Occurrence Of Nephrogenic Systemic Fibrosis Research Articles

Occurrence of Nephrogenic Systemic Fibrosis with Group II Gadolinium-Based Contrast Agent in a Pediatric Oncology Patient with AKI

Occurrence of Nephrogenic Systemic Fibrosis with Group II Gadolinium-Based Contrast Agent in a Pediatric Oncology Patient with AKI

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

Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents-current status.

Gadolinium-based contrast agents (GBCAs) have been used clinically since 1988 for contrast-enhanced magnetic resonance imaging (CE-MRI). Generally, GBCAs are considered to have an excellent safety profile. However, GBCA administration has been associated with increased occurrence of nephrogenic systemic fibrosis (NSF) in patients with severely compromised renal function, and several studies have shown evidence of gadolinium deposition in specific brain structures, the globus pallidus and dentate nucleus, in patients with normal renal function. Gadolinium deposition in the brain following repeated CE-MRI scans has been demonstrated in patients using T1-weighted unenhanced MRI and inductively coupled plasma mass spectroscopy. Additionally, rodent studies with controlled GBCA administration also resulted in neural gadolinium deposits. Repeated GBCA use is associated with gadolinium deposition in the brain. This is especially true with the use of less-stable, linear GBCAs. In spite of increasing evidence of gadolinium deposits in the brains of patients after multiple GBCA administrations, the clinical significance of these deposits continues to be unclear. Here, we discuss the current state of scientific evidence surrounding gadolinium deposition in the brain following GBCA use, and the potential clinical significance of gadolinium deposition. There is considerable need for further research, both to understand the mechanism by which gadolinium deposition in the brain occurs and how it affects the patients in which it occurs.

Revisiting the risks of MRI with Gadolinium based contrast agents-review of literature and guidelines.

Gadolinium based contrast agents (GBCA) have been linked to the occurrence of nephrogenic systemic fibrosis (NSF) in renal impaired patients. The exact interaction between the various different available formulations and occurrence of NSF is not completely understood, but has been postulated. This association has triggered public health advisory bodies to issue guidelines and best practice recommendations on its use. As a result, the reported incidence of NSF, as well as the published use of GBCA-enhanced magnetic resonance imaging in renal impairment, has seen a decline. Understanding of the events that led to these recommendations can increase clinical awareness and the implications of their usage. We present a review of published literature and a brief overview of practice recommendations, guidelines and manuals on contrast safety to aide everyday imaging practice.Teaching Points• Low risk gadolinium based contrast agents should be the choice in renal insufficiency.• Higher doses have been linked to NSF development. Doses should be as low as possible.• Clear documentation of date,dose and type of formulation used should be noted.• Post-scan dialysis should be arranged as soon as possible and feasible.• Pre-existing inflammatory state is a risk factor;liver insufficiency is not a contraindication.

The gadolinium-based contrast agent Omniscan® promotes in vitro fibroblast survival through in situ precipitation.

The current study aims to explore how the gadolinium (Gd)-based contrast agent (GBCA) Omniscan® enhanced cell viability of murine fibroblasts. The results of scanning electron microscopy showed that Omniscan® can precipitate in cell culture media and deposit on cell membranes. Energy-dispersive X-ray analysis and Fourier-transform infrared spectroscopy demonstrated the presence of Gd and phosphates in the agglomerated particles. By filtering the Omniscan®-containing medium through a 220 nm filter, it can be clearly found that the increased cell viability should be mainly attributed to the insoluble species of gadolinium rather than to chelated gadolinium. Moreover, the effects of other gadolinium-based contrast agents, Magnevist® and Dotarem®, were compared with that of Omniscan®. It is noted that the three contrast agents differed in their ability to induce cell viability, which is possibly ascribed to the different chemical stabilities of gadolinium chelates as demonstrated by the attenuation in cell growth upon the addition of excess ligands to the compounds. The results of flow cytometry analysis also showed that Omniscan® can promote cell growth via an increase in the S-phase cell population as evidenced by the elevated levels of cell cycle associated proteins cyclin D, cyclin A and the phosphorylated Rb protein. Furthermore, our results revealed that integrin-mediated signaling may play an important role in both Omniscan® and Magnevist®-enhanced focal adhesion formation since the blockade of integrins decreased the level of ERK phosphorylation induced by the two GBCAs. Taken together, these data suggested that in situ gadolinium phosphate precipitation formation mediated Omniscan®-promoted fibroblast survival, which is similar to that of gadolinium chloride. It was demonstrated that the application of GBCAs with more stable thermodynamic stability may cause less dissociation of the gadolinium ion and thus resulted in less precipitation, finally leading to lower occurrence of nephrogenic systemic fibrosis. The obtained results would also be helpful for the development of safe gadolinium-based contrast agents.

Dialysability of Gadoteric Acid in Patients With End-Stage Renal Disease Undergoing Hemodialysis

This study was designed to evaluate the dialysability of gadoteric acid in patients with end-stage renal disease (ESRD) requiring hemodialysis. Gadoteric acid is used for magnetic resonance imaging. It is cleared from the blood exclusively by glomerular filtration. In an attempt to decrease the occurrence of nephrogenic systemic fibrosis, hemodialysis has been advocated immediately after injection of gadolinium-based contrast agents in patients with ESRD. Ten patients with ESRD underwent 3 consecutive 4-hour hemodialysis sessions after a single intravenous injection (0.1 mmol/kg) of gadoteric acid. Blood samples were drawn from the vascular access just before and immediately after the end of each 4-hour session. Additional sampling was performed during session 1. Gadoteric acid was efficiently eliminated, with mean (95% confidence interval) clearance values (mL/min) of 224.6 (216.0-233.9) at 0.5 hours and 225.9 (215.6-237.2) at 1.5 hours during session 1. The gadolinium concentration decrease after a 4-hour hemodialysis (vs the corresponding predialysis values) was 97% after session 1. The decrease in gadolinium concentration after session 3 was 99.7% compared with the predialysis concentration of session 1. These percentages are similar to those reported after hemodialysis for other gadolinium-based contrast agents. No adverse effects related to gadoteric acid were reported. Although no unconfounded case of nephrogenic systemic fibrosis has been reported so far after injection of gadoteric acid, hemodialysis can be efficiently used to remove this molecule in patients with ESRD already undergoing long-term hemodialysis.

Retrospective analysis of patients for development of nephrogenic systemic fibrosis following conventional angiography using gadolinium-based contrast agents

The purpose was to retrospectively review the data of 27 patients with renal insufficiency who underwent conventional angiography with gadolinium-based contrast agents (GDBCA) as alternative contrast agents and assess the occurrence of nephrogenic systemic fibrosis (NSF) together with associated potential risk factors. This HIPAA-compliant study had institutional review board approval, and informed consent was waived. Statistical analysis was performed for all available laboratory and clinical data, including dermatology reports. Type and amount of the GDBCA used were recorded for angiography and additional MRI studies, if applicable. Serum creatinine levels (SCr) pre- and post-angiography were recorded, and estimated glomerular filtration rates (eGFR) were calculated. Ten female and 17 male patients who underwent angiography with GDBCA were included. The mean amount of GDBCA administered was 44 +/- 15.5 ml (range 15-60 ml) or 0.24 + 0.12 mmol/kg (range 0.1-0.53 mmol/kg). At the time of angiography all patients had renal insufficiency (eGFR <60 ml/min/1.73 m(2)). Mean eGFR pre-angiography was 26 ml/min/1.73 m(2) and 33 ml/min/1.73 m(2) post-angiography. The mean follow-up period covers 28 months, range 1-84 months. Additional MRI studies with GDBCA administration were performed in 15 patients. One patient with typical skin lesions had developed biopsy-confirmed NSF. Conventional arterial angiography with GDBCA may play a role in the development of NSF in patients with renal insufficiency. Alternative contrast agents, such as CO(2) angiography or rather the use of low doses of iodinated contrast agents, should be considered in these patients.

How Should Nephrologists Approach Gadolinium-based Contrast Imaging in Patients with Kidney Disease?

Since the initial description in early 2006 (1), a firm epidemiologic link has been established between gadolinium-based contrast (GBC) exposure and development of nephrogenic systemic fibrosis (NSF). When looking back in time, it is interesting to recall that GBC-magnetic resonance imaging (MRI) garnered increased use in patients with kidney disease in the early to mid-1990s based on a perceived safe renal profile (2). Also, higher than approved doses were being used to study renal and other arterial beds with MR angiography. Recognition of NSF in 1997 as a new disease of patients with kidney disease fits nicely as an entity that developed due to a “new exposure,” in this case from GBC. Notably, use of GBC MR studies in patients with end-stage renal disease (ESRD) increased significantly over a 6-yr period (January 2000 to June 2006), which also parallels the increased recognition of NSF (3). When one surveys the literature, multiple publications (40 case series; 8 case-control studies) strongly argue for an important role of GBC in increasing NSF risk in patients with advanced kidney disease. Greater than 80% had ESRD on dialysis, whereas no clear-cut cases have been described in chronic kidney disease (CKD) stages I to III. All of these studies show a temporal association of GBC exposure and occurrence of NSF, most within weeks to months of exposure. The odds ratio for development of NSF in exposed ESRD patients compared with those not exposed ranges from 20 to 46 (3–6). The prevalence of biopsy-proven NSF in exposed ESRD patients ranges between 1.5% and 5% (3–6), which …

A Preclinical Study to Investigate the Development of Nephrogenic Systemic Fibrosis: A Possible Role for Gadolinium-Based Contrast Media

Several recent publications have suggested an association between the administration of gadolinium (Gd)-based contrast agents and the occurrence of Nephrogenic Systemic Fibrosis (NSF), an acquired disorder marked by skin thickening and fibrosis occurring in patients with severe renal dysfunction. The aim of this study was to establish a preclinical experimental setting to investigate the possible link between NSF and Gd-based contrast agents, and specifically the role of Gd and/or depletion of endogenous metal ions as possible triggers for NSF. Thirty-five healthy male rats received repeated intravenous injections of Magnevist (gadopentetate dimeglumine; Gd-DTPA), Omniscan (gadodiamide; Gd-DTPA-BMA), or gadodiamide without caldiamide at a dose of 2.5 mmol Gd/kg body weight over at least 20 days to simulate the exposure to Gd-containing contrast agents in patients with severe renal dysfunction. In addition, caldiamide (the excess ligand in Omniscan) and Gd-ethylenediamine tetraacetic acid (Gd-EDTA) as a positive control, and saline as a negative control were studied. Histopathologic and immunohistochemical analysis of the skin was performed. Gd and zinc concentrations were measured in skin, femur, and liver tissue by atomic emission spectrometry. Rats receiving Gd-EDTA, gadodiamide without caldiamide, and Omniscan developed epidermal ulceration and acanthosis, dermo-epidermal clefts, minimal-to-slight dermal fibrosis, and increased dermal infiltration of different cells, partly positive for CD34 fibrocytes. No such NSF-like macroscopic lesions were observed in the saline, caldiamide, and Magnevist groups. High Gd concentrations in the skin were found in the Gd-EDTA, gadodiamide without caldiamide, and Omniscan groups. In the Magnevist group, Gd levels in the skin were 10-times lower than in the Omniscan-treated animals but elevated compared with saline. A preclinical experimental setting has been established where NSF-like lesions could be observed. The link between the application of Gd-based contrast media and the induction of NSF-like lesions was established. The data indicate that the observed skin lesions are related to the release of Gd and not to the depletion of endogenous ions. The investigations further suggest potential importance of the stability of Gd-based contrast agents.

Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a devastating complication of severe renal failure. Recent reports suggest that exposure to gadolinium-containing contrast agents (GCCA) is associated with the occurrence of NSF. The population of patients with ESRD in and around Bridgeport, CT, was studied during an 18-mo period. The incidence of NSF was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for NSF. The association between gadolinium exposure and NSF was highly significant (P < or = 0.001). It is concluded that GCCA exposure is a major risk factor for NSF in the ESRD population. Because of the significant morbidity and mortality with NSF, it is believed that gadolinium exposure should be avoided in patients with ESRD. In the event that exposure cannot be avoided, careful consideration of the potential consequences, including a thorough discussion of the risks and benefits of GCCA, is advised.