Since early 2014, there have been numerous articles published that report finding evidence of gadolinium deposition in the brain within the dentate nucleus (DN) and globus pallidus (GP) in patients with normal renal function.  The findings seem to have come as a surprise to some radiologists, but a review article by Huckle et al indicates that no one should be surprised by the findings.  The article, Gadolinium Deposition in Humans – When did we learn that Gadolinium was deposited in vivo?, takes a retrospective look back at gadolinium-based contrast agents (GBCAs) to describe the historical evidence of gadolinium (Gd) deposition in vivo.  According to the authors, it “shows that deposition in the basal ganglia should come as no surprise”.

The article notes that deposition of gadolinium in animals with normal renal function has been described in the peer-reviewed literature since at least 1984 when Weinmann et al reported that although gadolinium elimination in rats was largely complete 7 days after administration of Gd-DTPA, a small fraction (0.3%) was retained.  Other animal studies confirmed gadolinium retention that was proportional to the dose.  Gadolinium was found in bone, skin, and other organs in animals.

The higher stability of macrocyclic GBCAs compared to the linear agents has been confirmed in published animal studies.  However, while higher levels of gadolinium were detected in the skin and bones of animals injected with linear agents, the studies demonstrated that “quantifiable levels of gadolinium” are deposited after administration of all GBCAs – linear and macrocyclic agents.

The main sites of Gd deposition in mice and rats are the liver, kidneys, and femur in both species.  A 1995 study by Tweedle et al found that the concentration of gadolinium retained by the liver and kidneys of mice and rats continued to fall over the course of 7-14 days, but the gadolinium in the femur remained constant.  The review article states that the “elimination half-life from bone has been estimated to be 3500 days for gadolinium, consistent with other metal deposition studies in which elimination is significantly longer than for other tissues”.

Gadolinium retention in humans
Huckle and his colleagues found that the first report of gadolinium retention in humans may have been presented by Tien el al in 1989, a little over 1 year after FDA approval of Magnevist.  That report involved a case of Erdheim-Chester Disease.  Tien et al reported that intracerebral masses “remained enhanced on MR images obtained 8 days after injection of gadolinium DTPA dimeglumine” (Magnevist).  Subsequent chemical analysis revealed that a high concentration of gadolinium remained in the tissue.

In 1998, a report by Joffe et al was among the earliest studies to describe gadolinium retention in patients with severe renal insufficiency.  It was in 1997 that the first cases of NSF were identified in renal dialysis patients, but the connection between NSF and gadolinium-based contrast agents was not made until 2006, first by Grobner, and followed by Marckmann et al.

While there are many published reports about gadolinium deposition in patients with NSF, until recently there have been few reports of gadolinium retention in patients with normal renal function.  However, Huckle’s review article shows that there were early indications of potential problems that were not widely appreciated at that time.  The initial pharmacokinetic studies of Magnevist in 1991 provided an early insight into the potential for incomplete elimination of gadolinium by patients with normal renal function.  The urinary excretion of Magnevist after 48 hours was only 91% + 13.0% in patients with normal renal function.

An early indication of stability issues of GBCAs in healthy patients was reported by Prince et al in 2003 in an article that described spurious hypocalcemia.  Omniscan was the agent most identified with this finding.

In 2004, an important study by Gibby et al showed direct evidence of gadolinium deposition in humans with normal renal function.  Gadolinium was shown to be deposited in the resected femoral heads of patients who had previously undergone a GBCA-enhanced MRI with either Omniscan or ProHance, and then subsequently underwent femoral head replacement surgery.  They found gadolinium in the bone specimens and reported that 2.5 times more gadolinium was deposited with Omniscan than with ProHance.  The significance of that finding is that although Omniscan was deposited in the tissue, so was ProHance, a stable macrocyclic GBCA, which was not associated with NSF.  In 2006, White et al used a different technique for analysis of the same specimens and they determined that Omniscan left 4 times more gadolinium behind in bone than ProHance.

Further evidence of deposition in bone was described by Darrah et al in a 2009 study.  In that study, the gadolinium content of trabecular and cortical bone tissues in patients who underwent total hip replacement surgery with or without exposure to GBCAs was measured.  The results supported the findings of Gibby et al and White et al with high Gd concentrations deposited in bone tissues of patients exposed to both Omniscan and ProHance.  There was no correlation between the concentration of gadolinium deposited in the bone and the time elapsed since exposure to GBCAs.  One subject received the GBCA 8 years earlier, which supports the long elimination half-life of gadolinium in bone.

Gadolinium in the brain
In their summary, Huckle and his colleagues remind us of some important facts.  “Stability differences among GBCAs have long been recognized in vitro and deposition of gadolinium in tissues has been described in animal models since at least the 1980s.  The first major study that showed deposition in humans appeared in 1998 regarding patients with renal failure, and in 2004 in patients with normal renal function.  There has been a large body of evidence that describes deposition of unchelated Gd in tissues known to accumulate calcium, such as the bone and dentate nucleus.  So why does it come as a surprise to radiologists in 2015 that gadolinium can deposit in the basal ganglia of the brain in subjects with normal renal function?”

The authors said that there are likely many explanations.  They suggested that there are 2 main reasons.  “First, many articles have been written regarding gadolinium stability and deposition, although as no visual and highly toxic clinical symptoms have been associated with release in individuals with normal renal function the deposition has been largely overlooked.”  “Second, understanding the chemistry and the significance of certain chemical properties is not among the knowledge sources or bases with which radiologists are familiar.”  As an example, the importance of the conditional stability constant [K_cond] differences between agents is a scientific observation that the clinical radiologist would not recognize as of potential significance.

While there are many reports of gadolinium deposition in both animal models and humans, the authors noted that aside from the early report from Tien et al, there was no mention of deposition of gadolinium in the brain until 2014.  It was thought to occur primarily in the liver, kidney, and bone.

Even if they don’t know the long-term consequences of gadolinium deposition in patients, the authors said that “because unbound gadolinium is a toxic heavy metal, everything else being equal, it makes good sense to minimize the potential load of unchelated gadolinium that patients under our care are experiencing”.  “The starting point is likely the avoidance of the least stable chelates and to continue to search for novel contrast agents with greater thermodynamic and kinetic stability and higher relaxation, with higher relaxation allowing for smaller dose administrations.”

My thoughts
I agree that the starting point should be the avoidance of the least stable agents – immediately.

Everyone agrees that gadolinium is a toxic metal and it should not be in our body, but yet the least stable agents continue to be administered to patients, which puts them at greater risk of retaining gadolinium.  Although there may not be “visual and highly toxic clinical symptoms” as mentioned in the first reason above, patients with normal renal function are retaining gadolinium and many are being adversely affected by its toxic effects.

It is now 10 years since Grobner and Marckmann et al first made the connection between NSF and GBCAs in 2006, and despite all the research that has been performed, no one seems to understand the clinical significance of gadolinium that is retained.

While there are still many unanswered questions about the effects of gadolinium that has been deposited in the brain and elsewhere in the human body, no one can deny that there are safety issues with gadolinium-based contrast agents that have the potential to affect all exposed patients.

I want to thank Dr. Huckle and his colleagues for shedding more light on the issue of gadolinium retention in patients with normal renal function.  As their review article shows, it should not come as a surprise to anyone.

Sharon Williams

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Huckle, J. E., Altun, E., Jay, M., & Semelka, R. C. (9000). Gadolinium Deposition in Humans: When Did We Learn That Gadolinium Was Deposited In Vivo?. Investigative Radiology, Publish Ah. Retrieved from http://journals.lww.com/investigativeradiology/Fulltext/publishahead/Gadolinium_Deposition_in_Humans__When_Did_We_Learn.99255.aspx

Weinmann, H.-J., Brasch, R. C., Press, W.-R., & Wesbey, G. (1984). Characteristics of Gadolinium-DTPA Complex: A Potential NMR Contrast Agent. AJR. Am J Roentgenol., March(142), 619–624. Retrieved from http://www.ajronline.org/content/142/3/619.full.pdf

Tweedle, M. F., Wedeking, P., & Kumar, K. (1995). Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate, and gadodiamide in mice and rats. Investigative Radiology, 30(6), 372–80. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7490190

Tien, R. D., Brasch, R. C., Jackson, D. E., & Dillon, W. P. (1989). Cerebral Erdheim-Chester disease: persistent enhancement with Gd-DTPA on MR images. Radiology, 172(3), 791–2. Retrieved from http://doi.org/10.1148/radiology.172.3.2772189

Joffe, P., Thomsen, H. S., & Meusel, M. (2016). Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Academic Radiology, 5(7), 491–502. Retrieved from http://doi.org/10.1016/S1076-6332(98)80191-8

Grobner, T. (2006). Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association – European Renal Association, 21(4), 1104–8. Retrieved from http://ndt.oxfordjournals.org/content/21/4/1104.full

Marckmann, P., Skov, L., Rossen, K., Dupont, A., Damholt, M. B., Heaf, J. G., & Thomsen, H. S. (2006). Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging. J Am Soc Nephrol, 17, 2359–2362. Retrieved from http://jasn.asnjournals.org/content/17/9/2359.full.pdf

Schuhmann-Giampieri, G., & Krestin, G. (1991). Pharmacokinetics of Gd-DTPA in patients with chronic renal failure. Investigative Radiology, 26(11), 975–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1743921

Prince, M., & et al. (2003). Gadodiamide Administration Causes Spurious Hypocalcemia. Radiology, 227:639–646. Retrieved from http://radiology.rsna.org/content/227/3/639.full.pdf

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

White, G. W., Gibby, W. A., & Tweedle, M. F. (2006). Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Investigative Radiology, 41(3), 272–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16481910

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