Gadolinium Deposition Disease: A Case Report and the Prevalence of Enhanced MRI Procedures Within the Veterans Health Administration

Retention of Gd can be modeled as a function of time (t) by the half-lives of the fast, intermediate, and slow phases of elimination (T_a, T_b, and T_c, respectively):⁹

A, B, and C are the proportions (adding to 100%) that represent each of the compartments: quickly, intermediately, and slowly equilibrated spaces. The rate constants for renal elimination from the plasma (K_P0,) flux from the fast space to plasma (K_FP) and from the slowly equilibrated space to plasma (K_SP) are components of the total Gd elimination from these compartments, respectively (Figure 3). It is improbable that Gd is liberated from the multidentate formulations that constitute MRI contrast agents given the relatively high affinities for the toxic lanthanide metal, the low volume of distribution, and the rapid—essentially entirely renal—elimination rates (Figure 4). Nonetheless, Gd is retained long-term in subjects with normal renal function, in symptomatic patients, permanently in the brains of patients, and in every organ we have tested with our animal models.^3,7,8,10-12 Patients with normal renal function continue to report symptoms attributed to Gd-based contrast agents concomitant with retarded elimination.

Numerous patients with normal renal function developed similar or novel symptoms that have been attributed to Gd concomitant with detectable urinary Gd years after exposure.¹¹ Gd-based contrast agents are increasingly associated with cutaneous abnormalities even outside of nephrogenic systemic fibrosis. Gd-associated plaques develop in patients without kidney disease—these range from asymptomatic, pruritic, to burning.¹³ Histologic specimens reveal CD68 and factor XIIIa–positive spindle-shaped myeloid cells (the same mediators of iatrogenic systemic fibrosis) or CD34-positive cells. CD68 and factor XIIIa are distinctive for histologic specimens from patients with systemic fibrosis, and these markers have been detected in our preclinical models that demonstrated that bone marrow–derived cells are involved in mediating fibrosis.^3,4,14-19 Similarly, CD34-positive cells have been historically associated with systemic fibrosis lesions.^15,16,18-23 Plump osteocyte-appearing cells have also been noted (note that extraosseous metaplasia makes the histologic diagnosis of systemic fibrosis).¹⁴ Nephrogenic systemic fibrosis is an iatrogenic disease that can manifest years after exposure to Gd.⁵ Gd induces the recruitment of bone marrow–derived cells to the affected sites.⁴

The VA Health Service Research and Development Evidence Synthesis Program reviewed the safety of Gd-based contrast agents in patients with impaired kidney function.^24,25 The group found only a single study of Gd and veterans. “Awareness and concern are growing about the long-term deposition of gadolinium in [the] brain and other tissues among patients with normal kidney function,” according to Lunyera and colleagues.²⁵ The largest knowledge gap was that a comprehensive review “of all potential harms associated with gadolinium exposure” was not addressed. Furthermore, the group advised “caution in the use of [Gd-based contrast agents] in patients with severely impaired kidney function and acute kidney injury remains prudent, because the exact clinical factors contributing to [nephrogenic systemic fibrosis] risk in these subpopulations are still unknown.”²⁵

Gd-based contrast agents—contrary to a widely held misconception—are not biologically inert.¹ Gd-based contrast agents have a long history of association with acute renal injury. We have demonstrated that systemic treatment with MRI contrast agents leads to vacuolization of the proximal tubule and tubular injury.^7,8 Kidney injury may be mediated by the generation of reactive oxygen species from NADPH oxidase 4 (Nox4).²⁶

Gd retention, Gd-induced multisymptomatic illnesses, Gd-associated plaques, Gd-induced neurotoxicity, and nephrogenic systemic fibrosis are part of a continuum (with Gd as the common thread)—a theme of the September 8, 2017, US Food and Drug Administration (FDA) Medical Imaging Drugs Advisory Committee meeting.²⁷ Patients, patient advocacy groups, and regulating agencies are concerned about long-term retention of a nonphysiologic rare earth element such as Gd.^28-30 A patient advocacy group, The Lighthouse Project, collected information from patients linking the last date of Gd-based contrast agent exposure and urinary Gd.¹¹ Data from their report suggest that the rate constants (valuable for the elimination equation above) are obtainable from 24-hour urine collections. Conceptually, Gd-induced diseases may represent a continuum that results from the retention of a nonphysiologic, toxic heavy rare earth metal.

As a heavy metal, Gd is not a natural physiologic trace element. Similar to numerous nonphysiologic metals, Gd is toxic. Inhaled Gd oxide (Gd₂O₃) dust leads to a number of time-dependent pathologies. Animal lung studies demonstrate reduced elasticity, enlarged cells, thickened lung walls, and recruitment of immune cells.³¹ Symptoms of acute IV Gd toxicity include decreased respiration, lethargy, abdominal cramps, and diarrhea.³² Pharmacologically, Gd concentrates in the liver and kidney and accumulates in the bone.³² Animals demonstrate intestinal depression and low blood pressure in response to Gd and, with higher doses, cardiovascular collapse.³² IV Gd chloride leads to metal deposition in the small blood vessels diffusely throughout the body, particularly in the lung and kidney and the metal is absorbed by the scavenging white blood cells.³³ Gd chloride induces severe damage to the liver, spleen, and the digestive tract.³³ Furthermore, this form of the toxicant metal markedly impacted functions associated with bleeding and clotting, ie, decreased platelet numbers and an increase in the laboratory-measured coagulation parameters.³³ Semelka and colleagues have characterized chronic symptoms attributed to Gd-based contrast agents (not limited to chronic pain, headache, bone pain, skin thickening, and clouded mentation).^34,35 Because Gd-induced conditions are underrecognized and ill-defined, disinherited patients often resort to untested (and potentially dangerous) chelation therapies.³⁶

This patient presented with numerous symptoms that arose after Gd exposure. It is well established that Gd-based contrast agents (of any class) are retained in multiple organs (including the brain), for months to years. Gd-based contrast agents enter the cerebrospinal fluid within minutes of IV administration.³⁷ Gd was found in the cerebrospinal fluid 9 months after administration in a case presented to the FDA Medical Imaging Drugs Advisory Committee.³⁸ We know from intentional and accidental intrathecal administrations that Gd-based contrast agents are neurotoxic.³⁹ Runge and colleagues demonstrated that Gd-based contrast agents exert mitochondrial toxicity in cultured neurons in vitro.⁴⁰ McDonald and his team found Gd-rich nanoparticles within the brain neurons (cytoplasm and nuclei) from patients exposed to MRI contrast in the normal course of care.⁴¹ These nanoparticles are similar to what we have found in rodent models of Gd-induced disease.^7,8,42