A new study by Alwasiyah et al. concluded that the current reference range of 0.7 μg/24hr for 24-hour urinary gadolinium is not applicable to patients for at least 30 days following exposure to a gadolinium-based contrast agent (GBCA).  In the study, the authors “calculated an estimated average of 57 days for the urinary gadolinium to creatinine ratio to reach below the current reference range following GBCA exposure and possibly much longer (i.e., 80+ days)”.  The article, “Urinary Gadolinium Levels After Contrast-Enhanced MRI in Individuals with Normal Renal Function: a Pilot Study”, was published online December 12, 2018 in the Journal of Medical Toxicology.

This was a prospective, observational pilot study to determine urine gadolinium concentrations over a 30-day period after GBCA administration in patients with normal renal function.  The 13 subjects were between 18 and 65 years of age and were reported to have received a gadolinium-based contrast agent for the first time.  Prior to contrast administration, spot urine samples were obtained and tested for gadolinium and creatinine.  All testing was performed by Mayo Medical Laboratories in Rochester, MN.  Post-MRI 24-hour urine testing was performed on day 3, 10 and 30.  Eight subjects received gadobutrol (Gadavist®), four received gadopentetate dimeglumine (Magnevist®), and 1 received gadoxetate disodium (Eovist®) for their MRIs with contrast.  The authors reported that all 13 subjects had 24-hour gadolinium levels higher than 0.7 μg/24hr on day 3, day 10, and day 30 after contrast administration.  The authors estimated that “urinary gadolinium levels will often remain above the current reference range for >50 days”.

The paper notes that “early pharmacokinetic studies estimated that up to 100% of the GBCA dose given intravenously is excreted in the urine within 72-h”.  However, “Lancelot recently suggested a second, delayed phase of elimination” which led the authors “to hypothesize that gadolinium may be present in the urine for a prolonged period”.  The authors did not mention if any of the subjects complained of new, unexplained symptoms at any time point after contrast administration.  However, as the authors stated, the study clearly demonstrates that the current reference ranges are inappropriate.

My thoughts –

The findings of this pilot study by Alwasiyah et al. appear to confirm the gadolinium urine testing data published by The Lighthouse Project which reported prolonged excretion of gadolinium from MRI contrast agents in patients with normal renal function.  The authors referenced our 2017 paper, Gadolinium Retention from Contrast MRIs in 70 Cases with Normal Renal Function: 24-hour Urine Test Results.  However, we did not attribute various symptoms of “gadolinium toxicity” to “elevated” urinary gadolinium levels months after undergoing an MRI with a gadolinium-based contrast agent.  Since the symptoms of “gadolinium toxicity” are likely being caused by the gadolinium that an individual has retained in his or her bones and other tissues, the amount being excreted isn’t the real issue.

Hubbs Grimm and I utilized urine gadolinium levels as evidence of a problem with GBCAs that we believe likely explains the new symptoms that developed soon after contrast administration in those individuals whose testing data was included in the paper, as well as in the other affected people we know.

I believe the big takeaway from this study is confirmation of the fact that 100% of the injected gadolinium is not out of the patient’s body in two or three days as it was supposed to be in someone with normal kidney function.  According to the findings of this pilot study, patients are likely to be excreting gadolinium for at least a month or two after their MRIs with a GBCA.  In our December 2018 paper, we report urine test results from as long as 10 years after contrast administration.  Are we to believe that when urinary gadolinium levels fall well below the reference range that most of the injected gadolinium is out of the patient’s body?  We know from the literature that is likely not the case since gadolinium has been found in bone removed from patients with normal renal function in a matter of days after administration of a linear and macrocyclic GBCA (Gibby, 2004), and it was found in bone more than 8 years after contrast administration (Darrah, 2009).  A more recent study detected more gadolinium in bone than in brain or skin tissues (Murata, 2016).  Gadolinium deposited in bone and other tissues is no longer in circulation and readily available for excretion.  Urine levels of gadolinium do not tell us how much more gadolinium is in the patient’s bones and other tissues.

I hope that researchers won’t focus on trying to establish a more accurate “reference range”.  It is important to remember that the current reference range is not the same thing as a “normal” level of gadolinium since gadolinium is not found naturally in the human body.  In my opinion, no long-term excretion of gadolinium should be acceptable, and someone who never has had a contrast-enhanced MRI before should be excreting significant amounts of gadolinium in his or her urine, as a few subjects in this pilot study did prior to their “first” MRI with a GBCA.  If that much gadolinium came from their drinking water, then there is another potentially serious health risk that needs to be investigated – anthropogenic gadolinium.

Sharon Williams

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References
Alwasiyah, D., Murphy, C., Jannetto, P., Hogg, M., & Beuhler, M. C. (2018). Urinary Gadolinium Levels After Contrast-Enhanced MRI in Individuals with Normal Renal Function: a Pilot Study. Journal of Medical Toxicology. http://doi.org/10.1007/s13181-018-0693-1

Grimm H and Williams S, The Lighthouse Project (2017). Gadolinium Retention from Contrast MRIs in 70 Cases with Normal Renal Function: 24-hour Urine Test Results.  https://gadoliniumtoxicity.com/contrast-mri-gadolinium-retention-70-cases-final/

Grimm H and Williams S, The Lighthouse Project (2018). Gadolinium Clearance Times for 135 Contrast MRI Cases, Including Urine Test Results by Agent Administered for 63 Unconfounded Cases.  https://gadoliniumtoxicity.com/gadolinium-clearance-times-for-135-contrast-mri-cases-final-v1-1/

Gibby, W. A., Gibby, K. A., & Gibby, W. A. (2004). Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Investigative Radiology, 39(3), 138–42. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15076005

Darrah, T. H., Prutsman-Pfeiffer, J. J., Poreda, R. J., Ellen Campbell, M., Hauschka, P. V, & Hannigan, R. E. (2009). Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics : Integrated Biometal Science, 1(6), 479–488. Retrieved from http://pubs.rsc.org/en/content/articlehtml/2009/mt/b905145g

Murata, N., Gonzalez-Cuyar, L. F., Murata, K., Fligner, C., Dills, R., Hippe, D., & Maravilla, K. R. (9000). Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function. Investigative Radiology, Publish Ah. Retrieved from http://journals.lww.com/investigativeradiology/Fulltext/publishahead/Macrocyclic_and_Other_Non_Group_1_Gadolinium.99224.aspx

Hatje V, Bruland KW, F. A. (n.d.). Increases in anthropogenic gadolinium anomalies and rare earth element concentrations in San Francisco Bay over a twenty-year record. Retrieved January 24, 2016, from http://pubs.acs.org/doi/pdf/10.1021/acs.est.5b04322

Martino, C., Costa, C., Roccheri, M. C., Koop, D., Scudiero, R., & Byrne, M. (2018). Gadolinium perturbs expression of skeletogenic genes, calcium uptake and larval development in phylogenetically distant sea urchin species. Aquatic Toxicology, 194, 57–66. http://doi.org/https://doi.org/10.1016/j.aquatox.2017.11.004