Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update

REFERENCES

1. 1.↵
   2. Hao D,
   3. Ai T,
   4. Goerner F, et al

   . MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging 2012;36:1060–71 doi:10.1002/jmri.23725 pmid:23090917

   CrossRefPubMed
2. 2.↵
   2. Bleicher AG,
   3. Kanal E

   . Assessment of adverse reaction rates to a newly approved MRI contrast agent: review of 23,553 administrations of gadobenate dimeglumine. AJR Am J Roentgenol 2008;191:W307–11 doi:10.2214/AJR.07.3951 pmid:19020220

   CrossRefPubMedWeb of Science
3. 3.↵
   2. Kanal E,
   3. Tweedle MF

   . Residual or retained gadolinium: practical implications for radiologists and our patients. Radiology 2015;275:630–34 doi:10.1148/radiol.2015150805 pmid:25942418

   CrossRefPubMed
4. 4.↵
   2. Ersoy H,
   3. Rybicki FJ

   . Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging 2007;26:1190–97 doi:10.1002/jmri.21135 pmid:17969161

   CrossRefPubMedWeb of Science
5. 5.↵
   2. Lin SP,
   3. Brown JJ

   . MR contrast agents: physical and pharmacologic basics. J Magn Reson Imaging 2007;25:884–99 doi:10.1002/jmri.20955 pmid:17457803

   CrossRefPubMedWeb of Science
6. 6.↵
   2. Gierada DS,
   3. Bae KT

   . Gadolinium as a CT contrast agent: assessment in a porcine model. Radiology 1999;210:829–34 doi:10.1148/radiology.210.3.r99mr06829 pmid:10207488

   CrossRefPubMed
7. 7.↵
   2. Quinn AD,
   3. O'Hare NJ,
   4. Wallis FJ, et al

   . Gd-DTPA: an alternative contrast medium for CT. J Comput Assist Tomogr 1994;18:634–36 doi:10.1097/00004728-199407000-00022 pmid:8040451

   CrossRefPubMedWeb of Science
8. 8.↵
   2. Henson JW,
   3. Nogueira RG,
   4. Covarrubias DJ, et al

   . Gadolinium-enhanced CT angiography of the circle of Willis and neck. AJNR Am J Neuroradiol 2004;25:969–72 pmid:15205132

   Abstract/FREE Full Text
9. 9.↵
   2. Bonvento MJ,
   3. Moore WH,
   4. Button TM, et al

   . CT angiography with gadolinium-based contrast media. Acad Radiol 2006;13:979–85 doi:10.1016/j.acra.2006.03.019 pmid:16843850

   CrossRefPubMed
10. 10.↵
    2. Grobner T

    . Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2005;21:1104–08 doi:10.1093/ndt/gfk062 pmid:16431890

    CrossRefPubMed
11. 11.↵
    2. Marckmann P

    . Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17:2359–62 doi:10.1681/ASN.2006060601 pmid:16885403

    Abstract/FREE Full Text
12. 12.↵
    2. Thomsen HS

    . Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am 2009;47:827–31, vi doi:10.1016/j.rcl.2009.05.003 pmid:19744597

    CrossRefPubMed
13. 13.↵
    2. Broome DR

    . Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol 2008;66:230–34 doi:10.1016/j.ejrad.2008.02.011 pmid:18372138

    CrossRefPubMedWeb of Science
14. 14.↵
    2. Abujudeh HH,
    3. Kaewlai R,
    4. Kagan A, et al

    . Nephrogenic systemic fibrosis after gadopentetate dimeglumine exposure: case series of 36 patients. Radiology 2009;253:81–89 doi:10.1148/radiol.2531082160 pmid:19709997

    CrossRefPubMedWeb of Science
15. 15.↵
    2. Wertman R,
    3. Altun E,
    4. Martin DR, et al

    . Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology 2008;248:799–806 doi:10.1148/radiol.2483072093 pmid:18632533

    CrossRefPubMedWeb of Science
16. 16.↵
    2. Hope TA,
    3. Herfkens RJ,
    4. Denianke KS, et al

    . Nephrogenic systemic fibrosis in patients with chronic kidney disease who received gadopentetate dimeglumine. Invest Radiol 2009;44:135–39 doi:10.1097/RLI.0b013e31819343ba pmid:19151610

    CrossRefPubMed
17. 17.↵
    2. Fretellier N,
    3. Idée JM,
    4. Guerret S, et al

    . Clinical, biological, and skin histopathologic effects of ionic macrocyclic and nonionic linear gadolinium chelates in a rat model of nephrogenic systemic fibrosis. Invest Radiol 2011;46:85–93 doi:10.1097/RLI.0b013e3181f54044 pmid:20938344

    CrossRefPubMed
18. 18.↵
    2. Kanda T,
    3. Ishii K,
    4. Kawaguchi H, et al

    . High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 2014;270:834–41 doi:10.1148/radiol.13131669 pmid:24475844

    CrossRefPubMed
19. 19.↵
    2. Errante Y,
    3. Cirimele V,
    4. Mallio CA, et al

    . Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation. Invest Radiol 2014;49:685–90 doi:10.1097/RLI.0000000000000072 pmid:24872007

    CrossRefPubMed
20. 20.↵
    2. Quattrocchi CC,
    3. Mallio CA,
    4. Errante Y, et al

    . Gadodiamide and dentate nucleus T1 hyperintensity in patients with meningioma evaluated by multiple follow-up contrast-enhanced magnetic resonance examinations with no systemic interval therapy. Invest Radiol 2015;50:470–72 doi:10.1097/RLI.0000000000000154 pmid:25756685

    CrossRefPubMed
21. 21.↵
    2. Ramalho J,
    3. Castillo M,
    4. AlObaidy M, et al

    . High signal intensity in globus pallidus and dentate nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology 2015;276:836–44 doi:10.1148/radiol.2015150872 pmid:26079490

    CrossRefPubMed
22. 22.↵
    2. Kanda T,
    3. Osawa M,
    4. Oba H, et al

    . High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015;275:803–09 doi:10.1148/radiol.14140364 pmid:25633504

    CrossRefPubMed
23. 23.↵
    2. Roccatagliata L,
    3. Vuolo L,
    4. Bonzano L, et al

    . Multiple sclerosis: hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with the secondary progressive subtype. Radiology 2009;251:503–10 doi:10.1148/radiol.2511081269 pmid:19401576

    CrossRefPubMed
24. 24.↵
    2. Kasahara S,
    3. Miki Y,
    4. Kanagaki M, et al

    . Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology 2011;258:222–28 doi:10.1148/radiol.10100508 pmid:21045180

    CrossRefPubMed
25. 25.↵
    2. Adin ME,
    3. Kleinberg L,
    4. Vaidya D, et al

    . Hyperintense dentate nuclei on T1-weighted MRI: relation to repeat gadolinium administration. AJNR Am J Neuroradiol 2015;36:1859–65 doi:10.3174/ajnr.A4378 pmid:26294649

    Abstract/FREE Full Text
26. 26.↵
    2. McDonald RJ,
    3. McDonald JS,
    4. Kallmes DF, et al

    . Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275:772–82 doi:10.1148/radiol.15150025 pmid:25742194

    CrossRefPubMed
27. 27.↵
    2. Kanda T,
    3. Fukusato T,
    4. Matsuda M, et al

    . Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology 2015;276:228–32 doi:10.1148/radiol.2015142690 pmid:25942417

    CrossRefPubMed
28. 28.↵
    2. Robert P,
    3. Lehericy S,
    4. Grand S, et al

    . T1-weighted hypersignal in the deep cerebellar nuclei after repeated administrations of gadolinium-based contrast agents in healthy rats: difference between linear and macrocyclic agents. Invest Radiol 2015;50:473–80 doi:10.1097/RLI.0000000000000181 pmid:26107651

    CrossRefPubMed
29. 29.↵
    2. Radbruch A,
    3. Weberling LD,
    4. Kieslich PJ, et al

    . Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015;275:783–91 doi:10.1148/radiol.2015150337 pmid:25848905

    CrossRefPubMed
30. 30.↵
    2. Weberling LD,
    3. Kieslich PJ,
    4. Kickingereder P, et al

    . Increased signal intensity in the dentate nucleus on unenhanced T1-weighted images after gadobenate dimeglumine administration. Invest Radiol 2015:50:743–48 doi:10.1097/RLI.0000000000000206 pmid:26352749

    CrossRefPubMed
31. 31.↵
    2. Stojanov DA,
    3. Aracki-Trenkic A,
    4. Vojinovic S, et al

    . Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol. Eur Radiol 2015 Jun 25. [Epub ahead of print] pmid:26105022
32. 32.↵
    1. Thompson CC

    2. de Campos RO,
    3. Herédia V,
    4. Ramalho M, et al

    . Application of gadolinium based contrast agents in abdominal magnetic resonance imaging: important considerations. In: Thompson CC, ed. Gadolinium: Compounds, Production and Applications. New York: Nova Science Publishers; 2009:chap 5
33. 33.↵
    2. Frenzel T,
    3. Lengsfeld P,
    4. Schirmer H, et al

    . Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol 2008;43:817–28 doi:10.1097/RLI.0b013e3181852171 pmid:19002053

    CrossRefPubMedWeb of Science
34. 34.↵
    2. Idée JM,
    3. Port M,
    4. Robic C, et al

    . Role of thermodynamic and kinetic parameters in gadolinium chelate stability. J Magn Reson Imaging 2009;30:1249–58 doi:10.1002/jmri.21967 pmid:19938037

    CrossRefPubMedWeb of Science
35. 35.↵
    2. Prince MR,
    3. Erel HE,
    4. Lent RW, et al

    . Gadodiamide administration causes spurious hypocalcemia. Radiology 2003;227:639–46 doi:10.1148/radiol.2273012007 pmid:12773671

    CrossRefPubMedWeb of Science
36. 36.↵
    2. Laurent S,
    3. Elst LV,
    4. Copoix F, et al

    . Stability of MRI paramagnetic contrast media: a proton relaxometric protocol for transmetallation assessment. Invest Radiol 2001;36:115–22 doi:10.1097/00004424-200102000-00008 pmid:11224760

    CrossRefPubMedWeb of Science
37. 37.↵
    2. Tweedle MF,
    3. Wedeking P,
    4. Kumar K

    . Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate, and gadodiamide in mice and rats. Invest Radiol 1995;30:372–80 doi:10.1097/00004424-199506000-00008 pmid:7490190

    CrossRefPubMed
38. 38.↵
    2. Tweedle MF,
    3. Hagan JJ,
    4. Kumar K, et al

    . Reaction of gadolinium chelates with endogenously available ions. Magn Reson Imaging 1991;9:409–15 doi:10.1016/0730-725X(91)90429-P pmid:1881260

    CrossRefPubMedWeb of Science
39. 39.↵
    2. Corot C,
    3. Idée JM,
    4. Hentsch AM, et al

    . Structure-activity relationship of macrocyclic and linear gadolinium chelates: investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme. J Magn Reson Imaging 1998;8:695–702 doi:10.1002/jmri.1880080328 pmid:9626889

    CrossRefPubMed
40. 40.↵
    2. Aime S,
    3. Caravan P

    . Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging 2009;30:1259–67 doi:10.1002/jmri.21969 pmid:19938038

    CrossRefPubMedWeb of Science
41. 41.↵
    2. Altum E,
    3. Semelka RC,
    4. Cakit C

    . Nephrogenic systemic fibrosis and management of high-risk patients. Acad Radiol 2009;16:897–905 doi:10.1016/j.acra.2009.01.001 pmid:19375360

    CrossRefPubMed
42. 42.↵
    2. Quarles LD,
    3. Hartle JE 2nd.,
    4. Middleton JP, et al

    . Aluminum-induced DNA synthesis in osteoblasts: mediation by a G-protein coupled cation sensing mechanism. J Cell Biochem 1994;56:106–17 doi:10.1002/jcb.240560115 pmid:7806584

    CrossRefPubMedWeb of Science
43. 43.↵
    2. Pałasz A,
    3. Czekaj P

    . Toxicological and cytophysiological aspects of lanthanides action. Acta Biochim Pol 2000;47:1107–14 pmid:11996100

    PubMed
44. 44.↵
    2. Feng X,
    3. Xia Q,
    4. Yuan L, et al

    . Impaired mitochondrial function and oxidative stress in rat cortical neurons: implications for gadolinium-induced neurotoxicity. Neurotoxicology 2010;31:391–98 doi:10.1016/j.neuro.2010.04.003 pmid:20398695

    CrossRefPubMed
45. 45.↵
    2. Xia Q,
    3. Feng X,
    4. Huang H, et al

    . Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons. J Neurochem 2011;117:38–47 doi:10.1111/j.1471-4159.2010.07162.x pmid:21198628

    CrossRefPubMed
46. 46.↵
    2. Spencer AJ,
    3. Wilson SA,
    4. Batchelor J, et al

    . Gadolinium chloride toxicity in the rat. Toxicol Pathol 1997;25:245–55 doi:10.1177/019262339702500301 pmid:9210255

    Abstract/FREE Full Text
47. 47.↵
    2. Idée JM,
    3. Port M,
    4. Medina C, et al

    . Possible involvement of gadolinium chelates in the pathophysiology of nephrogenic systemic fibrosis: a critical review. Toxicology 2008;248:77–88 doi:10.1016/j.tox.2008.03.012 pmid:18440117

    CrossRefPubMedWeb of Science
48. 48.↵
    2. Piera-Velazquez S,
    3. Louneva N,
    4. Fertala J, et al

    . Persistent activation of dermal fibroblasts from patients with gadolinium-associated nephrogenic systemic fibrosis. Ann Rheum Dis 2010;69:2017–23 doi:10.1136/ard.2009.127761 pmid:20570839

    Abstract/FREE Full Text
49. 49.↵
    2. Bhagavathula N,
    3. Dame MK,
    4. DaSilva M, et al

    . Fibroblast response to gadolinium: role for platelet-derived growth factor receptor. Invest Radiol 2010;45:769–77 doi:10.1097/RLI.0b013e3181e943d2 pmid:20714270

    CrossRefPubMed
50. 50.↵
    2. Edward M,
    3. Quinn JA,
    4. Burden AD, et al

    . Effect of different classes of gadolinium-based contrast agents on control and nephrogenic systemic fibrosis-derived fibroblast proliferation. Radiology 2010;256:735–43 doi:10.1148/radiol.10091131 pmid:20663970

    CrossRefPubMedWeb of Science
51. 51.↵
    2. Varani J,
    3. DaSilva M,
    4. Warner RL, et al

    . Effects of gadolinium-based magnetic resonance imaging contrast agents on human skin in organ culture and human skin fibroblasts. Invest Radiol 2009;44:74–81 doi:10.1097/RLI.0b013e31818f76b5 pmid:19077912

    CrossRefPubMedWeb of Science
52. 52.↵
    2. Christensen KN,
    3. Lee CU,
    4. Hanley MM, et al

    . Quantification of gadolinium in fresh skin and serum samples from patients with nephrogenic systemic fibrosis. J Am Dermatol 2011;64:91–96 doi:10.1016/j.jaad.2009.12.044 pmid:21036418

    CrossRefPubMed
53. 53.↵
    2. Cowper SE,
    3. Bucala R,
    4. Leboit PE

    . Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: setting the record straight. Semin Arthritis Rheum 2006;35:208–10 doi:10.1016/j.semarthrit.2005.09.005 pmid:16461067

    CrossRefPubMedWeb of Science
54. 54.↵
    2. Gibby WA,
    3. Gibby KA,
    4. Gibby WA

    . Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Invest Radiol 2004;39:138–42 doi:10.1097/01.rli.0000112789.57341.01 pmid:15076005

    CrossRefPubMed
55. 55.↵
    2. White GW,
    3. Gibby WA,
    4. Tweedle MF

    . Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Invest Radiol 2006;41:272–78 doi:10.1097/01.rli.0000186569.32408.95 pmid:16481910

    CrossRefPubMedWeb of Science
56. 56.↵
    2. Darrah TH,
    3. Prutsman-Pfeiffer JJ,
    4. Poreda RJ, et al

    . Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics 2009;1:479–88 doi:10.1039/b905145g pmid:21305156

    CrossRefPubMedWeb of Science
57. 57.↵
    2. Rocklage SM,
    3. Worah D,
    4. Kim SH

    . Metal ion release from paramagnetic chelates: what is tolerable? Magn Reson Med 1991;22:216–21; discussion 229–32 doi:10.1002/mrm.1910220211 pmid:1812349

    CrossRefPubMed
58. 58.↵
    2. Abraham JL,
    3. Thakral C,
    4. Skov L, et al

    . Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2008;158:273–80 pmid:18067485

    PubMedWeb of Science
59. 59.↵
    2. Xia D,
    3. Davis RL,
    4. Crawford JA, et al

    . Gadolinium released from MR contrast agents is deposited in brain tumors: in situ demonstration using scanning electron microscopy with energy dispersive X-ray spectroscopy. Acta Radiol 2010;51:1126–36 doi:10.3109/02841851.2010.515614 pmid:20868305

    Abstract/FREE Full Text
60. 60.↵
    2. Sanyal S,
    3. Marckmann P,
    4. Scherer S, et al

    . Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis: an autopsy-based review. Nephrol Dial Transplant 2011;26:3616–26 doi:10.1093/ndt/gfr085 pmid:21441397

    Abstract/FREE Full Text
61. 61.↵
    2. Ogi S,
    3. Fukumitsu N,
    4. Tsuchida D, et al

    . Imaging of bilateral striopallidodentate calcinosis. Clin Nucl Med 2002;27:721–24 doi:10.1097/00003072-200210000-00008 pmid:12352115

    CrossRefPubMed
62. 62.↵
    2. Fretellier N,
    3. Idée JM,
    4. Dencausse A, et al

    . Comparative in vivo dissociation of gadolinium chelates in renally impaired rats: a relaxometry study. Invest Radiol 2011;46:292–300 doi:10.1097/RLI.0b013e3182056ccf pmid:21263333

    CrossRefPubMed
63. 63.↵
    2. Schroeder JA,
    3. Weingart C,
    4. Coras B, et al

    . Ultrastructural evidence of dermal gadolinium deposits in a patient with nephrogenic systemic fibrosis and end-stage renal disease. Clin J Am Soc Nephrol 2008;3:968–75 doi:10.2215/CJN.00100108 pmid:18385397

    Abstract/FREE Full Text
64. 64.↵
    2. Thakral C,
    3. Abraham JL

    . Gadolinium-induced nephrogenic systemic fibrosis is associated with insoluble Gd deposits in tissues: in vivo transmetallation confirmed by microanalysis. J Cutan Pathol 2009;36:1244–54 doi:10.1111/j.1600-0560.2009.01283.x pmid:19602073

    CrossRefPubMedWeb of Science
65. 65.↵
    2. Ray DE,
    3. Holton JL,
    4. Nolan CC, et al

    . Neurotoxic potential of gadodiamide after injection into the lateral cerebral ventricle of rats. AJNR Am J Neuroradiol 1998;19:1455–62 pmid:9763378

    Abstract
66. 66.↵
    2. Roman-Goldstein SM,
    3. Barnett PA,
    4. McCormick CI, et al

    . Effects of gadopentetate dimeglumine administration after osmotic blood-brain barrier disruption: toxicity and MR imaging findings. AJNR Am J Neuroradiol 1991;12:885–90 pmid:1950917

    Abstract/FREE Full Text
67. 67.↵
    Gadolinium Toxicity: A Survey of the Chronic Effects of Retained Gadolinium from Contrast MRIs. https://gdtoxicity.files.wordpress.com/2014/09/gd-symptom-survey.pdf. Accessed September 1, 2015.