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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
Results of a study to determine whether individuals with proposed gadolinium deposition disease (GDD) have elevated serum levels of pro-inflammatory and pro-fibrotic cytokines were recently published. GDD has been reported in patients with normal renal function after MRIs with a gadolinium-based contrast agent (GBCA). The study by Maecker et al., “An initial investigation of serum cytokine levels in patients with gadolinium retention”, also sought to determine whether specific cytokines are correlated with certain symptoms considered to be characteristic of GDD. The study involved 24 participants who were recruited between May 2016 and June 2017 and met the proposed GDD diagnostic criteria. Some of the participants were recruited from our MRI-Gadolinium-Toxicity support group. A control group of 64 subjects provided serum samples before their flu vaccination. Serum cytokine levels were obtained with Luminex serum cytokine assay using eBiosciences/Affymetrix human 62-plex kits.
In patients who had retained gadolinium, serum levels of 14 cytokines, including 9 pro-inflammatory cytokines, were “statistically significantly elevated” compared to controls (p ≤ 0.05). (more…)
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…)
The article, “Establishing Reference Intervals for Gadolinium Concentrations in Blood, Plasma, and Urine in Individuals Not Previously Exposed to Gadolinium-Based Contrast Agents” by Layne et al., was published in Investigative Radiology earlier this year. Their study set out to determine whether healthy people who have never received a gadolinium-based contrast agent (GBCA) have detectable concentrations of gadolinium (Gd) in their blood and urine, and to then develop a reference range for Gd concentrations in blood and spot urine. A secondary aim of the study was to determine whether spot urine Gd concentrations are equivalent to those in timed 24-hour urine collections. In the majority (93.3%) of their 120 healthy volunteers, the Gd concentrations were undetectable in blood, plasma, spot urine samples, and 24-hour urine collections. No participants had detectable concentrations of Gd in their plasma. The authors noted that those subjects who did have detectable Gd concentrations in their spot urine samples had considerably lower concentrations than those identified in the reference interval published on the Mayo Clinic web site, which is less than 0.8 mcg/g creatinine.
Proposed Gadolinium Reference Intervals, Layne et al. (2020):
- Whole blood: <0.008 ng/mL or <0.050 nmol/L
- Plasma: <0.009 ng/mL or <0.057 nmol/L
- Spot urine: <0.036 μg/g creatinine or <0.0250 nmol/mmol
More Study Details –
Twenty subjects also did a timed 24-hour urine collection, and urine Gd concentrations were measured in samples from those collections. None of the 24-hour urine collections had detectable Gd concentrations, and those 20 subjects also did not have detectable Gd in their spot urine specimens.
Study participants were recruited from the staff at Guy’s and St Thomas’ NHS Foundation Trust, London, and students from King’s College London who are based at St Thomas’ Hospital. Potential subjects completed a basic health questionnaire to determine suitability for inclusion in the study. Participants had to be 18 years or older with no significant medical history, no history of smoking or vaping within the previous 6 months, and no prior exposure to gadolinium or GBCAs. All participants had an estimated glomerular filtration rate (eGFR) of 70 or greater. Of the 120 subjects, 79 (65.8%) were female and 41 (34.2%) were male. The median age was 29.6 years.
Although no subjects reported having an MRI with a GBCA, detectable concentrations of Gd were found in 10 of the 120 subjects. Four of those 10 reported undergoing an MRI without contrast in the past, which could not be confirmed, so those 4 were excluded from further data analysis.
The authors noted that it is possible that subjects had a degree of background Gd exposure from anthropogenic gadolinium which is known to be in tap water. (more…)