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Are macrocyclic GBCAs safer than linear agents?
Editorial by Sharon Williams March 2021
What do we really know about the safety of gadolinium-based contrast agents? Are researchers looking in the right places for insight into the potential toxic effects of gadolinium? After reading a 1995 paper by Vogler et al., I came away thinking that it may be time to review findings from preclinical animal studies with all gadolinium-based contrast agents (GBCAs) while taking into consideration what is now known about GBCAs and what happens to them after administration into the human body.
When I started my gadolinium-related research in early 2010, it seemed that if you had good kidney function, all the gadolinium would be excreted in a matter of hours, and then that was pushed back to be a few days, and now it seems it could take months and even years to be eliminated. Based on gadolinium being found in various human tissues, I question if all of it will ever get out of the patient’s body. If gadolinium were not a toxic metal, we might be inclined not to worry about it, but it is toxic, and I believe everyone should be worried about the long-term effects of retaining it.
In 2006, the connection was first made between a potentially fatal disease known as nephrogenic systemic fibrosis (NSF) and gadolinium-based contrast agents that are frequently administered for MRIs and MRAs. But NSF involved patients who had severe kidney problems, and most of those patients had received one of the linear GBCAs, which are thought to be more likely to dissociate and leave gadolinium in the patient’s body. What about the patients with normal kidney function who have described the onset of new, unexplained symptoms soon after their MRIs with a GBCA, and who are still excreting gadolinium many years later? When will those patients’ gadolinium-induced symptoms be recognized?
Residual Gadolinium from all GBCAs –
It was not until 2015 that the FDA first acknowledged that gadolinium retention in patients with normal kidney function was happening as well, but the focus continued to be on the linear agents. The published literature has indicated that macrocyclic GBCAs are more stable and less likely to separate and leave residual gadolinium in patients’ bodies. However, recent research has shown that even macrocyclic GBCAs are remaining in the brain, bones, and elsewhere in the body, regardless of the patient’s level of kidney function at the time of his or her MRI. Despite that, the FDA continues to say that it has seen no evidence that retained gadolinium causes harm, even though the FDA and researchers agree that gadolinium is a toxic metal that has no biological use in the human body.
So, how safe is residual gadolinium? And what did preclinical studies show that may have been overlooked or perhaps misinterpreted based on results that were seen in animals? Remember, when GBCAs were first developed, they did not intend that they would be administered multiple times to the same patient. In fact, a 1991 paper by Rocklage et al. said it was “unlikely that MRI contrast agents would be administered repeatedly in patients,” and that was important since the same paper indicated that “minute amounts of chelated or unchelated metals are likely to remain in the body for an extended period and could possibly result in a toxic effect.” The authors acknowledged that this could result in accumulation of metal and that the “long-term effects of such potential deposition have yet to be determined.” Well, here we are 30 years later in 2021, and the long-term effects of gadolinium deposition are still unknown. Why is that?
Macrocyclic GBCAS may be more neurotoxic –
I recently learned of a 1995 preclinical study by Vogler et al. for gadobutrol that may explain some things. Gadobutrol is a macrocyclic gadolinium-based contrast agent that is better known by the brand name Gadovist® or Gadavist®. The title of the paper is “Pre-clinical evaluation of gadobutrol: a new, neural, extracellular contrast agent for magnetic resonance imaging.” The study involved the macrocyclic agents gadobutrol, ProHance®, and Dotarem®, and the linear or open chain agents Magnevist® and Omniscan®. Based on what I have read in numerous published papers, I had expected to find that the two linear agents were found to be less safe. By less safe, I mean that the LD50 for the two linear agents would have been much lower than that of the three macrocyclic agents, but that was not the case.
For those who may not be familiar with what LD50 represents, it is the median lethal dose, or dose at which 50% of the animals die from the administered drug. So, the higher the LD50, the better tolerated by study animals. Table 6 in the paper includes the LD50 and ED50 for each of the 5 GBCAs after the contrast agents were injected into the cisterna cerebellomedullaris in rats, which is a space filled with cerebrospinal fluid or CSF. (ED50 is the median effective dose of the administered drug).
As you can see below, the LD50 for the 3 macrocyclic agents gadobutrol, ProHance, and Dotarem is significantly lower than that for the linear agents Magnevist and Omniscan. According to the authors of the study, “the values of the macrocyclic compounds are lower by a factor of 5-20.”
The results of this study seem to indicate that macrocyclic GBCAS are potentially much more neurotoxic than linear GBCAs. The authors noted that as “cerebral tolerance after intracisternal injection is concerned, it is noticeable that the macrocyclic compounds exhibit side effects in rats after lower doses than the open-chained compounds.” But then they dismissed that finding and said that “it should be noted that this is of no clinical relevance, because the substance was injected directly into the liquor in these experiments and the resulting concentration in the liquor is much higher than concentrations which may occur in the clinical setting”. In plain English, it means, unlike GBCAs that are normally administered intravenously to patients, the GBCAs in the study were injected directly into an area filled with cerebrospinal fluid or CSF, which would result in much more gadolinium getting into the CSF and brain. Vogler and his colleagues did not expect that to occur in patients, especially those who had an intact blood-brain barrier (BBB). However, recent research seems to indicate otherwise.
Are all radiologists aware of the 1995 Vogler study? Was the FDA aware of it? If not, why not?
What we know today –
Remember, that preclinical study was done in 1995, and since then we have learned a lot more about the entry of GBCAs and gadolinium into the CSF and brain. For instance, a 2018 study by Berger et al. found that gadoterate meglumine (Dotarem®) easily penetrates in the CSF regardless of the patient’s level of renal function and in patients with an intact BBB. A 2018 study by Nehra et al. found that gadolinium is present in human CSF almost immediately after intravenous administration of gadobutrol (Gadavist®) in both adult and pediatric patients even in the setting of normal renal function and no dysfunction of the BBB. Interestingly, when comparing their findings to those seen in rats by Jost et al. (2016), the authors noted that “these findings imply significant limitations in the translational potential of the rat model as a surrogate for human gadolinium CSF clearance because substantial levels of gadolinium were detected well beyond 24 hours in the CSF of all human subjects with findings suggestive of an intact BBB.” In fact, gadolinium was detectable in CSF and serum for up to 24 days after intravenous administration of gadobutrol.
Since more radiology departments began using macrocyclic agents, I have told the FDA and several radiologists that we have seen a significant increase in the number of people joining our Gadolinium Toxicity support group who have only received a macrocyclic agent, and the initial symptoms reported by those people seem to be much more intense. I believe the 1995 study by Vogler et al. may provide some explanation as to why that is occurring.
I wonder what else might be learned by carefully reviewing the preclinical findings for all GBCAs while taking into consideration what has been learned about GBCAs and gadolinium’s entry into the CSF and brain, as well as deposition in the brain, bones, skin, and other parts of the human body.
Answers are needed about GBCA Safety –
Once again, we seem to have more questions than answers about GBCAs. I believe that must change before more patients’ lives are adversely affected. Patients who have been affected by retained gadolinium want and deserve answers, and I would expect that the FDA and Radiologists would want answers as well.
We cannot wait another 30 years to determine the long-term effects of gadolinium deposition, and which, if any, GBCAs are safe.
Berger, F., Kubik-Huch, R. A., Niemann, T., Schmid, H. R., Poetzsch, M., Froehlich, J. M., Kraemer, T. (2018). Gadolinium Distribution in Cerebrospinal Fluid after Administration of a Gadolinium-based MR Contrast Agent in Humans. Radiology, 171829. https://doi.org/10.1148/radiol.2018171829
Food & Drug Administration. (2015). FDA Drug Safety Communication, July 27, 2015. Retrieved from https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-evaluating-risk-brain-deposits-repeated-use-gadolinium-based
Jost, G., Frenzel, T., Lohrke, J., Lenhard, D. C., Naganawa, S., & Pietsch, H. (2017). Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue. European Radiology, 27(7), 2877–2885. https://doi.org/10.1007/s00330-016-4654-2
Nehra, A. K., McDonald, R. J., Bluhm, A. M., Gunderson, T. M., Murray, D. L., Jannetto, P. J., McDonald, J. S. (2018). Accumulation of Gadolinium in Human Cerebrospinal Fluid after Gadobutrol-enhanced MR Imaging: A Prospective Observational Cohort Study. Radiology, 171105. https://doi.org/10.1148/radiol.2018171105
Rocklage, S. M., Worah, D., & Kim, S.-H. (1991). Metal ion release from paramagnetic chelates: What is tolerable? Magnetic Resonance in Medicine, 22(2), 216–221. Retrieved from http://doi.wiley.com/10.1002/mrm.1910220211
Vogler, H., Platzek, J., Schuhmann-Giampieri, G., Frenzel, T., Weinmann, H.-J., Radüchel, B., & Press, W.-R. (1995). Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging. European Journal of Radiology, 21(1), 1–10. https://doi.org/https://doi.org/10.1016/0720-048X(95)00679-K
Possible connection between GBCAs and Small Fiber Neuropathy
A recent study by Radbruch et al. used a mouse model to assess intraepidermal nerve fiber density (IENFD) after injection of gadolinium-based contrast agents (GBCAs). The study, “Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents?”, was published in Investigative Radiology. Radbruch and his colleagues investigated changes of small fibers in the epidermis of mice as a potential cause of patient complaints about burning pain in their arms and legs after administration of a GBCA. As a possible additional marker for damage of small fibers, the appearance of terminal axonal swellings (TASs) was assessed. Small fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ-fibers and unmyelinated C-fibers, and it is typically associated with burning pain in the lower arms and legs. The authors noted that the cause of SFN remains unknown in up to 50% of cases.
The study involved 6 groups of 8 mice that were intravenously injected with one dose (1 mmol/kg body weight) of either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine), or saline. Four weeks after injection, the mice were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IEFND) was calculated, and the median number of terminal axonal swellings (TASs) per IEFND was determined. They found a significant reduction of IEFND in the footpad of mice for all GBCAs tested compared with the control group. There was a significantly larger decrease of IEFND for the linear GBCAs compared to macrocyclic GBCAs. They found a significant increase of TAS/IEFND for the linear GBCAs, whereas only a “trend without significance” was found for the macrocyclic agents.
The authors noted that, to the best of their knowledge, the study is the first to investigate a correlation between small fiber degeneration and GBCA exposure. (more…)
Study finds GBCAs induce Mitochondrial Toxicity and Cell Death
A preclinical study by Bower et al. found that gadolinium-based contrast agents (GBCAs) have a toxic effect on mitochondrial respiratory function and cell viability in human neurons. The study, Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases with Reduced Kinetic Stability of the Agent, was published online ahead of print in Investigative Radiology. For the study, neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is one of two brain regions that displays the greatest T1-dependent signal hyperintensity changes. Multiple studies have shown that T1-signal intensity changes in the brain are the result of gadolinium deposition. The authors noted that there is increasing evidence that all agents (linear and macrocyclic) remain in human brain tissue for some period of time, where they may be taken up into various cell types, including glia and neurons.
Reports of possible clinical symptoms experienced by patients after a contrast-enhanced MRI have been published. However, until this study, it was unknown whether GBCAs induce toxic effects on the cellular function of human neurons. This study provides the first definitive evidence that GBCAs induce mitochondrial toxicity and cell death in cultured human neurons. The authors said that the “magnitude of the measured toxicity broadly increases as the kinetic stability of the contrast agent decreases, and the lower stability agents induce toxicity at concentrations that fall within the range detected in some autopsy patients”. “For all agents, the magnitude of the toxicity increases with concentration.” (more…)
Article says that Gadolinium-Based Contrast Agents should be used with extreme caution
A recently released review article by Drs. Katarina Leyba and Brent Wagner, titled “Gadolinium-based contrast agents: why nephrologists need to be concerned”, doesn’t pull any punches when it comes to the use of gadolinium-based contrast agents (GBCAs) for contrast-enhanced MRIs. The authors said that ‘nephrogenic’ systemic fibrosis is a misnomer since GBCAs are the known trigger for the disease; kidney impairment is a risk factor. They note that “the experimental evidence demonstrates that gadolinium-based contrast agents are biologically active – that is, not inert”. Drs. Leyba and Wagner said that “because GBCAs are biologically active in vitro and in vivo, and patients with normal renal function have reported adverse events that overlap those of ‘nephrogenic’ systemic fibrosis (i.e., rash, muscle/tendon ‘tightness, pain…), and because the other risk factors are undetermined”, medical professionals need to be “open to the possibility that ‘nephrogenic’ systemic fibrosis and these gadolinium-based contrast agent-induced symptoms are part of a continuum”. (more…)