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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
Gadolinium detected in skin of patients with impaired renal function, but no NSF: What does that prove?
Editorial by Sharon Williams
If you only look at one specific patient population such as the renally-impaired, for predominantly one specific disease symptom like skin changes, how would you ever expect to know with any certainty whether or not other patient populations are also being harmed by GBCAs? (S. Williams, 2012 Letter to FDA)
I have been debating how to present the findings of a study that was published earlier this year, and I decided that the best thing for me to do was to write an editorial about it.
The paper by Kanal et al., Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration, says that the study “aimed to analyze any nephrogenic-systemic fibrosis-related risks and quantify skin gadolinium levels in patients with impaired renal function but without nephrogenic systemic fibrosis who had received gadobenate.”
I have read the paper several times and I am still not sure what the study hoped to prove. Is it that half-doses of gadobenate (MultiHance) are safe to use even in renally-impaired patients? That subclinical NSF does not exist? That low levels of gadolinium (Gd) in the skin means that the patient has not been adversely affected by retained gadolinium? With all due respect to the authors, I feel like something is missing.
The study used a screening questionnaire that is geared toward NSF and is primarily about skin changes (Lima et al., 2013). From what we know from the literature about NSF and gadobenate, I am not surprised that so few of the patients screened positive for NSF and that none were found to actually have NSF, especially when, according to the paper, “the vast majority” of them had received half-doses of gadobenate. As I have said many times about NSF and gadolinium retention, I believe we need to consider what might be happening on the inside of the patient, and not just look at the skin for visible evidence of a problem, and, indeed, not just look for NSF as the only point of concern when it comes to gadolinium retention.
Interestingly, in the 2007 paper by High et al. that was referenced, it said that gadolinium was detected in only 4 of the 13 tissue specimens from 7 NSF patients. However, all 7 patients were included in the NSF Registry. Perhaps that is why having evidence of Gd in tissue is not part of the Clinicopathological Definition and Workup Recommendations for NSF that was published by Girardi et al. (2010). Since a patient does not need to have evidence of gadolinium in tissue to be diagnosed with NSF, I would not expect that it would be required in order to prove someone has “subclinical NSF” either. Finding no gadolinium or extremely low levels of gadolinium in dermal tissue does not seem to prove or disprove whether someone has been adversely affected by retained gadolinium.
I understand that there may be situations when undergoing an MRI with contrast might be deemed medically necessary and agreed to by the patient. However, I sincerely hope that, after reading this paper, radiologists and clinicians do not feel there is no concern about using gadobenate as long as it is used in half-doses. We have to remember that, for inclusion in the study, only a single dose of gadobenate (MultiHance) was required, and the highest gadolinium level was found in a patient with an eGFR of 53 who had 1 MRI with an unspecified amount of contrast. I think it is still important to consider the cumulative effect of any gadolinium that is retained, and to remember that the damage caused by gadolinium is more than skin deep – it goes to patients’ bones and vital organs as well. The adverse effects of gadolinium in internal organs will not be visible with the naked eye, but that does not mean it is not happening.
Kanal, E., Patton, T. J., Krefting, I., & Wang, C. (2020). Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration. American Journal of Neuroradiology. https://doi.org/10.3174/ajnr.A6448
Williams, S. (2012). Letter to FDA Regarding Gadolinium Toxicity from GBCAs; made public 2016, The Lighthouse Project, GadoliniumToxicity.com. https://gdtoxicity.files.wordpress.com/2016/10/swilliams-2012fda-letter-gdtoxicity1.pdf
Lima, X. T., Alora-Palli, M. B., Kimball, A. B., & Kay, J. (2013). Validation of a Screening Instrument for Nephrogenic Systemic Fibrosis. Arthritis Care & Research, 65(4), 637–642. https://doi.org/10.1002/acr.21877
High, W. A., Ayers, R. A., Chandler, J., Zito, G., & Cowper, S. E. (2007). Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. Journal of the American Academy of Dermatology, 56(1), 21–26. https://doi.org/10.1016/j.jaad.2006.10.047
Girardi, M., Kay, J., Elston, D. M., Leboit, P. E., Abu-Alfa, A., & Cowper, S. E. (2011). Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. Journal of the American Academy of Dermatology, 65(6), 1095-1106.e7. https://doi.org/10.1016/j.jaad.2010.08.041
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…)
As of April 26, 2018, the revised Product Labeling with the Medication Guide for all gadolinium-based contrast agents (GBCAs) were posted on the FDA’s website. The FDA announced on December 15, 2017, that it was requiring GBCA manufacturers to revise product labeling and create a Medication Guide for each GBCA. The purpose of the Medication Guide is to provide patients with information about gadolinium retention in the body so that they can make an informed decision before agreeing to have an MRI with contrast – an MRI with a gadolinium-based contrast agent. Gadolinium (Gd) is a toxic metal and any amount that remains in the brain and other parts of the body has the potential to have a harmful effect. While the linear GBCAs are the least stable, macrocyclic agents have been found to leave residual gadolinium in patients’ bodies as well. The long-term effects of gadolinium deposition are still unknown; however, research is ongoing.
The Medication Guide for each agent mentions “many doses of gadolinium medicines” as a possible risk factor. Gadolinium-based contrast agents are intravenously administered prescribed drugs that can have a toxic effect even after one dose of contrast. Currently, no one knows why some patients become symptomatic after having one or more MRIs with a GBCA, while others do not. However, it appears that everyone retains an unknown amount of gadolinium from each dose of a gadolinium-based contrast agent they receive.
Links to the new Product Labeling for each agent are provided below. (more…)