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. London tap water has been previously shown to contain a Gd concentration of 12.3 pmol/L, and other large European cities have detectable Gd concentrations in their tap water and wastewater (Ebrahimi, 2019, & Kulaksiz, 2011).

For Comparison –

Here are the current reference values used by Mayo Clinic, Doctor’s Data, and Genova Diagnostics. Genova Diagnostics’ reference range is closest to the proposed Gd reference interval of <0.036 μg/g creatinine for a spot urine sample from someone who has never been exposed to a GBCA.  Note that μg and mcg both stand for microgram, and reference value, reference interval, and reference range mean the same thing.

Mayo Clinic, Gadolinium, 24 Hour, Urine – Reference Values: 0.0-1.0 mcg/24 Hr
Mayo Clinic, Gadolinium/Creatinine Ratio, Random, Urine – Reference Values: <0.8 mcg/g creatinine
Mayo Clinic, Gadolinium, Serum – Reference Values: <0.5 ng/mL

Doctor’s Data, Toxic Metals, 24 Hour Urine, includes Gd – Reference Intervals: Female, <0.6 mcg/ 24 Hr or <0.8 mcg/g creatinine; Male, <1.0 mcg/24 Hr or <0.5 mcg/g creatinine

Genova Diagnostics, Toxic Element Clearance Profile, Ratio to Creatinine – Gd Reference Range:  <0.019 mcg/g creatinine

My Thoughts –

While Mayo Clinic has not published the data from which its urine Gd reference value was derived, it is my understanding that the subjects used to establish Mayo’s current reference value indicated that they had not had any prior exposure to gadolinium-based contrast agents. I have questioned that with Mayo in the past, as I do not see how anyone who has never had any MRIs with contrast would be excreting enough gadolinium to establish a 24-hour reference interval that now goes up to 1.0 mcg/24 hours. The study by Layne et al. appears to support my thinking on that. (Note that in 2012, Mayo Clinic’s 24-hour urine Gd reference value was 0.0-0.4 mcg, then it went up to 0.7 mcg, and now it is up to 1.0 mcg/24 hours).

Based on the findings of the Layne et al. study, it does not appear that anthropogenic gadolinium can be used to explain the prolonged urinary excretion levels of Gd in patients with normal renal function after their exposure to a GBCA. According to the authors, London’s tap water has previously been shown to contain gadolinium at a concentration of 12.3 pmol/L. One would have to consume extremely large quantities of water to significantly raise the amount of gadolinium in a specimen from a 24-hour urine collection.

I am often asked, what is the “normal” amount of gadolinium to have in urine specimens?  My answer is always the same – there is no such thing as a “normal” amount of Gd since it has no biological use in our body; the FDA made a similar comment in its Briefing Document (footnote #7, page 16) for the September, 8, 2017, public meeting about gadolinium retention. I have told patients that I have always felt that Genova Diagnostics’ reference range is probably more in line with what might be considered “normal” in someone who has never had MRIs with contrast.  The study by Layne et al. seems to confirm that as well.

Urine Gd levels don’t tell us everything –

I think it is important to remember that urine test results just tell us how much gadolinium (Gd) was excreted in that one 24-hour or spot urine specimen. It does not tell us how much more Gd an individual may have deposited or retained in his or her brain, bones, skin, and other internal organs – that is the gadolinium that we should be concerned about, and it is likely the gadolinium that is causing the symptoms of gadolinium toxicity reported by patients after their MRIs with a GBCA.

Sharon Williams
______________________

References:
Layne, K. A., Wood, D. M., Dixon-Zegeye, M., Archer, J. R. H., Raja, K., & Dargan, P. I. (2020). Establishing Reference Intervals for Gadolinium Concentrations in Blood, Plasma, and Urine in Individuals Not Previously Exposed to Gadolinium-Based Contrast Agents. Investigative Radiology, 55(7), 405–411. https://doi.org/10.1097/rli.0000000000000657

Ebrahimi, P., & Barbieri, M. (2019). Gadolinium as an Emerging Microcontaminant in Water Resources: Threats and Opportunities. Geosciences. https://doi.org/10.3390/geosciences9020093

Kulaksız, S., & Bau, M. (2011). Anthropogenic gadolinium as a microcontaminant in tap water used as drinking water in urban areas and megacities. Applied Geochemistry, 26, 1877–1885. https://doi.org/10.1016/j.apgeochem.2011.06.011

Mayo Clinic Laboratories. Gadolinium, 24 Hour, Urine. Accessed July 8, 2020 at:
https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/89301

Mayo Clinic Laboratories. Gadolinium/Creatinine Ratio, Random, Urine. Accessed July 8, 2020 at: https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/60428

Mayo Clinic Laboratories. Gadolinium, Serum. Accessed July 8, 2020 at: https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/89299

Doctor’s Data, Inc. Toxic Metals, 24 Hour Urine, includes Gd. Accessed July 8, 2020 at: https://www.doctorsdata.com/urine-toxic-metals/

Genova Diagnostics, Toxic Element Clearance Profile, Ratio to Creatinine. Accessed July 8, 2020 at: https://www.gdx.net/product/toxic-element-clearance-test-urine

FDA. (2017). FDA Briefing Document, Sept 8, 2017, Medical Imaging Drugs Advisory Committee Meeting, Gadolinium Retention after Gadolinium-Based Contrast MRI in Patients with Normal Renal Function. Retrieved from https://www.fda.gov/media/107133/download