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FDA Public Meeting about Risk of Gadolinium Retention from GBCAs

On September 8, 2017, the FDA’s Medical Imaging Drugs Advisory Committee (MIDAC) will meet to discuss the potential risk of gadolinium retention in the brain and other body organs in patients receiving gadolinium-based contrast agents (GBCAs) for MRI procedures.

During the Open Public Hearing (OPH) portion of the meeting, 75 minutes have been allotted to interested persons to present data, information, or views, orally or in writing.   The deadline for requesting time to speak has passed.  However, interested parties have until September 7, 2017 to submit electronic or written/paper submissions related to the issue of gadolinium retention.  Note that the Docket No. for the meeting is FDA-2017-N-1957 and it must be included on all submissions

An updated announcement about the meeting can be found here: https://www.fda.gov/AdvisoryCommittees/Calendar/ucm571112.htm

CDER (Center for Drug Evaluation and Research) plans to provide a live webcast of the September 8, 2017 MIDAC meeting.  Information about the web address for the webcast will be made available at least 2 days before the meeting.  See the updated announcement for more information about the webcast.

The Medical Imaging Drugs Advisory Committee Meeting Briefing Document titled, Gadolinium Retention after Gadolinium Based Contrast Magnetic Resonance Imaging in Patients with Normal Renal Function, is available for download:  https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/MedicalImagingDrugsAdvisoryCommittee/UCM572848.pdf

Sharon Williams and Hubbs Grimm have submitted comments and supporting materials from The Lighthouse Project at GadoliniumToxicity.com for Docket No. FDA-2017-N-1957.

Open Letter to the FDA about Gadolinium-based Contrast Agents

Editorial – May 25, 2017
Sharon Williams

I am very disappointed and frustrated by the May 22, 2017, FDA Safety Announcement about gadolinium-based contrast agents (GBCAs).  I am beginning to wonder how many more people must be adversely affected by retained gadolinium before the FDA decides to take decisive action.

Personally, I don’t blame the FDA or radiologists for what happened to NSF patients.  What happened to those patients was terrible, but I want to believe that no one knew then just how unstable the linear agents are, especially when they remain in the body for longer periods of time like they might do in renally-impaired patients.  However, once the connection between NSF and GBCAs was discovered in 2006, that all began to change.  No longer could the FDA and radiology community say that they didn’t know that gadolinium might be retained from MRI contrast agents or what it might do to the human body when that occurred.

From 2006 until the end of 2013, the FDA and medical community thought that only patients with severe renal problems were at risk of retaining gadolinium.  Warnings were issued and action was taken to better screen renally-impaired patients and reports of new cases of Nephrogenic Systemic Fibrosis (NSF) dropped dramatically.  However, no one seemed to be investigating what might happen when less gadolinium was retained such as what might occur in patients with “normal” renal function or eGFRs greater than 60.

Since December of 2013 and the first paper by Kanda and his colleagues, the evidence has been mounting that clearly shows that patients with normal renal function retain gadolinium in their brains, bones, and elsewhere in their bodies. This seemed to be news to the FDA and radiology community, but it was something that patients affected by gadolinium have long been trying to tell their doctors.  I first brought it to the attention of the FDA in my letter of October 23, 2012.  In that letter, I noted that evidence of gadolinium retention in patients with normal renal function was reported by Gibby et al. in 2004 – that was 13 years ago, and it occurred after administration of both a linear and a macrocyclic GBCA.

The published literature clearly states that “gadolinium is toxic”.  The FDA has acknowledged that “all GBCAs may be associated with some gadolinium retention in the brain, and other body tissues”.  So why is it okay to keep injecting the least stable gadolinium-based contrast agents into patients when it is highly likely that those people are going to retain some unknown amount of a toxic metal?  Gadolinium is a toxic metal that has been found to be neurotoxic, to impair mitochondrial function, induce oxidative stress, and much more.  Researchers are looking for histological changes in the brain, but what about functional changes? (more…)

New Study Reports Gadolinium Retention in 70 Cases with Normal Kidney Function

Full-disclosure, we are reporting on our own retention paper.

Today we have released our fourth research paper on gadolinium retention from Gadolinium-based Contrast Agents (GBCAs) administered for contrast-enhanced MRIs. The paper is titled “Gadolinium Retention from Contrast MRIs in 70 Cases with Normal Renal Function – 24-hour Urine Test Results”.

Drawing on the contrast MRI history and 24-hour gadolinium urine testing results information that we have received from members of the MRI-Gadolinium-Toxicity Support Group, we reported retrospectively on 70 cases with 120 urine test results.  We are thankful to the members of our support group for being willing to share their information with us.  The participants all had normal kidney function and report having symptoms of gadolinium toxicity. We believe the results reported are dramatic.

About the Gadolinium Retention Study

The number of results presented is up significantly from our last paper in 2014 when we reported on 15 cases and 40 test results.  The additional data points allowed us to look at gender as a possible differentiator, but the data showed nearly identical test results for males and females.  With information about the number of contrast-enhanced MRIs for each case, we were able to analyze the results in three groups: cases with a single contrast MRI, cases with 2 to 4 contrast MRIs, and cases with 5 or more contrast MRIs.  Readers of this site will not be surprised that the analysis showed that for these cases, there was a discernible difference in test results based on these groupings.  The 2 to 4 contrast group generally had higher levels of gadolinium in their urine for a longer period of time than those with a single contrast.  Likewise, the results for the 5 or more MRIs group were higher longer than the cases in the 2-4 contrast MRIs group.  This is consistent with the cumulative effect of multiple contrast-enhanced MRIs that others have reported.

We also provided the raw test results data for each case, enabling other researchers as well as patients to look at the progression of test results over time.  Averages for time blocks since the last contrast MRI are also shown to help in understanding the progression of gadolinium urine levels.

A few observations regarding the test results are revealing.  21 cases had urine tests performed in the first month with results that range from 507 mcg Gd/24hr urine specimen 4 days after the contrast MRI to results around 17 mcg Gd/24hr near the end of the first month.  All of the results are enumerated in the report.  8 cases had urine test results more than 36 months after their contrast MRI with results as high as 0.6 mcg Gd/24hr more than 7 years after the individual’s last contrast-enhanced MRI.  There is no broadly utilized acceptable range for gadolinium in a 24-hour urine collection. Mayo Clinic has established a reference range that was recently updated to be 0.0-0.6 mcg Gd/24-hour urine specimen collected more than 96 hours after administration of a GBCA.  40 cases had urine tests in the first 3 months after their contrast MRI, with the lowest result being 1.74 mcg Gd/24hr, well above the Mayo reference range that is applicable once four days have elapsed since the contrast MRI.  Simply stated the results we observed are inconsistent with the clearance times indicated on GBCA product labeling and the understanding of most researchers and clinical practitioners.

Final Thoughts

To the best of our knowledge, this is the most comprehensive reporting of retained gadolinium as evidenced by urine testing that is available to the public.  While the methods we used do not meet the rigor of a clinical trial, and we do not know if similar results would be seen universally, we believe the consistency of the results and the lack of outliers on the low side are justification for concern.  We believe that further investigation by researchers, GBCA manufacturers, and licensing agencies is warranted.

This study does not stand alone, but confirms the many recently published research papers that reported unexpected retention of gadolinium from contrast MRIs by people with normal renal function.  We encourage stronger action by the FDA and others to inform patients about possible gadolinium retention from contrast-enhanced MRIs and the potential for long-term side-effects.

We urge patients, clinicians, and researchers to read the entire report and share as appropriate with your families, care-givers, and colleagues.  Read the Report.

Hubbs Grimm and Sharon Williams

Gadolinium Bioeffects and Toxicity – Special Issue of MRI Journal

A special issue of the journal Magnetic Resonance Imaging has been published and it is dedicated to “Gadolinium Bioeffects and Toxicity”.  The issue starts with a safety overview of GBCAs by MRI Safety expert Dr. Emanuel Kanal, and ends with articles by UNC Radiologist Dr. Richard Semelka.  One of the articles provides the initial description of Gadolinium Deposition Disease (GDD) which, while recently named, has been around for a while.

The issue is broken down into 4 sections as shown below.  The link will take you to the abstract, but you can access a PDF of the complete paper.

Introduction –
Kanal, E. (2016). Gadolinium based contrast agents (GBCA): Safety overview after 3 decades of clinical experience. Magnetic Resonance Imaging. http://doi.org/10.1016/j.mri.2016.08.017

MRI Findings –
Kanda, T., et al (2016). Gadolinium deposition in the brain. Magnetic Resonance Imaging, 34(10), 1346–1350. http://doi.org/10.1016/j.mri.2016.08.024

Radbruch, A. (2016). Are some agents less likely to deposit gadolinium in the brain? Magnetic Resonance Imaging, 34(10), 1351–1354. http://doi.org/10.1016/j.mri.2016.09.001

Ramalho, J., et al, (2016). Technical aspects of MRI signal change quantification after gadolinium-based contrast agents’ administration. Magnetic Resonance Imaging, 34(10), 1355–1358. http://doi.org/10.1016/j.mri.2016.09.004

Basic Sciences –
Murata, N., et al, (2016). Gadolinium tissue deposition in brain and bone. Magnetic Resonance Imaging, 34(10), 1359–1365. http://doi.org/10.1016/j.mri.2016.08.025

Prybylski, J. P., et al, 2016). Gadolinium deposition in the brain: Lessons learned from other metals known to cross the blood–brain barrier. Magnetic Resonance Imaging, 34(10), 1366–1372. http://doi.org/10.1016/j.mri.2016.08.018

Swaminathan, S., et al, (2016). Gadolinium toxicity: Iron and ferroportin as central targets. Magnetic Resonance Imaging, 34(10), 1373–1376. http://doi.org/10.1016/j.mri.2016.08.016

Tweedle, M. F., et al, (2016). Gadolinium deposition: Is it chelated or dissociated gadolinium? How can we tell? Magnetic Resonance Imaging, 34(10), 1377–1382. http://doi.org/10.1016/j.mri.2016.09.003

Future Directions –
Semelka, R. C., et al, (2016). Gadolinium deposition disease: Initial description of a disease that has been around for a while. Magnetic Resonance Imaging, 34(10), 1383–1390. http://doi.org/10.1016/j.mri.2016.07.016

Prybylski, J. P., et al, (2016). Can gadolinium be re-chelated in vivo? Considerations from decorporation therapy. Magnetic Resonance Imaging, 34(10), 1391–1393. http://doi.org/10.1016/j.mri.2016.08.001

Ramalho, J., et al, (2016). Gadolinium toxicity and treatment. Magnetic Resonance Imaging, 34(10), 1394–1398. http://doi.org/10.1016/j.mri.2016.09.005

Semelka, R. C., et al, (2016). Summary of special issue on gadolinium bioeffects and toxicity with a look to the future. Magnetic Resonance Imaging, 34(10), 1399–1401. http://doi.org/10.1016/j.mri.2016.09.002


My thoughts –
I believe this Special Issue is an important step in moving the discussion about gadolinium retention in patients with normal renal function forward.  It seems that everyone now agrees that all patients exposed to gadolinium-based contrast agents retain some gadolinium from each dose of contrast that they receive. However, regardless of what you call it, patients are suffering from the toxic effects of retained gadolinium.

There is no doubt in my mind or the minds of other affected patients that retained gadolinium can cause chronic clinical symptoms of varying severity. Hopefully a large population of affected patients will be interviewed and examined soon.  I believe that discussing symptoms with patients might trigger a thought process that leads researchers to uncover the missing pieces of the puzzle that explain the difference between what has been seen in brain tissue that contains gadolinium and the symptoms that patients are experiencing.

Sharon Williams
12/2/16

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