Risks and Options With Gadolinium-Based Contrast Agents in Patients With CKD: A Review.

Gadolinium-based contrast agents (GBCAs) improve the diagnostic capabilities of magnetic resonance imaging. Although initially believed to be without major adverse effects, GBCA use in patients with severe chronic kidney disease (CKD) was demonstrated to cause nephrogenic systemic fibrosis (NSF). Restrictive policies of GBCA use in CKD and selective use of GBCAs that bind free gadolinium more strongly have resulted in the virtual elimination of NSF cases. Contemporary studies of the use of GBCAs with high binding affinity for free gadolinium in severe CKD demonstrate an absence of NSF. Despite these observations and the limitations of contemporary studies, physicians remain concerned about GBCA use in severe CKD. Concerns of GBCA use in severe CKD are magnified by recent observations demonstrating gadolinium deposition in brain and a possible systemic syndrome attributed to GBCAs. Radiologic advances have resulted in several new imaging modalities that can be used in the severe CKD population and that do not require GBCA administration. In this article, we critically review GBCA use in patients with severe CKD and provide recommendations regarding GBCA use in this population.

Noncontrast Magnetic Resonance Angiography in the Era of Nephrogenic Systemic Fibrosis and Gadolinium Deposition.

ABSTRACT: Gadolinium-based contrast agents for clinical magnetic resonance imaging are overall safe. However, the discovery of nephrogenic systemic fibrosis in patients with severe renal impairment and gadolinium deposition in patients receiving contrast have generated developments in contrast-free imaging of the vasculature, that is, noncontrast magnetic resonance angiography. This article presents an update on noncontrast magnetic resonance angiography techniques, with comparison to other imaging alternatives. Potential benefits and challenges to implementation, and evidence to date for various clinical applications are discussed.

MR Imaging Safety Considerations of Gadolinium-Based Contrast Agents: Gadolinium Retention and Nephrogenic Systemic Fibrosis.

Gadolinium (Gd)-based contrast agents (GBCAs) have revolutionized of MR imaging, enabling physicians to obtain life-saving medical information that often cannot be obtained with unenhanced MR imaging or other imaging modalities. Since regulatory approval in 1988, more than 450 million intravenous GBCA doses have been administered worldwide, with an extremely favorable pharmacologic safety profile. Recent evidence has demonstrated, however, that a small fraction of Gd is retained in human tissues. No direct correlation between Gd retention and clinical effects has been confirmed; however, a subset of patients have attributed various symptoms to GBCA exposure. This review details current knowledge regarding GBCA safety.

[Kidney function in contrast media-enhanced imaging]. / Nierenfunktion bei kontrastmittelverstärkter Bildgebung.

BACKGROUND: The potential adverse reactions to contrast media-enhanced imaging regularly offer challenges in decision-making for nephrologists and radiologists. OBJECTIVE: 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. MATERIAL AND METHODS: The literature in PubMed and Medline was searched for the terms "kidney function" and "contrast media" and complemented by our own experiences. RESULTS: 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. CONCLUSION: Considering the results of the latest clinical research, the potential risk of CI-AKI has been overestimated for a long 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.

Use and Safety of Gadolinium Based Contrast Agents in Pediatric MR Imaging.

Gadolinium-based contrast agents (GBCA) used for MR imaging are a valuable imaging resource that has benefited patient management over last three decades and largely have a high safety profile. However, recently, adverse effects related to GBCA like nephrogenic systemic fibrosis (NSF) and asymptomatic gadolinium deposition in tissues including brain are concerning. While NSF has largely stopped occurring due to precautions and guidelines to not use GBCA in patients with poor renal function, the long term effects of gadolinium deposition, especially in brain, are not known at this stage. Cautious approach needs to be taken with risk-benefit analysis in each patient to avoid its administration when not necessary. In this review, authors discuss basics of gadolinium, mechanism of enhancement, agents in clinical use and safety issues, and in the end, offer some solutions for safety concerns.

Gadobutrol in Renally Impaired Patients: Results of the GRIP Study.

OBJECTIVE: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF). MATERIALS AND METHODS: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. RESULTS: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF. CONCLUSIONS: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases.

Imágenes del depósito de gadolinio en el sistema nervioso central / Images of gadolinio deposit in the central nervous system Abstract

Magnetic resonance imaging has been shown to be very useful in the diagnosis and monitoring of multiple diseases affecting the central nervous system. Gadolinium has been used extensively worldwide. It has been estimated that since its introduction more than two hundred million doses of GBCA have been administered globally. Gadolinium-based contrast agents (GBCAs) were long considered medicines with a high safety profile, the literature reports incidences of immediate adverse effects such as headache, dizziness, and altered sense of taste. Studies performed a few years after the introduction of GBCA showed that there were gadolinium deposits in the tissues but their clinical significance was not known. It wasn’t until 2006 when the first reports were published that associated the gadolinium ion tissue deposits from GBCA with a systemic inflammatory entity of the connective tissue similar to scleroderma known as Nephrogenic Systemic Fibrosis (NSF), in patients with chronic renal failure. In 2013, the association between the use of GBCAs and the progressive increase in the signal intensity of the dentate nucleus and the globus pallidus in T1-weighted MRI images without contrast medium, was described for the first time. This review describes the most relevant aspects of the pathophysiology of these findings taking into account their differential diagnosis.

Las imágenes por resonancia magnética han mostrado ser de gran utilidad en el diagnóstico y seguimiento de múltiples enfermedades que afectan el sistema nervioso central. El gadolinio se ha utilizado ampliamente a nivel mundial. Se estima que desde su introducción se han administrado más de doscientos millones de dosis de MCBG en el mundo. Los medios de contraste basados en Gadolinio (MCBG) fueron considerados por mucho tiempo medicamentos con un alto perfil de seguridad, la literatura reporta incidencia de efectos adversos inmediatos como cefalea, mareo y alteración del sentido del gusto. Estudios realizados pocos años después de la introducción de los MCBG mostraron que había depósitos de gadolinio en los tejidos, pero no se conocía su significancia clínica Fue hasta 2006 cuando se publicaron los primeros reportes que asociaban el depósito tisular del ion gadolinio proveniente de los MCBG con una entidad inflamatoria sistémica del tejido conectivo similar a la escleroderma conocida como Fibrosis Sistémica Nefrogénica (FSN) en pacientes con falla renal crónica. En 2013 se describió por primera vez la asociación entre el uso de los MCBG y el aumento progresivo de la intensidad de señal del núcleo dentado y los globos pálidos en las imágenes de RM ponderadas en T1 sin medio de contraste. En esta revisión se describen los aspectos más relevantes de la fisiopatología de estos hallazgos considerando su diagnóstico diferencial.

High signal intensity in dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in three patients with impaired renal function and vascular calcification.

Gadolinium-based contrast agents (primarily those with linear chelates) are associated with a dose-dependent signal hyperintensity in the dentate nucleus and the globus pallidus on unenhanced T1-weighted MRI following administration to selected patients with normal renal function. The accumulation of gadolinium has also been reported in the skin, heart, liver, lung, and kidney of patients with impaired renal function suffering from nephrogenic systemic fibrosis (NSF). Here we report on three patients with impaired renal function and vascular calcification (two with confirmed NSF) whose unenhanced T1-weighted MRIs showed conspicuous high signal intensity in the dentate nucleus and the globus pallidus after they had been exposed to relatively low doses of linear gadolinium-based contrast agents (0.27, 0.45, and 0.68 mmol/kg). Signal ratios between dentate nucleus and pons and between globus pallidus and thalamus were comparable with previously reported measurements in subjects without renal impairment. Of note, all three analysed patients suffered from transient signs of neurological disorders of undetermined cause. In conclusion, the exposure to 0.27-0.68 mmol/kg of linear gadolinium-based contrast agent was associated with probable gadolinium accumulation in the brain of three patients suffering from impaired renal function and vascular calcification. © 2016 The Authors. Contrast Media & Molecular Imaging published by John Wiley & Sons Ltd.

Nephrogenic Systemic Fibrosis on Mammography.

Nephrogenic systemic fibrosis, previously known as nephrogenic fibrosing dermopathy, is a multiorgan sclerotic disorder that is strongly linked to the administration of gadolinium-based chelates used for intravenous contrast in magnetic resonance imaging procedures. Although involvement of truncal skin is a relatively common, few reports of its appearance on mammography exist in the literature.

Biocompatible and high-performance amino acids-capped MnWO4 nanocasting as a novel non-lanthanide contrast agent for X-ray computed tomography and T(1)-weighted magnetic resonance imaging.

In the present work, a novel non-lanthanide dual-modality contrast agent, manganese tungstate (MnWO4), has been successfully constructed by a facile and versatile hydrothermal route. With the merits of a high atomic number and a well-positioned K-edge energy of tungsten, our well-prepared non-lanthanide nanoprobes provide a higher contrast efficacy than routine iodine-based agents in clinics. Additionally, the presence of Mn in these nanoparticles endow them with excellent T1-weighted MR imaging capabilities. As an alternative to T2-weighted MRI and CT dual-modality contrast agents, the nanoprobes can provide a positive contrast signal, which prevents confusion with the dark signals from hemorrhage and blood clots. To the best of our knowledge, this is the first report that a non-lanthanide imaging nanoprobe is applied for CT and T1-weighted MRI simultaneously. Moreover, comparing with gadolinium-based T1-weighted MRI and CT dual-modality contrast agents that were associated with nephrogenic systemic fibrosis (NSF), our contrast agents have superior biocompatibility, which is proved by a detailed study of the pharmacokinetics, biodistribution, and in vivo toxicology. Together with excellent dispersibility, high biocompatibility and superior contrast efficacy, these nanoprobes provide detailed and complementary information from dual-modality imaging over traditional single-mode imaging and bring more opportunities to the new generation of non-lanthanide nanoparticulate-based contrast agents.

Nephrogenic systemic fibrosis in a patient with renal failure demonstrating a "reverse superscan" on bone scintigraphy.

Nephrogenic systemic fibrosis (NSF) has been linked to utilization of gadolinium-based contrast agents in patients with renal impairment. We present a 19-year-old female patient with end-stage renal failure presenting with joint pains and subcutaneous nodules. She had a prior gadolinium-enhanced magnetic resonance angiography when she was 14 years old. Clinical findings revealed firm subcutaneous nodules in both thighs. Whole-body bone scan demonstrates tracer uptake predominantly in the soft tissues and muscles of the extremities with minimal bony uptake. Incisional biopsy of the left thigh nodule revealed features of NSF with a total pathological score of 4, highly consistent with NSF.

"Carcinoid-like" tricuspid valvulopathy associated with nephrogenic systemic fibrosis.

We present a case of a patient with end-stage renal disease and nephrogenic fibrosing dermopathy (NFD) whose echocardiogram demonstrated rare tricuspid valve abnormality with malcoaptation due to tethering and restricted motion of the leaflets causing severe tricuspid regurgitation. The cardiac abnormalities developed 3 years after her initial diagnosis of NFD was made by skin biopsy. The echocardiographic appearance of the tricuspid valve resembled that seen in patients with carcinoid heart disease; however, an evaluation for carcinoid tumor in our patient was negative. Myocardial biopsy performed at the time of right heart catheterization demonstrated trace gadolinium within the lysosomes of one cardiac fibroblast. This report is the first to describe the association between nephrogenic systemic fibrosis and severe valvular heart disease requiring valve replacement.

Quantification of gadolinium in fresh skin and serum samples from patients with nephrogenic systemic fibrosis.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a rare, potentially fatal fibrosing disorder associated with renal insufficiency and gadolinium (Gd)-based contrast exposure. The cause remains unknown. To date, all efforts to investigate skin Gd concentrations in patients with NSF have been performed on paraffin-embedded samples, and Gd deposition has not been correlated with disease activity by a statistically significant analysis. OBJECTIVE: We sought to: (1) quantify Gd concentration in fresh tissue skin biopsy specimens; (2) quantify and compare synchronous Gd concentration of affected skin and unaffected skin in patients with NSF (n = 13) with a control group (n = 13); and (3) quantify serum Gd. METHODS: We used inductively coupled plasma mass spectrometry. RESULTS: In patients with NSF, the mean ratio of paired Gd concentrations of affected skin to unaffected skin was 23.1, ranging from 1.2 to 88.9. Mean serum Gd concentrations in patients with NSF were 4.8 ng/mL, which is more than 10 times the level in control patients. A statistically significant correlation existed between serum and affected skin Gd concentrations (r(2) = .74, P < .0001). LIMITATIONS: Because of the feasibility of this study, the main limitation was the small sample size (n = 13 affected and 13 control). CONCLUSIONS: Determination of Gd concentrations in fresh skin samples and serum using inductively coupled plasma mass spectrometry demonstrates significant differences in the amounts of Gd in involved versus nonlesional skin of patients with NSF. This supports the role of differential free Gd deposition from Gd-based contrast in the pathogenesis of NSF.

Effects of magnetic resonance imaging contrast agents on human umbilical vein endothelial cells and evaluation of magnetic resonance imaging contrast media-triggered transforming growth factor-beta induction in dermal fibroblasts (HSF) as a model for nephrogenic systemic fibrosis.

RATIONALE AND OBJECTIVES: The objective of this study was to evaluate effects of 6 commercially available magnetic resonance contrast media (CM) on human umbilical vein endothelial cells (HUVEC) and the induction of transforming growth factor-beta (TGF-ß) in dermal fibroblasts (HSF) as a possible model for the pathogenesis of nephrogenic systemic fibrosis. METHODS: HUVECs were incubated with 10× and 20× of the molar standard blood concentration achieved with CM applications for magnetic resonance imaging examinations (10× and 20× concentration) for 24 hours using gadolinium-based CM Gadovist, Magnevist, Multihance, and Omniscan, as well as Teslascan (Manganese-based), and Resovist (Iron-based). Proliferation kinetics (PK), colony formation, and viability assays were performed. Additionally, human dermal fibroblasts (HSF) were incubated for 24 hours with 1× and 20× concentration in all 6 CM, and TGF-ß levels were assessed directly after the incubation period as well as on days 3 and 8 postincubation. RESULTS: HUVEC PK data show similar gains in cell numbers for all 6 CM in both concentration groups over the 17-day assessment period. Only cells incubated with Omniscan and Teslascan differed from the other groups on days 3 and 7 postincubation (P < 0.05). After day 7, a cell regain occurred in the Omniscan and Teslascan groups reaching the numbers of the other groups in sequel. Differences in colony formation were consistent with PK results with a statistically significant reduction in clonogenic activity for Teslascan and Omniscan in HUVEC cells, P < 0.05. No reduction in viability was seen for all groups and conditions. TGF-ß expression of HSF cells incubated with 1× concentration and all CM did not differ significantly from control cells for any point in time investigated. At 20× concentration directly after incubation, TGF-ß was significantly reduced for the Teslascan and Resovist group as 3 compared with control and all other CM groups, P < 0.05. On day 3 postincubation, only Resovist-incubated HSF cells showed a significant reduction of TGF-ß (1.614, standard deviations: 89) as compared with the control group (2.883, standard deviations: 30) and the other CM. TGF-ß was slightly reduced for all CM groups 8 days after incubation (not statistically significant, P > 0.05). CONCLUSIONS: After 24 hours of incubation with Omniscan and Teslascan (10× and 20× concentration), considerable short-term antiproliferative effects in HUVECs were observed. HSF cells (20× concentration) showed a reduction of TGF-ß for Resovist and Teslascan directly after incubation, whereas TGF-ß levels in HSF cells were slightly reduced for all CM 8 days after incubation. Therefore, TGF-ß-mediated proliferative effects on fibroblasts or on collagen synthesis potentially leading to nephrogenic systemic fibrosis may mainly be triggered by tissue monocytes and macrophages in the peripheral blood instead of dermal fibroblasts.

High-dose gadodiamide for catheter angiography and CT in patients with varying degrees of renal insufficiency: Prevalence of subsequent nephrogenic systemic fibrosis and decline in renal function.

OBJECTIVE: The purpose of our study was to evaluate the prevalence of nephrogenic systemic fibrosis (NSF) and nephrotoxicity among patients with differing degrees of renal dysfunction who are exposed to high doses of gadodiamide. MATERIALS AND METHODS: A search of medical records identified patients who received high-dose IV gadodiamide for catheter angiography or CT between January 2002 and December 2005. The cohort was limited to patients who had received a dose of at least 40 mL of gadodiamide during a single imaging session, who underwent at least 1 year of clinical follow-up, and who had moderate to end-stage renal disease (estimated glomerular filtration rate [GFR] < 60 mL/min/1.73 m(2)) established within the previous 48 hours. Any observation suggestive of NSF was recorded, as were all estimated GFR values obtained during the 2 weeks before and the 5 days after gadodiamide administration. RESULTS: Sixty-one patients met the inclusion criteria. The median estimated GFR was 30 mL/min/1.73 m(2) (range, 3-57 mL/min/1.73 m(2)). The median gadodiamide exposure was 80 mL (range, 40-200 mL). NSF eventually developed in one of the 61 patients, yielding a prevalence of 1.6%. Among the 33 patients not undergoing dialysis with estimated GFR documented within 5 days after contrast injection, the change in estimated GFR ranged from -8.8 to 42.9 mL/min/1.73 m(2), with a statistically significant median improvement of 2.4 mL/min/1.73 m(2) (p = 0.007). CONCLUSION: Although gadolinium exposure appears to be a necessary precondition for NSF, gadolinium-based contrast agents alone are not sufficient to cause the disorder, even in very high doses. Clinically relevant nephrotoxicity of gadolinium-based contrast agents was not found.

Case report. Appearance of nephrogenic fibrosing dermopathy on a bone scan.

We report a case of nephrogenic systemic fibrosis involving the thighs bilaterally in a patient who received multiple MRI scans with gadolinium. A recent bone scan demonstrated uptake of radiotracer in a region that correlates with CT and dermatopathological findings.