Cases Of Nephrogenic Systemic Fibrosis Research Articles

Safety and incremental prognostic value of stress cardiovascular magnetic resonance in patients with known chronic kidney disease

BackgroundCardiovascular disease (CVD) is the main cause of mortality in patients with chronic kidney disease (CKD). Although several studies have demonstrated the consistently high prognostic value of stress cardiovascular magnetic resonance (CMR), its prognostic value in patients with CKD is not well established. We aimed to assess the safety and the incremental prognostic value of vasodilator stress perfusion CMR in consecutive symptomatic patients with known CKD. MethodsBetween 2008 and 2021, we conducted a retrospective dual center study with all consecutive symptomatic patients with known stage 3 CKD, defined by estimated glomerular filtration rate (eGFR) between 30 and 60 ml/min/1.73 m2, referred for vasodilator stress CMR. All patients with eGFR < 30 ml/min/1.73 m2 (n = 62) were excluded due the risk of nephrogenic systemic fibrosis. All patients were followed for the occurrence of major adverse cardiovascular events (MACE) defined as cardiac death or recurrent nonfatal myocardial infarction (MI). Cox regression analysis was used to determine the prognostic value of stress CMR parameters. ResultsOf 825 patients with known CKD (71.4 ± 8.8 years, 70% men), 769 (93%) completed the CMR protocol. Follow-up was available in 702 (91%) (median follow-up 6.4 (4.0–8.2) years). Stress CMR was well tolerated without occurrence of death or severe adverse event related to the injection of gadolinium or cases of nephrogenic systemic fibrosis. The presence of inducible ischemia was associated with the occurrence of MACE (hazard ratio [HR] 12.50; 95% confidence interval [CI] 7.50–20.8; p < 0.001). In multivariable analysis, ischemia and late gadolinium enhancement were independent predictors of MACE (HR 15.5; 95% CI 7.72 to 30.9; and HR 4.67 [95% CI 2.83–7.68]; respectively, both p < 0.001). After adjustment, stress CMR findings showed the best improvement in model discrimination and reclassification above traditional risk factors (C-statistic improvement: 0.13; NRI = 0.477; IDI = 0.049). ConclusionsIn patients with known stage 3 CKD, stress CMR is safe and its findings have an incremental prognostic value to predict MACE over traditional risk factors.

Risk of nephrogenic systemic fibrosis (NSF) in oncology patients receiving gadoxetic acid and updated risk of estimate of NSF in patients receiving gadoxetic acid with moderate and severe renal impairment.

Gadoxetic acid (GA) is a half-biliary excreted gadolinium-based contrast agent (GBCA) administered at lower dose than gadobenic acid with similar ionic structure. Gadobenic acid is considered low-risk for nephrogenic systemic fibrosis (NSF) in patients with impaired renal function; however, safety of GA is unclear. The objective of this study was to determine the incidence of NSF in oncology patients undergoing GA-enhanced MRI and to update the risk estimate of NSF in patients receiving GA with severe renal impairment. We retrospectively identified GA-enhanced MRI performed for treatment planning in confirmed cancer patients between March 2011 and December 2020. Serum creatinine values within 180days of GA administration were retrieved and estimated glomerular filtration rate (eGFR) calculated. The eGFR value nearest to each MRI examination was used. The search result was linked to a prospectively maintained registry of reported cases of NSF. An updated literature review was conducted to identify published cases of NSF related to GA administration in patients with severe renal impairment (eGFR < 30mL/min/1.73 m2 or on dialysis) and the incidence of NSF with 95% confidence intervals (CI) was determined combining published data with our results. 192 oncology patients underwent GA-enhanced MRI, mean age was 65.6 ± 11.8years with 73 women. The mean eGFR was 89.6 ± 33.0mL/min/1.73 m2. There were 33 patients with moderate (eGFR 30-60mL/min/1.73 m2) and 1 patient with severe (eGFR < 30mL/min/1.73 m2) renal impairment. There were no reported cases of NSF. Updated literature review including our results identified 340 patients with severe renal impairment or on dialysis with zero cases of NSF (0/340; 95% confidence intervals 0% and 0.9%). No cases of NSF were documented in this study related to gadoxetic acid use in oncology patients, including those with moderate and severe renal impairment. Recent data indicate use of gadoxetic acid in patients with renal impairment can be considered low-risk.

Use of Intravenous Gadolinium-based Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation.

Inaugural consensus statements were developed and endorsed by the American College of Radiology (ACR) and the National Kidney Foundation to improve and standardize the care of patients with kidney disease who have indication(s) to receive ACR-designated group II or group III intravenous gadolinium-based contrast media (GBCM). The risk of nephrogenic systemic fibrosis (NSF) from group II GBCM in patients with advanced kidney disease is thought to be very low (zero events following 4931 administrations to patients with estimated glomerular filtration rate [eGFR] <30 mL/min per 1.73 m2; upper bounds of the 95% confidence intervals: 0.07% overall, 0.2% for stage 5D chronic kidney disease [CKD], 0.5% for stage 5 CKD and no dialysis). No unconfounded cases of NSF have been reported for the only available group III GBCM (gadoxetate disodium). Depending on the clinical indication, the potential harms of delaying or withholding group II or group III GBCM for an MRI in a patient with acute kidney injury or eGFR less than 30 mL/min per 1.73 m2 should be balanced against and may outweigh the risk of NSF. Dialysis initiation or alteration is likely unnecessary based on group II or group III GBCM administration. This article is a simultaneous joint publication in Radiology and Kidney Medicine. The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing 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.

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.

Risk of Nephrogenic Systemic Fibrosis in Patients With Stage 4 or 5 Chronic Kidney Disease Receiving a Group II Gadolinium-Based Contrast Agent

Risk of nephrogenic systemic fibrosis (NSF) to individual patients with stage 4 or 5 chronic kidney disease (CKD; defined as estimated glomerular filtration rate of <30 mL/min/1.73 m2) who receive a group II gadolinium-based contrast agent (GBCA) is not well understood or summarized in the literature. To assess the pooled risk of NSF in patients with stage 4 or 5 CKD receiving a group II GBCA. A health sciences informationist searched the Ovid (MEDLINE and MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citation, and Daily and Versions), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Open Grey databases from inception to January 29, 2019, yielding 2700 citations. Citations were screened for inclusion in a multistep process. Agreement for final cohort inclusion was determined by 2 blinded screeners using Cohen κ. Inclusion criteria consisted of stage 4 or 5 CKD with or without dialysis, administration of an unconfounded American College of Radiology classification group II GBCA (gadobenate dimeglumine, gadobutrol, gadoterate meglumine, or gadoteridol), and incident NSF as an outcome. Conference abstracts, retracted manuscripts, narrative reviews, editorials, case reports, and manuscripts not reporting total group II GBCA administrations were excluded. Data extraction was performed for all studies by a single investigator, including publication details, study design and time frame, patient characteristics, group II GBCA(s) administered, total exposures for patients with stage 4 or stage 5 CKD, total cases of unconfounded NSF, reason for GBCA administration, follow-up duration, loss to follow-up, basis for NSF screening, and diagnosis. Pooled incidence of NSF and the associated upper bound of a 2-sided 95% CI (risk estimate) for the pooled data and each of the 4 group II GBCAs. Sixteen unique studies with 4931 patients were included (κ = 0.68) in this systematic review and meta-analysis. The pooled incidence of NSF was 0 of 4931 (0%; upper bound of 95% CI, 0.07%). The upper bound varied owing to different sample sizes for gadobenate dimeglumine (0 of 3167; upper bound of 95% CI, 0.12%), gadoterate meglumine (0 of 1204; upper bound of 95% CI, 0.31%), gadobutrol (0 of 330; upper bound of 95% CI, 1.11%), and gadoteridol (0 of 230; upper bound of 95% CI, 1.59%). This study's findings suggest that the risk of NSF from group II GBCA administration in stage 4 or 5 CKD is likely less than 0.07%. The potential diagnostic harms of withholding group II GBCA for indicated examinations may outweigh the risk of NSF in this population. PROSPERO identifier: CRD42019123284.

Gadolinium Deposition and Nephrogenic Systemic Fibrosis: A Radiologist's Primer.

Gadolinium-based contrast agents (GBCAs) have an excellent safety profile. However, over the last 2 decades, two specific concerns have surfaced. GBCAs are associated with nephrogenic systemic fibrosis (NSF) and tissue retention of gadolinium. NSF is a rare fibrosing disorder with a poor prognosis, which is characterized by skin and subcutaneous thickening as well as systemic manifestations. The disease has been reported exclusively in patients with advanced renal disease, and it is associated with higher doses and specific types of GBCAs. The number of new cases of NSF has fallen over the past decade, presumably because of adherence by health care providers to regulatory guidelines, which continue to evolve. While gadolinium retention has been known to occur in the liver and bones, the relatively recent findings of deposition and retention in the brain have reignited the debate concerning the safety profile of GBCAs. Despite these concerns, there have been no proven health effects related to gadolinium deposition and retention other than NSF. The authors review the different categories of GBCAs available for commercial use, discuss NSF and gadolinium retention in the brain, and provide updates on the latest U.S. and European regulatory guidelines regarding use of these agents. Given the frequency with which GBCAs are used in clinical practice, it is imperative for all radiologists to learn the current guidelines to provide the safest and highest quality of patient care. ©RSNA, 2019.

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

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. To prospectively determine the incidence of NSF in patients with renal impairment after administration of gadoterate meglumine. Prospective. 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. 1.5T or 3.0T, sequence according to each site practice. 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. Descriptive. 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. 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. 2 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:607-614.

Renal Safety of Intravenous Gadolinium-enhanced MRI in Patients Following Liver Transplantation.

Intravenous contrast-enhanced imaging is invaluable in diagnosing pathology following liver transplantation. Given the potential risk of contrast nephropathy associated with iodinated computed tomography contrast, alternate contrast modalities need to be examined, especially in the setting of renal insufficiency. The purpose of this study was to examine the renal safety of MRI with gadolinium following liver transplantation. The study involved a retrospective analysis of 549 cases of abdominal MRI with low-dose gadobenate dimeglumine in liver transplant recipients at a single center. For each case, serum creatinine values before and after the MRI were compared. In addition, cases were analyzed for the development of nephrogenic systemic fibrosis. Pre-MRI creatinine values ranged from 0.32 to 6.57 mg/dL (median, 1.28 g/dL), with 191 cases having values ≥1.5 mg/dL (median, 1.86 g/dL). A comparison of the pre- and post-MRI creatinine values showed no significant difference, including those patients with pre-MRI values ≥1.5 mg/dL (mean change of -0.04 [95% confidence interval, -0.07 to -0.01; P = 0.004]). No cases of nephrogenic systemic fibrosis were noted. Our findings suggest that, irrespective of baseline renal function, MRI with gadobenate dimeglumine is a nonnephrotoxic imaging modality in liver transplant recipients. Importantly, this intravenous contrast-enhanced imaging modality can be considered in those posttransplant patients who have a contraindication to computed tomography contrast due to renal insufficiency.

Kidney function in contrast media-enhanced imaging

The potential adverse reactions to contrast media-enhanced imaging regularly offer challenges in decision-making for nephrologists and radiologists. The clinical pictures of contrast media-induced acute kidney injury (CI-AKI) and nephrogenic systemic fibrosis (NSF) were evaluated, which are both caused by contrast media and closely linked to the kidney function. The literature in PubMed and Medline was searched for the terms "kidney function" and "contrast media" and complemented by our own experiences. While there is an ongoing re-evaluation of the clinical relevance of CI-AKI, no new cases of NSF have recently been reported under consideration of certain preventive interventions and very restricted use of gadolinium-based contrast agents. Considering the results of the latest clinical research, the potential risk of CI-AKI has been overestimated for along time and should no longer outweigh the diagnostic benefit of contrast media-enhanced imaging. Nevertheless, the most effective prophylaxis for CI-AKI is the avoidance of unnecessary administration of contrast media.

Influence of excess ligand on Nephrogenic Systemic Fibrosis associated with nonionic, linear gadolinium-based contrast agents

BackgroundThe molecular structure, charge, thermodynamic and kinetic stability are approximately the same for gadodiamide and gadoversetamide, the main substantive difference is that gadodiamide is manufactured with 5% free ligand to form Omniscan® and gadoversetamide with 10% free ligand to form OptiMARK®. PurposeTo determine the relative risk of Nephrogenic Systemic Fibrosis (NSF) between gadodiamide (Omniscan®) and gadoversetamide (OptiMARK®) and to explore the potential contribution of the amount of excess ligand added to their commercial formulations. Materials and methodsIn this retrospective observational study, the number of doses and NSF cases associated with these agents were calculated based on two different approaches: the number of doses was determined based on pharmaceutical companies' information, and the number of unconfounded NSF cases was obtained from the previously published literature based on a legal database. A second analysis estimates the number of doses and NSF cases from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). ResultsApproximately 87 million and 12 million doses of Omniscan® and OptiMARK®, respectively, have been administered worldwide since their original approval for use in the various countries throughout the world. A total of 197 and 8 unconfounded cases of NSF have been reported with Omniscan® and OptiMARK®, rendering an incidence of 2.3/million and 0.7/million for these agents, respectively. The FAERS analysis suggested reported incidences of 13.1/million and 5.0/million. ConclusionThere is an approximately 3-fold greater incidence of NSF from Omniscan® than OptiMARK®. The difference in incidence might reflect the lesser quantity of added free ligand to the formulation of Omniscan®.

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

ObjectivesRecent 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).MethodsData 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.ResultsOf 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.ConclusionsThese 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.

Post-marketing surveillance of gadobutrol for contrast-enhanced magnetic resonance imaging in Japan.

To evaluate the safety of gadobutrol for magnetic resonance imaging in a prospective, non-interventional, post-marketing surveillance in Japan. Gadobutrol was administered in accordance with Japanese prescribing information over a 2-year enrollment period, using a standardized questionnaire to collect information. The primary outcome was the incidence of adverse reactions (ARs) following gadobutrol injection. Questionnaire data were analyzed for 3337 patients (age, 58.1 ± 17.4years [mean±SD]). Gadobutrol was administered at a dose of 0.10 ± 0.02mL/kg body weight. Thirty-three patients were observed to have 42 ARs suspected to be due to gadobutrol, an incidence proportion of 0.99%; 29 ARs were acute (<1h post-injection)-including one case of severe acute AR (0.03%). Patient subpopulations (with hepatic, renal, cardiovascular diseases) did not differ markedly in AR proportions categorized by age, sex, presence of comorbidity, or imaging indication. No cases of nephrogenic systemic fibrosis were reported. Investigators rated images as improved or profoundly improved following gadobutrol injection in 91.1% of examinations. Gadobutrol was well tolerated with a good safety profile in this post-marketing surveillance of a large patient population in Japan.

Gadolinium-Based Contrast Agents in Kidney Disease: A Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists.

Purpose of review:Use of gadolinium-based contrast agents (GBCA) in renal impairment is controversial, with physician and patient apprehension in acute kidney injury (AKI), chronic kidney disease (CKD), and dialysis because of concerns regarding nephrogenic systemic fibrosis (NSF). The position that GBCA are absolutely contraindicated in AKI, category G4 and G5 CKD (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2), and dialysis-dependent patients is outdated and may limit access to clinically necessary contrast-enhanced magnetic resonance imaging (MRI) examinations. This review and clinical practice guideline addresses the discrepancy between existing Canadian guidelines regarding use of GBCA in renal impairment and NSF.Sources of information:Published literature (including clinical trials, retrospective cohort series, review articles, and case reports), online registries, and direct manufacturer databases were searched for reported cases of NSF by class and specific GBCA and exposed patient population.Methods:A comprehensive review was conducted identifying cases of NSF and their association to class of GBCA, specific GBCA used, patient, and dose (when this information was available). Based on the available literature, consensus guidelines were developed by an expert panel of radiologists and nephrologists.Key findings:In patients with category G2 or G3 CKD (eGFR ≥ 30 and < 60 mL/min/1.73 m2), administration of standard doses of GBCA is safe and no additional precautions are necessary. In patients with AKI, with category G4 or G5 CKD (eGFR < 30 mL/min/1.73 m2) or on dialysis, administration of GBCA should be considered individually and alternative imaging modalities utilized whenever possible. If GBCA are necessary, newer GBCA may be administered with patient consent obtained by a physician (or their delegate) citing an exceedingly low risk (much less than 1%) of developing NSF. Standard GBCA dosing should be used; half or quarter dosing is not recommended and repeat injections should be avoided. Dialysis-dependent patients should receive dialysis; however, initiating dialysis or switching from peritoneal to hemodialysis to reduce the risk of NSF is unproven. Use of a macrocyclic ionic instead of macrocyclic nonionic GBCA or macrocyclic instead of newer linear GBCA to further prevent NSF is unproven. Gadopentetate dimeglumine, gadodiamide, and gadoversetamide remain absolutely contraindicated in patients with AKI, those with category G4 or G5 CKD, or those on dialysis. The panel agreed that screening for renal disease is important but less critical when using macrocyclic and newer linear GBCA. Monitoring for and reporting of potential cases of NSF in patients with AKI or CKD who have received GBCA is recommended.Limitations:Limited available literature (number of injections and use in renal impairment) regarding the use of gadoxetate disodium. Limited, but growing and generally high-quality, number of clinical trials evaluating GBCA administration in renal impairment. Limited data regarding the topic of Gadolinium deposition in the brain, particularly as it related to patients with renal impairment.Implications:In patients with AKI and category G4 and G5 CKD (eGFR < 30 mL/min/1.73 m2) and in dialysis-dependent patients who require GBCA-enhanced MRI, GBCA can be administered with exceedingly low risk of causing NSF when using macrocyclic agents and newer linear agents at routine doses.

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.

Observational study on the safety profile of gadoterate meglumine in 35,499 patients: The SECURE study.

PurposeTo investigate the safety of gadoterate meglumine and identify the incidence of nephrogenic systemic fibrosis (NSF).Materials and MethodsAn international prospective observational study was conducted from November 2008 to June 2013. A total of 35,499 adults and children who were scheduled to undergo contrast‐enhanced MRI using gadoterate meglumine were analyzed (female, 53.1%; mean age: 49.5 years; range: 0‐98 years). At least 3‐month follow‐up was planned for patients with an estimated creatinine clearance or glomerular filtration rate <60 mL/min (/1.73 m2) to detect any suspicion or occurrence of NSF. Adverse events (AEs) were prospectively recorded. Demographic data, risk factors, indications for MRI examinations, characteristics of gadoterate meglumine administration, and efficacy were documented.ResultsMRI examinations were mainly for central nervous system (61%). The most frequent risk factor was renal insufficiency (14.7%). Seventy AEs were observed in 44 patients (0.12%). Among the 70 AEs, 38 in 32 patients (0.09% of all patients) were considered related to gadoterate meglumine and classified as adverse drug reaction (ADR).The most frequent ADRs were urticaria (9 patients, 0.03%), nausea (7 patients, 0.02%), and vomiting (4 patients, 0.01%). Within the pediatric population (1,629 patients), only one AE (vomiting) was observed. Nine adult patients (0.03%) experienced serious AEs. Moderate to severe renal insufficiency at inclusion was reported in 514 patients (1.5%). Among them, 476 (92.6%) were followed‐up. No patients were suspected of having NSF and no cases of NSF were observed.ConclusionOur study confirms the excellent safety profile of gadoterate meglumine in routine practice. Level of Evidence: 1J. Magn. Reson. Imaging 2017;45:988–997

Renal safety of intravenous gadolinium-enhanced magnetic resonance imaging in patients awaiting liver transplantation.

Renal dysfunction in cirrhosis carries a high morbidity and mortality. Given the potential risk of contrast-induced nephropathy associated with iodinated intravenous contrast used in computed tomography (CT), alternate contrast modalities for abdominal imaging in liver transplant candidates need to be examined. The purpose of this study was to examine the renal safety of magnetic resonance imaging (MRI) with gadolinium in patients awaiting liver transplantation. The study involved a retrospective analysis of 352 patients of abdominal MRI with low-dose gadobenate dimeglumine (MultiHance) (0.05 mmol/kg) in patients with cirrhosis and without renal replacement therapy at a single center during the period from 2007 to 2013. For each case, serum creatinine before and within a few days after the MRI were compared. In addition, the patients were analyzed for the development of nephrogenic systemic fibrosis (NSF), a reported complication of gadolinium in chronic kidney disease. The pre-MRI serum creatinine values ranged from 0.36 to 4.86 mg/dL, with 70 patients (20%) having values ≥ 1.5 mg/dL. A comparison of the pre- and post-MRI serum creatinine values did not demonstrate a clinically significant difference (mean change = 0.017 mg/dL; P = 0.38), including those patients with a pre-MRI serum creatinine ≥ 1.5 mg/dL. In addition, no cases of NSF were noted. In conclusion, our findings suggest that MRI with low-dose gadobenate dimeglumine (MultiHance) is a nonnephrotoxic imaging modality in liver transplant candidates, and its use can be cautiously expanded to liver transplant candidates with concomitant renal insufficiency.

Prospective Cohort Study of Nephrogenic Systemic Fibrosis in Patients With Stage 3-5 Chronic Kidney Disease Undergoing MRI With Injected Gadobenate Dimeglumine or Gadoteridol.

The purpose of this study was to determine the incidence of nephrogenic systemic fibrosis (NSF) in patients with chronic kidney disease (CKD) and moderate-to-severe impairment of kidney function who had not previously been exposed to gadolinium-based contrast agents (GBCAs) or referred to undergo contrast-enhanced MRI with gadobenate dimeglumine or gadoteridol. Two multicenter prospective cohort studies evaluated the incidence of unconfounded NSF in patients with stage 3 CKD (estimated glomerular filtration rate [eGFR] in cohort 1, 30-59 mL/min/1.73 m(2)) or stage 4 or 5 CKD (eGFR in cohort 2, < 30 mL/min/1.73 m(2)) after injection of gadobenate dimeglumine (study A) or gadoteridol (study B). A third study (study C) determined the incidence of NSF in patients with stage 4 or 5 CKD who had not received a GBCA in the 10 years before enrollment. Monitoring for signs and symptoms suggestive of NSF was performed via telephone at 1, 3, 6, and 18 months, with clinic visits occurring at 1 and 2 years. For studies A and B, the populations evaluated for NSF comprised 363 and 171 patients, respectively, with 318 and 159 patients in cohort 1 of each study, respectively, and with 45 and 12 patients in cohort 2, respectively. No signs or symptoms of NSF were reported or detected during the 2 years of patient monitoring. Likewise, no cases of NSF were reported for any of the 405 subjects enrolled in study C. To our knowledge, and consistent with reports in the literature, no association of gadobenate dimeglumine or gadoteridol with unconfounded cases of NSF has yet been established. Study data confirm that both gadoteridol and gadobenate dimeglumine properly belong to the class of GBCAs considered to be associated with the lowest risk of NSF.

Physico-chimie et profil toxicologique d’agents de contraste pour l’imagerie par résonance magnétique, les chélates de gadolinium

Gadolinium chelates (GC) are contrast agents widely used to facilitate or to enable diagnosis using magnetic resonance imaging (MRI). From a regulatory viewpoint, GC are drugs. GC have largely contributed to the success of MRI, which has become a major component of clinician's diagnostic armamentarium. GC are not metabolised and are excreted by the kidneys. They distribute into the extracellular compartment. Because of its high intrinsic toxicity, gadolinium must be administered as a chelate. GC can be classified according to two key molecular features: (a) nature of the chelating moiety: either macrocyclic molecules in which gadolinium is caged in the pre-organized cavity of the ligand, or linear, open-chain molecules, (b) ionicity: Gd chelates can be ionic (meglumine or sodium salts) or non-ionic. The thermodynamic and kinetic stabilities of the various GCs differ according to these structural characteristics. The kinetic stability of macrocyclic GCs is much higher than that of linear GCs and the thermodynamic stability of ionic GCs is generally higher than that of non-ionic GC, thus leading to a lower risk of gadolinium dissociation. This class of drugs has enjoyed an excellent reputation in terms of safety for a long time, until a causal link with a recently-described serious disease, nephrogenic systemic fibrosis (NSF), was evidenced. It is acknowledged that the vast majority of NSF cases are related to the administration of some linear CG in renally-impaired patients. Health authorities, worldwide, released recommendations which drastically reduced the occurrence of new cases.

Advancing pharmacovigilance through academic-legal collaboration: the case of gadolinium-based contrast agents and nephrogenic systemic fibrosis-a Research on Adverse Drug Events and Reports (RADAR) report.

To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts. The Research on Adverse Drug events And Reports methodology was used for assessment-the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration. The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA. Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA. This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.