Gadolinium in Medical Imaging—Usefulness, Toxic Reactions and Possible Countermeasures—A Review
Abstract
:1. Introduction
2. Gadolinium in Medical Imaging
3. Pharmacokinetics and Toxicokinetics of Gd and Its Chelates
4. Toxic Effects of Gd-Compounds
4.1. Acute Reactions to GBCAs
4.2. Contrast Induced Nephropathy
4.3. Nephrogenic Systemic Fibrosis (NSF)
4.4. Gadolinium Retention/Deposition
4.5. Fetal Toxicity and the Use of GBCAs in Pregnancy
5. Biological Monitoring
6. Prevention and Treatment of Gd-Related Side Effects
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Tang, J.; Sheng, Y.; Hu, H.; Shen, Y. Macromolecular MRI contrast agents: Structures, properties and applications. Prog. Polym. Sci. 2012, 38, 462–502. [Google Scholar] [CrossRef]
- Caravan, P.; Ellison, J.J.; McMurry, T.J.; Lauffer, R.B. Gadolinium(III) chelates as MRI contrast agents: Structure, dynamics and applications. Chem. Rev. 1999, 99, 2293–2352. [Google Scholar] [CrossRef] [PubMed]
- Wahsner, J.; Gale, E.M.; Rodriguez-Rodriguez, A.; Caravan, P. Chemistry of MRI Contrast Agensts: Current Challenges and New frontiers. Chem. Rev. 2019, 119, 957–1057. [Google Scholar] [CrossRef]
- Do, C.; DeAguero, J.; Brearley, A.; Trejo, X.; Howard, T.; Escobar, G.P.; Wagner, B. Gadolinium-Based Contrast Agent Use, Their Safety, and Practice Evolution. Kidney360 2020, 1, 561–568. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rogosnitzky, M.; Branch, S.M. Gadolinium-based contrast agent toxicity: A review of known and proposed mechanisms. BioMetals 2016, 29, 365–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cowling, T.; Frey, N. Macrocyclic and linear gadolinium based contrast agents for adults undergoing magnetic resonance imaging: A review of safety. In CADTH Rapid Response Reports; Canadian Agency for Drugs and Technologies in Health: Ottawa, ON, Canada, 2019. [Google Scholar]
- Lux, J.; Sherry, A.D. Advances in gadolinium-based MRI contrast agent designs for monitoring biological processes in vivo. Curr. Opin. Chem. Biol. 2018, 45, 121–130. [Google Scholar] [CrossRef]
- Van der Molen, A.J.; Bellin, M.F. Extracellular gadolinium-based contrast media: Differences in diagnostic efficacy. Eur. J. Radiol. 2008, 66, 168–174. [Google Scholar] [CrossRef]
- Frenzel, T.; Apte, C.; Jost, G.; Schöckel, L.; Lohrke, J.; Pietsch, H. Quantification and assessment of the chemical form of residual gadolinium in the brain after repeated administration of gadolinium-based contrast agents: Comparative study in rats. Investig. Radiol. 2017, 52, 396–404. [Google Scholar] [CrossRef] [Green Version]
- Schieda, N.; Van Der Pol, C.B.; Walker, D.; Tsampalieros, A.K.; Maralani, P.J.; Woo, S.; Davenport, M.S. Adverse Events to the Gadolinium-based Contrast Agent Gadoxetic Acid: Systematic Review and Meta-Analysis. Radiology 2020, 297, 565–572. [Google Scholar] [CrossRef]
- Wikström, J.; Wasser, M.N.; Pattynama, P.M.; Bonomo, L.; Hamm, B.; Del Maschio, A.; Knopp, M.V.; Marchal, G.; Barentsz, J.O.; Oudkerk, M.; et al. Gadobenate Dimeglumine-Enhanced Magnetic Resonance Angiography of the Pelvic Arteries. Investig. Radiol. 2003, 38, 504–515. [Google Scholar] [CrossRef]
- Jbara, M.; Chen, Q.; Marten, P.; Morcos, M.; Beltran, J. Shoulder MR Arthrography: How, Why, When. Radiol. Clin. North. Am. 2005, 43, 683–692. [Google Scholar] [CrossRef] [PubMed]
- Wedeking, P.; Tweedle, M. Comparison of the biodistribution of 153Gd-labeled Gd(DTPA)2−, Gd(DOTA)−, and Gd(acetate) in in mice. Nucl. Med. Biol. 1988, 15, 395–402. [Google Scholar] [CrossRef]
- Barnhart, J.L.; Kuhnert, N.; Bakan, D.A.; Berk, R.N. Biodistribution of GdCl3 and Gd-DTPA and their influence on proton magnetic relaxation in rat tissues. Magn. Reson. Imaging 1987, 5, 221–231. [Google Scholar] [CrossRef]
- Laurent, S.; Vander Elst, L.; Muller, R.N. Comparative study of the physicochemical properties of six clinical low molecular weight gadolinium contrast agents. Contrast Media Mol. Imaging 2006, 1, 128–137. [Google Scholar] [CrossRef] [PubMed]
- Layne, K.A.; Dargan, P.I.; Archer, J.R.H.; Wood, D.M. Gadolinium deposition and the potential for toxicological sequelae—A literature review of issues surrounding gadolinium-based contrast agents. Br. J. Clin. Pharmacol. 2018, 84, 2522–2534. [Google Scholar] [CrossRef] [PubMed]
- Kanda, T.; Ishii, K.; Kawaguchi, H.; Kitajima, K.; Takenaka, D. 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, 834–841. [Google Scholar] [CrossRef] [PubMed]
- Neburkova, J.; Rulseh, A.M.; Chang, S.L.Y.; Raabova, H.; Vejpravova, J.; Dracinsky, M.; Tarabek, J.; Kotek, J.; Pingle, M.; Majer, P.; et al. Formation of gadolinium–ferritin from clinical magnetic resonance contrast agents. Nanoscale Adv. 2020, 2, 5567–5571. [Google Scholar] [CrossRef]
- Xia, D.; Davis, R.L.; Crawford, J.A.; Abraham, J.L. 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, 1126–1136. [Google Scholar] [CrossRef]
- Radbruch, A.; Weberling, L.D.; Kieslich, P.J.; Eidel, O.; Burth, S.; Kickingereder, P.V.; Heiland, S.; Wick, W.; Schlemmer, H.-P.; Bendszus, M. Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent. Radiology 2015, 275, 783–791. [Google Scholar] [CrossRef]
- Frenzel, T.; Lengsfeld, P.; Schirmer, H.; Hütter, J.; Weinmann, H.-J. Stability of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37 °C. Investig. Radiol. 2008, 43, 817–828. [Google Scholar] [CrossRef]
- Laurent, S.; Vander Elst, L.; Coprox, F.; Muller, R.N. Stability of MRI Paramagnetic Contrast Media A Proton Relaxometric Protocol for Transmetallation Assessment. Investig. Radiol. 2001, 36, 115–122. [Google Scholar] [CrossRef] [PubMed]
- Tweedle, M.; Hagan, J.; Kumar, K.; Mantha, S.; Chang, C. Reaction of gadolinium chelates with endogenously available ions. Magn. Reson. Imaging 1991, 9, 409–415. [Google Scholar] [CrossRef]
- Sherry, A.D.; Caravan, P.; Lenkinski, R.E. Primer on gadolinium chemistry. J. Magn. Reson. Imaging 2009, 30, 1240–1248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spencer, A.J.; Wilson, S.A.; Batchelor, J.; Reid, A.; Pees, J.; Harpur, E. Gadolinium Chloride Toxicity in the Rat. Toxicol. Pathol. 1997, 25, 245–255. [Google Scholar] [CrossRef] [PubMed]
- Le Mignon, M.M.; Chambon, C.; Warrington, S.; Davies, R.; Bonnemain, B. Gd-DOTA. Pharmacokinetics and tolerability after intravenous injection into healthy volunteers. Investig. Radiol. 1990, 25, 933–937. [Google Scholar] [CrossRef]
- Robert, P.; Frenzel, T.; Factor, C.; Jost, G.; Rasschaert, M.; Schuetz, G.; Fretellier, N.; Boyken, J.; Idée, J.M.; Pietsch, H. Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue Critical Appraisal and Suggestions for Harmonization-A Joint Initiative. Investig. Radiol. 2018, 53, 499–517. [Google Scholar] [CrossRef]
- McDonald, R.J.; Weinreb, J.C.; Davenport, M.S. Symptoms Associated with Gadolinium Exposure (SAGE): A Suggested Term. Radiology 2022, 302, 270–273. [Google Scholar] [CrossRef]
- Fok, J.S.; Smith, W.B. Hypersensitivity reactions to gadolinium-based contrast agents. Curr. Opin. Allergy Clin. Immunol. 2017, 17, 241–246. [Google Scholar] [CrossRef]
- Kato, K.; Fujimoto, S.; Inukai, S.; Takatsu, H.; Kono, Y.; Kasai, K. Late-onset acute respiratory distress syndrome induced by a gadolinium-based contrast agent. Respir. Med. Case Rep. 2019, 29, 100990. [Google Scholar] [CrossRef]
- Thomsen, H.S.; Almèn, T.; Morcos, S.K. Members of the Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR)). Gadolinium-containing contrast media for radiographic examinations: A position paper. Eur. Radiol. 2002, 12, 2600–2605. [Google Scholar] [CrossRef]
- Stacul, F.; van der Molen, A.J.; Reimer, P.; Webb, J.A.W.; Thomsen, H.S.; Morcos, S.K.; Almén, T.; Aspelin, P.; Bellin, M.-F.; Clement, O.; et al. Contrast induced nephropathy: Updated ESUR Contrast Media Safety Committee guidelines. Eur. Radiol. 2011, 21, 2527–2541. [Google Scholar] [CrossRef] [PubMed]
- George, S.; Webb, S.M.; Abraham, J.L.; Cramer, S.P. Synchrotron X-ray analyses demonstrate phosphate-bound gadolinium in skin in nephrogenic systemic fibrosis. Br. J. Dermatol. 2010, 163, 1077–1081. [Google Scholar] [CrossRef] [PubMed]
- Le Fur, M.; Caravan, P. The biological fate of gadolinium-based MRI contrast agents: A call to action for bioinorganic chemists. Metallomics 2019, 11, 240–254. [Google Scholar] [CrossRef] [PubMed]
- Weinreb, J.C.; Rodby, R.A.; Yee, J.; Wang, C.L.; Fine, D.; McDonald, R.J.; Perazella, M.A.; Dillman, J.R.; Davenport, M.S. Use of Intravenous Gadolinium-based Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation. Radiology 2021, 298, 28–35. [Google Scholar] [CrossRef]
- Mathur, M.; Jones, J.R.; Weinreb, J.C. Gadolinium Deposition and Nephrogenic Systemic Fibrosis: A Radiologist’s Primer. RadioGraphics 2020, 40, 153–162. [Google Scholar] [CrossRef]
- EMA. EMA’s Final Opinion Confirms Restrictions on Use of Linear Gadolinium Agents in Body Scans EMA/457616/2017; European Medicines Agency: London, UK; Amsterdam, The Netherlands, 2017. [Google Scholar]
- McDonald, R.J.; Levine, D.; Weinreb, J.; Kanal, E.; Davenport, M.S.; Ellis, J.H.; Jacobs, P.; Lenkinski, R.E.; Maravilla, K.R.; Prince, M.R.; et al. Gadolinium Retention: A Research Roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium Chelates. Radiology 2018, 289, 517–534. [Google Scholar] [CrossRef]
- Gulani, V.; Calamante, F.; Shellock, F.G.; Kanal, E.; Reeder, S.B. Gadolinium deposition in the brain: Summary of evidence and recommendations. Lancet Neurol. 2017, 16, 564–570. [Google Scholar] [CrossRef]
- Guo, B.J.; Yang, Z.L.; Zhang, L.J. Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives. Front. Mol. Neurosci. 2018, 11, 335. [Google Scholar] [CrossRef] [Green Version]
- Khairinisa, M.A.; Takatsuru, Y.; Amano, I.; Erdene, K.; Nakajima, T.; Kameo, S.; Koyama, H.; Tsushima, Y.; Koibuchi, N. The Effect of Perinatal Gadolinium-Based Contrast Agents on Adult Mice Behavior. Investig. Radiol. 2018, 53, 110–118. [Google Scholar] [CrossRef]
- Mervak, B.M.; Altun, E.; McGinty, K.A.; Hyslop, W.B.; Semelka, R.C.; Burke, L.M. MRI in pregnancy: Indications and practical considerations. J. Magn. Reson. Imaging 2019, 49, 621–631. [Google Scholar] [CrossRef]
- Oh, K.Y.; Roberts, V.H.J.; Schabel, M.C.; Grove, K.L.; Woods, M.; Frias, A.E. Gadolinium Chelate Contrast Material in Pregnancy: Fetal Biodistribution in the Nonhuman Primate. Radiology 2015, 276, 110–118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ray, J.G.; Vermeulen, M.J.; Bharatha, A.; Montanera, W.J.; Park, A.L. Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes. JAMA 2016, 316, 952–961. [Google Scholar] [CrossRef] [PubMed]
- Gatta, G.; Di Grezia, G.; Cuccurullo, V.; Sardu, C.; Iovino, F.; Comune, R.; Ruggiero, A.; Chirico, M.; La Forgia, D.; Fanizzi, A.; et al. MRI in Pregnancy and Precision Medicine: A Review from Literature. J. Pers. Med. 2021, 12, 9. [Google Scholar] [CrossRef]
- US FDA. Requirement for Pregnancy and Lactation Labeling. Fed. Regist. 2008, 73, 104. [Google Scholar]
- Hasegawa, M.; Duncan, B.R.; Marshall, D.A.; Gonzalez-Cuyar, L.F.; Paulsen, M.; Kobayashi, M.; Maravilla, K.R. Human hair as a possible surrogate marker of retained tissue gadolinium: A pilot autopsy study correlating gadolinium concentrations in hair with brain and other tissues among decedents who received gadolinium-based contrast agents. Investig. Radiol. 2020, 55, 636–642. [Google Scholar] [CrossRef] [PubMed]
- Telgmann, L.; Holtkamp, M.; Künnemeyer, J.; Gelhard, C.; Hartmann, M.; Klose, A.; Sperling, M.; Karst, U. Simple and rapid quantification of gadolinium in urine and blood plasma samples by means of total reflection X-ray fluorescence (TXRF). Metallomics 2011, 3, 1035–1040. [Google Scholar] [CrossRef]
- Tweedle, M.F. Gadolinium deposition: Is it chelated or dissociated gadolinium? How can we tell? Magn. Reson. Imaging 2016, 34, 1377–1382. [Google Scholar] [CrossRef]
- Christensen, K.N.; Lee, C.U.; Hanley, M.M.; Leung, N.; Moyer, T.P.; Pittelkow, M.R. Quantification of gadolinium in fresh skin and serum samples from patients with nephrogenic systemic fibrosis. J. Am. Acad. Dermatol. 2011, 64, 91–96. [Google Scholar] [CrossRef]
- Rees, J.A.; Deblonde, G.J.-P.; An, D.D.; Ansoborlo, C.; Gauny, S.S.; Abergel, R.J. Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents. Sci. Rep. 2018, 8, 4419. [Google Scholar] [CrossRef] [Green Version]
- Layne, K.A.; Wood, D.M.; Dargan, P.I. Gadolinium-based contrast agents–what is the evidence for ‘gadolinium deposition disease’and the use of chelation therapy? Clin. Toxicol. 2020, 58, 151–160. [Google Scholar] [CrossRef]
- Bose, C.; Megyesi, J.K.; Shah, S.V.; Hiatt, K.M.; Hall, K.A.; Karaduta, O.; Swaminathan, S. Evidence Suggesting a Role of Iron in a Mouse Model of Nephrogenic Systemic Fibrosis. PLoS ONE 2015, 10, e0136563. [Google Scholar] [CrossRef] [PubMed]
- Leung, N.; Pittelkow, M.R.; Lee, C.U.; Good, J.A.; Hanley, M.M.; Moyer, T.P. Chelation of gadolinium with deferoxamine in a patient with nephrogenic systemic fibrosis. Clin. Kidney J. 2009, 2, 309–311. [Google Scholar] [CrossRef] [PubMed]
- Ngamcherdtrakul, W.; Morry, J.; Sangvanich, T.; Reda, M.; Bejan, D.S.; Fryxell, G.E.; Yantasee, W. Removal of a gadolinium based contrast agent by a novel sorbent hemoperfusion in a chronic kidney disease (CKD) rodent model. Sci. Rep. 2019, 9, 709. [Google Scholar] [CrossRef] [PubMed]
- Aaseth, J.; Crisponi, G.; Anderson, O. Chelation Therapy in the Treatment of Metal Intoxication; Academic Press: London, UK, 2016. [Google Scholar]
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Blomqvist, L.; Nordberg, G.F.; Nurchi, V.M.; Aaseth, J.O. Gadolinium in Medical Imaging—Usefulness, Toxic Reactions and Possible Countermeasures—A Review. Biomolecules 2022, 12, 742. https://doi.org/10.3390/biom12060742
Blomqvist L, Nordberg GF, Nurchi VM, Aaseth JO. Gadolinium in Medical Imaging—Usefulness, Toxic Reactions and Possible Countermeasures—A Review. Biomolecules. 2022; 12(6):742. https://doi.org/10.3390/biom12060742
Chicago/Turabian StyleBlomqvist, Lennart, Gunnar F. Nordberg, Valeria M. Nurchi, and Jan O. Aaseth. 2022. "Gadolinium in Medical Imaging—Usefulness, Toxic Reactions and Possible Countermeasures—A Review" Biomolecules 12, no. 6: 742. https://doi.org/10.3390/biom12060742
APA StyleBlomqvist, L., Nordberg, G. F., Nurchi, V. M., & Aaseth, J. O. (2022). Gadolinium in Medical Imaging—Usefulness, Toxic Reactions and Possible Countermeasures—A Review. Biomolecules, 12(6), 742. https://doi.org/10.3390/biom12060742