Adverse Events Associated with Intra-Arterial Administration of Gadolinium-Based Contrast Agents: A Systematic Review and Meta-Analysis.

PURPOSE: To determine the risk of immediate hypersensitivity reactions (HRs), contrast-associated acute kidney injury (CA-AKI), nephrogenic systemic fibrosis (NSF), and gadolinium retention associated with use of intra-arterial gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched from 1988 (GBCAs approved for clinical use) to March 2021 for studies reporting adverse events associated with intra-arterial administration of GBCAs. The number of adverse events and GBCA administrations were used to calculate incidence in individual studies, and results across studies were pooled using random-effects meta-analysis. RESULTS: There were 72 studies (patients = 1,221) that reported on HR, 59 studies (patients = 1,142) that reported on CA-AKI, and 6 studies (patients = 291) that reported on NSF. No studies reported gadolinium retention as an outcome. Based on 5 events and 1,451 GBCA administrations, the incidence of HR per 100 administrations was 0.95 (95% CI, 0.52-1.51). Based on 90 events and 1,318 GBCA administrations, the incidence of CA-AKI per 100 administrations was 5.94 (95% CI, 3.92-8.34). Based on 7 events and 361 GBCA administrations, the incidence of NSF per 100 Group I GBCA administrations was 4.72 (95% CI, 0.35-13.70). There were no unconfounded NSF events after Group II GBCA administration. CONCLUSIONS: HRs to intra-arterial administration of GBCAs are rare, with no serious reactions. Limited data demonstrate a higher-than-expected rate of CA-AKI; however, multiple confounding factors were noted. Thus, any causative link of CA-AKI to GBCA remains controversial. Also, severe physiologic reactions (including life-threatening arrhythmias) during coronary angiography have been reported.

The need for prophylactic hemodialysis to protect against nephrogenic systemic fibrosis in patients with end-stage renal disease receiving gadolinium-based contrast agents.

BACKGROUND: The risk of gadolinium (Gd)-based contrast agent (GBCA)-induced nephrogenic systemic fibrosis (NSF) in patients with end-stage renal disease (ESRD) and the efficacy of prophylactic hemodialysis (HD) for protection against NSF are not well understood or summarized in the literature. PURPOSE: To determine the risk for NSF related to frequency and time per dialysis session after Gd-magnetic resonance imaging (MRI) by emphasizing the safety of Gd-MRI in patients with ESRD. MATERIAL AND METHODS: This retrospective observational study identified all GBCA injections for MRI examinations performed at two tertiary referral hospitals between 2005 and 2020. All clinical data, including dialysis records and medical history, were investigated for each patient through 2021. The end of follow-up coincided with the last hospital visit. RESULTS: Overall, 1129 patients with ESRD underwent 1461 Gd-MRI scans (41.5% gadoterate, 39.4% gadobutrol, and 7.7% gadoxetate); a total of 958 patients with 1229 (84.1%) examinations underwent HD on the day of the MRI study, within 2.1 ± 2.0 h (range = 0.2-15.7 h) immediately after Gd exposure. In 53.4% of scans, frequent HD had been performed urgently and then twice more on consecutive days to prophylactically avoid NSF. No cases of NSF were identified during the follow-up period (mean = 81.7 ± 50.5 months) regardless of dose of HD. CONCLUSION: No cases of NSF were reported in 1461 Gd-MRI examinations of 1129 inpatients with ESRD on HD. Our findings support the lack of benefit of frequent prophylactic HD being performed urgently within 4 h of the receipt of GBCA.

Was There Something Rotten in Denmark: Nephrogenic System Fibrosis Cases Occurring in Copenhagen.

More than half of all serious adverse drug reactions are identified seven years after FDA approval. One recent and unusual example involves a syndrome initially termed nephrogenic dermatopathic fibrosis, and then called nephrogenic systemic fibrosis (NSF).

Gadolinium retention: should pediatric radiologists be concerned, and how to frame conversations with families.

Gadolinium retention in the brain and other organs has recently been identified by imaging and confirmed histologically. No direct clinical effects of gadolinium retention, which occurs after gadolinium-based contrast agent (GBCA) administration for MRI, have been scientifically accepted at this time. However, there is understandable concern among medical professionals and the public about the potential effects of gadolinium retention, particularly in the brain. Part of this concern might stem from the identification of nephrogenic systemic fibrosis caused by GBCAs in people with severe renal failure in 2006. This article briefly describes the characteristics of GBCAs; reviews and differentiates gadolinium retention, nephrogenic systemic fibrosis, and "gadolinium deposition disease" or "gadolinium toxicity"; and discusses societal guidelines and current usage in children. With the belief that GBCAs should not be withheld for appropriate indications in the absence of evidence of its potential risks, we offer a framework for determining when GBCA use is appropriate and suggestions for discussing its risks and benefits with children and their families.

Overlapping roles of NADPH oxidase 4 for diabetic and gadolinium-based contrast agent-induced systemic fibrosis.

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.NEW & NOTEWORTHY 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.

Use of Intravenous Gadolinium-based Contrast Media in Patients with Kidney Disease and the Risk of Nephrogenic Systemic Fibrosis: Radiology In Training.

A 66-year-old male patient with end-stage chronic kidney disease undergoing maintenance dialysis and with a history of group I intravenous gadolinium-based contrast media (GBCM) administration presented with clinical and pathologic findings consistent with nephrogenic systemic fibrosis. A summary of the evidence and recommendations for use of intravenous GBCM in patients with kidney disease is presented. © RSNA, 2021.

The Use of Contrast Agents in Interventional Pain Procedures: A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

Risk for Nephrogenic Systemic Fibrosis After Exposure to Newer Gadolinium Agents: A Systematic Review.

BACKGROUND: The risk for nephrogenic systemic fibrosis (NSF) after exposure to newer versus older gadolinium-based contrast agents (GBCAs) remains unclear. PURPOSE: To synthesize evidence about NSF risk with newer versus older GBCAs across the spectrum of kidney function. DATA SOURCES: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science for English-language references from inception to 5 March 2020. STUDY SELECTION: Randomized controlled trials, cohort studies, and case-control studies that assessed NSF occurrence after GBCA exposure. DATA EXTRACTION: Data were abstracted by 1 investigator and verified by a second. Investigator pairs assessed risk of bias by using validated tools. DATA SYNTHESIS: Of 32 included studies, 20 allowed for assessment of NSF risk after exposure to newer GBCAs and 12 (11 cohort studies and 1 case-control study) allowed for comparison of NSF risk between newer and older GBCAs. Among 83 291 patients exposed to newer GBCAs, no NSF cases developed (exact 95% CI, 0.0001 to 0.0258 case). Among the 12 studies (n = 118 844) that allowed risk comparison between newer and older GBCAs, 37 NSF cases developed after exposure to older GBCAs (exact CI, 0.0001 to 0.0523 case) and 4 occurred (3 confounded) after exposure to newer GBCAs (exact CI, 0.0018 to 0.0204 case). Data were scant for patients with acute kidney injury or those at risk for chronic kidney disease. LIMITATIONS: Study heterogeneity prevented meta-analysis. Risk of bias was high in most studies because of inadequate exposure and outcome ascertainment. CONCLUSION: Although NSF occurrence after exposure to newer GBCAs is very rare, the relatively scarce data among patients with acute kidney injury and those with risk factors for chronic kidney disease limit conclusions about safety in these populations. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs. (PROSPERO: CRD42019135783).

Safety issues related to intravenous contrast agent use in magnetic resonance imaging.

Gadolinium-based contrast agents (GBCAs) have been used to improve image quality of MRI examinations for decades and have an excellent overall safety record. However, there are well-documented risks associated with GBCAs and our understanding and management of these risks continue to evolve. The purpose of this review is to discuss the safety of GBCAs used in MRI in adult and pediatric populations. We focus particular attention on acute adverse reactions, nephrogenic systemic fibrosis and gadolinium deposition. We also discuss the non-GBCA MRI contrast agent ferumoxytol, which is increasing in use and has its own risk profile. Finally, we identify special populations at higher risk of harm from GBCA administration.

Adverse Events to the Gadolinium-based Contrast Agent Gadoxetic Acid: Systematic Review and Meta-Analysis.

Background Gadoxetic acid is classified by the American College of Radiology as a group III gadolinium-based contrast agent (GBCA), which indicates that there are limited data regarding nephrogenic systemic fibrosis (NSF) risk, but there are few if any unconfounded cases of NSF. Purpose To perform a systematic review and meta-analysis of gadoxetic acid adverse events, including immediate hypersensitivity reactions, NSF, and intracranial gadolinium retention. Materials and Methods Original research studies, case series, and case reports that reported adverse events in patients undergoing gadoxetic acid-enhanced MRI were searched in MEDLINE (1946-2019), Embase (1947-2019), CENTRAL (March 2019), and Scopus (1946-2019). The study protocol was registered at Prospero (number 162811). Risk of bias was evaluated by using Quality Assessment of Diagnostic Accuracy Studies-2, or QUADAS-2. Meta-analysis of proportions was performed by using random-effects modeling. Upper bound of 95% confidence interval (CI) for risk of NSF was determined. Results Seventy-one studies underwent full-text review. From 17 studies reporting 14 850 administrations, hypersensitivity reactions occurred in 0.3% (31 of 14 850; 95% CI: 0.2%, 0.4%) with zero deaths. From four studies reporting 106 administrations in patients with stage 4 or 5 chronic kidney disease or undergoing dialysis, the upper bound 95% CI for the risk of NSF was 2.8%. Five studies evaluating intracranial retention of gadolinium after gadoxetic acid administration were at high risk of bias. Conclusion Gadoxetic acid had a similar safety profile to American College of Radiology group 2 gadolinium-based contrast agents for hypersensitivity reactions and nephrogenic systemic fibrosis (NSF) but had lower confidence for risk of NSF because of fewer administrations in patients with severe kidney impairment. There is incomplete information documenting intracranial gadolinium retention in patients administered gadoxetic acid. © RSNA, 2020 Online supplemental material is available for this article.

No Cases of Nephrogenic Systemic Fibrosis after Administration of Gadoxetic Acid.

Background Gadoxetic acid (GA) has distinctive pharmacokinetic properties with important applications in hepatobiliary imaging. However, there are limited data evaluating the safety of GA administration in patients with impaired kidney function and the incidence of nephrogenic systemic fibrosis (NSF). Purpose To evaluate safety of GA regarding risk of NSF in patients with impaired kidney function. Materials and Methods This retrospective study identified all GA-enhanced MRI (hereafter, GA MRI) examinations performed between July 2008 and December 2019 through a search of the electronic medical record. Serum creatinine values within 180 days or less of each GA MRI examination were retrieved and estimated glomerular filtration rate (eGFR) was calculated. The eGFR value nearest to each MRI examination was used. A separate search in the electronic medical record was also performed to identify patients with NSF. Dermatologists, nephrologists, and nephrologists at our institution were surveyed for any cases of NSF. In patients with NSF, all MRI examinations performed and contrast agents administered to these patients were recorded. Results Overall, 7820 GA MRI examinations were identified, performed in 5351 patients (3022 women and 2329 men). These included 299 examinations (242 patients) with eGFR of 30-44 mL/min/1.73 m2 and 183 examinations (157 patients) with eGFR less than 30 mL/min/1.73 m2. There were 109 examinations (in 94 patients) with eGFR of 15-29 mL/min/1.73 m2, 40 examinations (in 39 patients) with eGFR less than 15 mL/min/1.73 m2, and 34 examinations in 27 patients undergoing hemodialysis. Seventeen patients with eGFR less than 30 mL/min/1.73 m2 or undergoing dialysis underwent GA MRI two or more times. Eighteen patients with biopsy-confirmed NSF were identified, none of whom were exposed to GA. The mean follow-up period for GA MRI examinations performed in patients with severe kidney impairment was 4.2 years (range, 0.2-11.3 years). Conclusion Gadoxetic acid may be safe with respect to nephrogenic systemic fibrosis in this patient population, although further studies are needed to confirm this. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Davenport and Shankar in this issue.

Observational study on the incidence of nephrogenic systemic fibrosis in patients with renal impairment following gadoterate meglumine administration: the NSsaFe study.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a rare life-threatening condition strongly associated with the administration of gadolinium-based contrast agents in patients with severe or endstage renal impairment. PURPOSE: To prospectively determine the incidence of NSF in patients with renal impairment after administration of gadoterate meglumine. STUDY TYPE: Prospective. POPULATION: In all, 540 patients with moderate, severe, or endstage renal impairment, scheduled to undergo a routine contrast-enhanced MRI with gadoterate meglumine. Mean age was 69.7 ± 12.7 years (range: 21-95) with 58.4% of males. FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T, sequence according to each site practice. ASSESSMENT: Medical history, indication(s) for current MRI and adverse events were recorded for each patient. Patients were followed up over 2 years after administration with three visits separated by at least 3 months to detect any signs/symptoms suggestive of NSF. STATISTICAL TESTS: Descriptive. RESULTS: Renal impairment was graded as moderate for 69.4% of patients, severe for 16.0% and endstage for 12.1%; 2.6% had undergone a kidney transplant. Estimated glomerular filtration rate ranged from 4 to 59 mL/min/1.73 m2 except one value of 74 mL/min/1.73 m2 in a patient with kidney transplant. Central nervous system exploration was the main MRI indication (34.7%) and mean dose injected was 0.22 ± 0.09 mL/kg. Overall, 446 patients (82.6%) attended at least one follow-up visit and completed the NSF questionnaire and 329 (60.9%) attended the 2-year visit. No suspicion of NSF was reported in all 446 patients, including 119 patients with severe or endstage renal impairment. No deaths and no adverse events were reported during the MRI examination and the usual period of follow-up after gadoterate meglumine administration. DATA CONCLUSION: No cases of NSF were observed in the 446 patients with moderate to endstage renal impairment followed up over a maximum of 2 years after injection of gadoterate meglumine. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:607-614.

Gadolinium Retention and Breast MRI Screening: More Harm Than Good?

OBJECTIVE. The purpose of this article is to describe the risk-benefit balance of contrast-enhanced breast MRI (CE-BMRI) screening. CONCLUSION. CE-BMRI confers risk of effects associated with administration of gadolinium-based contrast agents (GBCAs), including nephrogenic systemic fibrosis and gadolinium retention. The risk-benefit balance of CE-BMRI screening is favorable for carriers of BRCA, TP53, or other deleterious mutations women who have undergone thoracic irradiation; and women at 20% or greater lifetime risk of breast cancer. The balance is uncertain, however, for women at intermediate to average risk. Women must always receive detailed information regarding possible GBCA-associated effects.

Gadolinium-based contrast agents: why nephrologists need to be concerned.

PURPOSE OF REVIEW: The hegemony of gadolinium-based contrast agent-induced adverse events stretches beyond those who have renal impairment. 'Nephrogenic' systemic fibrosis is a misnomer: gadolinium-based contrast agents are the known trigger for the disease; kidney impairment is a risk factor. Impaired (true) glomerular filtration may be one catalyst for gadolinium-based contrast agent-induced adverse events, but it is increasingly evident that the same cluster of symptoms occurs in patients with normal renal function. RECENT FINDINGS: It has been known for nearly 30 years that gadolinium-based contrast agents distribute and are cleared according to a three compartment model. Single doses of gadolinium-based contrast agents can trigger 'nephrogenic' systemic fibrosis in nondialysis dependent patients. Manifestations have occurred years after exposure. Renal insufficiency alone is not an adequate explanation for 'nephrogenic' systemic fibrosis, and the continuum of its symptoms with the adverse events reported by patients with normal renal function clearly indicate that the physiologic reactions are largely undefined. SUMMARY: Gadolinium-based contrast agents should be used with extreme caution.

Absence of potential gadolinium toxicity symptoms following 22,897 gadoteric acid (Dotarem®) examinations, including 3,209 performed on renally insufficient individuals.

OBJECTIVES: Recent safety concerns regarding gadolinium-based contrast agents (GdCAs) concluded with the suspension of some agents from the European market, yet a clinical consequence remains unknown. We used electronic health records to investigate the incidence of potential toxicity to gadoteric acid (Dotarem®) within our local population, including those with renal insufficiency (RI). METHODS: Data for patients who underwent contrast-enhanced MRI were identified, stratified by renal function at time of scan and retrospectively followed using routinely collected health data. Searches performed were: records of hypersensitivity reactions; diagnoses of nephrogenic systemic fibrosis (NSF); onset of chronic pain, a symptom that has been associated with NSF and the theorised gadolinium deposition disease (GDD); and post-contrast acute kidney injury (PC-AKI). Comparisons were made between patients and controls (those who underwent non-contrast scans) via chi-square and ANOVA statistical tests. RESULTS: Of the 22,897 contrast-enhanced MRI scans performed locally from 2004-2016 (adult, n = 22,325 and paediatric, n = 572), 14% were performed on patients with RI (30 ≤ eGFR < 60, n = 2,622; 15 ≤ eGFR < 30, n = 464; eGFR < 15, n = 123). Two adult patients (0.01%) suffered hypersensitivity reactions. Zero cases of NSF were reported, with an average follow-up time of 6.0 ± 2.5 years (range, 8 months-15 years). Analysis failed to highlight statistically higher rates of chronic pain onset post-MRI (adult: p = 0.777, paediatric: p = 0.578), or PC-AKI (adult: p = 0.566, paediatric: p = 0.841), in the patient groups compared to controls. CONCLUSIONS: These data indicate that administration of gadoteric acid to RI patients does not result in a higher rate of signs or symptoms that may be associated with gadolinium toxicity when compared to controls. KEY POINTS: • Following 22,897 administrations of gadoteric acid to a local population, there was no association with symptoms that may be associated with gadolinium toxicity. • Zero cases of nephrogenic systemic fibrosis were reported following 3,209 gadoteric acid administrations to a cohort of renally insufficient patients. • A low number of hypersensitivity reactions were observed (0.01%) and no higher rate of chronic pain or post-contrast acute kidney injury were noted when compared with a control cohort of non-contrast-enhanced examinations.

Practical administration of intravenous contrast media in children: screening, prophylaxis, administration and treatment of adverse reactions.

Administration of intravenous contrast media to children is a routine practice at many clinical imaging centers, that can involve special considerations. In this paper, we provide practical information to facilitate optimal performance and oversight of this task. We provide targeted screening questions that can help to identify high-risk pediatric patients for both iodine-based and gadolinium-based intravenous contrast media administration. These include children at risk for allergic-like reactions, thyroid dysfunction, contrast-induced nephropathy, and nephrogenic systemic fibrosis. We make recommendations for addressing "yes" responses to screening questions using risk stratification schema that are specific to children. We also present criteria for selecting children for premedication prior to intravenous contrast administration, and suggest pediatric regimens. Additionally, we discuss practical nuances of intravenous contrast media administration to children and provide a quick-reference table of appropriate treatments with pediatric dosages for adverse contrast reactions.

Gadolinium-Induced Fibrosis.

Gadolinium-based contrast agents (GBCAs), once believed to be safe for patients with renal disease, have been strongly associated with nephrogenic systemic fibrosis (NSF), a severe systemic fibrosing disorder that predominantly afflicts individuals with advanced renal dysfunction. We provide a historical perspective on the appearance and disappearance of NSF, including its initial recognition as a discrete clinical entity, its association with GBCA exposure, and the data supporting a causative relationship between GBCA exposure and NSF. On the basis of this body of evidence, we propose that the name gadolinium-induced fibrosis (GIF) more accurately reflects the totality of knowledge regarding this disease. Use of high-risk GBCAs, such as formulated gadodiamide, should be avoided in patients with renal disease. Restriction of GBCA use in this population has almost completely eradicated new cases of this debilitating condition. Emerging antifibrotic therapies may be useful for patients who suffer from GIF.

Notice of Withdrawal: No Incidence of Nephrogenic Systemic Fibrosis after Gadobenate Dimeglumine Administration in Patients Undergoing Dialysis or Those with Severe Chronic Kidney Disease.

The authors have requested to withdraw this manuscript from publication because the study was not conducted in full accordance with the relevant institutional IRB protocol. © RSNA, 2018.

Gadolinium-based contrast agents in children.

Gadolinium-based contrast agents (GBCAs) are widely used in medical imaging, with greater than 300 million doses administered since their introduction. The risk of adverse reactions is very low, and GBCAs were thought to be very safe until the discovery of nephrogenic systemic fibrosis (NSF). Since that time, gadolinium has been found to deposit throughout the body, including the brain, where it is visible on non-contrast T1-weighted MR images in people with normal renal function. The clinical effects of this deposition remain unknown and may not exist. In this review the authors provide a comprehensive update on GBCAs and their potential risks, within a historical context and through the lens of a pediatric radiologist.

Gadolinium-based contrast agents: A comprehensive risk assessment.

Gadolinium-based contrast agents (GBCAs) have been used in magnetic resonance imaging (MRI) since the 1980s and are now administered in up to 35% of all MRI examinations. While GBCAs were initially felt to carry minimal risk, the subsequent identification of GBCAs as the key etiologic factor in the development of nephrogenic systemic fibrosis (NSF) has raised concerns about the broader health impacts of gadolinium exposure. Clinicians, radiologists, and patients should be aware of the most up-to-date data pertaining to the risks of GBCA administration. Specific issues covered in this review article include immediate adverse reactions; pregnancy and lactation; and gadolinium deposition and toxicity, with a special focus on NSF. Practice recommendations based on the presented data, as well as current professional society guidelines, are provided for each section. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. MAGN. RESON. IMAGING 2017;46:338-353.