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 identified 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 creating a spatially resolved differentiation between highly water-soluble Gd species and insoluble Gd species (see figure 1).

The soluble gadolinium fraction leached from the lower half of the kidney was analysed 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.

Thermo Scientific - iCAP-TQ ICP-MS

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last time modified: September 18, 2024