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Gadolinium detected in skin of patients with impaired renal function, but no NSF: What does that prove?

Editorial by Sharon Williams
July 2020


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.

Sharon Williams
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References:
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

 

FDA makes change to GBCA Medication Guide requirement

On December 19, 2017, the FDA issued a new Safety Announcement related to gadolinium-based contrast agents (GBCAs) administered for MRIs.  One of the actions described in the announcement was the requirement that every patient be given a Medication Guide to read before receiving a GBCA.  The Medication Guides for all GBCAs are now available.  However, on May 16, 2018, the FDA issued an Update to the requirement that patients be given the Medication Guides prior to their MRIs.

It appears that the FDA has determined that, “hospital inpatients are not required to receive a Medication Guide unless the patient or caregiver requests it”.

Since most people are not aware that patients are retaining gadolinium from GBCAs administered for MRIs or that gadolinium is a toxic metal, they will not know to ask for a copy of the Medication Guide or that one even exists.  That will result in a vulnerable population of patients not being fully-informed about the potential risk of gadolinium deposition in their brain, bones, skin, and other tissues.

As documented in the medical literature, patients in hospitals are at greater risk of having an acute kidney injury or AKI which can impair patients’ kidney function and potentially cause them to retain more gadolinium.  I believe that patients in hospitals and/or their families should be informed about that risk and they should be given a Medication Guide for the GBCA that will be administered for any inpatient imaging procedures.

The following is the FDA’s May 16, 2018 Update – (more…)

FDA’s response to GBCA Safety Issues – More warnings and a Medication Guide

On December 19, 2017, the FDA issued an update to its Drug Safety Communication regarding brain retention of gadolinium-based contrast agents (GBCAs) used for MRIs.  Despite mounting evidence that GBCAs leave gadolinium in the brain, bones, and other tissues of all patients who undergo MRIs with contrast, the FDA has decided not to suspend the use of any GBCAs.  This is in stark contrast to the actions taken by the European Medicine’s Agency and the U.K.’s Medicines and Healthcare Products Regulatory Agency.   Those agencies suspended the use of the linear agents Magnevist, Omniscan, and OptiMark, while requiring changes to all GBCA product labeling. The Japanese Ministry of Health, Labour and Welfare restricted the use of non-specific linear GBCAs only to cases where there is no alternative and it also required changes to product labeling.

In its Safety Alert, the FDA acknowledged that “linear GBCAs result in more retention and retention for a longer time than macrocyclic GBCAs”.  However, the FDA concluded that “the benefit of all approved GBCAs continues to outweigh any potential risks”.  This action was taken despite “reports of adverse events involving multiple organ systems in patients with normal kidney function”.

In response to the issue of gadolinium retention, the FDA is requiring several actions to alert health care professionals and patients about gadolinium retention after an MRI using a GBCA.  These include requiring a new patient Medication Guide for each agent, providing educational information that every patient will be asked to read before receiving a GBCA, and taking actions that can help minimize problems.  The FDA is also requiring manufacturers of GBCAs to conduct human and animal studies to further assess the safety of gadolinium-based contrast agents.  Product labeling for all GBCAs must be changed to include new warnings and precautions.

Each GBCA will have a patient Medication Guide with agent specific information, and content that is required for all gadolinium-based contrast agents; the Medication Guide for MultiHance and ProHance have recently been released.  The Radiology Department of each institution will create educational handouts that every patient will be asked to read before signing the consent form for his or her MRI or MRA with a GBCA.

Patients must be fully-informed about potential risks. (more…)

FDA Advisory Committee votes to revise warnings for all gadolinium-based contrast agents

On September 8, 2017, after a day filled with presentations by drug industry representatives, medical professionals, FDA personnel, and people who have been affected by retained gadolinium, the FDA’s Medical Imaging Drugs Advisory Committee (MIDAC) took two important votes related to gadolinium-based contrast agents (GBCAs) and gadolinium retention.

First, MIDAC members agreed with the FDA’s plan to “revise the prescribing information for GBCAs as a class to include: a warning for retention for all GBCAs, with greater retention of all or some of the linear GBCAs compared to the macrocyclics in certain organs including the brain; recommended risk minimization steps for certain patient populations”.   From the discussions, those populations appear to be pregnant women and children.

Second, MIDAC members agreed, that pending the results of a number of ongoing clinical and preclinical studies, the FDA “might request that manufacturers conduct additional studies that will inform our decisions about the need for further regulatory actions including withdrawal of approval and restriction of indicated populations”.

During his comments to the committee, Dr. Emanuel Kanal formally recommended that “the FDA encourage and/or support formal investigation” of our group.  We hope that one or more additional studies will include members of our MRI-Gadolinium-Toxicity support group.  We fully support Dr. Kanal’s recommendation since we believe people who have been affected by retained gadolinium can provide important data that is not available anywhere else.

During the meeting, no one disputed that gadolinium is toxic or that everyone who has an MRI with contrast retains an unknown amount of gadolinium.  However, there is still disagreement about what, if any, long-term harm retained gadolinium might do to a patient, including someone who has evidence of gadolinium retention months and even years after his or her last contrast-enhanced MRI.

Until the September 8th MIDAC meeting, patients who believe they have been adversely affected by retained gadolinium have been left to their own devices to try to get their chronic health issues recognized as being caused by gadolinium toxicity and to find a way to remove gadolinium from their bodies.  Hopefully, that will soon change.

The Center for Drug Evaluation and Research (CDER) provided a live webcast of the September 8, 2017, MIDAC meeting.  A recording of the webcast can be found at the four following addresses:

Start of Meeting to Morning Break: https://collaboration.fda.gov/p7goy94tum9/
Morning Break to Lunch Break: https://collaboration.fda.gov/p25a1oiwhqd/
Lunch Break to Afternoon Break: https://collaboration.fda.gov/p96q45ae2t3/
Afternoon Break to End of Meeting: https://collaboration.fda.gov/p1qe35bmdkj/

Hubbs Grimm and I, representing The Lighthouse Project and other affected patients, are speaker #2 in the Lunch Break to Afternoon Break video.  That video includes all presentations made during the Open Public Hearing portion of the meeting.

Sharon Williams

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