Gadolinium is a toxic lanthanide metal with ideal paramagnetic properties to enhance T1-weighted magnetic resonance images. Gadolinium-based contrast agents are formulated ligands with very strong affinities for the metal to reduce it’s toxicity. Gadolinium-based contrast agents are formulated polyamino carboxylate ligands with strong affinities for the metal (Table).
*Agents in bold represent macrocyclic ligands, and italicized brands are ionic. Generic names were searched in PubMed. ACR, American College of Radiology. †Search terms were for ‘nephrogenic systemic fibrosis’ and ‘gadolinium deposition disease.’
Gadolinium-induced systemic fibrosis has been a recognized chronic and severe reaction since 2006. (‘Nephrogenic’ systemic fibrosis is a misnomer. Gadolinium is the cause of gadolinium-induced systemic fibrosis; renal insufficiency seems to be a catalyst [see PDF link to transcript of an FDA meeting]). This condition manifests after gadolinium-based contrast agent exposure with symptoms occurring immediately, days to years after administration. From many different case control studies (reviewed in table 1 here), the odds ratio for the association between gadolinium based contrast exposure and subsequent systemic fibrosis may range from 20.6 to 40.3, i.e., higher than the association between smoking and lung cancer.
The syndrome was recognized in 1997, yet there are still no cures. Gadolinium-induced systemic fibrosis is not universally fatal. Therefore many are still living with this affliction. For instance, the woman presented as case 37-2009 in the New England Journal of Medicine was present at the 2017 Food & Drug Administration Medical Imaging Drugs Advisory Committee meeting concerning gadolinium retention in patients with normal renal function.
Although renal insufficiency (acute or chronic) is the most common risk factor for gadolinium-induced systemic fibrosis, there are rare cases have been documented even with GFRs above 30 (albeit with other risk factors such as multiple gadolinium doses) (even with American College of Radiology (ACR) group II agents). As multiple brands of these agents have induced systemic fibrosis, it is well-recognized that gadolinium is the cause, a case well laid out in this literature review. Whether the chemical properties lend some to trigger the disease more than others is debatable.
Gadolinium induces infiltration of bone marrow-derived cells to target organs in a redox-dependent manner. Macrocyclic agents demonstrate greater in vitro toxicity and in vivo pro-fibrotic markers (transforming growth factor β) in skin. Bone marrow retains a ‘memory’ of prior gadolinium-based contrast agent exposure. Gadolinium-based contrast agents lead to the formation of gadolinium-rich nanostructures in the skin and kidney, akin to what has been found in the brain neurons of exposed patients. Gadolinium-based contrast agents are quite active biologically.
Based on retrospective data, the ACR grouped the brands of gadolinium-based contrast: Group I, associated with a relatively high number of single-agent-induced systemic fibrosis cases (‘group I’); Group II, associated with few unconfounded cases; Group III, where data were limited (Table).
Dr. Prasad Shankar, M.D., and his colleagues sought to re-examine the purported risk of systemic fibrosis with these group II agents by conducting a literature review and meta-analysis. By focusing only on single-agent or unconfounded cases, the authors hoped to detect differences among group II agents (see footnote 1).
Several institutions and agencies urge reduction in the use of gadolinium: (regardless of renal function): the National Institutes of Health, the American College of Radiology/American Society of Nuclear Radiology, Health Canada, the Australian Government, the European Medicines Agency, the International Society of Magnetic Resonance Medicine, Medsafe (New Zealand), Japan’s Pharmaceuticals and Medical Devices Agency, the United States Food & Drug Administration, and the Canadian Association of Radiology.
A small market share and appearance of newer agents well after practices changed biases any retrospective analysis that seeks to measure relative risk. ‘Nephrogenic’ systemic fibrosis is a black swan; risk estimates are very difficult to ascertain from retrospective data. Critically, the authors found a non-zero risk for systemic fibrosis with group II agents despite the very large limitations of studies that are underpowered to detect a very rare disorder.
The consequences of long-term and intracellular retention of gadolinium are of concern. Gadolinium should be used only when medically necessary. For ethical reasons, don’t expect prospective safety trials. This meta-analysis measured the risk of a black swan disease over limited time windows in just sixteen publications.
Can gadolinium-associated systemic fibrosis occur with ACR group II agents?
MultiHance has caused gadolinium-induced systemic fibrosis (at a seemingly normal plasma creatinine in a malnourished patient). Gadavist has induced gadolinium-induced systemic fibrosis. It should be noted, “In 11 reports, a macrocyclic [gadolinium-based contrast agent] was administered in closest temporal association to the onset of” systemic fibrosis-like symptoms.
The authors state, “the harms of delayed diagnosis and misdiagnosis resulting from withholding of contrast material in at-risk patients are incompletely measured but likely real.” This is true, which is why a full understanding of why gadolinium has this profound and unpredictable effect is so pertinent. Zealous administration of contrast agents, the momentum of our healthcare systems to overuse pharmaceuticals presupposed to be safe, and overtesting patients led to frequent exposure of high-risk patients to gadolinium before 2007 (see footnote 2). This study was about estimating the risk of gadolinium-induced systemic fibrosis, not about the hypothetical benefits of contrast (see footnote 3). For patients (and for patient-centered diagnosticians), this is a critical point, as recipients deserve to know that the decision to undergo a contrast-enhanced procedure should balance the non-zero risk of a life-long tortuous condition versus what potential beneficial information the MRI will produce.
Gadolinium is the cause of gadolinium-induced systemic fibrosis. Many—if not most—cases of gadolinium-induced systemic fibrosis are multiagent/confounded reports. This reflects contemporary diagnostic practices. Most patients with gadolinium-induced symptoms who contact us have had multiple exposures with different brands of contrast agent (see footnote 4). Despite severely limiting the cases of gadolinium-induced systemic fibrosis down to single-agent reports in Dr. Woolen’s et al. analysis, the confidence interval for systemic fibrosis from ACR group II agents remained non-zero. If the medical system is cavalier about administering gadolinium into high-risk patients expect more black swan cases of systemic fibrosis. Perhaps we shouldn’t gamble using patients’ lives. Perhaps we should not make our mistakes in haste.
Commentary by Brent Wagner, Director, Kidney Institute of New Mexico; Associate Professor of Medicine, Division of Nephrology, University of New Mexico Health Science Center; Renal Section Chief and acting Associate Chief of Staff for the Research & Development Service, New Mexico Veterans Administration Health Care System
Footnotes:
The American College of Radiology group II agents are Dotarem, Gadavist, MultiHance, and ProHance
Often at high doses for off-label uses such as contrast-enhanced magnetic resonance angiographies.
An appropriate interpretation, grounded in the statistical results of narrowly-selected papers, would be that the risk of systemic fibrosis with ACR group II gadolinium-based contrast is not zero.
Finding single-agent cases is akin to finding an individual who has never tasted a Pepsi, Dr. Pepper, Mountain Dew, or a—blech!—Big Red.