New Mexico Geological Society Annual Spring Meeting — Abstracts

Background: Attributed to its strong paramagnetic properties, gadolinium, a rare earth metal in the lanthanide series of the periodic table, has been extensively used in modern diagnostic medicine as an enhancer of magnetic resonance imaging (MRI) procedures. Free gadolinium is cytotoxic and may interfere with multiple intracellular processes. It has been shown that gadolinium is a potent calcium channel blocker, augments oxygen species production and prostaglandin E2, dysregulates mitochondrial membrane potential, and influences cytokine expression. To reduce these unfavorable properties, gadolinium is chelated to organic ligands. Although gadolinium-based contrast agents (GBCA) are considered safe, they have been linked to ‘nephrogenic’ systemic fibrosis (NSF), a potentially fatal medical condition characterized by skin fibrosis associated with severe pain, burning, and itching, leading to inhibition or loss of joint flexibility and movement. Numerous studies in animals and humans have shown that gadolinium is detectable in both symptomatic and asymptomatic patients in the urine, hair, and nails after MRI contrast exposure. Based on the chemical structure of the ligand, GBCAs are grouped into categories: linear (Omniscan) or macrocyclic (Dotarem). Generally, macrocyclic GBCAs are thermodynamically very stable and more kinetically inert and, hence, safer than linear GBCAs. For diagnostic purposes, two types of cases have been categorized: unconfounded, in which only one specific GBCA was administered in single or multiple doses, and confounded, in which more than one specific GBCA was administered. However, the effect of unconfounding or confounding scenarios on gadolinium retention in kidneys or livers in animals has not been examined.

Methods: In our present study, 18 mice were randomized to five experimental groups: (1) saline-treated controls; gadolinium-based contrast agent-treated (2) Omniscan (2.5 mM), (3) Dotarem (2.5 mM), or in combination (4) Omniscan (1 week) followed by Dotarem administration for 3 weeks or (5) Dotarem (1 week) followed by Omniscan treatment for 3 weeks. Saline or contrast agents were administered via intraperitoneal injections 5 days a week for 4 weeks. Tissues were excised and snap-frozen in liquid nitrogen. On average, 15 mg of tissue was digested in nitric acid, and gadolinium concentrations were quantified using PerkinElmer NexION 300D Inductively Coupled Plasma Mass Spectrometry (ICP/MS) with a detection limit of 0.01 ppb.

Results: In animals exposed to 4 weeks of treatment with Omniscan or Dotarem alone or in combination (Omniscan-Dotarem or Dotarem-Omniscan), there was significant retention in the kidneys, liver, skin, and bone marrow. Regardless of the MRI agents (Omniscan or Dotarem), the kidneys, compared to other organs, accumulated the highest levels of gadolinium. Regardless of the organ, the animals exposed to Omniscan had the highest levels of gadolinium. In the liver, skin, and bone marrow of animals exposed to Dotarem alone or in combination with Omniscan (Omniscan-Dotarem group), gadolinium levels were the lowest compared to other experimental groups. The levels of phosphorus in the kidneys, skin, or bone marrow were not influenced by the treatment. But in the liver of animals treated with Omniscan, Omniscan-Dotarem, Dotarem-Omniscan, the levels of phosphorus were elevated compared to those in control unexposed animals. Similarly, in the liver of animals exposed to Omniscan alone or in combination with Dotarem (Omniscan-Dotarem), zinc levels were augmented compared with the levels in saline-treated animals. Calcium levels were not affected by any treatment in the kidney, liver, or skin. Our previous studies have shown the formation of gadolinium-rich nanoparticles in the kidneys from magnetic resonance imaging contrast agent exposure. In the present study, we analyzed Gd atomic % in the renal nanoparticles purified on the sucrose gradient. Interestingly, two groups with the longest Omniscan exposures (Omniscan alone or Dotarem-Omniscan group) showed the highest levels of atomic % gadolinium, calcium, and phosphorous in the renal nanoparticles when compared with untreated animals.

Conclusions: Our data indicate that prior GBCA exposures influence gadolinium retention in the kidney or liver. Future studies are needed to determine if this factor is influential in the pathophysiology of NSF in humans.