –1108. 12. 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 –2362. 13. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356: 1000–1001. 14. U.S. Food and Drug Administration. Public Health Advisory: update on magnetic resonance imaging (mri) contrast agents containing gadolinium and nephrogenic fibrosing dermopathy. Department of Health and Human Services. Available at http://www.fda.gov. Accessed January 21, 2007. 15. Murphy KJ, Hansen R, Prince MR. Cutaneous nodules, pain, and thrombophlebitis as an adverse reaction to gadolinium contrast media. AJR Am J Roentgenol 1997; 169:318 –319. 16. Murphy KJ, Szopinski KT, Cohan RH, Mermillod B, Ellis JH. Occurrence of adverse reactions to gadolinium-based
Chewning and Murphy
17.
18.
19. 20.
21.
22.
23.
contrast material and management of patients at increased risk: a survey of the American Society of Neuroradiology fellowship directors. Acad Radiol 1999; 6:656 – 664. Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazques S, Jiminez SA. Description of twelve cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006; 35:238 –249. Ting WW, Stone MA, Madison KC, Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003; 139:903–906 Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15:785–790. Cowper SE. Nephrogenic fibrosing dermopathy [NFD/NSF Website]. 2001–2007. Available at http://www.icnfdr.org. Accessed January 23, 2007. Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis 2005; 46: 763–765. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissues of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007; 56:21–26. Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007; 56:27–30.
•
333
24. Idee J, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 2006; 20:563–576. 25. Puttagunta NR, Gibby WA, Puttagunta VL. Comparative transmetallation kinetics and thermodynamic stability of gadolinium-DTPA bis-glucosamide and other magnetic resonance imaging contrast media. Invest Radiol 1996; 31:619– 624. 26. Dharnidharka VR, Wesson SK, Fennell RS. Gadolinium and nephrogenic fibrosing dermopathy in pediatric patients. Available at http:// www.springerlink.com/content/1432198X. Accessed January 23, 2007. 27. 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. 28. Bartolini ME, Pekar J, Chettle DR, et al. An investigation of the toxicity of gadolinium-based MRI contrast agents using neutron activation analysis. Magn Reson Imaging 2003; 21:541–544. 29. Okada S, Katagiri K, Kumazaki T, Yokoyama H. Safety of gadolinium contrast agent in hemodialysis patients. Acta Radiol 2001; 42:339–341.