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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…)
The increasing levels of gadolinium found in lakes, bays, rivers, and water supplies around the world correlate with the increased administration of gadolinium-based contrast agents (GBCAs) for MRIs. The gadolinium (Gd) from those GBCAs that gets into our water is called anthropogenic gadolinium since it comes from human activity. Some studies refer to it as a Gd anomaly and note that it is difficult to remove by the usual sewage treatment technology. This is not a new problem, but it is one that requires further investigation to confirm that gadolinium is not absorbed by the GI tract since it could be ingested via drinking water. It seems that might be of even greater concern for infants, children, and pregnant women. Besides being in our drinking water, a 2019 study by Schmidt et al. found anthropogenic gadolinium, in similar concentrations, in tap-water and in a related water-based popular fountain soft drink from two fast food restaurants in six major German cities. That study provided the first evidence that anthropogenic gadolinium in contrast agents enters the human food chain.
A recent study by Inoue et al. reported a significant increase in the Gd anomaly in the rivers in Tokyo, compared to data obtained 22 years ago, depending on the location of the wastewater treatment plants. The amount of Gd had increased by as much as 6.6 times since the assessment 22 years ago. That coincides with the significant increase in the number of MRI scanners in Japan and scans performed with a GBCA. The study notes that common wastewater treatment plants cannot remove gadolinium, so it is released back into the environment. That fact is well-documented in the literature.
A 2020 study by Brünjes and Hofmann found that “contrary to previous assumptions that GBCAs are stable throughout the water cycle, they can degrade.” The authors noted that there is specific concern that “UV end-of-pipe treatment” may enhance the risks posed by GBCAs in drinking water. They noted that increasing GBCA concentrations could become a concern in settings where drinking water is produced from raw water resources with a high proportion of recycled wastewater. They said that during drinking water production, improved water purification would require using expensive reverse osmosis as it is the only efficient way to fully remove GBCAs. The authors suggested a novel way to reduce the input of gadolinium into the aquatic environment and its potential health risk, and it is to have patients collect urine in leakproof collection bags that include super absorbent polymers for at least 24 hours following administration of GBCAs. Urine would need to be collected not only in hospitals, but also in patients’ homes. It appears that a pilot study by Niederste-Hollenberg et al. was done in Germany in 2018 that had a high level of acceptance by patients.
Is collecting urine after contrast-enhanced MRIs enough to solve the potential problems that might be caused by anthropogenic gadolinium in our drinking water? (more…)
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