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Combined speciation analysis and elemental bioimaging provides new information about the retention of gadolinium in kidney following the application of some MRI contrast agents


Gadolinium-based contrast agents (GBCAs) have been used for more than three decades to improve the image quality for clinical diagnostics by magnetic resonance imaging (MRI). GBCAs can be divided based on their chemical structure into macrocyclic and linear complexes. While both types have been considered to be safe because of their high stability and fast excretion via the kidney, recently the retention of gadolinium (Gd) has been reported for healthy subjects. Retained gadolinium has been found in different organs such as brain, skin, liver, kidney and bone even after prolonged periods of time following application. The observation that the level of retention is higher for linear complexes than for macrocyclic ones has been explained by the somewhat poorer in-body stability of these complexes, allowing for reactions with endogenous cations.

In order to fully understand the mechanisms of such reactions and the resulting retention, the species involved must be identifies and their distribution within the tissue should be determined. Despite the efforts of different research groups, there is still a lack of knowledge in this area. The consent of their studies has shown that retained Gd species are found either as small soluble molecules, soluble macromolecules or insoluble Gd species. Since the soluble fraction of the Gd species is only a minor fraction, chromatographic methods for their identification cannot provide species information about the major fraction nor about the spatial distribution of the soluble fraction.

On the other hand, elemental imaging by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has the necessary sensitivity to obtain the information about the spatial distribution of the retained gadolinium in the tissue, but unfortunately cannot directly provide species information apart from colocalization with other elements.

The new study:
A group of researchers from Germany and France present a simple and fast method that combines a leaching procedure on fresh-frozen kidney thin-sections with LA-ICP-MS to gain spatially resolved species information. In this approach, the tissue sections are dipped half-way into water, selectively washing out the soluble species, while all gadolinium species remain in the upper sample half. Subsequent mapping of Gd by LA-ICP-MS then allows to create a spatially resolved differentiation between highly water-soluble Gd species and insoluble Gd species (see figure 1).

Figure 1: LA-ICP-MS analysis of rat kidney samples after 3 and 12 months with injection of either gadobutrol or gadodiamide. Lower half of the kidney shows the effects of a leaching procedure with water.

The soluble gadolinium fraction leached from the lower half of the kidney was analyzed by means of hydrophilic interaction liquid chromatography (HILIC) coupled with ICP-MS. In this way information on the water-soluble species could not only be obtained from the full kidney, but also be traced back to its localization in the tissue from which it was extracted. As can be seen in the left part of figure 1, kidney samples from gadodiamide-treated rats showed a higher fraction of water-insoluble Gd deposition in both cortex and medulla than kidneys of rats treated with gadobutrol. The water soluble fraction was even below the limit of detection after 12 months.

In the kidney of a rat treated with gadobutrol (see the right part of figure 1), the water-insoluble, permanent Gd deposition was mainly found in the renal cortex. A much greater fraction of water-soluble species was found in the medulla. This fraction contains the intact contrast agent (Gadobutrol) up to one year after injection.

The results clearly show that the retained Gd fraction is related to the structure of the Gd-based contrast agent, and the retained species is dependent on the localization in the kidney tissue. The obtained distribution pattern indicate that the Gd deposition might be related to the spatial proximity to arteries. The obtained results also emphasize the importance of the sample preparation for the bioimaging. It is obvious that any treatment with solvents has to be avoided, if the distribution of soluble Gd species is of interest.

The authors concluded with the statement, that further studies targeting the exact identification of the insoluble Gd species is required for a full understanding of the Gd retention mechanism.

The original publication

Patrick Bücker, Sabrina K.I. Funke, Cécile Factor, Marlène Rasschaert, Philippe Robert, Michael Sperling, Uwe Karst, Combined speciation analysis and elemental bioimaging provides new insight into gadolinium retention in kidney, Metallomics, 14 (2022) mfac004. DOI: 10.1093/mtomcs/mfac004

Instrumentation used:

Dionex UltiMate 3000 HPLC

Related studies (newest first)

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Michael D. Ringler, Nicholas G. Rhodes, Jennifer R. Ayers-Ringler, Daniel R. Jakaitis, Robert J. McDonald, David F. Kallmes, Jennifer S. McDonald, Gadolinium retention within multiple rat organs after intra-articular administration of gadolinium-based contrast agents, Skeletal Radiology, 50 (2021) 1419–1425. DOI: 10.1007/s00256-020-03695-3

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S. Bussi, A. Coppo, R. Celeste, A. Fanizzi, A. Fringuello Mingo, A. Ferraris, C. Botteron, M.A. Kirchin, F. Tedoldi, F. Maisano, Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats, Insights Imaging 2020, 11, No. 11. DOI: 10.1186/s13244-019-0824-5

Mariane Le Fur, Peter Caravan, The biological fate of gadolinium-based MRI contrast agents: a call to action for bioinorganic chemists, Metallomics, 11(2 (2019) 240-254. DOI: 10.1039/c8mt00302e

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Jessica Wahsner, Eric M. Gale, Aurora Rodríguez-Rodríguez, Peter Caravan, Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers, Chem. Rev. 2019, 119, 957−1057. DOI: 10.1021/acs.chemrev.8b00363

P. Robert, S. Fingerhut, C. Factor, V. Vives, J. Letien, M. Sperling, M. Rasschaerts, R. Santus, S. Ballet, Jean-Marc Idée, C. Corot, U. KarstOne-year retention of gadolinium in the brain: comparison of gadodiamide and gadoterate meglumine in a rodent model. Radiology., 288 (2018) 424–433. DOI: 10.1148/radiol.2018172746

Val M. Runge, Dechelation (Transmetalation) - Consequences and Safety Concerns With the Linear Gadolinium-Based Contrast Agents, In View of Recent Health Care Rulings by the EMA (Europe), FDA (United States), and PMDA (Japan), Invest. Radiol., 53 (2018) 571–578. DOI: 10.1097/RLI.0000000000000507

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S. Fingerhut, A.C. Niehoff, M. Sperling, A. Jeibmann, W. Paulus, T. Niederstadt, T. Allkemper, W. Heindel, M. Holling, U. Karst, Spatially resolved quantification of gadolinium deposited in the brain of a patient treated with gadolinium-based contrast agents. J. Trace Elem. Med. Biol., 45 (2018) 125–130. DOI: 10.1016/j.jtemb.2017.10.004

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R.J. McDonald, J.S. McDonald, D. Dai, D. Schroeder, M.E. Jentoft,D.L. Murray, R. Kadirvel, L.J. Eckel, D.F. Kallmes, Comparison of gadolinium concentrations within multiple rat organs after intravenous administration of linear versus macrocyclic gadolinium chelates. Radiology, 285 (2017) 536-545. DOI: 10.1148/radiol.2017161594

T. Frenzel, C. Apte, G. Jost, L. Schockel, J. Lohrke, H. Pietsch, Quantification and assess-ment of the chemical form of residualgadolinium in the brain after repeated administration of gadolinium-based contrast agents comparative study in rats. Invest. Radiol.,  52 (2017) 396–404. DOI: 10.1097/Rli.0000000000000352

N. Murata, K. Murata, L.F. Gonzalez-CuyarF, K.R. Maravilla, Gadolinium tissue deposition in brain and bone. Magn. Reson. Imaging, 34 (2016) 1359-1365. DOI: 10.1016/j.mri.2016.08.025

M. Birka, C.A. Wehe, O. Hachmöller, M. Sperling, U. Karst, Tracing gadolinium based contrast agents from surface water to drinking water by means of speciation analysis, J. Chromatogr. A, 1440 (2016) 105–111. DOI: 10.1016/j.chroma.2016.02.050

D.R. Roberts, S.M. Lindhorst, C.T. Welsh, K.R. Maravilla, M.N. Herring, K.A. Braun, B.H. Thiers, W.C. Davis, High levels of gadolinium deposition in the skin of a patient with normal renal function, Invest. Radiol., 51/5 (2016) 280–289. DOI: 10.1097/RLI.0000000000000266

T. Kanda, T. Fukusato, M. Matsuda, K. Toyoda, H. Oba, J. Kotoku, T. Haruyama, K. Kitajima, S. Furui, 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, 276/1 (2015) 228–232. DOI: 10.1148/radiol.2015142690

M. Birka, K.S. Wentker, E. Lusmöller, B. Arheilger, C.A. Wehe, M. Sperling, R. Stadler, U. Karst, Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis, Anal. Chem., 87/6 (2015) 3321–3328. DOI: 10.1021/ac504488k

T. Kanda, K. Ishii, H. Kawaguchi, K. Kitajima, D. Takenaka, 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, 270/3 (2014) 834–841. DOI: 10.1148/radiol.13131669

Charu Thakral, Jerrold L. Abraham, Gadolinium-Induced Nephrogenic Systemic Fibrosis Is Associated with Insoluble Gd Deposits in Tissues: In Vivo Transmetallation Confirmed by Microanalysis, J. Cutan Pathol., 36 (2009) 1244–1254. DOI: 10.1111/j.1600-0560.2009.01283.x

J.L. Abraham, C. Thakral, L. Skov, K. Rossen, P. Marckmann, Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis, Br. J. Dermatol., 158 (2008) 273–280.  DOI: 10.1111/j.1365-2133.2007.08335.x

Thomas Frenzel, Philipp Lengsfeld, Heiko Schirmer, Joachim  Hütter, Hanns-Joachim Weinmann, Stability of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37°C, Invest. Radiol., 43/12 (2008) 817-828. DOI: 10.1097/RLI.0b013e3181852171

Jens Künnemeyer, Lydia Terborg, Sascha Nowak, Andy Scheffer, Lena Telgmann, Faruk Tokmak, Andreas Günsel, Gerhard Wiesmüller, Stephan Reichelt, Uwe Karst, Speciation Analysis of Gadolinium-Based MRI Contrast Agents in Blood Plasma by Hydrophilic Interaction Chromatography/Electrospray Mass Spectrometry, Anal. Chem. , 80/21 (2008) 8163-8170. DOI: 10.1021/ac801264j

Gregory W. White, Wendell A. Gibby, Michael F. Tweedle, 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., 41/3 (2006) 272-278. DOI: 10.1097/01.rli.0000186569.32408.95 

Wendell A. Gibby, Krissa A. Gibby, W. Andrew Gibby, 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., 39/3 (2004) 138-142. DOI: 10.1097/01.rli.0000112789.57341.01

December 12, 2020: Speciation analysis of Gadolinium-based contrast agents using hydrophilic interaction liquid chromatography hyphenated with inductively coupled plasma-mass spectrometry by avoiding organic solvents
May 23, 2017: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs
March 11, 2017: European Medicines Agency recomments to pull linear Gadolinium-based MRI contrast agents from market
April 10, 2016: New Studies Question Safety of MRI Contrast Agents
August 13, 2015: FDA investigating risk of gadolinium contrast agent brain deposits
March 4, 2015: Detection of Gd-based contrast agent in the skin of a patient eight years after administration
October 29, 2012: Identification and quantification of potential metabolites of Gd-based contrast agents 
September 15, 2010: US FDA Announces Gadolinium-Based MRI Contrast Agent Warning
March 25, 2010: Publication on the separation of Gd-based contrast agents awarded
May 4, 2009: Gadolinium speciation analysis in search for the cause of nephrogenic systemic fibrosis (NSF)

last time modified: February 28, 2022

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