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Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights. OVERVIEW 1565 Nephrogenic Systemic Fibrosis and Its Impact on Abdominal Imaging1 CME FEATURE See accompanying test at http:// www.rsna.org /education /rg_cme.html LEARNING OBJECTIVES FOR TEST 2 After reading this article and taking the test, the reader will be able to: ■■Describe the features of nephrogenic systemic fibrosis and its association with GBCA administration. ■■Identify the risk factors for nephrogenic systemic fibrosis. ■■Discuss ways to minimize the chance of nephrogenic systemic fibrosis while still ensuring safe diagnostic imaging. TEACHING POINTS See last page Martin R. Prince, MD, PhD • Hong Lei Zhang, MD • Joan C. Prowda, MD • Marc E. Grossman, MD • David N. Silvers, MD 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. © RSNA, 2009 • radiographics.rsna.org Abbreviations: FDA = Food and Drug Administration, GBCA = gadolinium-based contrast agent, GFR = glomerular filtration rate, NSF = nephrogenic systemic fibrosis, SNR = signal-to-noise ratio RadioGraphics 2009; 29:1565–1574 • Published online 10.1148/rg.296095517 • Content Codes: 1 From the Departments of Radiology, Dermatology, and Dermatopathology, Weill Cornell Medical Center, Columbia College of Physicians and Surgeons, 416 E 55th St, New York, NY 10022. Received April 14, 2009; revision requested May 20 and received June 15; accepted June 30. M.R.P. has patent agreements with GE Healthcare, Hitachi, Siemens, Koninklijke Philips Electronics, Nemoto, Bayer, EPIX Pharmaceuticals, Bracco Group, Covidien, and Topspins; all other authors have no financial relationships to disclose. Address correspondence to M.R.P. (e-mail: [email protected]). © RSNA, 2009 1566 October Special Issue 2009 Introduction Gadolinium-based contrast agents (GBCAs) have proved to be among the safest available for clinical imaging. In particular, with the doses used for magnetic resonance (MR) imaging, there are low rates of occurrence of nephrotoxicity (1,2) and allergic reactions (3) compared with those rates for iodinated contrast agents. The use of gadolinium with MR imaging allows contrast enhancement to be assessed without exposure to ionizing radiation. Until recently, these agents were used at ever increasing doses in patients with renal failure and patients undergoing dialysis. However, the recent discovery of an association between GBCA administration and nephrogenic systemic fibrosis Teaching (NSF) has changed the way that gadolinium is Point used. High doses are now rare because most applications have been adjusted to use a standard dose of 0.1 mmol/kg, especially in patients undergoing dialysis or patients with a glomerular filtration rate (GFR) of less than 30 mL/min. When patients are undergoing dialysis, MR imaging with a GBCA is scheduled for just before the next dialysis appointment to facilitate prompt clearance. NSF is a rare fibrosing condition occurring in patients with profound renal failure or patients undergoing dialysis. In NSF, patches of skin become thickened and tethered to the underlying tissue, reducing range of motion and leading to contractures. The fibrosing process can also involve internal organs, including the lungs, heart, and muscles (4). Although many cases are mild and limited to dermatologic manifestations, an estimated 5% of cases have a more fulminant course resulting in death (5). Because treatment options are limited, an emphasis on prevention has been under way, limiting GBCA exposure in patients with severe renal failure (estimated GFR < 30 mL/min) and dialysis patients. A virtual absence of new cases with onset in 2008 or 2009 suggests that these preventive measures have been successful and are now allowing safe judicious use of GBCAs in patients with renal failure and dialysis patients when clinically necessary (6). The purpose of this review article is to outline what is known about NSF and how to prevent it. The article covers the history of gadolinium and NSF, as well as the risk factors for NSF, its features, and its treatment. The impact of NSF on abdominal imaging is discussed, and recommendations to prevent NSF are presented. History of Gadolinium and NSF Although gadolinium is a rare earth metal, with the atomic number 64 on the periodic table, it is actually common in the earth’s crust (7). When radiographics.rsna.org discovered and isolated in 1880, gadolinium was named for the Finnish chemist Johan Gadolin, although it was actually discovered by Jean Charles Galissard de Marignac and Paul Émile Lecoq de Boisbaudran. Gadolinium has seven unpaired electrons, making it one of the strongest paramagnetic atoms of the periodic table. Even when bound to a chelator, unpaired electrons are available to interact with protons and other nearby nuclei to facilitate longitudinal relaxation time (T1) and enhance T1-weighted images. The susceptibility of gadolinium influences transverse relaxation time (T2), allowing perfusion and other types of imaging that rely on gadolinium-induced shortening of the transverse relaxation rate as affected by magnetic field inhomogeneity (T2*). The first clinically successful chelator was pentetic acid (diethylenetriaminepentaacetic acid [DTPA]), an ionic linear agent (8) that was borrowed from nuclear medicine and became enormously popular as a gadolinium chelator after receiving approval from the Food and Drug Administration (FDA) in 1988. At that time, nonionic iodinated agents were being discovered to have safety advantages compared with ionic iodinated agents (9). Accordingly, it was only a matter of time before nonionic based contrast agents were introduced in 1992 (gadoteridol) and 1993 (gadodiamide). As more and more reports then emerged about the relative safety of GBCAs in patients with renal failure compared with iodinated contrast agents, the use of GBCAs began to increase in patients with renal failure and patients undergoing dialysis. In the mid-1990s, greater awareness of the relationship of the signal-to-noise ratio (SNR) to the contrast agent dose led to increasing GBCA use at high doses for SNR-limited applications such as liver MR imaging and contrast-enhanced MR angiography. The lower viscosity and lower osmolarity, with lower irritation in the event of extravasation, led to preferential use of nonionic agents for the high-dose high-injection-rate applications. Body MR applications in the abdomen commonly used GBCAs at high doses because renal artery, portal vein, and liver MR imaging were noted to benefit from the higher SNR of a high GBCA dose (10). The first known case of NSF occurred in 1997, after the use of GBCAs at high doses in patients with renal failure had become routine. At that time, the entity was called nephrogenic fibrosing dermopathy because of its manifestation primarily with skin symptoms. After the discovery of internal organ involvement, the name was changed to reflect manifestations deep to the skin. The cause of NSF remained mysterious until a breakthrough observation by Grobner (11) in Denmark in 2006. Grobner, a nephrologist, had five RG ■ Volume 29 • Number 6 cases of NSF out of nine patients with renal failure whom he had sent for gadolinium-enhanced MR imaging. Most of the radiologic community was skeptical about this association until High et al (12,13) and Wiginton et al (14) discovered gadolinium in the biopsy specimens of NSF patients. An ensuing rush of articles reporting more than 240 cases of NSF after GBCA administration has further buttressed this hypothesis. After reviewing the scientific articles and in consultation with the imaging and chemistry experts, regulatory authorities in Europe and in the United States issued a series of warnings culminating in a black-box warning label for all GBCAs sold in the United States (15). This warning recommends caution in the use of GBCAs in patients with acute or chronic renal dysfunction, a GFR of less than 30 mL/min, or acute renal failure that is due to the hepatorenal syndrome or in patients during the perioperative period for liver transplantation. Risks and benefits of GBCAs should be assessed, and MR imaging without GBCAs or other alternate diagnostic procedures should be considered in patients at risk of NSF. Prompt hemodialysis after GBCA administration should be considered for patients already undergoing long-term therapy with hemodialysis. The European authorities have issued similar warnings, as well as contraindications, for certain GBCAs in patients undergoing dialysis or patients with a GFR of less than 30 mL/min. NSF Risk Factors Renal Failure Teaching Point NSF is only observed in patients with severe renal dysfunction, primarily patients undergoing or approaching dialysis, hence the use of nephrogenic in its name. Chronic renal failure has been categorized into multiple grades on the basis of the estimated GFR. GFR is typically estimated from the Modification of Diet in Renal Disease (MDRD) model that is based on age, gender, ethnicity, and serum creatinine level. Online calculators are readily available for determining GFR (16). It is no longer considered appropriate to base clinical decision making about the risk of NSF on the serum creatinine level alone. Most cases of NSF are occurring in patients undergoing dialysis or in patients with end-stage renal dysfunction, with a GFR of less than 15 mL/min, who are not yet undergoing dialysis. The published literature includes more than 300 cases of NSF, all in patients with severe renal dysfunction and a GFR of less than 30 mL/min (17). No known cases of NSF have occurred in patients with a GFR of more than 30 mL/min without acute renal failure. Accordingly, 30 mL/min has become the standard cutoff value for determining whether a patient Prince et al 1567 with chronic renal dysfunction could be at risk for NSF. Furthermore, all patients who develop NSF are known to have severe renal dysfunction. Accordingly, there is minimal, if any risk in patients for whom the renal status is unknown. It is possible to have acute renal failure with a GFR of less than 30 mL/min but an erroneous estimated GFR that is greater than 30 mL/min because the serum creatinine level is increasing. For this reason, the recommendation is to avoid GBCA administration in patients with acute renal failure who have increasing serum creatinine levels (18). Patients with acute renal failure can undergo GBCA-enhanced MR imaging after starting dialysis or after the creatinine level has peaked and begun to decrease (18). Originally, dialysis was believed to be a risk factor for NSF because 70%–80% of the NSF patients were undergoing dialysis at the time of diagnosis. However, it now appears that some NSF patients may have received GBCAs prior to starting dialysis. Therapy with dialysis may then have been initiated by the time that NSF was diagnosed, reflecting the severity of the renal dysfunction at the time of the GBCA administration. Furthermore, patients who received GBCAs to evaluate a failing dialysis fistula may not undergo adequate dialysis after GBCA administration. In a more detailed study, investigators have suggested that dialysis performed the same day after GBCA administration is protective (18). Accordingly, for patients undergoing dialysis who receive GBCAs, dialysis should be performed as quickly as possible afterward. It is recommended to schedule MR imaging to be performed just before a routine dialysis to make sure that the dialysis is occurring well within 24 hours of any GBCA injection. Teaching Point GBCA Dose In multiple case series, investigators have reported that high doses of GBCAs, and possibly Teaching the use of linear nonionic GBCAs, contribute Point to an increased risk of NSF. Broome et al (19) reported zero cases of NSF in 94 dialysis patients receiving the standard dose, 0.1 mmol/kg, of gadodiamide, a linear nonionic agent; but 12 of 207 dialysis patients receiving a high dose of gadodiamide developed NSF, with an odds ratio of 12 to 1. In a larger but still retrospective study, investigators found zero cases of NSF in approximately 74,000 unscreened patients receiving a standard dose of a GBCA (80% received gadodiamide) but 15 cases of NSF in approximately 9000 patients receiving a high dose of a GBCA (18). In case-control studies, Kallen et al (20), Marckmann et al (21), and Collidge et al (22) radiographics.rsna.org 1568 October Special Issue 2009 further implicated the use of high GBCA doses as a major risk factor for NSF. In a comprehensive review of the literature, there were 180 cases of NSF reported in which the gadolinium dose could be estimated (23). In 157 (87%) of these cases, a high dose was administered. These data suggest that the risk of NSF can be reduced by an order of magnitude simply by avoiding the use of a high dose of more than 0.1 mmol/kg in patients undergoing dialysis or patients with a GFR of less than 30 mL/min. GBCA Type Considerable debate surrounds the apparent differences in chelate stability between macrocyclic and linear agents, as well as between ionic and nonionic linear agents. Linear agents have an advantage compared with macrocyclic agents in that they are simpler and generally less expensive to synthesize. Macrocyclic agents, on the other hand, have greater kinetic stability that is due to the complete encircling of the Gd3+ ion with covalent bonds. Indeed, the macrocyclic bond is so tight for some macrocyclic agents that the kinetic dissociation time constant is on the order of months (24), making it virtually impossible for Gd3+ ions to be released into the tissue even when there is delayed excretion. To the extent that the etiology of NSF may be related to dissociation of the gadolinium ion from the chelator, one can surmise that macrocyclic agents should be completely safe and essentially free of risk of NSF. Indeed, there are few cases of NSF associated with macrocyclic agents, although because of the substantially lower market share of these contrast agents, caution should be exercised about assuming that macrocyclic agents are completely without risk. Another controversy surrounds the differences between ionic and nonionic agents. It is well known with iodinated contrast agents that nonionic agents are safer, with a far lower incidence of allergic reactions (25). However, it appears that the in vitro stability of the nonionic linear agents is less than that for ionic agents, and there are more cases of NSF with nonionic agents, even after correcting for market share. One wonders if in vivo stability of the nonionic agents may also be lower and that this may contribute to the increased risk of NSF. Because of these theoretical reasons, the use of linear nonionic agents, in spite of their favorable adverse-event profile with a low risk of life-threatening allergic reactions (3), has not been recommended, especially at high doses, in patients with a GFR of less than 30 mL/min (26). Proinflammatory Events In their case series, Sadowski et al (27) noticed that all NSF cases were occurring in relatively sick inpatients. No cases of NSF were found in outpatients. All of the NSF patients had underlying proinflammatory conditions, which were defined as recent major surgery, infection, or vascular event. In the case-control analysis, these investigators demonstrated a significantly greater number of proinflammatory conditions per patient in NSF patients (P < .001) compared with similar control patients who did not develop NSF. This observation is consistent with a prevalent theory about the etiology of NSF. In this theory, fibrocytes circulating in the blood because of an ongoing proinflammatory event are attracted to where gadolinium has deposited in the skin and other organs. This attraction may be due to phagocytosis of gadolinium by macrophages and to the release of cytokines that attract circulating fibrocytes. If there is no ongoing intense inflammation in the body, there will be insufficient fibrocytes in circulation to cause NSF. In addition, proinflammatory conditions are associated with edema, which locally increases the extravascular-extracellular compartment. In theory, the expansion of the interstitial compartment may give edematous areas slower egress of the GBCA, with more time to cause NSF. Age In numerous articles, investigators have reported that younger age is associated with a higher incidence of NSF in the at-risk population with a GFR of less than 30 mL/min (18,27). This may be partly explained by inaccuracies in the Modification of Diet in Renal Disease (MDRD) model’s estimation of GFR in older patients. However, the peak incidence of NSF occurs in patients around 50–60 years of age, even though patients older than 60 have a substantially higher rate of GBCA-enhanced MR imaging studies and renal disease. One hypothesis is that this observation reflects the stronger more-active immune system of younger patients and the reduced collagen synthesis in older patients (23). Hyperphosphatemia One theory about the cause of NSF relates to gadolinium ions dissociating from the chelator. Normally, Gd3+ would quickly reassociate with the chelator. However, if Gd3+ irreversibly binds to phosphates and precipitates out of solution into tissues, then the reaction releasing gadolinium from the chelator becomes unidirectional. This unidirectional reaction will accelerate in RG ■ Volume 29 • Number 6 Prince et al 1569 Figure 1. Photographs of skin lesions in NSF, including skin thickening with erythematous plaques (a) and thickened skin with hyperpigmented plaques (b). patients who have more phosphate in the serum. Indeed, a higher incidence of NSF has been associated with hyperphosphatemia (23). Epoetin, Acidosis, and Other Factors In various case series, investigators have reported a number of additional associations that have not been consistently corroborated. Epoetin is commonly used to treat anemia in patients undergoing dialysis and patients with renal failure. Because epoetin stimulates the bone marrow relatively indiscriminately, including both red and white blood cells, it is considered to be proinflammatory. In several cases series, investigators have noted a high percentage of NSF patients who are receiving epoetin, including “high-dose” epoetin therapy (28,29). Dissociation of gadolinium from the chelator is known to occur more readily in an acid environment, where there are more positively charged protons competing for the gadolinium ionic binding sites. In several case series, including the first report by Grobner (11), investigators have noticed a high prevalence of acidosis in the patients with NSF (14,30). However, acidosis is common in patients with renal failure. Additional factors hypothesized to have a relationship to NSF include elevated concentrations of serum cations, including iron, zinc, and calcium. Comparison to Other Radiologic Risks Although the historical risk of NSF with high-dose GBCA administration (mainly linear nonionic agents) has been reported to be in the 1%–7% range for patients undergoing dialysis, this risk has now been reduced by orders of magnitude by the current practice of using the standard dose, 0.1 mmol/kg, and having patients undergo dialysis immediately after GBCA administration. The use of more-stable agents may also contribute to less risk. At the hospitals of our institution, more than 100,000 single-dose GBCA administrations have now been given, including more than 10,000 in patients with a GFR of less than 30 mL/min, with no cases of NSF developing. This risk is less than the risk of nephrotoxicity, which has been reported to be as high as 50%–90% in patients with renal insufficiency (31–33). NSF Features Clinical Manifestation NSF is different from the contrast reactions usually encountered by radiologists because it does not occur at the time of the imaging study. Instead, NSF typically occurs weeks to months later. NSF lesions usually involve the dermis in the extremities symmetrically and, less commonly, the trunk. The face is commonly spared, an important differential diagnostic point that allows clinical distinction from other entities with hard skin (34). The tempo of disease onset is variable. Symptoms and signs of NSF may be overlooked by both the patient and the physician or may rarely be rapidly progressive (fulminant) with systemic involvement. It is more common for patients to have a moreindolent disease course, with several weeks to months of symptoms before diagnosis. The clinical manifestation of NSF more closely resembles scleromyxedema or eosinophilic fasciitis. The primary lesions are firm to hard skincolored or erythematous papules and plaques that may coalesce to involve large areas of the trunk or extremity. The skin lesions are described as a hyperpigmented thickened brawny induration that is woody or edematous or has a peau d’orange or cobblestoned appearance (Fig 1) (34). radiographics.rsna.org 1570 October Special Issue 2009 Figures 2–4. (2) Axial CT image shows trunk and breast skin thickening in a patient with biopsy-confirmed NSF. (3) Axial CT image of the left thigh shows skin thickening and stranding in the subcutaneous fat in a region of dermal NSF. (4) Coronal MR image of thighs of a patient with NSF shows subcutaneous edema, skin thickening, and deep dermal stranding from thickened fibrous bands. These plaques typically spare the antecubital and popliteal fossae and have advancing ameboid projections on the distinctive irregular edge. NSF is characterized by progressive skin hardening and tethering. Joint contractures may develop when the fibrosis spans the joint and may severely impair physical function, including ambulation. The flexion contractures may progress to the point of patients becoming wheelchair bound. Patients commonly complain of severe extremity pain, pruritus, skin tightness, or a burning sensation. Radiologic Manifestation Because of the nonspecific symptoms of NSF, these patients commonly undergo radiologic studies, which may show (a) diffuse soft-tissue tracer uptake on bone scans, (b) skin thickening and subcutaneous stranding on mammographic, computed tomographic (CT) (Figs 2, 3), MR (Fig 4), and ultrasonographic (US) images, and (c) skin and muscle activity on positron emission tomographic images (35). NSF is not vis- ible at digital subtraction angiography, and the practice of using high-dose GBCAs in place of iodine-based contrast agents for digital subtraction angiography in patients with renal failure can no longer be justified until more is learned about preventing and treating NSF. Histologic Findings Because of the involvement of the subcutaneous tissues and underlying muscle in NSF, a deep dermal biopsy is necessary to confirm the diagnosis histologically. However, because the histopathologic finding is nonspecific inflamma- RG ■ Volume 29 • Number 6 Prince et al 1571 Impact on Abdominal Imaging Figure 5. Three-dimensional nonenhanced MR angiographic image of a renal transplant recipient obtained at 1.5 T (Enhance pulse sequence; GE Healthcare, Chalfont Saint Giles, United Kingdom). tory changes, biopsy can be used only to confirm a clinical diagnosis. Both characteristic clinical features and the biopsy findings together are necessary for definitive diagnosis (4). Histologic specimens show thickened collagen bundles, mucin deposition, spindle cell proliferation, and fibroblasts that stain for CD3, indicating that they are circulating fibrocytes. Treatment There is no consistently effective therapy for NSF. Improving renal dysfunction from any cause appears to slow or arrest the progression of NSF. In numerous case series, investigators have reported instances of cure or a reduction of symptoms after successful renal transplantation or recovery from acute renal failure (11,36,37). Physical therapy should be started early to maintain and improve the range of motion of contracted joints. Multiple case reports of different therapeutic interventions have appeared since the first published report of NSF by Cowper et al (38). Extracorporeal photopheresis (39), plasmapheresis, photodynamic therapy, pentoxifylline therapy, high-dose intravenous immunoglobulin therapy, thalidomide therapy, steroid therapy, and other immunosuppressive therapies have been attempted. The latest additions to the list of treatments include imatinib mesylate (Gleevec; Novartis, East Hanover, NJ) (40) and sodium thiosulfate. One of the areas of greatest impact of NSF has been the imaging of patients with renal failure, especially a patient with a kidney transplant who is undergoing MR angiography to look for renal artery stenosis (Fig 5). Previously, these patients had been imaged with a high dose of a GBCA. However, now a number of techniques that do not use contrast agents may be able to be used to assess the renal arteries without GBCA administration, including two- or threedimensional steady-state free precession (41), three-dimensional phase contrast (42), and a more advanced version of time of flight that allows a longer time for inflow after an inversion pulse (43). When these fail and three-dimensional GBCA-enhanced MR angiography is still necessary in a patient with a GFR of less than 30 mL/ min, it can be performed on state-of-the-art MR imagers by using no more than a standard dose of 0.1 mmol/kg. Some benefit may be seen from higher-relaxivity agents (44), including gadofosveset trisodium, which has recently received FDA approval for use in MR angiography at a dose of only 0.03 mmol/kg (45). Hepatic imaging has also been impacted because high-dose GBCA-enhanced MR imaging had been increasingly used to characterize hepatic lesions and detect hepatocellular carcinoma in patients with cirrhosis. It is now possible to get diagnostic liver MR imaging with standard-dose GBCA administration by using a state-of-the-art MR imager with high-SNR phased-array coils and highly optimized three-dimensional fatsuppressed spoiled gradient-echo sequences (eg, liver acquisition with volume acceleration [LAVA; GE Healthcare], volumetric interpolated breathhold examination [VIBE; Siemens, Erlangen, Germany], T1-weighted high-resolution isotropic volume examination [THRIVE; Philips, Andover, Mass]). Because using the standard dose of 0.1 mmol/kg reduces risk by more than an order of magnitude, most protocols have adopted this standard dose for liver MR imaging and portal venous MR angiography. Similarly, for characterizing renal masses by imaging before and after GBCA injection, a standard dose of 0.1 mmol/kg helps to minimize risk. 1572 October Special Issue 2009 Some have advocated using less than the standard dose. This is possible with gadoxetic acid (gadoxetate disodium [Eovist; Bayer Healthcare, Wayne, NJ]), which has now received FDA approval for liver imaging at a dose of 0.025 mmol/ kg. Gadoxetic acid comes with a reduced concentration, half that of regular GBCAs, so the injection rate needs to be high, preferably 3 mL/ sec. However, the bolus will then be short, so it is helpful to use a short arterial phase of 15–20 seconds or less and to use fluoro-triggering or some other bolus timing and/or triggering method to ensure precise synchronization of the arterial phase with acquisition of the center of k-space. In patients with profound renal insufficiency with a GFR of less than 15 mL/min or patients with acute renal failure who are not undergoing dialysis, diffusion-weighted MR imaging has been proposed as an alternative to contrastenhanced sequences. On the apparent diffusion coefficient images, malignant liver tumors have higher diffusivity than benign lesions do (46,47). Although diffusion-weighted MR imaging is difficult in the abdomen, where breathing motion confuses images of molecular motion, the use of echo-planar techniques has substantially improved image quality. In some instances, it may be possible to switch to another type of examination in patients at risk of NSF. If US or nonenhanced CT can resolve the clinical issue, then these modalities can be used. However, because the risk of NSF is less than the risk of nephrotoxicity from iodinated contrast agents and because the risk of death from NSF is less than the risk of death from allergic reactions to iodinated contrast agents, it does not make sense to switch patients to contrast-enhanced CT just to avoid NSF. In addition, the use of iodinated contrast agents in patients undergoing dialysis should not be considered lightly because this may destroy any remaining nephrons that are able to sustain the patient between dialysis treatments. Recommendations to Prevent NSF Because there is no consistently effective treatment for NSF, prevention is important. Screening to identify patients at high risk is essential (48). Considerable controversy remains with regard radiographics.rsna.org to what level of screening is necessary. Because 70%–80% of NSF cases occur in patients undergoing dialysis, screening for dialysis is important. Dialysis patients should be scheduled to undergo their MR imaging just before dialysis so that if administration of a GBCA is necessary, it will be quickly removed after MR imaging. Data on the serum creatinine level should be looked up for all inpatients, and the GFR should be calculated to identify patients with a GFR of less than 30 mL/ min. The GFR calculation can be done with any of a number of online calculators (16). Outpatients who are not undergoing dialysis rarely get NSF and generally do not have recent data on the serum creatinine level available, so the screening procedures for outpatients are more controversial. Because 20% of NSF cases occur in patients with renal transplants, these outpatients should have the serum creatinine level checked to calculate the GFR. Usually it is not necessary to draw blood because kidney transplantation patients are having their serum creatinine level checked on a regular basis. All outpatients should be asked if they have renal disease, and any outpatients responding positively should have the serum creatinine level checked. Because patients with profound liver disease in the peritransplantation period may readily develop hepatorenal failure, it is important to check the serum creatinine level in these patients as well. Because it is necessary to have a proinflammatory condition together with severe renal failure in order to develop NSF and because patients with proinflammatory conditions generally have undergone recent serum creatinine testing, drawing blood to check the serum creatinine level is rarely necessary. For any patients with a calculated GFR of less than 30 mL/min, the precontrast MR images should be checked before giving the contrast agent to be sure GBCA use is necessary. If GBCA administration is necessary, a maximum of the standard dose, 0.1 mmol/kg, should be used. Hydration has been recommended to help with GBCA elimination after administration. Some authors have suggested obtaining informed consent prior to administering the GBCA. Informed consent is complicated by the need to provide patients with an accurate estimate of the risk of NSF. At our hospital, with no screening for renal function, the risk of NSF is RG ■ Volume 29 • Number 6 less than one in 100,000 and is estimated to be less than one in 10,000 for patients with a GFR of less than 30 mL/min with the 0.1-mmol/kg dose. This risk is similar to the risk of allergic reaction to GBCA (3), for which we do not routinely obtain informed consent. There is only one contrast agent, gadofosveset trisodium, that has FDA approval for use in MR angiography, and this agent is only just becoming commercially available. To our knowledge, no known cases of NSF have been reported with this contrast agent, and it has six times the relaxivity of standard GBCAs. High relaxivity offers the possibility of high-SNR MR angiography with a low dose. In the future, it may be possible to perform contrast-enhanced MR angiography with iron oxide–based contrast agents, which would completely eliminate the risk of gadolinium-induced NSF (18). Conclusion Teaching Point Although the discovery of NSF has shattered the safety reputation of GBCAs, understanding the NSF risk mechanisms now allows safe use of lowdose GBCA administration in most patients. References 1.Prince MR, Arnoldus C, Frisoli JK. Nephrotoxicity of high-dose gadolinium compared with iodinated contrast. J Magn Reson Imaging 1996;6:162–166. 2.Rofsky NM, Weinreb JC, Bosniak MA, Libes RB, Birnbaum BA. Renal lesion characterization with gadolinium-enhanced MR imaging: efficacy and safety in patients with renal insufficiency. Radiology 1991;180:85–89. 3.Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to gadolinium contrast media: a review of 36 cases. AJR Am J Roentgenol 1996;167:847–849. 4.Cowper SE. Nephrogenic systemic fibrosis: an overview. J Am Coll Radiol 2008;5:23–28. 5.Cowper SE. The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR). ICNFDR Web site. http://www.icnfdr.org. Updated June 18, 2009. Accessed August 25, 2009. 6.Leiner T. Current insights into NSF [abstr]. In: Proceedings of the 16th Meeting of the International Society for Magnetic Resonance in Medicine. International Society for Magnetic Resonance in Medicine Web site. http://cds.ismrm.org/ismrm-2008 /isv7/main.htm. Accessed August 25, 2009. 7.Gadolinium. Wikipedia Web site. http://en.wikipedia .org/wiki/Gadolinium. Updated July 31, 2009. Accessed August 25, 2009. Prince et al 1573 8.Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol 1984;142:619–624. 9.Yamaguchi K, Katayama H, Takashima T, Kozuka T, Seez P, Matsuura K. 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Renal masses: characterization with diffusion-weighted MR imaging—a preliminary experience. Radiology 2008;247:458–464. 47.Kim S, Naik M, Sigmund E, Taouli B. Diffusionweighted MR imaging of the kidneys and the urinary tract. Magn Reson Imaging Clin N Am 2008; 16:585–596. 48.Kribben A, Witzke O, Hillen U, Barkhausen J, Daul AE, Erbel R. Nephrogenic systemic fibrosis: pathogenesis, diagnosis, and therapy. J Am Coll Cardiol 2009;53:1621–1628. This article meets the criteria for 1.0 credit hour in category 1 of the AMA Physician’s Recognition Award. To obtain credit, see accompanying test at http://www.rsna.org/education/rg_cme.html. RG Volume 29 • October Special Issue 2009 Prince et al Nephrogenic Systemic Fibrosis and Its Impact on Abdominal Imaging Martin R. Prince, MD, PhD, et al RadioGraphics 2009; 29:1565–1574 • Published online 10.1148/rg.296095517 • Content Codes: Page 1566 However, the recent discovery of an association between GBCA administration and nephrogenic systemic fibrosis (NSF) has changed the way that gadolinium is used. High doses are now rare because most applications have been adjusted to use a standard dose of 0.1 mmol/kg, especially in patients undergoing dialysis or patients with a glomerular filtration rate (GFR) of less than 30 mL/min. Page 1567 NSF is only observed in patients with severe renal dysfunction, primarily patients undergoing or approaching dialysis, hence the use of nephrogenic in its name. Page 1567 For patients undergoing dialysis who receive GBCAs, dialysis should be performed as quickly as possible afterward. It is recommended to schedule MR imaging to be performed just before a routine dialysis to make sure that the dialysis is occurring well within 24 hours of any GBCA injection. Page 1567 High doses of GBCA, and possibly the use of linear nonionic GBCAs, contribute to an increased risk of NSF. Page 1573 Although the discovery of NSF has shattered the safety reputation of GBCAs, understanding the NSF risk mechanisms now allows safe use of low-dose GBCA administration in most patients.