Review

Authors: Lennart Blomqvist, Gunnar F Nordberg, Valeria M Nurchi...

Gadolinium (Gd) is one of the rare-earth elements. The properties of its trivalent cation (Gd) make it suitable to serve as the central ion in chelates administered intravenously to patients as a contrast agent in magnetic resonance imaging. Such Gd-chelates have been used for more than thirty years. During the past decades, knowledge has increased about potential harmful effects of Gd-chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially disabling and lethal disease, nephrogenic systemic fibrosis. Restricting the use of Gd-chelates in persons with severely impaired renal function has decreased the occurrence of this toxic effect in the last decade. There has also been an increasing awareness of Gd-retention in the body, even in patients without renal dysfunction. The cumulative number of doses given, and the chemical structure of the chelate given, are factors of importance for retention in tissues. This review describes the chemical properties of Gd and its medically used chelates, as well as its toxicity and potential side effects related to injection of Gd-chelates.

Topics: Chelating Agents; Contrast Media; Fibrosis; Gadolinium; Humans; Kidney Diseases; Magnetic Resonance Imaging

PubMed: 35740867
DOI: 10.3390/biom12060742

Review

Authors: Julie Davies, Petra Siebenhandl-Wolff, Francois Tranquart...

Gadolinium-based contrast agents (GBCAs) have transformed magnetic resonance imaging (MRI) by facilitating the use of contrast-enhanced MRI to allow vital clinical diagnosis in a plethora of disease that would otherwise remain undetected. Although over 500 million doses have been administered worldwide, scientific research has documented the retention of gadolinium in tissues, long after exposure, and the discovery of a GBCA-associated disease termed nephrogenic systemic fibrosis, found in patients with impaired renal function. An understanding of the pharmacokinetics in humans and animals alike are pivotal to the understanding of the distribution and excretion of gadolinium and GBCAs, and ultimately their potential retention. This has been well studied in humans and more so in animals, and recently there has been a particular focus on potential toxicities associated with multiple GBCA administration. The purpose of this review is to highlight what is currently known in the literature regarding the pharmacokinetics of gadolinium in humans and animals, and any toxicity associated with GBCA use.

Topics: Animals; Contrast Media; Gadolinium; Humans; Magnetic Resonance Imaging; Nephrogenic Fibrosing Dermopathy; Renal Insufficiency

PubMed: 34997254
DOI: 10.1007/s00204-021-03189-8

Clinical practice of epidermal growth factor receptor-tyrosine kinase inhibitor targeted drugs combined with gadolinium oxide nanoparticles in the treatment of non-small cell lung cancer.

Authors: Xuan Zhou, Ting Jin, Likun Wang...

It was to explore the clinical efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted drugs combined with hyaluronic acid-gadolinium sesquioxide-nanoparticles (HA-Gd2O3-NPs) in non-small cell lung cancer (NSCLC). In this study, 70 patients with stage IV EGFR mutant NSCLC diagnosed in the First Affiliated Hospital of Jinzhou Medical University were selected. They were randomly divided into the combined group (35 cases) and the control group (35 cases). HA-Gd2O3-NPs were prepared by hydrothermal polymerization, and combined with EGFR-TKI in the clinical treatment of NSCLC. The results showed that HA-Gd2O3-NPs were spherical with a uniform particle size of about 124 nm. The NSCLC survival rate of the combined group was 37.2 ± 5.3% under 6 Gy X-ray irradiation, and that of the control group was 98.4 ± 12.6% under 6 Gy X-ray irradiation. The total effective rate of the control group (20%) was significantly lower than that of the study group (42.86%) ( 0.05). The one-year survival rate of the combined group (94%) was significantly higher than that of the control group (75%) ( 0.05). The median progression-free survival (PFS) in the control group was 8 months, and that in the combined group was 12 months, with statistical difference ( 0.05). EGFR-TKI targeted drugs combined with HA-Gd2O3-NPs can significantly improve the clinical efficacy of stage IV EGFR mutant NSCLC patients and benefit their survival.

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Drug Resistance, Neoplasm; Drug Synergism; Female; Gadolinium; Humans; Hyaluronic Acid; Lung Neoplasms; Male; Middle Aged; Nanoparticles; Neoplasm Staging; Particle Size; Protein Kinase Inhibitors; Radiotherapy, Conformal; Random Allocation; Survival Analysis; Treatment Outcome

PubMed: 34818973
DOI: 10.1080/21655979.2021.2009969

Prospective multicenter assessment of patient preferences for properties of gadolinium-based contrast media and their potential socioeconomic impact in a screening breast MRI setting.

Authors: Sean A Woolen, Jonathan P Troost, Shokoufeh Khalatbari...

OBJECTIVE

It is unknown how patients prioritize gadolinium-based contrast media (GBCM) benefits (detection sensitivity) and risks (reactions, gadolinium retention, cost). The purpose of this study is to measure preferences for properties of GBCM in women at intermediate or high risk of breast cancer undergoing annual screening MRI.

METHODS

An institutional reviewed board-approved prospective discrete choice conjoint survey was administered to patients at intermediate or high risk for breast cancer undergoing screening MRI at 4 institutions (July 2018-March 2020). Participants were given 15 tasks and asked to choose which of two hypothetical GBCM they would prefer. GBCMs varied by the following attributes: sensitivity for cancer detection (80-95%), intracranial gadolinium retention (1-100 molecules per 100 million administered), severe allergic-like reaction rate (1-19 per 100,000 administrations), mild allergic-like reaction rate (10-1000 per 100,000 administrations), out-of-pocket cost ($25-$100). Attribute levels were based on published values of existing GBCMs. Hierarchical Bayesian analysis was used to derive attribute "importance." Preference shares were determined by simulation.

RESULTS

Response (87% [247/284]) and completion (96% [236/247]) rates were excellent. Sensitivity (importance = 44.3%, 95% confidence interval = 42.0-46.7%) was valued more than GBCM-related risks (mild allergic-like reaction risk (19.5%, 17.9-21.1%), severe allergic-like reaction risk (17.0%, 15.8-18.1%), intracranial gadolinium retention (11.6%, 10.5-12.7%), out-of-pocket expense (7.5%, 6.8-8.3%)). Lower income participants placed more importance on cost and less on sensitivity (p < 0.01). A simulator is provided that models GBCM preference shares by GBCM attributes and competition.

CONCLUSIONS

Patients at intermediate or high risk for breast cancer undergoing MRI screening prioritize cancer detection over GBCM-related risks, and prioritize reaction risks over gadolinium retention.

KEY POINTS

• Among women undergoing annual breast MRI screening, cancer detection sensitivity (attribute "importance," 44.3%) was valued more than GBCM-related risks (mild allergic reaction risk 19.5%, severe allergic reaction risk 17.0%, intracranial gadolinium retention 11.6%, out-of-pocket expense 7.5%). • Prospective four-center patient preference data have been incorporated into a GBCM choice simulator that allows users to input GBCM properties and calculate patient preference shares for competitor GBCMs. • Lower-income women placed more importance on out-of-pocket cost and less importance on cancer detection (p < 0.01) when prioritizing GBCM properties.

Topics: Bayes Theorem; Contrast Media; Female; Gadolinium; Humans; Magnetic Resonance Imaging; Patient Preference; Prospective Studies; Socioeconomic Factors

PubMed: 34047845
DOI: 10.1007/s00330-021-07982-y

Authors: Chandrashekhar Honrao, Nathalie Teissier, Bo Zhang...

Gadolinium is a paramagnetic relaxation enhancement (PRE) agent that accelerates the relaxation of metabolite nuclei. In this study, we noted the ability of gadolinium to improve the sensitivity of two-dimensional, non-uniform sampled NMR spectral data collected from metabolomics samples. In time-equivalent experiments, the addition of gadolinium increased the mean signal intensity measurement and the signal-to-noise ratio for metabolite resonances in both standard and plasma samples. Gadolinium led to highly linear intensity measurements that correlated with metabolite concentrations. In the presence of gadolinium, we were able to detect a broad array of metabolites with a lower limit of detection and quantification in the low micromolar range. We also observed an increase in the repeatability of intensity measurements upon the addition of gadolinium. The results of this study suggest that the addition of a gadolinium-based PRE agent to metabolite samples can improve NMR-based metabolomics.

Topics: Gadolinium; Image Enhancement; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Metabolomics; Signal-To-Noise Ratio

PubMed: 34500549
DOI: 10.3390/molecules26175115

Authors: Michael D Ringler, Nicholas G Rhodes, Jennifer R Ayers-Ringler...

OBJECTIVE

To characterize the extent of retention and biodistribution of gadolinium (Gd) following intra-articular (IA) injection of linear and macrocyclic gadolinium-based contrast agents (GBCAs) into the knee joint of a rat model.

MATERIALS AND METHODS

Fifteen Wistar rats were divided into five groups and underwent fluoroscopically-guided injections of both knee joints of (1) clinical 1:200 dilution (low dose, LD) gadodiamide (linear GBCA), (2) LD gadobutrol (macrocyclic GBCA), (3) undiluted (high dose, HD) gadodiamide, (4) HD gadobutrol, and (5) saline. Gd concentrations were quantified by inductively coupled plasma mass spectrometry in (1) blood and urine samples obtained over a 72 h period and (2) knee joint tissues, brain, kidney, and bone marrow at 3 days post-injection.

RESULTS

Both HD and LD gadodiamide and gadobutrol were rapidly absorbed from the joint with peak serum and urine concentration at 1 h post-injection, with relatively faster clearance of gadobutrol. All GBCA-exposed groups had detectable levels of Gd in the joint tissues, bone marrow, and/or kidneys (median tissue gadolinium range: 0.1-71 μg Gd/g tissue), with higher amounts observed with gadodiamide versus gadobutrol. Retention within brain tissues was only detected following HD gadodiamide administration but not LD gadodiamide nor HD or LD gadobutrol.

CONCLUSION

There was rapid systemic absorption, redistribution, and widespread multi-organ retention of Gd following IA injection of both linear and macrocyclic GBCAs, despite substantial amounts of urinary excretion. Higher concentrations of Gd were observed with administration of gadodiamide compared to gadobutrol in most tissues and biofluids.

Topics: Animals; Contrast Media; Gadolinium; Gadolinium DTPA; Magnetic Resonance Imaging; Organometallic Compounds; Rats; Rats, Wistar; Tissue Distribution

PubMed: 33404669
DOI: 10.1007/s00256-020-03695-3

Authors: Liqiang Ren, Nathan Huber, Kishore Rajendran...

PURPOSE

The aims of this study were to develop a single-scan dual-contrast protocol for biphasic liver imaging with 2 intravenous contrast agents (iodine and gadolinium) and to evaluate its effectiveness in an exploratory swine study using a photon-counting detector computed tomography (PCD-CT) system.

MATERIALS AND METHODS

A dual-contrast CT protocol was developed for PCD-CT to simultaneously acquire 2 phases of liver contrast enhancement, with the late arterial phase enhanced by 1 contrast agent (iodine-based) and the portal venous phase enhanced by the other (gadolinium-based). A gadolinium contrast bolus (gadobutrol: 64 mL, 8 mL/s) and an iodine contrast bolus (iohexol: 40 mL, 5 mL/s) were intravenously injected in the femoral vein of a healthy domestic swine, with the second injection initiated after 17 seconds from the beginning of the first injection; PCD-CT image acquisition was performed 12 seconds after the beginning of the iodine contrast injection. A convolutional neural network (CNN)-based denoising technique was applied to PCD-CT images to overcome the inherent noise magnification issue in iodine/gadolinium decomposition task. Iodine and gadolinium material maps were generated using a 3-material decomposition method in image space. A set of contrast samples (mixed iodine and gadolinium) was attached to the swine belly; quantitative accuracy of material decomposition in these inserts between measured and true concentrations was calculated using root mean square error. An abdominal radiologist qualitatively evaluated the delineation of arterial and venous vasculatures in the swine liver using iodine and gadolinium maps obtained using the dual-contrast PCD-CT protocol.

RESULTS

The iodine and gadolinium samples attached to the swine were quantified with root mean square error values of 0.75 mg/mL for iodine and 0.45 mg/mL for gadolinium from the contrast material maps derived from the denoised PCD-CT images. Hepatic arteries containing iodine and veins containing gadolinium in the swine liver could be clearly visualized. Compared with the original images, better distinctions between 2 liver phases were achieved using CNN denoising, with approximately 60% to 80% noise reduction in contrast material maps acquired with the denoised PCD-CT images compared with the original images.

CONCLUSIONS

Simultaneous biphasic liver imaging in a single multienergy PCD-CT acquisition using a dual-contrast (iodine and gadolinium) injection protocol and CNN denoising was demonstrated in a swine study, where the enhanced hepatic arteries (containing iodine) and the enhanced hepatic veins (containing gadolinium) could be clearly visualized and delineated in the swine liver.

Topics: Animals; Contrast Media; Gadolinium; Iodine; Liver; Phantoms, Imaging; Photons; Swine; Tomography, X-Ray Computed

PubMed: 34411033
DOI: 10.1097/RLI.0000000000000815

Authors: Marta Orts-Arroyo, Amadeo Ten-Esteve, Sonia Ginés-Cárdenas...

The paramagnetic gadolinium(III) ion is used as contrast agent in magnetic resonance (MR) imaging to improve the lesion detection and characterization. It generates a signal by changing the relaxivity of protons from associated water molecules and creates a clearer physical distinction between the molecule and the surrounding tissues. New gadolinium-based contrast agents displaying larger relaxivity values and specifically targeted might provide higher resolution and better functional images. We have synthesized the gadolinium(III) complex of formula [Gd(thy)(HO)](ClO)·2HO () [thy = 5-methyl-1H-pyrimidine-2,4-dione or thymine], which is the first reported compound based on gadolinium and thymine nucleobase. has been characterized through UV-vis, IR, SEM-EDAX, and single-crystal X-ray diffraction techniques, and its magnetic and relaxometric properties have been investigated by means of SQUID magnetometer and MR imaging phantom studies, respectively. On the basis of its high relaxivity values, this gadolinium(III) complex can be considered a suitable candidate for contrast-enhanced magnetic resonance imaging.

Topics: Contrast Media; Crystallography, X-Ray; Gadolinium; Heterocyclic Compounds; Magnetic Resonance Imaging; Magnetics; Molecular Structure; Protons; Thymine; Water

PubMed: 33925589
DOI: 10.3390/ijms22094586

Authors: Francesca Bruno, Joshua DeAguero, Catherine Do...

Dozens of millions of people are exposed to gadolinium-based contrast agents annually for enhanced magnetic resonance imaging. Gadolinium-based contrast agents are known nephrotoxins and can trigger the potentially fatal condition of systemic fibrosis. Risk factors are practically entirely undefined. We examined the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Age- and weight-matched mice were randomized to experimental diabetes (streptozotocin) and control groups followed by systemic gadolinium-based contrast agent treatment. Nox4-deficient mice were randomized to experimental diabetes and gadolinium-based contrast agent treatment. Skin fibrosis and cellular infiltration were apparent in both gadolinium-based contrast agent-treated and experimental diabetes groups. Similarly, both groups demonstrated renal pathologies with evidence of reactive oxygen species generation. Deletion of Nox4 abrogated both skin and renal pathology, whether from diabetes or gadolinium-based contrast agent treatment. These discoveries demonstrate the importance of Nox4 in gadolinium-based contrast agent- and diabetes-induced fibrosis. A mouse model of gadolinium-based contrast agent- and diabetes-induced fibrosis was used to demonstrate the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Using these models, we established the role of Nox4 as a mediator of reactive oxygen species generation and subsequent skin and kidney fibrosis. These novel findings have defined Nox-4-mediated mechanisms by which gadolinium-based contrast agents induce systemic diseases.

Topics: Animals; Contrast Media; Diabetes Mellitus, Experimental; Fibrosis; Gadolinium; Kidney; Kidney Diseases; Mice; NADPH Oxidase 4; Nephrogenic Fibrosing Dermopathy; Renal Insufficiency

PubMed: 33615889
DOI: 10.1152/ajprenal.00456.2020

Randomized Controlled Trial

Authors: Huanhuan Zheng, Guolang Wang, Qianqian Cao...

OBJECTIVE

This is the first study to explore the risk factors for nephropathy caused by gadolinium-based contrast agents and establish a prediction model to identify high-risk patients.

METHODS

A total of 1404 patients who received gadolinium-based contrast agents in our hospital were included. The participants were randomly assigned in a 7:3 ratio to the modeling and validation groups. The modeling group was divided into a contrast-induced nephropathy group and a non-contrast-induced nephropathy group. The clinical characteristics before the use of contrast agents were compared between the two groups. The risk factors for contrast-induced nephropathy were analyzed by logistic regression. A nomogram that could predict the incidence of contrast-induced nephropathy was plotted. The validation group was used to verify the predictive model.

RESULTS

The incidence of contrast-induced nephropathy caused by gadolinium-based contrast agents was 3.92% (55/1404). The logistic stepwise regression analysis showed that sex, systolic pressure (SBP), absolute neutrophil count, albumin, fasting blood glucose level, and furosemide use were significant predictors of contrast-induced nephropathy caused by gadolinium-based contrast agents. The above predictors were then included in the nomogram construction. The area under the receiver operating characteristic (ROC) curve was 0.82 ( < 0.001). The specificity and sensitivity corresponding to the optimal cutoff point (0.039) based on the area under the ROC curve were 71.9% and 80.5%, respectively.

CONCLUSION

Sex, SBP, absolute neutrophil count, albumin, fasting blood glucose levels, and furosemide use are significant predictors of contrast-induced nephropathy caused by gadolinium-based contrast agents. Therefore, the incidence of contrast-induced nephropathy may be estimated by the prediction model established in this study before the use of contrast agents.

Topics: Albumins; Blood Glucose; Contrast Media; Female; Furosemide; Gadolinium; Humans; Kidney Diseases; Male; ROC Curve; Retrospective Studies; Risk Factors

PubMed: 35509178
DOI: 10.1080/0886022X.2022.2069579