Nephrogenic Systemic Fibrosis In Patients Research Articles

Recent topics related to nephrogenic systemic fibrosis associated with gadolinium‐based contrast agents

Nephrogenic systemic fibrosis is a progressive, potentially fatal, multiorgan-system fibrosing disease related to exposure of patients with renal failure to gadolinium-based contrast agents used in magnetic resonance imaging. Between 1997 and 2007, more than 500 cases of nephrogenic systemic fibrosis in patients with severe renal insufficiency (glomerular filtration rate less than 30 mL/min/1.73 m(2)) were reported, and no known cases of nephrogenic systemic fibrosis have occurred in patients with a glomerular filtration rate of more than 30 mL/min/1.73 m(2) without acute kidney injury. Additional major risk factors are use of high-dose and specific gadolinium-based contrast agents, a pro-inflammatory state. Although the mechanism of nephrogenic systemic fibrosis is unclear and there is no consistently-effective therapy, nephrogenic systemic fibrosis is an entity that can be eliminated by observing recent recommended guidelines for gadolinium-based contrast agents and nephrogenic systemic fibrosis. This article reviews current knowledge about nephrogenic systemic fibrosis and focuses mainly on how to prevent it.

Copper nanocolloids: a new thrombus molecular imaging approach to ruptured plaque

Summary Molecular imaging of fibrin offers a sensitive way to detect ruptured atherosclerotic plaque with MRI. To date we and others have heavily explored the use of gadolinium and manganese as paramagnetic metals to provide T1 contrast. In this project, we developed the first bivalent copper nanocolloids for MR molecular imaging of thrombus. Background Robust detection of fibrin expressed in the microfissues of ruptured plaque of the carotid artery offers an opportunity to intercede prophylatically in patients at high risk for stroke. Given the abundance of fibrin in microthrombus, we have focused on developing gadoliniumfree nanomedicine strategies for paramagnetic imaging of clot, respecting recent concerns regarding the pathological link between the lanthanide and Nephrogenic Systemic Fibrosis in patients with severe renal disease. The objective of this research was to develop and characterize the first molecular imaging (MI) agent for fibrin using copper-based nanocolloids (NanoQ). Methods Nanocolloids incorporating copper (II) complexes were synthesized (Dav=217 nm, ζ=-13mV) and characterized for MI of thrombus. MR properties of NanoQ in suspension were defined at 3.0 T at 25°C. Single slice inversion recovery and multi-echo spin echo sequences were used to calculate the ionic (per metal) and particulate (per particle) relaxivities from serial dilutions. T1weighted gradient echo imaging of fibrin clots with NanoQ or a control (n=3/group) using fibrin-specific antibodies (NIB5F3) were acquired. In vivo pharmacokinetics and 24 hour biodistribution, and bioelimination of NanoQ were evaluated in rodents. Results The particulate relaxivity of the NanoQ was high, r1=66,000±2200 (s●mmol [NanoQ])-1, while the ionic r1 relaxivitiy (4.3±0.1 (s●mmol [Cu])-1) was similar to Gd-DTPA. The particulate r2 relaxivities were r2=135,000±2900 and ionic r2 relaxivities of 10.4±0.34 (s●mmol [Cu])-1, respectively. NanoQ targeted to fibrin clot phantoms provided strong improvement in contrast-to-noise ratio (CNR) (40x p 0.99). ICP analysis of tissue copper 24 hours post injection revealed that approximately 90% of the metal was already eliminated from the animal. Conclusions

Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease

Background.In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark’s identification and subsequent rapid eradication of NSF.Methods.NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002–11).Results.In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide’s renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported.Conclusion.A confluence of factors led to the development and eradication of NSF in Denmark.

Safety of Older Generations of Gadolinium in Mild-to-Moderate Renal Failure

Nephrogenic systemic fibrosis (NSF) is a rare disease that is mostly reported in patients with chronic kidney disease (CKD) who have received gadolinium as a contrast in imaging techniques. The exact pathogenetic role of renal failure or gadolinium is not known. The aim of this study is to show whether mild-to-moderate renal failure is a risk for NSF as it is described in severe renal failure. In this cross-sectional study, we enrolled 164 patients with serum creatinine levels >1.5 mg/dL who were in different stages of CKD and had received gadolinium (gadopentetate). The average lag time between the gadolinium administration and the study was 4 months. The most prevalent skin symptom was itching (19%) and the least frequent was induration and papules (<1%). At the follow-up, all skin lesions were relieved. No patients had characteristic lesions of NSF. Twenty-five percent of patients had acute kidney injury at the time of gadolinium exposure. No patients had liver disease and only five were receiving erythropoietin. None of our patients were taking immunosuppressive agents, but all of them suffered from cardiovascular diseases. We conclude that in patients with mild-to-moderate renal failure, it seems that gadolinium is associated with no or very low risk for NSF. We did not find any NSF in patients with severe renal failure. However, because of the rarity of NSF, the low number of such patients in the study, and the high mortality, the use of gadolinium in these patients should be avoided.

Nephrogenic Systemic Fibrosis (NSF): What It Really Means for Materials Scientists?

Noninvasive MR molecular imaging and targeted drug delivery systems, often referred to as theranostic agents, are being developed to enable improved detection, patient risk stratification, site-specific treatment and longitudinal monitoring [1]. Gadolinium (Gd), a paramagnetic lanthanide has been the dominant metal for T1 weighted MR contrast agents to produce bright signal in vivo. With seven unpaired electron (+3 oxidation state) in the outer d-orbital, it strongly influences the T1 relaxation times of the soft, biological tissues to which the metal has access. Gd exhibits a tendency to alter signal intensities by shortening the T1 time in its surroundings. The efficacy is measured by the relaxivity, which is dependent on the chemical properties of the metal, typically as a coordinated complex. Gadolinium is toxic in its free form [2]. The free ion (i.e. chloride, sulfate, or acetate form) has inadequate solubility in water in the neutral pH range, and is poorly tolerated in vivo. However in the clinics it is routinely administered in a chelated (linear or macrocylics) form such as DTPA or DOTA, still maintaining the strong relaxivity [3]. By far, in terms of their chemical properties, Gd is superior in comparison to the other paramagnetic metals e.g. manganese (Mn) and copper (Cu). Despite the long history of Gd blood pool contrast agents [4] and the preclinical success of nanotechnology platforms [5] based on this metal, the recent discovery of nephrogenic systemic fibrosis (NSF) has raised concern on currently approved MR contrast agents [6]. NSF is a serious and unexpected side effect of gadolinium blood pool agents observed in some patients with renal disease or following liver transplant [7]. It was first identified in 1997 in the US when a small group of renal transplant patients were found to have developed complications such as joint contractures, brawny in duration and hyper pigmentation of the skin in their extremities. The disease was initially referred to as ‘nephrogenic fibrosing dermopathy’; however, the close connection of visceral led to the name ‘nephrogenic systemic fibrosis’. Interestingly, all affected individuals were observed to have chronic kidney disease. Later, its association with Gd was clinically observed by Grobner et al. [8] and subsequently by others [9-10] (Figure 1). Patients with NSF develop thickening of the skin and connective tissues that can inhibit arm and leg movements and even lead to bone fractures. Approximately 5% of patients experience a rapidly progressive course, which may result in death due to widespread fibrosis [11]. The cause of NSF is unknown, and there is no effective treatment of this condition. All these findings prompted the FDA to issue a boxed warning of gadolinium blood pool agents specifying that gadolinium based contrast agents (GBCAs) increase the risk for NSF in patients with: 1) acute or chronic, severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m2), 2) acute renal insufficiency of any severity due to the hepato-renal syndrome, or 3) in the perioperative liver transplantation period [12]. Although dialysis of patients may be considered promptly following GBCA administration, there is no evidence that hemodialysis prevents NSF. Linear chelates (e.g. Omniscan®, Magnevist® and OptiMARK®) are the most commonly reported agents differentiating them from macrocyclic molecules. In terms of the kinetic, thermodynamic, conditional stability as well as their tendency for transmetallation with zinc and other cations, macrocyclic chelates are superior to the linear forms [13]. Myriad of advancement has been made to create targeted nanoagents carrying high payload of paramagnetic Gd to characterize tissues based on the presence of pathognomonic biosignatures [14]. Some of these examples include e.g. metal chelates bearing liposomal vesicles [15] and lipoprotein micelles; [16] ανβ3-targeted paramagnetic polymerized liposome [17] and perfluorocarbon (PFC) nanoparticles; [18] paramagnetic micelles for macrophage imaging within atherosclerotic plaque [19] etc.

Feasibility of Non-contrast-enhanced Magnetic Resonance Angiography for Imaging Upper Extremity Vasculature Prior to Vascular Access Creation

Objectives Preoperative mapping of arterial and venous anatomy helps to prevent postoperative complications after vascular access creation. The use of gadolinium in contrast-enhanced (CE) magnetic resonance angiography (MRA) has been linked to nephrogenic systemic fibrosis in patients with end-stage renal disease (ESRD). The purpose of this study was to evaluate non-contrast-enhanced (NCE) MRA for assessment of upper extremity and central vasculature and to compare it with CE-MRA. Methods NCE and CE-MRA images were acquired in 10 healthy volunteers and 15 patients with ESRD. In each data set, two observers analysed 11 arterial and 16 venous segments with regard to image quality (0–4), presence of artefacts (0–2) and vessel-to-background ratio. Results More arterial segments were depicted using CE-MRA compared to NCE-MRA (99% vs. 96%, p = 0.001) with mean image quality of 3.80 vs. 2.68, ( p < 0.001) and mean vessel-to-background ratio of 6.47 vs. 4.14 ( p < 0.001). Ninety-one percent of the venous segments were portrayed using NCE-MRA vs. 80% using CE-MRA ( p < 0.001). Mean image quality and vessel-to-background ratio were 2.41 vs. 2.21 ( p = 0.140) and 5.13 vs. 3.88 ( p < 0.001), respectively. Conclusions Although arterial image quality and vessel-to-background ratios were lower, NCE-MRA is considered a feasible alternative to CE-MRA in patients with ESRD who need imaging of the upper extremity and central vasculature prior to dialysis access creation.

Risk of Nephrogenic Systemic Fibrosis in Liver Transplantation Patients

The purpose of our study was to evaluate the exposure of our institution's liver transplantation population to gadolinium-based contrast agents and assess the rate of nephrogenic systemic fibrosis (NSF) within this unique group. Institutional review board approval was obtained for a retrospective review of medical records of patients who had undergone liver transplantation at our institution between 1997 and 2008. Informed consent was not required. Demographic information, history of gadolinium-based contrast agent exposure, stage of chronic kidney disease (CKD), and evidence of NSF were recorded. A total of 2142 patients who had undergone liver transplantation at our institution between 1997 and 2008 were identified. Of this total, 33% (709/2142) had documented gadolinium-based contrast agent exposure peritransplantation. Patients in CKD1 and 2, CKD3, CKD4, and CKD5 comprised 50% (352/709), 28% (200/709), 8% (60/709), and 14% (97/709), respectively. Of patients in CKD5, 76% (74/97) required dialysis. Thorough review of all patients' medical records identified one biopsy-confirmed case of NSF in the 709 patients. This patient was also in CKD5 and required dialysis. Within our institution, only 0.1% (1/709) of all liver transplantation patients exposed to gadolinium-based contrast agents or 1.4% (1/74) of CKD5 patients requiring dialysis had biopsy proof of NSF. This incidence is consistent with the rate of NSF in all patients exposed to gadolinium-based contrast agents regardless of liver transplantation reported in the literature. Therefore, liver transplantation may not be an independent risk factor in development of NSF in patients exposed to gadolinium-based contrast agents.

A new contrast media for functional MR urography: Gd-MAG3

Tc-99m-MAG3 (tubular agent) provides high imaging quality and extraction efficiency; and has become one of the most widely used agent for scintigraphic examinations of urinary system pathologies and renal transplants. Recently, it was reported that functional magnetic resonance urography (FMRU) can be sufficient in detection of urinary tract obstruction, renal artery stenosis, calculation of kidney functions and evaluation of renal transplants. However the pharmacokinetics of magnetic resonance (MR) contrast-media used in FMRU and Tc-99m-MAG3 differs from each other. This may cause discordant results between the FMRU and most of the scintigraphic studies. To our knowledge, there is no contrast-media which is specific for FMRU. A kidney specific contrast material can be developed for FMRU studies as well. MAG3 is a good candidate for this chelation. In conclusion, MR imaging (MRI) will be the most useful and important technique for morphologic–functional evaluation of urinary system. FMRU examinations performed with MAG3 chelated gadolinium can be sufficient for the complete evaluation of urinary tract even in patients with impaired renal functions (“all in one MRI”). MRI has some important advantages including no risk for radiation exposure, high temporal and spatial resolution, no need for nephrotoxic contrast agent; besides being a fast and feasible technique. Gadolinium-containing contrast agents may cause a life-threatening adverse reaction known as nephrogenic systemic fibrosis in patients with severe renal impairment, but Gd-MAG3 may reduce the risk of nephrogenic systemic fibrosis due to its higher extraction capacity and other features.

Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis--an autopsy-based review

Nephrogenic systemic fibrosis (NSF) is a systemic disorder of patients with severe renal insufficiency who have received gadolinium (Gd)-based magnetic resonance contrast agents (GBCAs). The causative association with Gd exposure was strengthened by the demonstration of Gd in various tissues of NSF patients, predominantly at the bulk chemical level. The distribution of Gd at the histologic level of organs other than skin has not been reported previously. We analysed tissues from an autopsy case with verified advanced NSF by light microscopy and scanning electron microscopy/energy-dispersive X-ray spectroscopy. Furthermore, we reviewed published literature to compare the histological and histochemical findings in NSF patients and chronic renal failure (CRF) patients without NSF. Insoluble Gd-phosphate deposits were detected in the skin, liver, lungs, intestinal wall (ileum), kidney, lymph node, skeletal muscle, dura mater and cerebellum of the NSF autopsy case, primarily in vascular walls. Some, but not all, Gd deposits were seen in fibrotic areas. Literature review highlighted that non-specific tissue fibrosis and calcification are frequent findings in tissues of patients with CRF with and without NSF. Vascular and extracellular Gd deposits are found in multiple organs of NSF patients, associated with calcification, and often in fibrotic areas. Gd deposits are not seen in patients with CRF unexposed to GBCAs but rarely may be seen in GBCA-exposed patients without clinical signs of NSF. Apart from diagnostic findings in skin, fibrosis of muscle and dura may be more prominent in NSF patients. Our findings should stimulate further investigation of mechanisms of fibrosis and pathologic calcification.

Gadolinium exposure disrupts iron homeostasis in cultured cells

Human exposure to gadolinium-based contrast agents can be complicated by nephrogenic systemic fibrosis (NSF). Demonstration of significant quantities of insoluble gadolinium in the skin of NSF patients suggested transmetallation as a mechanism of toxicity of this injury. An alternative pathway for the biological effect of gadolinium is a disruption of iron homeostasis. We tested the postulate that cell exposure to gadolinium increases iron uptake to disrupt intracellular metal homeostasis and impact inflammatory events. Alveolar macrophages, THP1 cells, NHBE cells, and BEAS-2B cells all demonstrated a capacity to import gadolinium from both GdCl(3) and Omniscan. All four cell types similarly imported iron following exposure to ferric ammonium citrate (FAC). Exposure of all cell types to gadolinium and iron resulted in increased iron import relative to cell concentrations following incubation with FAC alone. To analyze for further evidence of changes in iron homeostasis, cell ferritin concentration was determined. Relative to incubation with FAC alone, co-incubation of BEAS-2B cells with gadolinium and FAC resulted in significant increases in ferritin level. Finally, potential effects of gadolinium uptake and associated changes in iron homeostasis on the inflammatory response were evaluated by measuring IL-8. Co-incubation of BEAS-2B cells with both gadolinium and iron resulted in diminished release of IL-8 relative to levels of the cytokine following incubation with gadolinium alone. We conclude that gadolinium impacts cell iron homeostasis to change import and storage of the metal and biological effects of exposure.

Tailoring the flow sensitivity of fast spin‐echo sequences for noncontrast peripheral MR angiography

There has recently been renewed interest in noncontrast techniques for peripheral MR angiography following the discovery of an association between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with renal insufficiency. The "fresh blood imaging" technique proposed by Miyazaki et al. involves the subtraction of two three-dimensional fast spin-echo image sets, one acquired in systole, when the arteries appear dark due to flow-related dephasing, and the other obtained in diastole, when the arteries are brighter. Our goal was to investigate how parameters of the fast spin-echo sequence influence its flow sensitivity, and how that in turn impacts the depiction of large and small arteries. Results from phantom experiments and human studies in the calf suggest that the flow sensitivity is governed largely by the flip angle of the radiofrequency refocusing pulses. The area of the spoiler gradients has a lesser effect, and at low flip angles the echo time plays a role. These parameters can be optimized to obtain good depiction of the calf arteries in healthy subjects. It remains to be seen whether they provide sufficient control over flow sensitivity to achieve diagnostic-quality images in other vascular beds and in the presence of pathology.

Safety in magnetic resonance units: an update

The number of anaesthetists who are involved in magnetic resonance (MR) units is increasing. Magnetic resonance systems are becoming more powerful and interventional procedures are now possible. This paper updates information relating to safety terminology, occupational exposure, reactions to gadolinium-based contrast agents and the risk of nephrogenic systemic fibrosis. Magnetic resonance examinations of patients with pacemakers are still generally contra-indicated but have been carried out in specialist centres under strictly controlled conditions. As availability of MR increases, so the education of anaesthetists, who are occasionally required to provide a service, must be considered.Anaesthesia in MR units was first described in the 1980s. Guidelines on the provision of anaesthetic services in MR units were published by the Association of Anaesthetists of Great Britain and Ireland (AAGBI) in 2002 [1]. Since then, the number of hospitals with MR units, and hence the number of patients requiring anaesthesia for MR, has increased. While the issues relating to setting up anaesthetic services in MR have not changed, there have been a number of developments that warrant this update:Safety terminology and guidelines have changed.MR systems utilise higher magnetic-field strengths and more open designs are available.Interventional and intra-operative MR are now routine in some centres.Mobile MR scanners are increasingly used to reduce waiting lists.Although still generally contra-indicated, some patients with pacemakers have been scanned under strictly controlled conditions in specialist centres.‘MR safe’ medical implants are now being produced.New equipment is now available for use in MR.Out-of-hours availability of MR investigations has increased.Reports of allergic reactions to MR contrast media have increased.Gadolinium based contrast agents (Gd-CAs) are associated with a varying degree of risk of nephrogenic systemic fibrosis in patients with impaired renal function.

Balance of Profibrotic and Antifibroting Signaling in Nephrogenic Systemic Fibrosis Skin Lesions

Nephrogenic systemic fibrosis (NSF) is an uncommon fibrotic disorder occurring after administration of linear gadolinium contrast agents in patients with severely decreased kidney function. The underlying pathogenetic mechanism of fibrosis remains to be elucidated. Transforming growth factor beta (TGF-beta), a key player in the pathogenesis of fibrotic disorders, has been found to be overexpressed in NSF skin lesions. The aim of this study is to analyze the TGF-beta-SMAD-connective tissue growth factor (CTGF) axis in NSF skin lesions compared with skin specimens from patients with systemic sclerosis, hemodialysis patients without NSF, and healthy controls. Additionally, expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and antifibrotic tumor necrosis factor alpha (TNF-alpha) were examined. Observational study. Full-thickness skin biopsy specimens from fibrotic lesions or healthy skin were obtained from 10 patients with NSF, 16 patients with systemic sclerosis, 8 non-NSF hemodialysis patients, and 17 healthy participants. Patient diagnosis of NSF, systemic sclerosis, non-NSF hemodialysis patients, and healthy participants, as defined using skin biopsy. Dermal messenger RNA and protein expression of profibrotic TGF-beta, SMAD2, SMAD3, SMAD4, SMAD7, CTGF, TIMP-1, antifibrotic SMAD7, and TNF-alpha were analyzed using real-time reverse transcription-polymerase chain reaction and immunohistologic examination on formalin-embedded tissue. Dermal expression of nearly all parameters differed in hemodialysis patients compared with healthy controls. In comparison to hemodialysis patients and healthy participants, we found increased messenger RNA levels for TGF-beta, the profibrotic receptor-activated SMAD2 and SMAD3, CTGF, and TIMP-1 in NSF and systemic sclerosis lesions. Few differences between NSF and non-NSF hemodialysis patients were observed for common SMAD4, inhibitory SMAD7, and TNF-alpha. Small patient cohort. Our results suggest a profibrotic imbalance in the TGF-beta-SMAD-CTGF axis in NSF skin lesions. Significantly increased dermal expression of TGF-beta and TIMP-1 in non-NSF hemodialysis patients in comparison to healthy participants emphasizes the need for a hemodialysis control group for future investigations and suggests a pre-existing profibrotic situation in the skin of hemodialysis patients.

The Outcome of Patients with Nephrogenic Systemic Fibrosis after Successful Kidney Transplantation

Nephrogenic systemic fibrosis (NSF) is a debilitating disease in patients with severely diminished kidney function. Currently, no standard treatment exists but improvement has been reported after restoration of kidney function. We retrospectively studied 17 NSF patients with and without successful kidney transplantation (KTx) to evaluate the effects of KTx on NSF. Nine of the 11 KTx developed NSF pretransplant whereas two developed NSF immediately after KTx with delayed graft function. Two of the six dialysis patients had previous failed kidney transplants. Age and sex were well matched. All but one patient was dialysis dependent at the time of NSF. Median follow-up was 35 months for KTx patients and 9 months for dialysis patients. Kidney transplants achieved adequate renal function with median serum creatinine of 1.4 (0.9-2.8) mg/dL and a glomerular filtration rate of 42 (19-60) mL/min/1.73 m(2). NSF improved in 54.6% of the transplanted patients and 50% of the nontransplanted patients (p = 0.86). Two KTx patients had complete resolution of their symptoms whereas four had partial improvement. Improvement in the dialysis patients was all partial. Successful KTx did not insure improvement in NSF and in fact appeared to have no significant benefit over dialysis.

Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast‐enhanced MRI protocols

To retrospectively determine the incidence of nephrogenic systemic fibrosis (NSF) in patients on dialysis administered either a lower dose high-relaxivity linear gadolinium-chelate, gadobenate dimeglumine (MultiHance, MH), compared to a standard dose linear gadolinium chelate, gadodiamide (Omniscan, OM). This study was Health Insurance Portability and Accountability Act (HIPAA)-compliant and Institutional Review Board (IRB)-approved. As per institution standardized contrast-enhanced magnetic resonance imaging (MRI) protocols, patients on dialysis were imaged using either MH, between 2/2007 to 9/2008, or OM between 10/2003 and 1/2007. Rates of NSF were compared using 95% score-based confidence intervals (CI). The Wilcoxon rank sum test was used to test similarity/difference between contrast doses given to each patient group. Overall, 312 patients on dialysis received OM and eight (2.6%) developed NSF (95% CI: 1.30%-4.98%). In all, 784 patients on dialysis received MH at a mean cumulative dose of 0.11 mmol/kg (0.05-0.75 mmol/kg) and no cases of NSF were identified (upper 95% confidence bound of 0.45%). The mean cumulative dose of OM was 0.16 mmol/kg (0.1-0.9 mmol/kg) for all patients and 0.28 mmol/kg (0.1-0.8 mmol/kg) for the patients with NSF. The median OM dose was greater in patients who developed NSF (P = 0.03), and was greater than the median MH dose (P < 0.005). NSF incidence in at-risk patients receiving contrast-enhanced MRI can be reduced after changing contrast administration protocols that includes changing the type and dose of contrast agent.

Gadolinium-associated nephrogenic systemic fibrosis in patients with renal failure: the need for an interdisciplinary helping network

Gadolinium-associated nephrogenic systemic fibrosis in patients with renal failure: the need for an interdisciplinary helping network

Gadolinium‐containing magnetic resonance image contrast agent promotes fibrocyte differentiation

Gadolinium-containing magnetic resonance imaging (MRI) contrast agents such as Omniscan are associated with nephrogenic systemic fibrosis (NSF). To determine if Omniscan can affect the differentiation of monocytes into fibroblast-like cells called fibrocytes that are found in the fibrotic lesions of NSF, peripheral blood mononuclear cells (PBMCs) from NSF patients, hemodialysis patients without NSF, and healthy, renally sufficient controls were exposed to Omniscan in a standardized in vitro fibrocyte differentiation protocol. When added to PBMCs, the gadolinium-containing MRI contrast agent Omniscan generally had little effect on fibrocyte differentiation. However, 10(-8) to 10(-3) mg/mL Omniscan reduced the ability of the fibrocyte differentiation inhibitor serum amyloid P (SAP) to decrease fibrocyte differentiation in PBMCs from 15 of 17 healthy controls and one of three NSF patients. Omniscan reduced the ability of SAP to decrease fibrocyte differentiation from purified monocytes, indicating that the Omniscan effect does not require the presence of other cells (such as T cells) in the PBMCs. Omniscan also reduced the ability of a different fibrocyte differentiation inhibitor, interleukin-12, to decrease fibrocyte differentiation. These data suggest that Omniscan interferes with the regulatory action of signals that inhibit the differentiation of monocytes to fibrocytes. J. Magn. Reson. Imaging 2009;30:1284-1288. (c) 2009 Wiley-Liss, Inc.

Nephrogenic systemic fibrosis in liver disease: A systematic review

Nephrogenic systemic fibrosis (NSF) may develop in patients with liver disease, a fact highlighted by Food and Drug Administration (FDA) announcements cautioning against the use of gadolinium-based contrast agents (GBCAs) in select liver disease patients. The purpose of this systematic literature review is to characterize the risk of NSF in patients with liver disease. All published articles on NSF from September 2000 through August 2008, were identified via PubMed searches and examination of articles' reference lists. Two reviewers independently read each article and identified unique patients with biopsy-proven or suspected NSF. Data on demographics, liver status, renal status, and GBCA exposure were collected. A total of 324 articles were reviewed, with 108 articles containing case descriptions of 335 unique NSF patients. After excluding the 95/335 (28%) patients in whom the presence or absence of liver disease was uncertain, liver disease was confirmed present in 41/239 (17%) patients. Renal insufficiency could be assessed in 35 of the liver disease patients; severe renal insufficiency, defined as a glomerular filtration rate (GFR) or estimated GFR (eGFR) <30 mL/min/1.73 m(2) or dialysis requirement, was present in 34/35 (97%) patients. The lone patient who developed NSF with mild/moderate renal insufficiency was atypical and received a total gadodiamide load of 0.76 mmol/kg over a 10-week period periliver transplantation. The published medical literature demonstrates that patients with liver disease who develop NSF also have severe renal insufficiency, suggesting that liver disease does not confer a risk for NSF beyond that of the underlying renal insufficiency. J. Magn. Reson. Imaging 2009;30:1313-1322. (c) 2009 Wiley-Liss, Inc.

Focus on contrast‐associated nephrogenic systemic fibrosis

The first published reports of presumed gadolinium-associated nephrogenic systemic fibrosis “NSF” (1-3) drew the attention of the international community to the development of apparent new risks for clinical applications of gadolinium contrast-enhanced MRI studies in patients with renal disease. Subsequently, priority attention has been directed to this problem in an effort to understand the basic mechanisms, chemistry, and risks in various stages of renal failure, and to develop protocols and guidelines for the safe use of gadolinium-enhanced MRI. In addition, since patients in renal failure are at increased risk of developing NSF, exclusion criteria have been developed for gadolinium-enhanced MRI studies. The focus of scientific societies and institutions on this critically important problem included an NSF workshop, “Nephrogenic Systemic Fibrosis (NSF)/Nephrogenic Fibrosing Dermopathy (NFD),” sponsored by the 2007 International Society for Magnetic Resonance in Medicine at its annual meeting in Berlin and moderated by Georg Bongartz, MD, and Walter Kucharczyk, MD (4). Participants in this workshop included scientists, clinicians, and nephrologists of the international community. Guest editorials from this workshop were published in the Journal of Magnetic Resonance Imaging (5, 6). Numerous investigations and analyses of NSF and reporting systems have been published in multiple journals, including the Journal of Magnetic Resonance Imaging (7-14). Furthermore, a summary report on MR safety by the American College of Radiology included a separate section entitled “Renal Disease, Gadolinium-based MR Contrast Agents, and Nephrogenic Systemic Fibrosis (NSF)” (15). A more recent interdisciplinary team will publish their study of decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols (16). The Journal of Magnetic Resonance Imaging seeks to develop special issues entirely devoted to timely and important clinical topics as they become apparent. Recently these special issues have included “Interventional MRI” (17-20), “Molecular Imaging” (21), “Cardiac MR and CT” (22), “Clinical Potential of Brain Mapping Using MRI” (23), “Frontiers in Musculoskeletal Imaging” (24), and “MR Safety” (25). Continuing in the tradition of publishing special issues on timely clinical topics, it is a pleasure to present in this issue gadolinium-associated nephrogenic systemic fibrosis, with guest editors Tim Leiner, MD, PhD, and Walter Kucharczyk, MD. In this special issue, 18 invited articles have been developed and reviewed by a wide range of investigators and institutions. The entire JMRI issue is, as usual, totally devoted to this topic as a vehicle to enhance the production, distribution, and understanding of information related to NSF. This process highlights the commitment of the Board of Trustees, the Safety Committee, and the journals of the ISMRM to address and help resolve issues related to ensuring the safe clinical use of MRI and MRS studies, including, but not limited to, gadolinium-based enhanced MRI studies. As Editor, I want to take this opportunity to express my sincere appreciation to each contributor and reviewer for a timely and significant contribution. As usual, your comments, critical review, and analyses of the content of this special issue, as well as others in the literature, will be welcome as submissions to JMRI as we continue to evaluate this exceedingly important clinical challenge. It is my hope that our ongoing efforts to share information and encourage dialogue will result in a deeper level of understanding of the mechanisms of and indications for contrast-enhanced MRI studies and the development of exclusion criteria for patients in renal failure.

Nephrogenic Systemic Fibrosis and Its Impact on Abdominal Imaging

The objective of this article is to review the current knowledge about nephrogenic systemic fibrosis (NSF) and how to prevent it. More than 300 cases of NSF in patients with severe chronic renal insufficiency or acute renal failure or in patients undergoing dialysis have been reported in the peer-reviewed literature, with an overwhelming majority occurring within weeks to months after injection of a gadolinium-based contrast agent (GBCA). Because administration of a high dose of a GBCA is a primary risk factor and because most high-dose magnetic resonance (MR) imaging applications involve abdominal imaging (eg, liver and abdominal MR angiography), NSF cases have been associated with abdominal MR imaging. Additional major risk factors for developing NSF include proinflammatory conditions, failure to perform dialysis promptly after GBCA administration, use of nonionic linear contrast agents, hyperphosphatemia, and younger age. Recent recommendations to use GBCAs with caution in patients with acute renal failure, patients receiving dialysis, or patients with an estimated glomerular filtration rate of less than 30 mL/min have resulted in virtually no new NSF cases being reported with onset in 2008 or 2009 in spite of a high level of awareness about this entity. In conclusion, NSF has been virtually eliminated by using caution in administering GBCAs to patients known to have severe or acute renal failure. In these patients, avoid high doses; and for patients undergoing dialysis, schedule MR imaging to occur just before a dialysis session to ensure rapid elimination of gadolinium.