Mapping Gadolinium-based Contrast Agent Residues in the Rat Kidney
Luis Hummel1, Janina Boyken, Thomas Gladytz
1Institute of Translational Physiology, Charité - Universitätsmedizin Berlin, Germany (L.H., E.S.); MR and CT Contrast Media Research, Bayer AG, Berlin, Germany (J.B., H.P.); Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Ultrahigh Field Facility (B.U.F.F.), Berlin, Germany (T.G., E.T., T.N.); Bioanalytics, Bayer AG, Wuppertal, Germany (A.T.).
Objectives:
Gadolinium-based contrast agents (GBCAs) are routinely used to enhance magnetic resonance (MR) imaging. In recent years, GBCA residues were detected in multiple organs, with the kidney as the primary organ of excretion showing the highest concentrations. This study aimed to map the intricate spatial distribution of GBCA residues in rat kidneys at an early and a late time point.
Materials And Methods:
Rats received one of 6 marketed GBCAs [3 macrocyclic, 3 linear; cumulative dose 4.8 mmol gadolinium (Gd)/kg] or saline and were sacrificed at day 5 or week 14 post administration (n = 5 per GBCA and time point). In whole renal tissue slices, the distribution of elemental Gd was determined by laser ablation-inductively coupled plasma-mass spectrometry and the distribution of intact GBCA chelates by matrix-assisted laser desorption ionization-mass spectrometry imaging. In ex vivo kidneys, MR relaxometry was used to assess MR-detectable GBCA residues.
Results:
At day 5, Gd was predominantly localized in the renal cortex across all GBCAs, with 10- to 100-fold lower medullary levels. Distribution patterns corresponded well with those of exemplary intact GBCA chelates. At week 14, Gd levels had decreased by 1 to 2 orders of magnitude. Distribution patterns from linear GBCAs showed Gd remaining predominantly in the cortex, while Gd from macrocyclic GBCAs was similar in cortex and medulla. Several GBCAs exhibited a prominent Gd presence at the transition zone between outer and inner medulla. Intact chelate was only detectable for the exemplary macrocyclic GBCA, with a spatial distribution pattern matching that of elemental Gd. MR relaxometry detected GBCA residues within ex vivo kidneys but also in the surrounding water-based fixative. This indicated the presence and washout of intact GBCAs, which was greater for macrocyclic versus linear GBCAs.
Conclusions:
This study provides the first comprehensive spatially resolved characterization of renal GBCA residues at an early and a late time point. GBCA residues exhibited specific intrarenal distribution patterns and distinct changes in these patterns over the course of their elimination. Our findings of specific retention patterns suggest that renal microanatomy and local physicochemical conditions play critical roles in GBCA retention. These insights provide a foundation for future investigations into retention mechanisms and potential long-term tissue effects.
