Gadolinium-based contrast agents: What we learned from acute adverse events, nephrogenic systemic fibrosis and brain retention

Abstract

Background Radiologists have been administering gadolinium-based contrast agents (GBCA) in magnetic resonance imaging for several decades, so that there is abundant experience with these agents regarding allergic-like reactions, nephrogenic systemic fibrosis (NSF) and gadolinium retention in the brain.

Methods This review is based on a selective literature search and reflects the current state of research on acute adverse effects of GBCA, NSF and brain retention of gadolinium.

Results Due to the frequent use of GBCA, data on adverse effects of these compounds are available in large collectives. Allergic-like reactions occurred rarely, whereas severe acute reactions were very rarely observed. Systemic changes in NSF also occur very rarely, although measures to avoid NSF resulted in a significantly reduced incidence of NSF. Due to gadolinium retention in the body after administration of linear MR contrast agents, only macrocyclic preparations are currently used with few exceptions. Clear clinical correlates of gadolinium retention in the brain could not be identified so far. Although the clinical added value of GBCA is undisputed, individual risks associated with the injection of GBCA should be identified and the use of non-contrast enhanced MR techniques should be considered. Alternative contrast agents such as iron oxide nanoparticles are not clinically approved, but are currently undergoing clinical trials.

Conclusion GBCA have a very good risk profile with a low rate of adverse effects or systemic manifestations such as NSF. Gadolinium retention in the brain can be minimized by the use of macrocyclic GBCA, although clear clinical correlates due to gadolinium retention in the brain following administration of linear GBCA could not be identified yet.

Key Points:

• Acute adverse effects are predominantly mild/moderate, rarely severe reactions occur.

• International guidelines resulted in significant reduction of nephrogenic systemic fibrosis.

• Application of macrocyclic contrast agents minimizes gadolinium retention in the brain.

Citation Format

• Bäuerle T, Saake M, Uder M. Gadolinium-based contrast agents: What we learned from acute adverse events, nephrogenic systemic fibrosis and brain retention. Fortschr Röntgenstr 2021; 193: 1010 – 1018

Key words

gadolinium-based contrast agents - acute adverse events - nephrogenic systemic fibrosis - gadolinium retention

Publication History

Received: 22 July 2020

Accepted: 24 November 2020

Article published online:
21 December 2020

• References

• 1 Frenzel T, Lengsfeld P, Schirmer H. et al Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol 2008; 43: 817-828 DOI: 10.1097/RLI.0b013e3181852171.
• 2 Idee JM, Port M, Robic C. et al Role of thermodynamic and kinetic parameters in gadolinium chelate stability. J Magn Reson Imaging 2009; 30: 1249-1258 DOI: 10.1002/jmri.21967.
• 3 Matsumura T, Hayakawa M, Shimada F. et al Safety of gadopentetate dimeglumine after 120 million administrations over 25 years of clinical use. Magn Reson Med Sci 2013; 12: 297-304 DOI: 10.2463/mrms.2013-0020.
• 4 Ramalho M, Ramalho J. Gadolinium-Based Contrast Agents: Associated Adverse Reactions. Magn Reson Imaging Clin N Am 2017; 25: 755-764 DOI: 10.1016/j.mric.2017.06.006.
• 5 Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?. Nephrol Dial Transplant 2006; 21: 1104-1108 DOI: 10.1093/ndt/gfk062.
• 6 Kanda T, Ishii K, 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: 834-841 DOI: 10.1148/radiol.13131669.
• 7 Costello JR, Kalb B, Martin DR. Incidence and Risk Factors for Gadolinium-Based Contrast Agent Immediate Reactions. Top Magn Reson Imaging 2016; 25: 257-263 DOI: 10.1097/RMR.0000000000000109.
• 8 Fok JS, Smith WB. Hypersensitivity reactions to gadolinium-based contrast agents. Curr Opin Allergy Clin Immunol 2017; 17: 241-246 DOI: 10.1097/ACI.0000000000000371.
• 9 Tasker F, Fleming H, McNeill G. et al Contrast media and cutaneous reactions. Part 2: Delayed hypersensitivity reactions to iodinated contrast media. Clin Exp Dermatol 2019; 44: 844-860 DOI: 10.1111/ced.13991.
• 10 Dillman JR, Trout AT, Davenport MS. Allergic-like contrast media reaction management in children. Pediatr Radiol 2018; 48: 1688-1694 DOI: 10.1007/s00247-018-4241-6.
• 11 Radiology ESoU. ESUR Guidelines on Contrast Agents 2020.
• 12 Radiology ACo. ACR Manual on contrast media 2020.
• 13 Behzadi AH, Zhao Y, Farooq Z. et al Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2018; 286: 471-482 DOI: 10.1148/radiol.2017162740.
• 14 Raynaud JS, Darmon-Kern E, Lancelot E. et al Immediate Allergic Reactions to Gadolinium-based Contrast Agents. Radiology 2018; 286: 1094-1095 DOI: 10.1148/radiol.2018172414.
• 15 de Kerviler E, Maravilla K, Meder JF. et al Adverse Reactions to Gadoterate Meglumine: Review of Over 25 Years of Clinical Use and More Than 50 Million Doses. Invest Radiol 2016; 51: 544-551 DOI: 10.1097/RLI.0000000000000276.
• 16 Endrikat J, Vogtlaender K, Dohanish S. et al Safety of Gadobutrol: Results From 42 Clinical Phase II to IV Studies and Postmarketing Surveillance After 29 Million Applications. Invest Radiol 2016; 51: 537-543 DOI: 10.1097/RLI.0000000000000270.
• 17 Shellock FG, Parker JR, Venetianer C. et al Safety of gadobenate dimeglumine (MultiHance): Summary of findings from clinical studies and postmarketing surveillance. Invest Radiol 2006; 41: 500-509 DOI: 10.1097/01.rli.0000209661.99225.c2.
• 18 McDonald JS, Hunt CH, Kolbe AB. et al Acute Adverse Events Following Gadolinium-based Contrast Agent Administration: A Single-Center Retrospective Study of 281 945 Injections. Radiology 2019; 292: 620-627 DOI: 10.1148/radiol.2019182834.
• 19 Uhlig J, Lucke C, Vliegenthart R. et al Acute adverse events in cardiac MR imaging with gadolinium-based contrast agents: results from the European Society of Cardiovascular Radiology (ESCR) MRCT Registry in 72839 patients. Eur Radiol 2019; 29: 3686-3695 DOI: 10.1007/s00330-019-06171-2.
• 20 Cowper SE, Robin HS, Steinberg SM. et al Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356: 1000-1001 DOI: 10.1016/S0140-6736(00)02694-5.
• 21 Wagner B, Drel V, Gorin Y. Pathophysiology of gadolinium-associated systemic fibrosis. Am J Physiol Renal Physiol 2016; 311: F1-F11 DOI: 10.1152/ajprenal.00166.2016.
• 22 Attari H, Cao Y, Elmholdt TR. et al A Systematic Review of 639 Patients with Biopsy-confirmed Nephrogenic Systemic Fibrosis. Radiology 2019; 292: 376-386 DOI: 10.1148/radiol.2019182916.
• 23 Davenport MS. Virtual Elimination of Nephrogenic Systemic Fibrosis: A Medical Success Story with a Small Asterisk. Radiology 2019; 292: 387-389 DOI: 10.1148/radiol.2019191158.
• 24 Radbruch A, Weberling LD, Kieslich PJ. et al Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015; 275: 783-791 DOI: 10.1148/radiol.2015150337.
• 25 Kanda T, Matsuda M, Oba H. et al Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology 2015; 277: 924-925 DOI: 10.1148/radiol.2015150697.
• 26 Radbruch A, Haase R, Kieslich PJ. et al No Signal Intensity Increase in the Dentate Nucleus on Unenhanced T1-weighted MR Images after More than 20 Serial Injections of Macrocyclic Gadolinium-based Contrast Agents. Radiology 2017; 282: 699-707 DOI: 10.1148/radiol.2016162241.
• 27 McDonald RJ, McDonald JS, Kallmes DF. et al Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology 2015; 275: 772-782 DOI: 10.1148/radiol.15150025.
• 28 Murata N, Gonzalez-Cuyar LF, Murata K. et al Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function. Invest Radiol 2016; 51: 447-453 DOI: 10.1097/RLI.0000000000000252.
• 29 Minaeva O, Hua N, Franz ES. et al Nonhomogeneous Gadolinium Retention in the Cerebral Cortex after Intravenous Administration of Gadolinium-based Contrast Agent in Rats and Humans. Radiology 2020; 294: 377-385 DOI: 10.1148/radiol.2019190461.
• 30 Quattrocchi CC, Ramalho J, van der Molen AJ. et al Standardized assessment of the signal intensity increase on unenhanced T1-weighted images in the brain: the European Gadolinium Retention Evaluation Consortium (GREC) Task Force position statement. Eur Radiol 2019; 29: 3959-3967 DOI: 10.1007/s00330-018-5803-6.
• 31 Saake M, Hepp T, Schmidle A. et al Influence of Artifact Corrections on MRI Signal Intensity Ratios for Assessment of Gadolinium Brain Retention. Acad Radiol 2020; 27: 744-749 DOI: 10.1016/j.acra.2019.07.013.
• 32 Kang KM, Choi SH, Hwang M. et al T1 Shortening in the Globus Pallidus after Multiple Administrations of Gadobutrol: Assessment with a Multidynamic Multiecho Sequence. Radiology 2018; 287: 258-266 DOI: 10.1148/radiol.2017162852.
• 33 Deike-Hofmann K, Reuter J, Haase R. et al No Changes in T1 Relaxometry After a Mean of 11 Administrations of Gadobutrol. Invest Radiol 2020; 55: 381-386 DOI: 10.1097/RLI.0000000000000650.
• 34 Saake M, Schmidle A, Kopp M. et al MRI Brain Signal Intensity and Relaxation Times in Individuals with Prior Exposure to Gadobutrol. Radiology 2019; 290: 659-668 DOI: 10.1148/radiol.2018181927.
• 35 Choi Y, Jang J, Kim J. et al MRI and Quantitative Magnetic Susceptibility Maps of the Brain after Serial Administrations of Gadobutrol: A Longitudinal Follow-up Study. Radiology 2020; 297: 143-150 DOI: 10.1148/radiol.2020192579.
• 36 Gulani V, Calamante F, Shellock FG. et al Chelated or dechelated gadolinium deposition – Authors' reply. Lancet Neurol 2017; 16: 955-956 DOI: 10.1016/S1474-4422(17)30365-4.
• 37 Gulani V, Calamante F, Shellock FG. et al Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol 2017; 16: 564-570 DOI: 10.1016/S1474-4422(17)30158-8.
• 38 Frenzel T, Apte C, Jost G. et al 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. Invest Radiol 2017; 52: 396-404 DOI: 10.1097/RLI.0000000000000352.
• 39 Radbruch A, Roberts DR, Clement O. et al Chelated or dechelated gadolinium deposition. Lancet Neurol 2017; 16: 955 DOI: 10.1016/S1474-4422(17)30364-2.
• 40 Rasschaert M, Weller RO, Schroeder JA. et al Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review. J Magn Reson Imaging 2020; DOI: 10.1002/jmri.27124.
• 41 McKnight CD, Rouleau RM, Donahue MJ. et al The Regulation of Cerebral Spinal Fluid Flow and Its Relevance to the Glymphatic System. Curr Neurol Neurosci Rep 2020; 20: 58 DOI: 10.1007/s11910-020-01077-9.
• 42 Robert P, Fingerhut S, Factor C. et al One-year Retention of Gadolinium in the Brain: Comparison of Gadodiamide and Gadoterate Meglumine in a Rodent Model. Radiology 2018; 288: 424-433 DOI: 10.1148/radiol.2018172746.
• 43 Lord ML, Chettle DR, Grafe JL. et al Observed Deposition of Gadolinium in Bone Using a New Noninvasive in Vivo Biomedical Device: Results of a Small Pilot Feasibility Study. Radiology 2018; 287: 96-103 DOI: 10.1148/radiol.2017171161.
• 44 Radbruch A. The Gadolinium Deposition Debate and the Streetlight Effect: Should We Really Focus on the Brain?. Radiology 2020; 297: 417-418 DOI: 10.1148/radiol.2020203143.
• 45 Williams S. Open Letter to FDA, Radiologists & Researchers 2020.
• 46 Gibby WA, Gibby KA, 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: 138-142 DOI: 10.1097/01.rli.0000112789.57341.01.
• 47 Tweedle MF, Wedeking P, Kumar K. Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate, and gadodiamide in mice and rats. Invest Radiol 1995; 30: 372-380 DOI: 10.1097/00004424-199506000-00008.
• 48 Fretellier N, Granottier A, Rasschaert M. et al Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats. Invest Radiol 2019; 54: 61-71 DOI: 10.1097/RLI.0000000000000517.
• 49 Alkhunizi SM, Fakhoury M, Abou-Kheir W. et al Gadolinium Retention in the Central and Peripheral Nervous System: Implications for Pain, Cognition, and Neurogenesis. Radiology 2020; 297: 407-416 DOI: 10.1148/radiol.2020192645.
• 50 Radbruch A, Richter H, Bucker P. et al Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents?. Invest Radiol 2020; 55: 473-480 DOI: 10.1097/RLI.0000000000000677.
• 51 Forslin Y, Martola J, Bergendal A. et al Gadolinium Retention in the Brain: An MRI Relaxometry Study of Linear and Macrocyclic Gadolinium-Based Contrast Agents in Multiple Sclerosis. AJNR Am J Neuroradiol 2019; 40: 1265-1273 DOI: 10.3174/ajnr.A6112.
• 52 Mallio CA, Piervincenzi C, Gianolio E. et al Absence of dentate nucleus resting-state functional connectivity changes in nonneurological patients with gadolinium-related hyperintensity on T1 -weighted images. J Magn Reson Imaging 2019; 50: 445-455 DOI: 10.1002/jmri.26669.
• 53 Chehabeddine L, Al Saleh T, Baalbaki M. et al Cumulative administrations of gadolinium-based contrast agents: risks of accumulation and toxicity of linear vs macrocyclic agents. Crit Rev Toxicol 2019; 49: 262-279 DOI: 10.1080/10408444.2019.1592109.
• 54 Mallio CA, Piervincenzi C, Carducci F. et al Within-network brain connectivity in Crohn's disease patients with gadolinium deposition in the cerebellum. Neuroradiology 2020; 62: 833-841 DOI: 10.1007/s00234-020-02415-x.
• 55 McDonald JS, McDonald RJ. MR Imaging Safety Considerations of Gadolinium-Based Contrast Agents: Gadolinium Retention and Nephrogenic Systemic Fibrosis. Magn Reson Imaging Clin N Am 2020; 28: 497-507 DOI: 10.1016/j.mric.2020.06.001.
• 56 Smith TE, Steven A, Bagert BA. Gadolinium Deposition in Neurology Clinical Practice. Ochsner J 2019; 19: 17-25 DOI: 10.31486/toj.18.0111.
• 57 Ramalho J, Ramalho M, Jay M. et al Gadolinium toxicity and treatment. Magn Reson Imaging 2016; 34: 1394-1398 DOI: 10.1016/j.mri.2016.09.005.
• 58 Semelka RC, Ramalho J, Vakharia A. et al Gadolinium deposition disease: Initial description of a disease that has been around for a while. Magn Reson Imaging 2016; 34: 1383-1390 DOI: 10.1016/j.mri.2016.07.016.
• 59 Layne KA, Wood DM, Dargan PI. Gadolinium-based contrast agents – what is the evidence for 'gadolinium deposition disease' and the use of chelation therapy?. Clin Toxicol (Phila) 2020; 58: 151-160 DOI: 10.1080/15563650.2019.1681442.
• 60 Harisinghani MG, Barentsz J, Hahn PF. et al Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003; 348: 2491-2499 DOI: 10.1056/NEJMoa022749.
• 61 Nguyen KL, Yoshida T, Kathuria-Prakash N. et al Multicenter Safety and Practice for Off-Label Diagnostic Use of Ferumoxytol in MRI. Radiology 2019; 293: 554-564 DOI: 10.1148/radiol.2019190477.
• 62 Anderson MA, Harrington SG, Kozak BM. et al Strategies to Reduce the Use of Gadolinium-Based Contrast Agents for Abdominal MRI in Children. Am J Roentgenol 2020; 214: 1054-1064 DOI: 10.2214/Am J Roentgenol.19.22232.
• 63 Falk Delgado A, Van Westen D, Nilsson M. et al Diagnostic value of alternative techniques to gadolinium-based contrast agents in MR neuroimaging-a comprehensive overview. Insights Imaging 2019; 10: 84 DOI: 10.1186/s13244-019-0771-1.