Gadolinium-based Contrast Agents Exposure Research Articles

Toxicity Mechanisms of Gadolinium and Gadolinium-Based Contrast Agents-A Review.

Gadolinium-based contrast agents (GBCAs) have been used for more than 30 years to improve magnetic resonance imaging, a crucial tool for medical diagnosis and treatment monitoring across multiple clinical settings. Studies have shown that exposure to GBCAs is associated with gadolinium release and tissue deposition that may cause short- and long-term toxicity in several organs, including the kidney, the main excretion organ of most GBCAs. Considering the increasing prevalence of chronic kidney disease worldwide and that most of the complications following GBCA exposure are associated with renal dysfunction, the mechanisms underlying GBCA toxicity, especially renal toxicity, are particularly important. A better understanding of the gadolinium mechanisms of toxicity may contribute to clarify the safety and/or potential risks associated with the use of GBCAs. In this work, a review of the recent literature concerning gadolinium and GBCA mechanisms of toxicity was performed.

Brain Tumor Imaging without Gadolinium-based Contrast Agents: Feasible or Fantasy?

Gadolinium-based contrast agents (GBCAs) form the cornerstone of current primary brain tumor MRI protocols at all stages of the patient journey. Though an imperfect measure of tumor grade, GBCAs are repeatedly used for diagnosis and monitoring. In practice, however, radiologists will encounter situations where GBCA injection is not needed or of doubtful benefit. Reducing GBCA administration could improve the patient burden of (repeated) imaging (especially in vulnerable patient groups, such as children), minimize risks of putative side effects, and benefit costs, logistics, and the environmental footprint. On the basis of the current literature, imaging strategies to reduce GBCA exposure for pediatric and adult patients with primary brain tumors will be reviewed. Early postoperative MRI and fixed-interval imaging of gliomas are examples of GBCA exposure with uncertain survival benefits. Half-dose GBCAs for gliomas and T2-weighted imaging alone for meningiomas are among options to reduce GBCA use. While most imaging guidelines recommend using GBCAs at all stages of diagnosis and treatment, non-contrast-enhanced sequences, such as the arterial spin labeling, have shown a great potential. Artificial intelligence methods to generate synthetic postcontrast images from decreased-dose or non-GBCA scans have shown promise to replace GBCA-dependent approaches. This review is focused on pediatric and adult gliomas and meningiomas. Special attention is paid to the quality and real-life applicability of the reviewed literature.

Gadolinium-based contrast agents suppress adipocyte differentiation in 3T3-L1 cells

Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) to improve the sensitivity and enhance diagnostic performance. GBCAs are mostly eliminated from the body through the kidney after administration; however small amounts of gadolinium are retained in the brain and other tissues. Although there is increasing concern about the adverse health effects of gadolinium, the cellular effects of GBCAs remains poorly understood. Here, we elucidated the potential cytotoxicity of the GBCAs Omniscan and Gadovist in 12 different cell lines, especially 3T3-L1 adipocyte cell line. Omniscan and Gadovist treatments significantly increased intracellular gadolinium levels in 3T3-L1 cells in a time- and dose-dependent manner. Additionally, Omniscan and Gadovist treatments downregulated the expression of adipocyte differentiation markers, including peroxisome proliferator-activated receptor γ (PPARG), adiponectin (ADIPOQ), and fatty acid-binding protein (FABP4), in 3T3-L1 cells, especially during early differentiation (day 0–2). Moreover, histological analysis using Oil red O staining showed that gadolinium chloride (GdCl3) treatment suppressed lipid droplet accumulation and the expression of adipocyte differentiation markers. Overall, the results showed that Omniscan and Gadovist treatment suppressed adipocyte differentiation in 3T3-L1 cells, contributing to the understanding of the potential toxic effects of GBCA exposure.

Gadolinium-Based Contrast Agents in Pregnant Women: A Literature Review of MRI Safety.

Gadolinium-based contrast agents (GBCAs) are commonly used in magnetic resonance imaging (MRI) to enhance the visualisation and characterisation of the region of interest/lesion. Internal structures are well seen with MRI with good spatial resolution. Although MRI is generally considered safe during pregnancy, concerns have been raised regarding the safety of GBCAs, particularly during the first trimester. Limited studies have been conducted to assess the safety of GBCAs in pregnant women, with conflicting results. A comprehensive literature search was conducted using PubMed, SpringerLink, Medscape, ResearchGate and Wiley Online Library. The search terms included various combinations of MRI, pregnancy, first trimester, gadolinium contrast agents, foetus, risk, and toxicity. The search criteria were articles published in English in the last 20 years and indexed in the MEDLINE or Embase databases. The majority of studies found no definitive evidence that GBCAs are harmful during pregnancy, particularly during the first trimester. Some studies reported no increased risk of adverse outcomes in infants exposed to GBCAs during the first trimester. However, other studies showed inconsistent results. Retrospective cohort studies provided some reassurance regarding the safety of GBCAs when indicated in pregnant women but did not address potential long-term adverse outcomes in infants exposed to GBCAs during gestation. The literature review also highlights the importance of further evaluating the subacute and chronic effects of GBCA exposure in infants. The safety of GBCAs during pregnancy, particularly during the first trimester, remains uncertain. More large-scale, long-term studies are needed to clarify the safety of GBCAs in pregnant women and their potential effects on foetal and neonatal outcomes. Until conclusive evidence is available, healthcare providers should carefully weigh the benefits and risks of using GBCAs during pregnancy and consider alternative imaging modalities, such as non-contrast MRI or ultrasound, when necessary.

Skin Toxicity After Exposure to Gadolinium-Based Contrast Agents in Normal Renal Function, Using Clinical Approved Doses: Current Status of Preclinical and Clinical Studies.

The aim of this study was to summarize the current preclinical and clinical evidence on the association between exposure to gadolinium (Gd) compounds and skin toxicity in a setting similar to clinical practice. A search of MEDLINE and PubMed references from January 2000 to December 2022 was performed using keywords related to gadolinium deposition and its effects on the skin, such as "gadolinium," "gadolinium-based contrast agents," "skin," "deposition," and "toxicity." In addition, cross-referencing was added when appropriate. For preclinical in vitro studies, we included all the studies that analyzed the response of human dermal fibroblasts to exposure to various gadolinium compounds. For preclinical animal studies and clinical studies, we included only those that analyzed animals or patients with preserved renal function (estimated glomerular filtration rate >30 mL/min/1.73 m2), using a dosage of gadolinium-based contrast agents (GBCAs) similar to that commonly applied (0.1 mmol/kg). Forty studies were selected. Preclinical findings suggest that Gd compounds can produce profibrotic responses in the skin in vitro, through the activation and proliferation of dermal fibroblasts and promoting their myofibroblast differentiation. Gadolinium influences the process of collagen production and the collagen content of skin, by increasing the levels of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1. Preclinical animal studies show that Gd can deposit in the skin with higher concentrations when linear GBCAs are applied. However, these deposits decrease over time and are not associated with obvious macroscopic or histological modifications. The clinical relevance of GBCAs in inducing small fiber neuropathy remains to be determined. Clinical studies show that Gd is detectable in the skin and hair of subjects with normal renal function in higher concentrations after intravenous administration of linear compared with macrocyclic GBCA. However, these deposits decrease over time and are not associated with cutaneous or histological modifications. Also, subclinical dermal involvement related to linear GBCA exposure may be detectable on brain MRI. There is no conclusive evidence to support a causal relationship between GBCA administration at the clinical dose and cutaneous manifestations in patients with normal renal function. Gadolinium can produce profibrotic responses in the skin, especially acting on fibroblasts, as shown by preclinical in vitro studies. Gadolinium deposits are detectable in the skin even in subjects with normal renal function with higher concentrations when linear GBCAs are used, as confirmed by both preclinical animal and human studies. There is no proof to date of a cause-effect relationship between GBCA administration at clinical doses and cutaneous consequences in patients with normal renal function. Multiple factors, yet to be determined, should be considered for sporadic patients with normal renal function who develop clinical skin manifestations temporally related to GBCA administration.

Synthesizing MR Image Contrast Enhancement Using 3D High-Resolution ConvNets.

Gadolinium-based contrast agents (GBCAs) have been widely used to better visualize disease in brain magnetic resonance imaging (MRI). However, gadolinium deposition within the brain and body has raised safety concerns about the use of GBCAs. Therefore, the development of novel approaches that can decrease or even eliminate GBCA exposure while providing similar contrast information would be of significant use clinically. In this work, we present a deep learning based approach for contrast-enhanced T1 synthesis on brain tumor patients. A 3D high-resolution fully convolutional network (FCN), which maintains high resolution information through processing and aggregates multi-scale information in parallel, is designed to map pre-contrast MRI sequences to contrast-enhanced MRI sequences. Specifically, three pre-contrast MRI sequences, T1, T2 and apparent diffusion coefficient map (ADC), are utilized as inputs and the post-contrast T1 sequences are utilized as target output. To alleviate the data imbalance problem between normal tissues and the tumor regions, we introduce a local loss to improve the contribution of the tumor regions, which leads to better enhancement results on tumors. Extensive quantitative and visual assessments are performed, with our proposed model achieving a PSNR of 28.24 dB in the brain and 21.2 dB in tumor regions. Our results suggest the potential of substituting GBCAs with synthetic contrast images generated via deep learning.

Gadolinium-based contrast agent exposures and physical and cognitive disability in multiple sclerosis.

The clinical correlation of gadolinium-based contrast agents (GBCAs) has not been well studied in multiple sclerosis (MS). We investigated the extent to which the number of GBCA administrations relates to self-reported disability and performance measures. A cohort of MS patients was analyzed in this retrospective observational study. The main outcome was the association between the cumulative number of GBCA exposures (linear or macrocyclic GBCA), Patient-Determined Disease Steps (PDDS), and measures of physical and cognitive performance (walking speed test, manual dexterity test [MDT], and processing speed test [PST]). The analysis was performed first cross-sectionally and then longitudinally. The cross-sectional data included 1059 MS patients with a mean age of 44.0years (standard deviation=11.2). While the contrast ratio in globus pallidus weakly correlated with PDDS, MDT, and PST in a univariate correlational analysis (coefficients, 95% confidence interval [CI] = 0.11 [0.04, 0.18], 0.15 [0.08, 0.21], and -0.16 [-0.10, -0.23], respectively), the associations disappeared after covariate adjustment. A significant association was found between number of linear GBCA administrations and PDDS (coefficient [CI] = -0.131 [-0.196, -0.067]), and MDT associated with macrocyclic GBCA administrations (-0.385 [-0.616, -0.154]), but their signs indicated better outcomes in patients with greater GBCA exposures. The longitudinal data showed no significant detrimental effect of macrocyclic GBCA exposures. No detrimental effects were observed between GBCA exposure and self-reported disability and standardized objective measures of physical and cognitive performance. While several weak associations were found, they indicated benefit on these measures.

Allergic-like Hypersensitivity Reactions to Gadolinium-based Contrast Agents: An 8-year Cohort Study of 154 539 Patients.

Background With the widespread use of gadolinium-based contrast agents (GBCAs), the incidence of allergic-like hypersensitivity reactions (HSRs) to GBCAs is increasing. Research on the incidence and risk factors for HSRs to GBCAs is needed for their safe use. Purpose To determine the incidence of acute and delayed reactions to GBCAs and to discuss the risk factors and strategies for the prevention of HSRs to GBCAs. Materials and Methods All cases of HSRs to contrast media that occurred at the Seoul National University Hospital from July 1, 2012, to June 30, 2020, were assessed. Information including age, sex, GBCA type, onset, and severity of HSRs was retrospectively analyzed. Results Among the 331070 cases of GBCA exposure in 154539 patients, 1304 cases of HSRs (0.4%) were reported. Acute HSRs accounted for 1178 cases (0.4%), while 126 cases (0.04%) were delayed HSRs. While both premedication (odds ratio [OR] = 0.7, P = .041) and changing the type of GBCA (OR = 0.2, P < .001) showed preventative effects in patients with a history of acute HSRs, only premedication (OR = 0.2, P = .016) significantly reduced the incidence of HSRs in patients with a history of delayed reactions. The risk of an HSR to GBCA was higher in those with a history of an HSR to iodinated contrast media (OR = 4.6, P < .001). Conclusion The rate of hypersensitivity reactions (HSRs) to gadolinium-based contrast agents (GBCAs) was 0.4%. The absence of premedication, repeated exposures to the culprit GBCA, and a history of HSRs to iodinated contrast media and GBCAs were risk factors for HSRs to GBCAs. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kallmes and McDonald in this issue.

Potential toxicity evaluation and comparison within multiple mice organs after repeat injections of linear versus macrocyclic gadolinium-based contrast agents: A comprehensive and time course study

As nephrogenic systemic fibrosis (NSF) and increased signal intensities in deep cerebellar nuclei (DCN) were successively discovered in renal insufficiency patients and healthy persons after gadolinium-based contrast agents (GBCAs) exposure, an awareness of potential toxicity with GBCAs exposure has been heightening. Herein, we performed a multi-organ/tissue toxicity assessment after different GBCAs administration with a large number of samples, and long-term, time-course schedule investigation. ICR mice were randomized to five exposure groups (n = 42/group) and received intravenous injection of GBCAs (2.5 mmol Gd/kg) or saline four time a week for 5 consecutive weeks. Gadolinium concentration detection, sensory tests, histological and hematological analyses were performed at corresponding timepoints (4th or 6th or 10th week). Our results showed that (i) gadodiamide could cause reversible vacuolar changes in the renal tubular epithelial cells, which appeared at 6th week and recovered at 10th week, and severe skin lesion in mice tail with consecutive injection for 10 weeks, that (ii) linear GBCAs (gadodiamide and gadopentetate dimeglumine) markedly elevated heat hyperalgesia and white blood cells of mice at 6th week and most of these changes could recovery at 10th week, and that (iii) linear GBCAs exhibited more gadolinium retention in multi-organ/tissue versus macrocyclic GBCAs and in most case, linear GBCAs showed faster accumulation and regression speed in examined tissues than macrocyclic GBCAs excepting gadodiamide in skin which showed slowest regression speed. Collectively, macrocyclic GBCAs presents more stable, lower propensity to release Gd and safer profiles versus linear GBCAs.

Repeated gadoteric acid and gadobutrol exposure causes deterioration of behavior and memory functions in rats: MRI, histopathological and biochemical evidence

Gadolinium-based contrast agents (GBCAs) exert effects in different regions of the brain; however, studies on this topic are mostly focused on radiological outcomes of GBCA exposure. This paper is a preliminary attempt to identify whether there are changes in behavioral, cognitive, histopathological, radiological and biochemical characteristics with repeated exposure to gadobutrol and gadoteric acid.The effects of GBCAs were tested with the assessment of 4 groups –each comprised of 6 rats [controls, gadobutrol, gadoteric acid (Doteram), and gadoteric acid (Clariscan)]. Respective treatments of 0.1 ml/kg were administered for 3 weeks, followed by a recovery period of 1 week without any treatment. At the end of this regimen, behavioral tests (open field and passive learning test) were performed. Additionally, histopathological analysis of the hippocampal CA1 and CA3 regions (GFAP measurement and total neuron count), biochemical measurements [TNF-a, Malondialdehyde (MDA), Superoxide dismutase (SOD), homovalinic acid (HVA) and choline acetyl transferase (ChAT) levels], and radiological findings (MRI-region of interest) were carried out in each group.There was a significant impairment in all groups that had received gadolinium in open field and passive avoidance learning tests. Oxidative stress and inflammation markers were significantly elevated in all gadolinium groups. Additionally, increased hippocampal gliosis and decreased MRI-ROIs were observed in rats exposed to gadolinium.Chronic gadoteric acid and gadobutrol exposure causes hippocampal gliosis and elevates oxidative stress and inflammation in rats. Radiological outcomes are also consistent with these findings. Long-term studies might be required to conclude whether gadolinium deposition in the brain causes subtle neurological deficits.

Twitter and Gadolinium Retention: Patient-Reported Perceptions of Gadolinium-Based Contrast Agents.

Despite the overall excellent safety profile of gadolinium-based contrast agents (GBCAs) and long history of clinical use [ 1 Schieda N. Blaichman J.I. Costa A.F. et al. Gadolinium-based contrast agents in kidney disease: a comprehensive review and clinical practice guideline issued by the Canadian Association of Radiologists. Can J Kidney Health Dis. 2018; 69: 136-150 Google Scholar , 2 ACRManual on Contrast Media, version 9. http://www.acr.org/Quality-Safety/Resources/Contrast-ManualDate accessed: April 1, 2020 Google Scholar ], recent concerns have arisen because of recognition that gadolinium from GBCAs can be retained in humans for months to years after exposure. The clinical effects are unknown, and to date there is no scientific evidence linking gadolinium retention to adverse clinical outcomes. Nevertheless, a small number of patients have reported symptoms to health care regulatory bodies that they attribute to GBCA exposure and gadolinium retention. These self-reported symptoms vary in type and timing, with many occurring within 48 hours, but have not been substantiated or confirmed to be related to gadolinium retention [ 3 Costa A.F. van der Pol C.B. Maralani P.J. et al. Gadolinium deposition in the brain: a systematic review of existing guidelines and policy statement issued by the Canadian Association of Radiologists. Can Assoc Radiol J. 2018; 69: 373-382 Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar , 4 McDonald R.J. Levine D. Weinreb J. et al. Gadolinium retention: a research roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium Chelates. Radiology. 2018; 289: 517-534 Crossref PubMed Scopus (169) Google Scholar , 5 Croteau D. Adverse events with gadolinium retention after gadolinium-based contrast agent exposure: FDA Adverse Event Reporting System and medical literature review. https://www.fda.gov/media/107662/downloadDate accessed: December 8, 2019 Google Scholar ].

Conservative gadolinium administration to patients with Duchenne muscular dystrophy: decreasing exposure, cost, and time, without change in medical management.

Cardiac MR (CMR) is increasingly used to assess for cardiac involvement in patients with Duchenne muscular dystrophy (DMD). The frequent use of gadolinium based contrast agents (GBCAs) has been called into question with reports of intracranial gadolinium deposition in patients receiving multiple administrations. We adopted a conservative GBCA administration policy, limiting the frequency of GBCA exposure in patients with previously documented late gadolinium enhancement. The aim of our study was to evaluate the clinical effects of this policy change. Data were retrospectively reviewed on 405 consecutive patients with DMD who underwent CMR evaluation. Patients were grouped into conservative GBCA administration or historical control. CMR reports were evaluated and clinical reports were reviewed to determine actionable changes. Ohio Medicaid reimbursements were used to estimate costs. A total of 187 patients comprised the conservative GBCA group and 218 patients the historical cohort. The conservative GBCA group had lower contrast administration rates (84% vs. 99%, p < 0.0001), shorter scan times (35.2 vs. 39.0min, p < 0.0001), and lower estimated medical costs ($339 vs. $351/study). There was no change regarding the initial presence of first-time late gadolinium enhancement, and no difference in actionable change. Contrast administration substantially decreased 7months post-policy change (65%) compared to the initial 7months (96%, p < 0.0001). In the current era with unclear concern for intracranial gadolinium deposition, thoughtful GBCA administration is warranted in patients anticipated to undergo multiple CMRs. Our updated approach has resulted in fewer patients receiving contrast, shorter scan times, and less medical costs, without appreciable changes to patient management.

Can Virtual Contrast Enhancement in Brain MRI Replace Gadolinium?: A Feasibility Study.

Gadolinium-based contrast agents (GBCAs) have become an integral part in daily clinical decision making in the last 3 decades. However, there is a broad consensus that GBCAs should be exclusively used if no contrast-free magnetic resonance imaging (MRI) technique is available to reduce the amount of applied GBCAs in patients. In the current study, we investigate the possibility of predicting contrast enhancement from noncontrast multiparametric brain MRI scans using a deep-learning (DL) architecture. A Bayesian DL architecture for the prediction of virtual contrast enhancement was developed using 10-channel multiparametric MRI data acquired before GBCA application. The model was quantitatively and qualitatively evaluated on 116 data sets from glioma patients and healthy subjects by comparing the virtual contrast enhancement maps to the ground truth contrast-enhanced T1-weighted imaging. Subjects were split in 3 different groups: enhancing tumors (n = 47), nonenhancing tumors (n = 39), and patients without pathologic changes (n = 30). The tumor regions were segmented for a detailed analysis of subregions. The influence of the different MRI sequences was determined. Quantitative results of the virtual contrast enhancement yielded a sensitivity of 91.8% and a specificity of 91.2%. T2-weighted imaging, followed by diffusion-weighted imaging, was the most influential sequence for the prediction of virtual contrast enhancement. Analysis of the whole brain showed a mean area under the curve of 0.969 ± 0.019, a peak signal-to-noise ratio of 22.967 ± 1.162 dB, and a structural similarity index of 0.872 ± 0.031. Enhancing and nonenhancing tumor subregions performed worse (except for the peak signal-to-noise ratio of the nonenhancing tumors). The qualitative evaluation by 2 raters using a 4-point Likert scale showed good to excellent (3-4) results for 91.5% of the enhancing and 92.3% of the nonenhancing gliomas. However, despite the good scores and ratings, there were visual deviations between the virtual contrast maps and the ground truth, including a more blurry, less nodular-like ring enhancement, few low-contrast false-positive enhancements of nonenhancing gliomas, and a tendency to omit smaller vessels. These "features" were also exploited by 2 trained radiologists when performing a Turing test, allowing them to discriminate between real and virtual contrast-enhanced images in 80% and 90% of the cases, respectively. The introduced model for virtual gadolinium enhancement demonstrates a very good quantitative and qualitative performance. Future systematic studies in larger patient collectives with varying neurological disorders need to evaluate if the introduced virtual contrast enhancement might reduce GBCA exposure in clinical practice.

Gadolinium Deposition in Neurology Clinical Practice.

Background: Magnetic resonance imaging (MRI) enhanced with gadolinium-based contrast agents (GBCAs) is an essential tool in the diagnosis and management of many neurologic diseases, including multiple sclerosis, brain tumors, and infections. The clinical utility of GBCAs is evidenced by their widespread use. GBCAs are produced in macrocyclic and linear forms. Since 2014, evidence has suggested that repeated administration of GBCAs can lead to gadolinium deposition in the brain. Methods: We review the literature on gadolinium deposition, including both animal and human studies, as well as the literature on GBCA-associated health outcomes. Additionally, we summarize and discuss the updated medical society recommendations and perspectives on GBCA use in clinical practice. Results: The first publication reporting gadolinium deposition in the human brain was published in 2014. Since that seminal report, multiple studies have demonstrated that exposure to linear GBCAs is associated with gadolinium deposition in the dentate nucleus and globus pallidus as seen on brain MRI. Macrocyclic GBCA exposure has not convincingly been associated with gadolinium deposition evident on brain MRI. Conclusion: Clear evidence demonstrates that GBCAs lead to gadolinium deposition in the brain in a dose-dependent manner; however, only linear GBCAs have been associated with gadolinium deposition visualized on MRI. To date, no evidence links gadolinium deposition with any adverse health outcome. Updated medical society guidelines emphasize the importance of an individualized risk-benefit analysis with each administration of GBCAs.

Urinary Gadolinium Levels After Contrast-Enhanced MRI in Individuals with Normal Renal Function: a Pilot Study.

Gadolinium-based contrast agents (GBCA) have been used to enhance magnetic resonance imaging (MRI) since 1985. Recently, the media and online groups have voiced concerns about gadolinium deposition in patients with normal renal function based on "elevated" urinary gadolinium levels. The determination of increased urinary gadolinium levels is based on reference ranges developed in individuals with normal renal function who were never exposed to GBCA. Studies suggest an elevated gadolinium urinary elimination greater than 72h post GBCA scan. We evaluated urine gadolinium concentrations over a 30-day period in patients administered GBCA. In this prospective, observational pilot study, we enrolled subjects between 18 and 65years of age with normal renal function who received GBCA for the first time. Urinary gadolinium was measured at days zero (prior to GBCA exposure), 3, 10, and 30 after GBCA exposure. We compared urinary gadolinium levels after GBCA exposure to the current reference range and calculated an estimated duration of "elevated" gadolinium urine levels in the average patient. All 13 subjects had 24-h urinary gadolinium levels higher than 0.7μg/24h with means of 1944 (± 1432) μg/24h on day 3, 301 (± 218) μg/24h on day 10, and 34 (± 33) μg/24h on day 30. Based on calculated urinary gadolinium elimination kinetics, we estimate urinary gadolinium levels will often remain above the current reference range for > 50days. The current reference range of 0.7μg/24h for 24h urinary gadolinium is not applicable to patients for at least 30days following GBCA exposure.

Evaluating the Patient with Reported Gadolinium-Associated Illness.

Gadolinium-based contrast agents (GBCAs) have been increasingly used in clinical practice since their introduction in the 1980s. Recently, increased public attention has been given to patients who report new symptoms following GBCA exposure. This review details the current knowledge surrounding GBCAs, with a focus on the known and proposed disease states that may be associated with GBCAs. Recommendations for the appropriate clinical workup of a patient suspected of having symptoms attributable to gadolinium exposure are included. GBCAs are known to precipitate the disease state nephrogenic systemic fibrosis (NSF), a syndrome characterized by skin thickening in patients with preexisting renal disease. An additional syndrome, termed gadolinium deposition disease, has been proposed to describe patients with normal renal function who develop an array of symptoms following GBCA exposure. While there is a potential physiologic basis for the development of this condition, there is no conclusive evidence to support a causal relationship between GBCA administration and the reported symptoms yet. Clinical evaluation revolves around focused history-taking and physical examination, given the absence of a reliable link between patient symptoms and measured gadolinium levels. There are no recommended treatments for suspected gadolinium deposition disease. Chelation therapy, which is not approved for this indication, carries undue risk without documented efficacy. The extent to which GBCAs contribute to clinically relevant adverse effects remains an important and evolving field of study. NSF remains the only proven disease state associated with GBCA exposure. Additional data are required to evaluate whether other symptoms should be attributed to GBCAs.

Pregnancy outcomes following gadolinium-based contrast agents exposure during the first trimester: Preliminary results of 13 cases

Healthcare administrative databases of Italy's Lombardy Region were analyzed with the aim to assess perinatal outcomes and healthcare resource utilization during the first year of life in infants exposed to antiepileptic drugs (AEDs) during pregnancy.Drug prescriptions dispensed in the 12 months before delivery to women, who delivered between 2005 and 2011, were analyzed. Neonates were classified as cases if exposed to AEDs, and each case was randomly matched to seven controls.No significant differences were observed in the risk of congenital malformations between 526 cases and 3682 controls except for valproic acid (odds ratio (OR): 2.29; 95% confidence interval (CI): 1.24–4.22) where cases were more likely to be small for gestational age (χ2 = 7.66; p = 0.006). Cases also had a higher probability than controls of needing at least one specialist visit in a child neuropsychiatry outpatient service (OR: 1.74; 95% CI: 1.22–2.49).

Observed Deposition of Gadolinium in Bone Using a New Noninvasive in Vivo Biomedical Device: Results of a Small Pilot Feasibility Study.

Purpose To perform a preliminary evaluation of a noninvasive measurement system to assess gadolinium deposition in bone and to investigate the relationship between the administration of gadolinium-based contrast agents (GBCAs) and gadolinium retention in bone. Materials and Methods In vivo measurement of gadolinium retention in tibia bones was performed in 11 exposed subjects who previously received GBCAs (six exposed subjects were from a study performed 5 years previously involving injection of GBCAs in healthy volunteers; five exposed subjects had self-reported GBCA exposure), and 11 sex- and age-matched control subjects without a history of GBCA exposure. Each subject underwent one measurement of gadolinium retention in the tibia with x-ray fluorescence in a laboratory at McMaster University. A one-tailed t test was performed to compare gadolinium concentration in the exposed group with that in the control group. The relationship between the dose of GBCA administered and the gadolinium concentration measured in bone was analyzed with linear regression. Results Gadolinium concentration in bone was significantly higher in exposed subjects (mean, 1.19 μg Gd/g bone mineral ± 0.73 [standard deviation]) than in control subjects (mean, -1.06 μg Gd/g bone mineral ± 0.71) (P = .01). There was also a positive correlation between the dose of GBCA administered and the gadolinium concentration measured in bone (R2 = 0.41); gadolinium concentration in bone increased by 0.39 μg Gd/g bone mineral ± 0.14 per 1 mL of GBCA administered. Gadolinium was detected in bone up to 5 years after one GBCA administration. Conclusion This x-ray fluorescence system is capable of measuring gadolinium deposition in bone noninvasively in vivo. Gadolinium can be retained in bone after one dose of GBCA in healthy subjects. © RSNA, 2017 Online supplemental material is available for this article.

Gadolinium Retention and Toxicity-An Update.

Until 2006, the main considerations regarding safety for all gadolinium-based contrast agents (GBCAs) were related to short-term adverse reactions. However, the administration of certain "high-risk" GBCAs to patients with renal failure resulted in multiple reported cases of nephrogenic systemic fibrosis. Findings have been reported regarding gadolinium deposition within the body and various reports of patients who report suffering from acute and chronic symptoms secondary to GBCA's exposure. At the present state of knowledge, it has been proved that gadolinium deposits also occur in the brain, irrespective of renal function and GBCAs stability class. To date, no definitive clinical findings are associated with gadolinium deposition in brain tissue. Gadolinium deposition disease is a newly described and probably infrequent entity. Patients presenting with gadolinium deposition disease may show signs and symptoms that somewhat follows a pattern similar but not identical, and also less severe, to those observed in nephrogenic systemic fibrosis. In this review, we will address gadolinium toxicity focusing on these 2 recently described concerns.

Effect of Renal Function on Gadolinium-Related Signal Increases on Unenhanced T1-Weighted Brain Magnetic Resonance Imaging.

The purpose of this study was to determine if renal function affects signal changes in the deep brain nuclei on unenhanced T1-weighted images after administration of linear gadolinium-based contrast agents (GBCAs). An electronic medical records search of 2 large medical centers identified 25 patients who received linear GBCA while on hemodialysis and had unenhanced T1-weighted images of the brain before and after. The dentate-to-cerebellar peduncle (DCP) ratio, globus pallidus-to-mid thalamus (GPT) ratio, and choroid plexus-to-nearby white matter ratio were measured and compared with 25 age/sex/GBCA exposure-matched control patients with normal or near-normal renal function (estimated glomerular filtration rate >60 mL/min per 1.73 m). Two additional control groups included 13 patients on hemodialysis without GBCA exposure and 13 age/sex-matched patients with estimated glomerular filtration rate greater than 60 mL/min per 1.73 m. Hemodialysis patients (n = 25) with an average of 1.8 linear GBCA administrations had a 4.9% mean increase (1.00 ± 0.04 vs 1.05 ± 0.05; P < 0.001) in DCP, which was greater than the 1.6% change (0.99 ± 0.04 vs 1.00 ± 0.05; P = 0.08) observed in matched controls (P = 0.01). There was no significant signal change in the DCP ratio in the 13 hemodialysis patients (0.99 ± 0.04 vs 0.99 ± 0.04; P = 0.78) and 13 age/sex-matched patients (0.99 ± 0.02 vs 0.99 ± 0.03; P = 0.78) who did not receive GBCA. The hemodialysis patients had a baseline GPT that was higher than nondialysis patients (P < 0.001). However, the GPT change after GBCA administration was not significantly different from controls. Increased signal in the choroid plexus on unenhanced T1-weighted images after GBCA administration was noted in hemodialysis patients (0.72 ± 0.20 vs 0.86 ± 0.23; P = 0.006); however, a multivariate analysis showed this to be primarily related to hemodialysis (P = 0.003) with only a trend toward relating to GBCA exposure (P = 0.07). Hemodialysis patients receiving linear GBCA have greater dentate nucleus signal increases on unenhanced T1-weighted images, suggesting that renal function may affect the rate of gadolinium accumulation in the brain after linear GBCA-enhanced magnetic resonance imaging.