This article reports known and emerging adverse health effects associated with the administration of gadolinium-based contrast agents. It focuses on the issue of the incomplete excretion of these drugs leading to the deposition of gadolinium in the tissues of the patients. The evidence of deposition is reviewed. The analysis presents gaps in our knowledge but also suggests neglected or still poorly considered parameters to possibly explain discrepancies among studies (e.g. off-label use; rate of administration; gadolinium concentration in the pharmaceutical formulation, cumulative metal toxicity). The article also presents a critical assessment of some aspects reported in the literature as well as future needs. Potential biases in the investigation and evaluation of the health/clinical implications associated with gadolinium deposition are pointed out. The analysis emphasizes that the vast majority of the clinical studies conducted up to date on gadolinium-based contrast agents were designed to assess acute toxicity and diagnostic efficacy of the agents, not to identify long-term health effects.
Citation: Silvia Maria Lattanzio. Toxicity associated with gadolinium-based contrast-enhanced examinations[J]. AIMS Biophysics, 2021, 8(2): 198-220. doi: 10.3934/biophy.2021015
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This article reports known and emerging adverse health effects associated with the administration of gadolinium-based contrast agents. It focuses on the issue of the incomplete excretion of these drugs leading to the deposition of gadolinium in the tissues of the patients. The evidence of deposition is reviewed. The analysis presents gaps in our knowledge but also suggests neglected or still poorly considered parameters to possibly explain discrepancies among studies (e.g. off-label use; rate of administration; gadolinium concentration in the pharmaceutical formulation, cumulative metal toxicity). The article also presents a critical assessment of some aspects reported in the literature as well as future needs. Potential biases in the investigation and evaluation of the health/clinical implications associated with gadolinium deposition are pointed out. The analysis emphasizes that the vast majority of the clinical studies conducted up to date on gadolinium-based contrast agents were designed to assess acute toxicity and diagnostic efficacy of the agents, not to identify long-term health effects.
The choice of studying model systems of porphyrins is highly practical, because of the associated properties of this functional class of molecules. Porphyrin and metalloporphyrin systems are excellent materials for molecular electronics, due to their diverse structural motifs and associated electrical, optical and chemical properties, and thermal stability [1,2,3,4,5,6]. At a basic level, electronic properties are controlled by the degree of π delocalization[7]. Porphyrins can be organized into supramolecular arrays, aggregates and crystals with diverse functions. The rigid planar structures and π- conjugated backbone of porphyrins convey robust electrical characteristics. The porphyrin macrocycle consists of four pyrrole rings joined by four methine carbons. The architecture of porphyrins has been proposed as viable for electronic components for molecular-based information-storage devices [8,9,10,11], gas sensors[12,13], photovoltaic cells[14,15], organic light-emitting diodes [16,17,18,19], and molecular wires [20,21,22].
Synthesis of cobaltacarborane porphyrin conjugates was first reported by Vicenteet al[23,24,25]. The cobaltacarborane ligand consists of an alkoxy chain terminated with two carborane cages with a single cobalt atom situated between the carboranes [23,24,25,26,27]. The abundance of boron in the cobaltacarborane ligands was studied for potential applications in boron neutron capture therapy [23,24]. The cobaltabisdicarbollide anion in the cobaltacarborane ligand were studied for attributes ofchemical, thermal, and photostability [5,24]. In this report, the conductive properties of selected cobaltacarboranes were investigated for potential applications in molecular electronics.
Research in the molecular electronics field has been advanced by the invention of the scanning tunneling and atomic force microscopes. Scanning probe microscopes have advantages for investigating nanoscale phenomena, with capabilities to acquire images with nanometer resolution as well as to make spectroscopy measurements of single molecules or clusters [28]. Scanning probe techniques (e.g. scanning tunneling microscopy, conductive probe AFM, scanning ionic capacitance microscopy, scanning electrochemical microscopy, Kelvin Probe AFM, electrostatic force AFM) can be used to obtain electronic information of molecular systems [28,29,30,31,32,33]. Scanning probe measurements have been used to examine electronic properties such as conductance, dielectric constants and capacitance while providing surface views and topographic information of the samples [29,30,31,32,33,34,35,36]. For conductive probe atomic force microscopy (CP-AFM), a conductive tip is scanned across the sample, while a bias is applied to the substrate. Most commonly, the current is measured by a sensitive preamp, located near the probe. With CP-AFM, two types of data acquisition are possible: a conductive map of the sample surface and a current voltage profile of selected local areas of the surface. The feedback mechanism of CP-AFM is based on applying a chosen force set-point; therefore, theconductive AFM probe remains in direct contact with the sample during spectroscopy measurements.
For these investigations, selected cobaltacarborane porphyrins were investigated using contact mode and CP-AFM to evaluate the role of molecular structure for surface assembly, self-aggregation and conductive properties. Specifically, changes with surface measurements were evaluated and compared according to the numbers and arrangement of substituents.
Gold substrates, Au(111)/mica, were purchased from Agilent Technologies, Inc. (Chandler, AZ). Cobaltacarborane porphyrins were synthesized as previously reported [24]. The gold substrates were rinsed with deionized water, then a 15 µl drop of porphyrin solution (10−6 M) was deposited on the gold substrate and dried in ambient conditions overnight.
Conductive probe atomic force microscopy (CP-AFM) experiments were accomplished in air with a model 5500 AFM/SPM from Agilent equipped with Picoscan v5.3 software. Triangular cantilevers with a tip radius of less than 35 nm, tip height of 20-25 µm and a force constant of 6.0 N m-1 were used for contact modeimaging and CP-AFM, the tips were acquired from MikroMasch (San Jose, CA). A copper wire was placed in physical contact with the gold substrate, so that a bias could be applied to the sample (± 10.0 V). Digital images were processed using Gwyddion software [37].
Tetraphenyl porphyrin macrocycles were functionalized with 2, 4, or 8 cobaltacarborane substituents arranged as shown in Figure 1. The cobaltacarborane porphyrins were synthesized via a ring-opening zwitterionic reaction in high yields (90-97%), as previously reported [23,38]. Each of the substituents contains a cobalt atom which is coordinated between two carborane cages. The numbers and arrangement of the cobaltacarboranes should systematically influence the measured I-V characteristics, thus providing a model surface material for CP-AFM.
Figure 1. Cobaltacarborane porphyrins selected for AFM studies.
The symmetry of the molecules and arrangement of cobaltacarborane moieties was found to influence the surface assembly and molecular aggregation of samples prepared on Au(111). Representative images (topography and corresponding lateral force frames) of the three cobaltacarborane porphyrin (Co-Por) samples of Figure 1 are presented in Figure 2. Typically, porphyrin macrocycles orient on the surface in a coplanar configuration, and stack together to form columnar assemblies. However, the nature and size of substituents influences the surface arrangement and self-aggregation of the nanocrystals. With two cobaltacarborane ligand for Co-Por 1, the surface assemblies exhibit polydisperse sizes arranged randomly across the surface of gold (Figures 2A-2B). The nanocrystals tend to attach near the edges of the gold steps, however there is sufficient surface density for stacks to locate at terrace sites.The thickness and lateral dimensions of the nanostructures were disperse, however the geometry retained a nearly spherical shape. With four cobaltacarborane ligands oriented symmetrically as shown for Co-Por 2, the surface structures changed to exhibit a rod-like or needle shape (Figures 2C-2D). There does not seem to be any preferential attachment to the edges of gold steps, the nanocrystals of Co-Por 2 are regularly shaped and randomly distributed throughout areas of the surface. With eight cobaltacarborane ligands, Co-Por 3 forms exquisitely regular spherical stacks that locate at the step edges of the gold surface (Figures 2E-2F). The vertical and lateral dimensions of the nanocrystals are relatively monodisperse, and tended to form linear assemblies that decorate step edges.
Figure 2. Cobaltacarborane porphyrin samples prepared on gold, imaged with contact mode AFM. The top row shows the topography frames, and the simultaneously acquired lateral force images are shown below. (A) Co-Por 1, topography;(B) Co-Por 2, lateral force frame; (C) Co-Por 2, topography frame; (D) Co-Por 2, lateral force frame; (E) Co-Por 3, topography frame; (F) Co-Por 3, lateral force image.
The systematic changes in surface shapes and dispersity highlight the role of molecular structure for surface assembly of the cobaltacarborane porphyrins. Previous studies with porphyrins have shown that pi-pi intermolecular interactions are a dominant force for directing macrocycles to assemble into stack structures, with the plane of the macrocycle aligning with the substrate. Differences in the number and placement of cobaltacarborane ligands led to changes in the shapes of surface assemblies, as well as in the arrangement to form linear chains or dispersed islands. The asymmetric arrangement of two cobaltacarborane ligands for Co-Por 1 produced a wider range of sizes and dispersity. The symmetric para arrangement of four ligands for Co-Por 2 produced elliptical rod shapes of symmetric crystals. A highly uniform spherical shape and size was observed for Co-Por 3, with eight ligands arranged symmetrically around the macrocycle. The selected cobaltacarborane molecules nicely demonstrate that molecular symmetry directs the 3-D assembly of macromolecules to form nanocrystal shapes.
Azoom-in view of the cobaltacarborane porphyrin nanocrystals is shown side-by-side in Figure 3. The shapes and surface arrangement of each molecular structure arecompared with topography frames in the top row, and the edges of the crystals are more clearly resolved in the corresponding lateral force images in the middle row. The heights of a few nanocrystals are shown with example cursor line profiles in the bottom panels. For the nonsymmetric structure of Co-Por 1 (Figures 3A and 3B) the nanocrystals have a mostly spherical shape, exhibiting a range of sizes. Many of the crystals are located at step edges, however a few are located within terrace sites. The step edges can be resolved in the lateral force frame, Figure 3B. A cursor profile indicated the heights of three nanocrystals of Co-Por 1 were 11, 23 and 18 nm, from left to right. In contrast, the rod-like shape of the para substituents of Co-Por 2 are viewed in Figures 3D and 3E. The segregated islands of Co-Por 2 do not appear to attach preferentially at sites of step edges and are randomly distributed across the surface. The heights of three nanocrystals outlined in Figure 3D were 11, 13, and 12 nm (Figure 3F).
Figure 3. Magnified view of cobaltacarborane porphyrin nanocrystals on gold, imaged with contact mode AFM. (A) Topography; (B) lateral force and (C) example cursor profile for Co-Por 1. (D) Topography; (E) lateral force and (F) corresponding cursor profile for Co-Por 2.(G) Topography; (H) lateral force and (I) cursor profile for Co-Por 3.
A close-up view (3 × 3 µm2) of densely packed nanostructures of Co-Por 3 is shown in Figures 3G-3H. At this magnification the linear arrangement of chains of near-spherical nanocrystals can be resolved, and some of the crystals have begun to pile together into taller aggregations. A cursor profile across nine nanocrystals (Figure 3I) indicates heights ranging from 2 to 8 nm.
The distribution of heights for the cobaltacarborane porphyrins is presentedwith size histograms in Figure 4. The widest range of sizes is observed for Co-Por 1, ranging up to 40 nm in height with an average measuring 15 ± 7.2 nm. A smaller range of sizes (up to 25 nm in height) was observed for tetra-substituted Co-Por 2, with an average height measuring 14 ± 3 nm. The narrowest size range and smallest nanostructures wereobserved for the octa-substituted Co-Por 3, with an average height measuring 4 ± 1 nm. Porphyrin nanocrystals consist of multiple molecular layers assembled in a stacked arrangement. The cobaltacarborane ligands appear to interfere with the molecular self-assembly. The structure with the fewest ligands (Co-Por 1) formed taller stacks, whereas increasing the numbers of substituents produced smaller structures. With a fully substituted arrangement with eight cobaltacarborane ligands, smaller crystals formed, likelydue to steric effects. Very slight changes in the concentration of the sample or the volume of deposited liquid can lead to polydispersity at the nanoscale. In the examples shown, the arrangement of cobaltacarborane substituents around the macrocycle also has an influence on the polydispersity and general size of the nanodots.
Figure 4. Height distributionmeasured with cursor profiles for cobaltacarborane porphyrins(n = 100): (A) Co-Por 1; (B) Co-Por 2; and (C) Co-Por 3.
Representative current-voltage profiles of the cobaltacarborane porphyrins are compared in Figure 5. To ensure that the sample is not oxidized, a single measurement was made for each nanostructure, and the images shown are representative of multiple measurements within the sample area. The electrical transport properties of the three samples are distinct as regards the magnitude of the measured current and onset of conduction. A staircase profile was reproduciblydetected for Co-Por 1, indicative of Coulombic charging (Figure 5A). Discrete increments of 2 nA currentwere measured at approximately 1 V intervals for the molecule designed with two cobaltacarborane substituents. Coulombic behavior was not detected for the other samples. An I-V curve that is typical of a semiconductive sample was revealed for Co-Por 2, with an asymmetric profile (Figure 5B). The onset of current was detected at −8 V and + 5 V, within a measuring range below 0.1 nA. The I-V profile for Co-Por 3 was also asymmetric, (Figure 5C) however the magnitude of current ranged ±2 nA. The current onset was detected at ~ 0.05 V for this sample.
Figure 5. Height distribution measured with cursor profiles for cobaltacarborane porphyrins (n = 100): (A) Co-Por 1; (B) Co-Por 2; and (C) Co-Por 3.
The size of the nanostructures did not show apparent differences in I-V profiles. Regarding the Coulombic profiles of Co-Por 1, there have been previous reports of current profiles with Coulombic staircase characteristics obtained at room temperature.[39,40] Wakayama et al. reported that organic molecules could be used as Coulomb islands of single-electron tunneling devices; a porphyrin derivative (tetrakis-3,5 di-t-butylphenyl-porphyrin (H2-TBPP)) was found to be suitable as a Coulomb island. The H2-TBPP was layered between SiO2 on Si(100) and was investigated with STM at 5K under ultra-high vacuum.[41]
The selected cobaltacarborane porphyrins provide an interesting comparison of how the length of the pathways influence the transport of electrons through the molecules. The asymmetric arrangement of substituents for CoPor1 resulted in a molecular pathway that produced a staircase shaped I-V profile. Both the molecular configuration and size of nanostructures of Co-Por 2 and CoPor 3 influenced the magnitude and symmetry of I-V profiles (Figure 5). Comparing 2 and 3 we observe that the larger (Co-Por 2) nanostructures sustained a wider range of current, whereas the smaller nanoislands of Co-Por 3 ranged within ±1 V.
In the future, the conductive properties of selected molecular architectures will be accurately computed using theoretical approaches. However, currently there is a need for accurate and reproducible experimental measurements of conductive properties of molecular architectures for reliable comparison to theoretical models of charge transport in molecular systems. Systematic changes in surface shapes and dispersity shown with AFM images of porphyrin nanostructures illustrated the critical role of molecular structure for the self-assembly of cobaltacarborane porphyrins on surfaces. The conductive properties of cobaltacarborane porphyrins changed according to the numbers and arrangement of substituents. It is critical to know the organization and arrangement of molecules on surfaces when modeling charge transport. We anticipate that well-defined arrangements of molecules and aggregates on surfaces will lead to accurate and reproducible local measurements of charge transport for different pathways through the molecules and provide insight on structure/property relationships.
The authors gratefully acknowledge support from the National Science Foundation (DMR-0906873), the National Institutes of Health (R01 CA179902), the American Chemical Society Petroleum Research Fund (New Directions Program) and the Camille Dreyfus Teacher-Scholar Program. The authors also thank L. E. Englade-Franklin for careful editing and manuscript review.
The authors declare no competing financial interest.
| [1] |
Tamburrini O, Aprile I, Falcone C, et al. (2011) Off-label use of intravascular iodinated organic and MR contrast media. Radiol Med 116: 1-14. doi: 10.1007/s11547-010-0601-5
|
| [2] |
Meloni MM, Barton S, Xu L, et al. (2017) Contrast agents for cardiovascular magnetic resonance imaging: an overview. J Mater Chem B 5: 5714-5725. doi: 10.1039/C7TB01241A
|
| [3] |
Lauffer RB (1987) Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chem Rev 87: 901-927. doi: 10.1021/cr00081a003
|
| [4] |
Schörner W, Kazner E, Laniado M, et al. (1984) Magnetic resonance tomography (MRT) of intracranial tumours: Initial experience with the use of the contrast medium gadolinium-DTPA. Neurosurg Rev 7: 303-312. doi: 10.1007/BF01892910
|
| [5] |
Essig M, Anzalone N, Combs SE, et al. (2012) MR imaging of neoplastic central nervous system lesions: review and recommendations for current practice. Am J Neuroradiol 33: 803-817. doi: 10.3174/ajnr.A2640
|
| [6] |
Anzalone N, Gerevini S, Scotti R, et al. (2009) Detection of cerebral metastases on magnetic resonance imaging: intraindividual comparison of gadobutrol with gadopentetate dimeglumine. Acta Radiol 50: 933-940. doi: 10.1080/02841850903095385
|
| [7] |
Malayeri AA, Brooks KM, Bryant LH, et al. (2016) National Institutes of health perspective on reports of gadolinium deposition in the brain. J Am Coll Radiol 13: 237-241. doi: 10.1016/j.jacr.2015.11.009
|
| [8] |
Weinmann HJ, Brasch RC, Press WR, et al. (1984) Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. Am J Roentgenol 142: 619-624. doi: 10.2214/ajr.142.3.619
|
| [9] |
Lin SP, Brown JJ (2007) MR contrast agents: Physical and pharmacologic basics. J Magn Reson Imaging 25: 884-899. doi: 10.1002/jmri.20955
|
| [10] |
Ersoy H, Rybicki FJ (2007) Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging 26: 1190-1197. doi: 10.1002/jmri.21135
|
| [11] |
Bellin MF, Van Der Molen AJ (2008) Extracellular gadolinium-based contrast media: an overview. Eur J Radiol 66: 160-167. doi: 10.1016/j.ejrad.2008.01.023
|
| [12] |
Evans CH (1990) Biochemistry of the Lanthanides New York: Plenum Press. doi: 10.1007/978-1-4684-8748-0
|
| [13] |
De León-Rodríguez LM, Martins AF, Pinho MC, et al. (2015) Basic MR relaxation mechanisms and contrast agent design. J Magn Reson Imaging 42: 545-565. doi: 10.1002/jmri.24787
|
| [14] |
Levine D, McDonald RJ, Kressel HY (2018) Gadolinium retention after contrast-enhanced MRI. JAMA 320: 1853-1854. doi: 10.1001/jama.2018.13362
|
| [15] | Shepherd M, Lata S, Mani S, et al. (2009) Anaphylaxis to gadolinium radiocontrast: a case report and review of the literature. J La State Med Soc 161: 282-284. |
| [16] |
Raisch DW, Garg V, Arabyat R, et al. (2014) Anaphylaxis associated with gadolinium-based contrast agents: Data from the food and drug administration's adverse event reporting system and review of case reports in the literature. Expert Opin Drug Saf 13: 15-23. doi: 10.1517/14740338.2013.832752
|
| [17] |
Franckenberg S, Berger F, Schaerli S, et al. (2018) Fatal anaphylactic reaction to intravenous gadobutrol, a gadolinium-based MRI contrast agent. Radiol Case Rep 13: 299-301. doi: 10.1016/j.radcr.2017.09.012
|
| [18] |
Jung JW, Kangand HR, Kim MH, et al. (2012) Immediate hypersensitivity reaction to gadolinium-based MR contrast media. Radiology 264: 414-422. doi: 10.1148/radiol.12112025
|
| [19] |
Morzycki A, Bhatia A, Murphy KJ (2017) Adverse reactions to contrast material: a Canadian update. Can Assoc Radiol J 68: 187-193. doi: 10.1016/j.carj.2016.05.006
|
| [20] |
Behzadi AH, Farooq Z, Newhouse JH, et al. (2018) MRI and CT contrast media extravasation a systematic review. Medicine 97: e0055. doi: 10.1097/MD.0000000000010055
|
| [21] |
Varela DC, Sepulveda P, Prieto J, et al. (2015) Extravasation of intravenous contrast media: What every radiologist should know. Rev Chil Radiol 21: 151-157. doi: 10.4067/S0717-93082015000400006
|
| [22] |
Blasco-Perrin H, Glaser B, Pienkowski M, et al. (2013) Gadolinium induced recurrent acute pancreatitis. Pancreatology 13: 88-89. doi: 10.1016/j.pan.2012.12.002
|
| [23] |
Unal O, Arslan H (1999) Cardiac arrest caused by IV gadopentetate dimeglumine. Am J Roentgenol 172: 1141. doi: 10.2214/ajr.172.4.10587169
|
| [24] | US Food and Drug AdministrationMedical Imaging Drugs Advisory Committee Meeting, FDA briefing document: Gadolinium retention after gadolinium based contrast magnetic resonance imaging in patients with normal renal function. (2017) . |
| [25] |
Maramattom BV, Manno EM, Wijdicks EFM, et al. (2005) Gadolinium encephalopathy in a patient with renal failure. Neurology 64: 1276-1278. doi: 10.1212/01.WNL.0000156805.45547.6E
|
| [26] |
Hui FK, Mullins M (2009) Persistence of gadolinium contrast enhancement in CSF: A possible harbinger of gadolinium neurotoxicity? Am J Neuroradiol 30: e1. doi: 10.3174/ajnr.A1205
|
| [27] |
Kim SH, Jo EJ, Kim MY, et al. (2013) Clinical value of radiocontrast media skin tests as a prescreening and diagnostic tool in hypersensitivity reactions. Ann Allergy Asthma Immunol 110: 258-262. doi: 10.1016/j.anai.2013.01.004
|
| [28] |
Shellock FG, Kanal E (1999) Safety of magnetic resonance imaging contrast agents. J Magn Res Im 10: 477-484. doi: 10.1002/(SICI)1522-2586(199909)10:3<477::AID-JMRI33>3.0.CO;2-E
|
| [29] |
Grobner T (2006) Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transpl 21: 1104-1108. doi: 10.1093/ndt/gfk062
|
| [30] |
Thomson LK, Thomson PC, Kingsmore DB, et al. (2015) Diagnosing nephrogenic systemic fibrosis in the post-FDA restriction era. J Magn Reson Imaging 41: 1268-1271. doi: 10.1002/jmri.24664
|
| [31] |
Larson KN, Gagnon AL, Darling MD, et al. (2015) Nephrogenic systemic fibrosis manifesting a decade after exposure to gadolinium. JAMA Dermatol 151: 1117-1120. doi: 10.1001/jamadermatol.2015.0976
|
| [32] |
Bernstein EJ, Schmidt-Lauber C, Kay J (2012) Nephrogenic systemic fibrosis: a systemic fibrosing disease resulting from gadolinium exposure. Best Pract Res Cl Rheumatol 26: 489-503. doi: 10.1016/j.berh.2012.07.008
|
| [33] |
Sanyal S, Marckmann P, Scherer S, et al. (2011) Multiorgan gadolinium (Gd) deposition and fibrosis ina patient with nephrogenic systemic fibrosis-an autopsy-based review. Nephrol Dial Transplant 26: 3616-3626. doi: 10.1093/ndt/gfr085
|
| [34] |
Kay J, Bazari H, Avery LL, et al. (2008) Case 6-2008: a 46-year-old woman with renal failure and stiffness of the joints and skin. New Engl J Med 358: 827-838. doi: 10.1056/NEJMcpc0708697
|
| [35] |
Bhave G, Lewis JB, Chang SS (2008) Association of gadolinium based magnetic resonance imaging contrast agents and nephrogenic systemic fibrosis. J Urol 180: 830-835. doi: 10.1016/j.juro.2008.05.005
|
| [36] |
Cowper SE, Su LD, Bhawan J, et al. (2001) Nephrogenic fibrosing dermopathy. Am J Dermatopath 23: 383-393. doi: 10.1097/00000372-200110000-00001
|
| [37] |
Cowper SE, Robin HS, Steinberg SM, et al. (2000) Scleromyxedema-like cutaneous disease in renal dialysis patients. Lancet 356: 1000-1001. doi: 10.1016/S0140-6736(00)02694-5
|
| [38] |
Weigle JP, Broome DR (2008) Nephrogenic systemic fibrosis: chronic imaging findings and review of the medical literature. Skeletal Radiol 37: 457-464. doi: 10.1007/s00256-008-0464-1
|
| [39] |
Zou Z, Zhang HL, Roditi GH, et al. (2011) Nephrogenic systemic fibrosis: review of 370 biopsy-confirmed cases. JACC: Cardiovasc Imag 4: 1206-1216. doi: 10.1016/j.jcmg.2011.08.013
|
| [40] |
Morris MF, Zhang Y, Zhang H, et al. (2009) Features of nephrogenic systemic fibrosis on radiology examinations. Am J Roentgenol 193: 61-69. doi: 10.2214/AJR.08.1352
|
| [41] |
Tsushima Y, Kanal E, Thomsen HS (2010) Nephrogenic systemic fibrosis: risk factors suggested from Japanese published cases. Brit J Radiol 83: 590-595. doi: 10.1259/bjr/17689538
|
| [42] |
Thomsen HS, Morcos SK, Almén T, et al. (2013) Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR contrast medium safety committee guidelines. Eur Radiol 23: 307-318. doi: 10.1007/s00330-012-2597-9
|
| [43] |
Mazhar SM, Shiehmorteza M, Kohl CA, et al. (2009) Nephrogenic systemic fibrosis in liver disease: a systematic review. J Magn Reson Imaging 30: 1313-1322. doi: 10.1002/jmri.21983
|
| [44] | Elmholdt TR, Jørgensen B, Ramsing M, et al. (2010) Two cases of nephrogenic systemic fibrosis after exposure to the macrocyclic compound gadobutrol. NDT Plus 3: 285-287. |
| [45] |
Kay J (2008) Gadolinium and nephrogenic systemic fibrosis: The evidence of things not seen. Clev Clin J Med 75: 112. doi: 10.3949/ccjm.75.2.112
|
| [46] |
Todd DJ, Kay J (2008) Nephrogenic systemic fibrosis: an epidemic of gadolinium toxicity. Curr Rheumatol Rep 10: 195-204. doi: 10.1007/s11926-008-0033-6
|
| [47] |
Sieber MA, Lengsfeld P, Frenzel T, et al. (2008) Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol 18: 2164-2173. doi: 10.1007/s00330-008-0977-y
|
| [48] |
Semelka RC, Prybylskib JP, Ramalho M (2019) Influence of excess ligand on nephrogenic systemic fibrosis associated with nonionic, linear gadolinium-based contrast agents. Magn Res Imaging 58: 174-178. doi: 10.1016/j.mri.2018.11.015
|
| [49] | US Food and Drug Administration FDA request boxes warning for contrast agents used to improve MRI images (2007) .Available from: http://wayback.archive-it.org/7993/20170112033008/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108919.htm. |
| [50] |
Khawaja AZ, Cassidy DB, Al Shakarchi J, et al. (2015) Revisiting the risks of MRI with Gadolinium based contrast agents: review of literature and guidelines. Insights Imaging 6: 553-558. doi: 10.1007/s13244-015-0420-2
|
| [51] | Canga A, Kislikova M, Martínez-Gálvez M, et al. (2014) Renal function, nephrogenic systemic fibrosis and other adverse reactions associated with gadolinium-based contrast media. Nefrologia 34: 428-438. |
| [52] |
Martin DR, Krishnamoorthy SK, Kalb B, et al. (2010) Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols. J Magn Reson Imaging 31: 440-446. doi: 10.1002/jmri.22024
|
| [53] |
Altun E, Martin DR, Wertman R, et al. (2009) Nephrogenic systemic fibrosis: Change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy—report from two US universities. Radiology 253: 689-696. doi: 10.1148/radiol.2533090649
|
| [54] |
Xia D, Davis RL, Crawford JA, et al. (2010) 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 51: 1126-1136. doi: 10.3109/02841851.2010.515614
|
| [55] |
Kanda T, Ishii K, Kawaguchi H, et al. (2014) 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 270: 834-841. doi: 10.1148/radiol.13131669
|
| [56] |
McDonald RJ, McDonald JS, Kallmes DF, et al. (2015) Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 275: 772-782. doi: 10.1148/radiol.15150025
|
| [57] |
Olchowy C, Cebulski K, Łasecki M, et al. (2017) The presence of the gadolinium-based contrast agent depositions in the brain and symptoms of gadolinium neurotoxicity-a systematic review. PLoS One 12: e0171704. doi: 10.1371/journal.pone.0171704
|
| [58] |
Pullicino R, Radon M, Biswas S, et al. (2018) A review of the current evidence on gadolinium deposition in the brain. Clin Neuroradiol 28: 159-169. doi: 10.1007/s00062-018-0678-0
|
| [59] |
Gianolio E, Gregorio ED, Aime S (2019) Chemical insights into the issues of Gd retention in the brain andother tissues upon the administration of Gd-containing MRI contrast agents. Eur J Inorg Chem 2019: 137-151. doi: 10.1002/ejic.201801220
|
| [60] |
Kanda T, Osawa M, Oba H, et al. (2015) High signal intensity in dentate nucleus on unenhanced T1-weightedMR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 275: 803-809. doi: 10.1148/radiol.14140364
|
| [61] |
Weberling LD, Kieslich PJ, Kickingereder P, et al. (2015) Increased signal intensity in the dentate nucleus on unenhanced T1-weighted images after gadobenate dimeglumine administration. Invest Radiol 50: 743-748. doi: 10.1097/RLI.0000000000000206
|
| [62] |
Errante Y, Cirimele V, Mallio CA, et al. (2014) 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 49: 685-690. doi: 10.1097/RLI.0000000000000072
|
| [63] |
Zhang Y, Cao Y, Shih GL, et al. (2017) Extent of signal hyperintensity on unenhanced T1-weighted brain MR images after more than 35 administrations of linear gadolinium-based contrast agents. Radiology 282: 516-525. doi: 10.1148/radiol.2016152864
|
| [64] |
Radbruch A, Weberling LD, Kieslich PJ, et al. (2015) Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 275: 783-791. doi: 10.1148/radiol.2015150337
|
| [65] |
Malhotra A, LeSar B, Wu X, et al. (2018) Progressive T1 shortening of the dentate nucleus in patients with multiple sclerosis: Result of multiple administrations of linear gadolinium contrast agents versus intrinsic disease. Am J Roentgenol 211: 1099-1105. doi: 10.2214/AJR.17.19155
|
| [66] |
Flood TF, Stence NV, Maloney JA, et al. (2017) Pediatric brain: Repeated exposure to linear gadolinium-based contrast material is associated with increased signal intensity at unenhanced T1-weighted MR imaging. Radiology 282: 222-228. doi: 10.1148/radiol.2016160356
|
| [67] |
Adin ME, Kleinberg L, Vaidya D, et al. (2015) Hyperintense dentate nuclei on T1-weighted MRI: relation to repeat gadolinium administration. Am J Neuroradiol 36: 1859-1865. doi: 10.3174/ajnr.A4378
|
| [68] |
Miller JH, Hu HH, Pokorney A, et al. (2015) MRI brain signal intensity changes of a child during the course of 35 gadolinium contrast examinations. Pediatrics 136: e1637-e1640. doi: 10.1542/peds.2015-2222
|
| [69] |
Hu HH, Pokorney A, Towbin RB, et al. (2016) Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatr Radiol 46: 1590-1598. doi: 10.1007/s00247-016-3646-3
|
| [70] |
Bae S, Lee H, Han K, et al. (2017) Gadolinium deposition in the brain: association with various GBCAs using a generalized additive model. Eur Radiol 27: 3353-3361. doi: 10.1007/s00330-016-4724-5
|
| [71] |
Quattrocchi CC, Mallio CA, Errante Y, et al. (2015) 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 50: 470-472. doi: 10.1097/RLI.0000000000000154
|
| [72] |
McDonald JS, McDonald RJ, Jentoft ME, et al. (2017) Intracranial gadolinium deposition following gadodiamide-enhanced magnetic resonance imaging in pediatric patients: a case-control study. JAMA Pediatr 171: 705-707. doi: 10.1001/jamapediatrics.2017.0264
|
| [73] |
Mallio CA, Vullo GL, Messina L, et al. (2020) Increased T1 signal intensity of the anterior pituitary gland on unenhanced magnetic resonance images after chronic exposure to gadodiamide. Invest Radiol 55: 25-29. doi: 10.1097/RLI.0000000000000604
|
| [74] |
Gianolio E, Bardini P, Arena F, et al. (2017) Gadolinium retention in the rat brain: Assessment of the amounts of insoluble gadolinium-containing species and intact gadolinium complexes after repeated administration of gadolinium-based contrast agents. Radiology 285: 839-849. doi: 10.1148/radiol.2017162857
|
| [75] |
Rasschaert M, Schroeder JA, Wu TD, et al. (2018) Multimodal imaging study of gadolinium presence in rat cerebellum: differences between Gd chelates, presence in the Virchow-Robin space, association with lipofuscin, and hypotheses about distribution pathway. Invest Radiol 53: 518. doi: 10.1097/RLI.0000000000000490
|
| [76] |
Radbruch A, Richter H, Fingerhu S, et al. (2019) Gadolinium deposition in the brain in a large animal model. Comparison of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol 54: 531-536. doi: 10.1097/RLI.0000000000000575
|
| [77] |
Boyken J, Frenzel T, Lohrke J, et al. (2018) Gadolinium accumulation in the deep cerebellar nuclei and globus pallidus after exposure to linear but not macrocyclic gadolinium-based contrast agents in a retrospective pig study with high similarity to clinical conditions. Invest Radiol 53: 278-285. doi: 10.1097/RLI.0000000000000440
|
| [78] |
Robert P, Violas X, Grand S, et al. (2016) Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Invest Radiol 51: 73-82. doi: 10.1097/RLI.0000000000000241
|
| [79] |
Strzeminska I, Factor C, Robert P, et al. (2020) Long-term evaluation of gadolinium retention in rat brain after single injection of a clinically relevant dose of gadolinium-based contrast agents. Invest Radiol 55: 138-143. doi: 10.1097/RLI.0000000000000623
|
| [80] |
Radbruch A, Haase R, Kieslich PJ, et al. (2017) 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 282: 699-707. doi: 10.1148/radiol.2016162241
|
| [81] |
Radbruch A, Haase R, Kickingereder P, et al. (2017) Pediatric brain: no increased signal intensity in the dentate nucleus on unenhanced T1-weighted MR images after consecutive exposure to a macrocyclic gadolinium-based contrast agent. Radiology 283: 828-836. doi: 10.1148/radiol.2017162980
|
| [82] |
Tibussek D, Rademacher C, Caspers J, et al. (2007) Gadolinium brain deposition after macrocyclic gadolinium administration: a pediatric case-control study. Radiology 285: 223-230. doi: 10.1148/radiol.2017161151
|
| [83] |
Schneider GK, Stroeder J, Roditi G, et al. (2017) T1 signal measurements in pediatric brain: findings after multiple exposures to gadobenate dimeglumine for imaging of non neurologic disease. Am J Neuroradiol 38: 1799-1806. doi: 10.3174/ajnr.A5270
|
| [84] |
Conte G, Preda L, Cocorocchio E, et al. (2017) Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study. Eur Radiol 27: 4372-4378. doi: 10.1007/s00330-017-4810-3
|
| [85] |
Ryu YJ, Choi YH, Cheon J, et al. (2018) Pediatric brain: Gadolinium deposition in dentate nucleus and globus pallidus on unenhanced T1-weighted images is dependent on the type of contrast agent. Invest Radiol 53: 246-255. doi: 10.1097/RLI.0000000000000436
|
| [86] |
Stanescu AL, Shaw DW, Murata N, et al. (2020) Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation. Pediatr Radiol 50: 388-396. doi: 10.1007/s00247-019-04535-w
|
| [87] |
Bjørnerud A, Vatnehol SAS, Larsson C, et al. (2017) Signal enhancement of the dentate nucleus at unenhanced MR imaging after very high cumulative doses of the macrocyclic gadolinium-based contrast agent gadobutrol: an observational study. Radiology 285: 434-444. doi: 10.1148/radiol.2017170391
|
| [88] |
Splendiani A, Perri M, Marsecano C, et al. (2018) Effects of serial macrocyclic based contrast materials gadoterate meglumine and gadobutrol administrations on gadolinium related dentate nuclei signal increases in unenhanced t1-weighted brain: a retrospective study in 158 multiple sclerosis (MS) patients. Radiol Med 123: 125-134. doi: 10.1007/s11547-017-0816-9
|
| [89] |
Stojanov DA, Aracki-Trenkic A, Vojinovic S, et al. (2016) 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 26: 807-815. doi: 10.1007/s00330-015-3879-9
|
| [90] |
Tedeschi E, Palma G, Canna A, et al. (2016) In vivo dentate nucleus MRI relaxometry correlates with previous administration of gadolinium-based contrast agents. Eur Radiol 26: 4577-4584. doi: 10.1007/s00330-016-4245-2
|
| [91] |
Lattanzio SM, Imbesi F (2020) Fibromyalgia associated with repeated gadolinium contrast-enhanced MRI examinations. Radiol Case Rep 15: 534-541. doi: 10.1016/j.radcr.2020.02.002
|
| [92] |
Roberts DR, Welsh CA, LeBel DP, et al. (2017) Distribution map of gadolinium deposition within the cerebellum following GBCA administration. Neurology 88: 1206-1208. doi: 10.1212/WNL.0000000000003735
|
| [93] |
Gibby WA, Gibby KA, Gibby WA (2004) Comparison of Gd-DTPA-BMA (Omniscan) versus Gd-HPDO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Invest Radiol 39: 138-142. doi: 10.1097/01.rli.0000112789.57341.01
|
| [94] |
White GW, Gibby WA, Tweedle MF (2006) Comparison of Gd(DTPA-BMA)(Omniscan) versus Gd(HPDO3A)(ProHance) relative to gadolinium retention in human bone tissue by inductively coupled mass spectroscopy. Invest Radiol 41: 272-278. doi: 10.1097/01.rli.0000186569.32408.95
|
| [95] |
Darrah TH, Prutsman-Pfeiffer JJ, Poreda RJ, et al. (2009) Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics 1: 479-488. doi: 10.1039/b905145g
|
| [96] |
Murata N, Gonzalez-Cuyar LF, Murata K, et al. (2016) 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 51: 447-53. doi: 10.1097/RLI.0000000000000252
|
| [97] |
Lord ML, Chettle DR, Gräfe JL, et al. (2018) Observed deposition of gadolinium in bone using a new noninvasive in vivo biomedical device: Results of a small pilot feasibility study. Radiology 287: 96-103. doi: 10.1148/radiol.2017171161
|
| [98] |
Turyanskaya A, Rauwol M, Pichler V, et al. (2020) Detection and imaging of gadolinium accumulation inhuman bone tissue by micro- and submicro-XRF. Sci Rep 10: 6301. doi: 10.1038/s41598-020-63325-9
|
| [99] |
Vidaud C, Bourgeois D, Meyer D (2012) Bone as target organ for metals: the case of f-elements. Chem Res Toxicol 25: 1161-1175. doi: 10.1021/tx300064m
|
| [100] |
Gräfe JL, McNeill FE (2018) Measurement of gadolinium retention: current status and review from an applied radiation physics perspective. Physiol Meas 39: 06TR01. doi: 10.1088/1361-6579/aacc16
|
| [101] |
Hasegawa M, Duncan BR, Marshall DA, et al. (2020) 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. Invest Radiol 55: 636-642. doi: 10.1097/RLI.0000000000000681
|
| [102] |
Saussereau E, Lacroix C, Cattaneo A, et al. (2008) Hair and fingernail gadolinium ICP-MS contents in an overdose case associated with nephrogenic systemic fibrosis. Forensic Sci Int 176: 54-57. doi: 10.1016/j.forsciint.2007.06.026
|
| [103] | US Food and Drug Administration, 5-18, 2015 Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-evaluating-risk-brain-deposits-repeated-use-gadolinium-based. |
| [104] | EMA/625317/2017. EMA's final opinion confirms restrictions on use of linear gadolinium agents in body scans Available at: http://www.ema.europa.eu/docs/en _ GB/document _ library/ Referrals _ document/gadolinium _ contrast _ agents _ 31/ European _ Commission _ final _ decision/WC500240575.pdf. |
| [105] |
Lancelot E, Desché P (2020) Gadolinium retention as a safety signal: experience of a manufacturer. Invest Radiol 55: 20-24. doi: 10.1097/RLI.0000000000000605
|
| [106] | PMDA, Revision of Precautions, Gadodiamide hydrate Meglumine gadopentetate, 2017 Available from: http://www.pmda.go.jp/files/000221377.pdf. |
| [107] | PMDA, Revision of Precautions, Gadoxetate sodium, Gadoteridol, Meglumine gadoterate, Gadobutrol, 2017 Available from: http://www.pmda.go.jp/files/000221376.pdf. |
| [108] |
Kanda T, Nakai Y, Hagiwara A, et al. (2017) Distribution and chemical forms of gadolinium in the brain: a review. Br J Radiol 90: 20170115. doi: 10.1259/bjr.20170115
|
| [109] | Bracco Diagnostics Bayer, Guerbet GE Healthcare Important drug warning for all gadolinium-based contrast agents [dear health care provider letter] (2018) .Available from: https://www.guerbet.com/media/uh4h4kon/dhcp-letter-05-02-2018-signed.pdf. |
| [110] |
Harvey HB, Gowda V, Cheng G (2019) Gadolinium deposition disease: a new risk management threat. J Am Coll Radiol 17: 546-550. doi: 10.1016/j.jacr.2019.11.009
|
| [111] |
Semelka RC, Commander CW, Jay M, et al. (2016) Presumed gadolinium toxicity in subjects with normal renal function a report of 4 cases. Invest Radiol 51: 661-665. doi: 10.1097/RLI.0000000000000318
|
| [112] |
Semelka RC, Ramalho M, Jay M (2016) Summary of special issue on gadolinium bioeffects and toxicity with a look to the future. Magn Reson Imaging 34: 1399-1401. doi: 10.1016/j.mri.2016.09.002
|
| [113] | US Food and Drug AdministrationMedical Imaging Drugs Advisory Committee Meeting, FDA briefing document: Gadolinium retention after gadolinium-based contrast magnetic resonance imaging in patients with normal renal function, 27–28. (2017) . |
| [114] |
Burke LMB, Ramalho M, AlObaidy M, et al. (2016) Self-reported gadolinium toxicity: A survey of patients with chronic symptoms. Magn Reson Imaging 34: 1078-1080. doi: 10.1016/j.mri.2016.05.005
|
| [115] |
Semelka RC, Ramalho J, Vakharia A, et al. (2016) Gadolinium deposition disease: initial description of adisease that has been around for a while: a family of disorders. Magn Res Imaging 34: 1383-1390. doi: 10.1016/j.mri.2016.07.016
|
| [116] |
Roberts DR, Lindhorst SM, Welsh CT, et al. (2016) High levels of gadolinium deposition in the skin of a patient with normal renal function. Invest Radiol 51: 280-289. doi: 10.1097/RLI.0000000000000266
|
| [117] |
Barbieri S, Schroeder C, Froehlich JM, et al. (2016) High signal intensity in dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in three patients with impaired renal function and vascular calcification. Contrast Media Mol Imaging 11: 245-250. doi: 10.1002/cmmi.1683
|
| [118] |
Swaminathan S (2016) Gadolinium toxicity: iron and ferroportin as central targets. Magnet Reson Imaging 34: 1373-1376. doi: 10.1016/j.mri.2016.08.016
|
| [119] |
Di Gregorio ED, Furlan C, Atlante S, et al. (2020) Gadolinium retention in erithrocytes and leukocytes from human and murine blood upon treatment with gadolinium-based contrast agents for magnetic resonance imaging. Invest Radiol 55: 30-37. doi: 10.1097/RLI.0000000000000608
|
| [120] |
Di Gregorio E, Ferrauto G, Furlan C, et al. (2018) The issue of gadolinium retained in tissue. Invest Radiol 53: 167-172. doi: 10.1097/RLI.0000000000000423
|
| [121] |
Kartamihardja AAP, Hanaoka H, Andriana P, et al. (2019) Quantitative analysis of Gd in the protein content of the brain following single injection of gadolinium-based contrast agents (GBCAs) by size exclusion chromatography. Br J Radiol 92: 20190062. doi: 10.1259/bjr.20190062
|
| [122] |
Newton BB, Jimenez SA (2009) Mechanism of NSF: New evidence challenging the prevailing theory. J Magn Reson Imaging 30: 1277-1283. doi: 10.1002/jmri.21980
|
| [123] |
Taoka T, Jost G, Frenzel T, et al. (2018) Impact of the glymphatic system on the kinetic and distribution of gadodiamide in rat brain. Invest Radiol 53: 529-534. doi: 10.1097/RLI.0000000000000473
|
| [124] |
Nehra AK, McDonald RJ, Bluhm AM, et al. (2018) Accumulation of gadolinium in human cerebrospinal fluid after gadobutrol-enhanced MR imaging: a prospective observational cohort study. Radiology 288: 416-423. doi: 10.1148/radiol.2018171105
|
| [125] |
McDonald RJ, Levine D, Weinreb J, et al. (2018) Gadolinium retention: A research roadmap from the 2018 NIH/ACR/RSNA workshop on gadolinium chelates. Radiology 289: 517-534. doi: 10.1148/radiol.2018181151
|
| [126] |
Le Fur M, Caravan P (2019) The biological fate of gadolinium-based MRI contrast agents: a call to action for bioinorganic chemists. Metallomics 11: 240-254. doi: 10.1039/C8MT00302E
|
| [127] |
Tweedle MF (2016) Gadolinium deposition: Is it chelated or dissociated gadolinium? How can we tell? Magn Res Imaging 34: 1377-1382. doi: 10.1016/j.mri.2016.09.003
|
| [128] |
Kiviniemi A, Gardberg M, Ek P, et al. (2019) Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents. Neuroradiology 61: 535-544. doi: 10.1007/s00234-019-02172-6
|
| [129] |
Kanda T, Fukusato T, Matsuda M, et al. (2015) 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 276: 228-232. doi: 10.1148/radiol.2015142690
|
| [130] |
Herculano-Houzel S (2009) The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci 3: 31. doi: 10.3389/neuro.09.031.2009
|
| [131] |
Popescu BFG, Robinson CA, Rajput A, et al. (2009) Iron, copper, and zinc distribution of the cerebellum. Cerebellum 8: 74-79. doi: 10.1007/s12311-008-0091-3
|
| [132] |
Kromrey ML, Liedtke KR, Ittermann T, et al. (2017) Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5years. Eur Radiol 27: 772-777. doi: 10.1007/s00330-016-4418-z
|
| [133] |
Staks T, Schuhmann-Giampieri G, Frenzel T, et al. (1994) Pharmacokinetics, dose proportionality and tolerability of gadobutrol after single intravenous injection in healthy volunteers. Invest Radiol 29: 709-715. doi: 10.1097/00004424-199407000-00008
|
| [134] |
Gutierrez JE, Rosenberg M, Duhaney M, et al. (2015) Phase 3 efficacy and safety trial of gadobutrol, a 1.0 molar macrocyclic MR imaging contrast agent, in patients referred for contrast-enhanced MR imagingof the central nervous system. J Magn Reson Imaging 41: 788-796. doi: 10.1002/jmri.24583
|
| [135] |
Kuwatsuru R, Takahashi S, Umeoka S, et al. (2015) A multicenter, randomized, controlled, single-blind comparison phase III study to determine the efficacy and safety of gadobutrol 1.0 M versus gadopentetate dimeglumine following single injection in patients referred for contrast-enhanced MRI of the body regions or extremities. J Magn Reson Imaging 41: 404-413. doi: 10.1002/jmri.24566
|
| [136] | Liang Z, Ma L, Wang D, et al. (2012) Efficacy and safety of gadobutrol (1.0 M) versus gadopentetate dimeglumine (0.5 M) for enhanced MRI of CNS lesions: A phase III, multicenter, single-blind, randomized study in Chinese patients. Mag Res Insights 5: MRI-S9348. |
| [137] |
Naito S, Tazaki H, Okamoto T, et al. (2017) Comparison of nephrotoxicity between two gadolinium-contrasts, gadodiamide and gadopentetate in patients with mildly diminished renal failure. J Toxicol Sci 42: 379-384. doi: 10.2131/jts.42.379
|
| [138] |
Semelka RC, Hernandes MA, Stallings CG, et al. (2013) Objective evaluation of acute adverse events andimage quality of gadolinium-based contrast agents (gadobutrol and gadobenate dimeglumine) by blinded evaluation. Pilot study. Magn Reson Imaging 31: 96-101. doi: 10.1016/j.mri.2012.06.025
|
| [139] |
Tanaka A, Masumoto T, Yamada H, et al. (2016) A Japanese, multicenter, open-label, phase 3 study to investigate the safety and efficacy of gadobutrol for contrast-enhanced MR imaging of the central nervous system. Magn Reson Med Sci 15: 227-236. doi: 10.2463/mrms.mp.2015-0083
|
| [140] | Zech CJ, Schwenke C, Endrikat J (2019) Diagnostic efficacy and safety of gadoxetate disodium vs gadobenate dimeglumine in patients with known or suspected focal liver lesions: Results of a clinical phase III study. Magn Reson Insight 12: 1178623X19827976. |
| [141] |
Tweedle MF, Wedeking P, Kumar K (1995) Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate, and gadodiamide in mice and rats. Invest Radiol 30: 372-380. doi: 10.1097/00004424-199506000-00008
|
| [142] |
Rocklage SM, Worah D, Kim SH (1991) Metal ion release from paramagnetic chelates: what is tolerable? Magn Reson Med 22: 216-221. doi: 10.1002/mrm.1910220211
|
| [143] |
Khairinisa MA, Takatsuru Y, Amano I, et al. (2018) The effect of perinatal gadolinium-based contrast agents. Invest Radiol 53: 110-118. doi: 10.1097/RLI.0000000000000417
|
| [144] |
Ray JG, Vermeulen MJ, Bharatha A, et al. (2016) Association between MRI exposure during pregnancy and fetal and childhood outcomes. JAMA 316: 952-961. doi: 10.1001/jama.2016.12126
|
| [145] |
Runge VM, Kuehl TJ, Jackson CB, et al. (2005) Subchronic toxicity of the gadolinium chelates. Acad Radiol 12: S6-S9. doi: 10.1016/j.acra.2005.02.015
|
| [146] |
Alkhunizi SM, Fakhoury M, Abou-Kheir W, et al. (2020) Gadolinium retention in the central and peripheral nervous system: implications for pain, cognition, and neurogenesis. Radiology 297: 407-416. doi: 10.1148/radiol.2020192645
|
| [147] |
Wang S, Hesse B, Roman M, et al. (2019) Increased retention of gadolinium in the inflamed brain after repeated administration of gadopentetate dimeglumine. Invest Radiol 54: 617-626. doi: 10.1097/RLI.0000000000000571
|
| [148] |
Reimer P, Vosshenrich R (2008) Off-label use of contrast agents. Eur Radiol 18: 1096-1101. doi: 10.1007/s00330-008-0886-0
|
| [149] |
Essig M, Shiroishi MS, Nguyen TB, et al. (2013) Perfusion MRI: The five most frequently asked technical questions. Am J Roentgenol 200: 24-34. doi: 10.2214/AJR.12.9543
|
| [150] |
Wolansky LJ, Cadavid D, Punia V, et al. (2015) Hypophosphatemia is associated with the serial administration of triple-dose gadolinium to patients for brain MRI. J Neuroimaging 25: 379-383. doi: 10.1111/jon.12241
|
| [151] |
Essig M, Giesel E, Le-Huu M, et al. (2004) Perfusion MRI in CNS disease: current concepts. Neuroradiology 46: S201-S207. doi: 10.1007/s00234-004-1331-y
|
| [152] |
Lee JY, Park JE, Kim HS, et al. (2017) Up to 52 administrations of macrocyclic ionic MR contrast agent are not associated with intracranial gadolinium deposition: multifactorial analysis in 385 patients. PloS One 12: e0183916. doi: 10.1371/journal.pone.0183916
|
| [153] | Ng KH, Ahmad AC, Nizam M, et al.Magnetic resonance imaging: Health effects and safety, Proceedings of the international conference on non-ionizing radiation at UNITEN, Electromagnetic Fields and our Health. (2003) . |
| [154] |
Cho S, Lee Y, Choi YJ, et al. (2014) Enhanced cytotoxic and genotoxic effects of gadolinium following ELF-EMF irradiation in human lymphocytes. Drug Chem Toxicol 37: 440-447. doi: 10.3109/01480545.2013.879662
|
| [155] |
Sadiq S, Ghazala Z, Chowdhury A, et al. (2012) Metal toxicity at the synapse: presynaptic, postsynaptic, and long-term effects. J Toxicol 2012: 132671. doi: 10.1155/2012/132671
|
| [156] | Food U S, Drug Administration, Safety Announcement 2017 Available from: https://www.fda.gov/media/109825/download. |
| [157] |
Veiga M, Mattiazzi P, de Goisc JS, et al. (2020) Presence of other rare earth metals in gadolinium-based contrast agents. Talanta 216: 120940. doi: 10.1016/j.talanta.2020.120940
|
| [158] |
Parfrey P (2005) The clinical epidemiology of contrast-induced nephropathy. Cardiovasc Intervent Radiol 28: S3-S11. doi: 10.1007/s00270-005-0196-8
|
| [159] |
Karcaaltincaba M, Oguz B, Haliloglu M (2009) Current status of contrast-induced nephropathy and nephrogenic systemic fibrosis in children. Pediatr Radiol 39: S382-S384. doi: 10.1007/s00247-009-1236-3
|
| [160] |
Kulaksiz S, Bau M (2011) Anthropogenic gadolinium as a micro-contaminant in tap water used as drinking water in urban areas and megacities. Appl Geochem 26: 1877-1885. doi: 10.1016/j.apgeochem.2011.06.011
|
| [161] |
Hatje V, Bruland KW, Flegal AR (2016) Increases in anthropogenic gadolinium anomalies and rare earth element concentrations in San Francisco bay over a 20 year record. Environ Sci Technol 50: 4159-4168. doi: 10.1021/acs.est.5b04322
|
| [162] |
Rabiet M, Brissaud F, Seidel JL, et al. (2009) Positive gadolinium anomalies in wastewater treatment plant effluents and aquatic environment in the Hérault watershed (South France). Chemosphere 75: 1057-1064. doi: 10.1016/j.chemosphere.2009.01.036
|
| [163] |
Chen Y, Cao XD, Lu Y, et al. (2000) Effects of rare earth metal ions and their EDTA complexes on antioxidant enzymes of fish liver. B Environ Contam Tox 65: 357-365. doi: 10.1007/s001280000136
|
| [164] |
Henriques B, Coppola F, Monteiro R, et al. (2019) Toxicological assessment of anthropogenic gadolinium in seawater: Biochemical effects in mussels mytilus galloprovincialis. Sci Total Environ 664: 626-634. doi: 10.1016/j.scitotenv.2019.01.341
|
| [165] |
Hanana H, Turcotte P, André C, et al. (2017) Comparative study of the effects of gadolinium chloride and gadolinium-based magnetic resonance imaging contrast agent on freshwater mussel, dreissena polymorpha. Chemosphere 181: 197-207. doi: 10.1016/j.chemosphere.2017.04.073
|
| [166] |
Martino C, Costa C, Roccheria MC, et al. (2018) Gadolinium perturbs expression of skeletogenic genes, calcium uptake and larval development in phylogenetically distant sea urchin species. Aquat Toxicol 194: 57-66. doi: 10.1016/j.aquatox.2017.11.004
|
| [167] |
Schmidt K, Bau M, Merschel G, et al. (2019) Anthropogenic gadolinium in tap water and in tap-based beverages from fast-food franchises in six major cities in Germany. Sci Total Environ 687: 1401-1408. doi: 10.1016/j.scitotenv.2019.07.075
|
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