Broome et al.

Gadodiamide-Associated Nephrogenic Systemic Fibrosis

MR Imaging Original Research

Gadodiamide-Associated Nephrogenic Systemic Fibrosis: Why Radiologists Should Be Concerned

Dale R. Broome1 Mark S. Girguis1 Pedro W. Baron2 Alfred C. Cottrell3 Ingrid Kjellin1 Gerald A. Kirk1
Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA OBJECTIVE. Nephrogenic systemic fibrosis (NSF) is a rare multisystemic fibrosing disorder that principally affects the skin but may affect other organs of patients with renal insufficiency. The purpose of our study was to identify any common risk factors and determine whether IV gadodiamide is associated with the development of NSF. MATERIALS AND METHODS. A retrospective chart review was performed for all 12 patients diagnosed with NSF at our institution between 2000 and 2006 to identify the clinical manifestations, timing, and dose of gadodiamide administration; dialysis records; concurrent medications; comorbid conditions and surgeries; laboratory findings; imaging findings; and clinical outcome. A review of the dialysis and MR records between 2000 and 2006 showed 559 MRI examinations on 168 dialysis patients (including 301 contrast-enhanced examinations). RESULTS. NSF was diagnosed by clinical findings and tissue diagnosis. All 12 patients had renal insufficiencyeight with dialysis-dependent chronic renal insufficiency and four with acute hepatorenal syndrome. All 12 patients developed skin fibrosis within 211 weeks after gadodiamide administration. The odds ratio for development of NSF after gadodiamide exposure was 22.3. No other common event or exposure could be found. Four patients had abnormal scintigraphic bone scans with skin and muscle uptake and lower-extremity MRI finding of edema in the muscles, intermuscular fascia, and skin. Despite the fact that 10 patients were dialyzed within 2 days of gadodiamide administration, this did not prevent the development of NSF. CONCLUSION. Development of NSF was strongly associated with gadodiamide administration in the setting of either acute hepatorenal syndrome or dialysis-dependent chronic renal insufficiency. ephrogenic systemic fibrosis (NSF) is a rare disease that has been described with increasing frequency in the medical literature. This entity was first recognized in several patients in 1997 and was first described in the literature in 2000 [1]. Approximately 200 cases have been reported to date to the International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR) [2]. Originally, it was termed nephrogenic fibrosing dermopathy (NFD) because this fibrosing skin condition occurred exclusively in patients with renal failure. The skin changes can mimic progressive systemic sclerosis with a predilection for peripheral extremity involvement that can extend to the torso. But unlike scleroderma, NSF spares the face and lacks the serologic markers of scleroderma such as antinuclear antibodies, anti-Scl 70 antibodies, and anticentromere antibodies. Specific histologic findings are associated with this con-

Keywords: dialysis, MR contrast agents, MR imaging, nephrogenic systemic fibrosis, nuclear medicine, renal disease DOI:10.2214/AJR.06.1094 Received August 16, 2006; accepted after revision November 21, 2006.
1Department

of Radiology, Loma Linda University Medical Center, 11234 Anderson St., MC Room 2605, Loma Linda, CA 92354. Address correspondence to D. R. Broome. of Surgery, Transplant Division, Loma Linda University Medical Center, Loma Linda, CA.

2Department

3Department of Medicine, Nephrology Division, Loma Linda

University Medical Center, Loma Linda, CA. AJR 2007; 188:586592 0361803X/07/1882586 American Roentgen Ray Society

dition including thickened collagen bundles with surrounding clefts, mucin deposition, and increased numbers of fibrocytes and elastic fibers. Later autopsy series of this disease have shown systemic manifestations including fibrosis of the skeletal muscle, bone, lungs, pleura, pericardium, myocardium, kidney, muscle, bone, testes, and dura [3, 4]. Thus, the terminology recently has changed from NFD to NSF to reflect this systemic involvement. This condition can be quite disabling because the skin tightening and musculotendinous involvement result in joint contractures that can reduce the range of motion of joints. Some patients become severely disabled due to contractures, muscle weakness, and arthralgia. In this article, we present a retrospective chart review of 12 patients with NSF at our institution, all of whom received IV doubledose gadodiamide 211 weeks before the development of skin fibrosis.

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Gadodiamide-Associated Nephrogenic Systemic Fibrosis Materials and Methods

After institutional review board approval, a list of all patients diagnosed with NSF at our institution from January 2000 and July 2006 was acquired from the departments of nephrology, transplant surgery, and dermatology. Their medical records were retrospectively reviewed to identify onset and clinical manifestations of NSF and verify histologic diagnosis, timing, and dose of gadodiamide for MRI examinations; dialysis records; concurrent medications; comorbid conditions and surgeries; laboratory findings; imaging findings; and clinical outcome. These data were entered into a database and analyzed for common associations or risk factors for the development of NSF. The names of all patients receiving inpatient and outpatient dialysis at our medical center from January 2000August 2006 were entered into our PACS system to determine how many had undergone MRI examinations either with or without contrast enhancement. During this time, only one gadoliniumbased contrast medium, gadodiamide, was administered to patients at our institution. The contrast dose (0.1 or 0.2 mmol/kg) and body part imaged were recorded. Nearly all the abdominal and pelvic MRI examinations included an MR angiogram and were dosed at 0.2 mmol/kg. Nearly all the remaining MRI examinations were dosed at 0.1 mmol/kg during this time period. The prevalence, likelihood ratio, and odds ratio for developing NSF after gadodiamide exposure compared with unenhanced MRI examinations were calculated using a 2 2 contingency table. The likelihood ratio and odds ratio for developing NSF after double-dose (0.2 mmol/kg) gadodiamide administration compared with single dose (0.1 mmol/kg) administration also was calculated using a 2 2 contingency table.

Results A summary of the chart review findings is presented in Table 1. The clinical information and dermopathic findings of three of our patients have been previously described in the literature [5]. The scintigraphic bone scan findings of two of those three patients have also been previously reported in the literature [6]. We include them in this article with permission from the corresponding authors because they were not previously reported to be associated with gadodiamide administration. The patient population included eight men and four women who ranged in age from 26 to 64 years. All 12 patients had renal insufficiency at the time of gadodiamide administration. Four patients had acute renal failure associated with hepatorenal syndrome, and eight had dialysisdependent chronic renal failure from various causes. Ten patients were on hemodialysis at

the time of gadolinium injection. The two patients who were not on dialysis had calculated creatinine clearance of 12 and 26 mL/min at the time of injection (CrockcroftGault formula) [7]. All 12 patients had received 0.2 mmol/kg of IV gadodiamide (Omniscan, GE Healthcare) 211 weeks before development of skin fibrosis. The MRI examinations were performed with IV injection at rates of 23 mL/s, primarily for abdominal or pelvic imaging, including MR angiography. Ten patients were dialyzed at least once within 12 days after contrast injection, and one patient was not dialyzed until 1 week after injection because of dialysis access problems. Of the patients who were dialyzed, three were dialyzed on the day of injection and then daily for 3 days. The one patient with the estimated creatinine clearance of 26 mL/min did not require dialysis and did not have any deterioration of renal function after gadodiamide administration. Six patients had a vascular surgery performed within a 17-day period after gadodiamide injection, including liver transplantation (four patients), arteriovenous graft revision (one patient), and thrombectomy of renal transplant and right external iliac vein thrombus (one patient). A left thigh fasciotomy was performed on one patient for suspected necrotizing fasciitis 4 weeks after gadodiamide injection. Two patients had acute venous thrombosis including the patient who required arteriovenous graft revision and the patient who required renal transplant venous thrombectomy. Two other patients had systemic lupus erythematosus with antiphospholipid syndrome and history of recurrent deep venous thrombosis, but no episode of acute deep venous thrombosis in the interval between IV gadodiamide injection and development of NSF symptoms. Evaluation of the patient medications taken at time of gadodiamide injection and during the interval before the development of disease symptoms showed no common medications among the patients. However, six patients were taking prednisone during this time interval, and six patients were on erythropoietin. Two patients had previously received gadodiamide for MRI examinations before they were on dialysis and did not subsequently develop NSF with those exposures. Five patients received a second IV injection of gadodiamide 12 months after the primary exposure but after the onset of clinical symptoms of NSF. None of the NSF patients received any other gadolinium-based contrast material at our facility or any other MRI facility in the 3 months before their development of skin fibrosis.

Signs and symptoms of NSF were divided into early (< 2 weeks after the gadodiamide injection) and late (211 weeks after the gadodiamide injection). Most signs and symptoms described were bilateral and symmetric, usually starting in the peripheral extremities and spreading proximally. Lower extremity involvement was noted in all 12 patients, and upper extremity involvement was seen in eight patients. Three patients had abdominal wall involvement, but none had face or neck involvement. Early signs or symptoms were seen in all patients, most frequently consisting of extremity edema or swelling (eight patients), arthralgia or myalgia (four patients), and extremity weakness (three patients). These nonspecific signs and symptoms were difficult to prospectively attribute to the gadodiamide because they may be seen with renal failure and other coexisting medical conditions. Late signs and symptoms consisted of persistent skin fibrosis changes in the extremities described as woody induration, skin tightness, or skin thickening. These findings developed in 11 patients between 2 and 8 weeks after gadodiamide injection and in one patient 11 weeks after gadodiamide injection. The skin findings showed slightly raised and erythematous or brawny nodular plaques, linear striations, or confluent regions of fibrosis (Fig. 1A). Seven patients developed contractures or symptoms described as stiffness in both lower and/or upper extremities (Fig. 1B). An additional four patients developed extremity myopathy/weakness during this latent period. Laboratory findings for all 12 patients showed no confirmatory serologic evidence of progressive systemic sclerosis. Although three patients had positive antinuclear antibodies, none had anti-Scl 70 or anticentromere antibodies. Skin biopsies showed dermal fibrosis with increased collagen and mucin deposition in 11 of 12 patients. The twelfth patient (patient no. 12 in Table 1) had two skin biopsiesone of which by history was consistent with NSF according to the chart, although we could not locate this pathology report. The second biopsy on that patient did not show dermal fibrosis but was felt not to be adequately sampled according to the pathology report. This patient, along with three other patients, had muscle biopsies that showed findings of myonecrosis. We did not have sufficient arterial blood gas results for our patients to assess the severity of acidosis at the time of gadodiamide administration. The other laboratory findings were noncontributory.

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Broome et al. TABLE 1: Nephrogenic Systemic Fibrosis in Patients Exposed to Gadodiamide

Patient No. 1 2 Age, Sex 45, M 46, M Contrast Volume (mL) Renal System 40 40 ARF-HRS ARF-HRS eCrCl 26 mL/min ARF-HRS eCrCl 12 mL/min ARF-HRS Signs and Symptoms Dialysis (at time of MR) HD daily for 3 d starting day of MRI None Early (< 2 wk) Late (2 wk11 wk) Vascular Procedures (within 17 d after MR) Liver transplant Liver transplant

MR Exam Abd MRI Abd MRA Abd MRI Abd MRA

Disability None Mild

BLE edema and Skin induration of weakness BLE BLE and hand weakness Skin induration, weakness, and contractures of BLE and BUE Bilateral thigh erythema and skin induration Skin induration, contractures and weakness of BLE

64, M

Abd MRI Abd MRA Abd MRI Abd MRA Pelvic MRI Pelvic MRA Abd MRI Abd MRA

40

HD daily for 3 d BLE weakness starting day after MRI HD daily for 3 d starting day of MRI HD daily for 3 d starting day of MRI HD 3/wk BLE pain and stiffness BLE swelling

Liver transplant

None

49, M

32

Liver transplant

Mild

55, F

30

Failed renal transplant 2 wk prior CRF-HN

Skin induration of Thrombectomy Mild BLE, BUE, low back Renal transplant vein and abdomen Skin induration of BLE and abd wall; BUE swelling; BUE and BLE contractures and skin ulceration Skin induration, weakness and contractures of BUE and BLE BLE and BUE swelling and skin tightening BLE and BUE swelling, skin tightening, and contractures BLE skin tightening; BLE and BUE contractures BLE skin induration and stiffness; BLE and BUE myalgia and weakness BLE myopathy, swelling, pain, and skin induration None Severe

42, M

40

BLE swelling

30, F

Abd MRI Abd MRA

40

CRF-SLE HN

HD 3/wk

BLE and hand edema

None

Severe

26, M

Abd MRI Abd MRA Abd MRI Abd MRA

40

CRF-HN

HD 3/wk

Bilateral ankle and wrist arthralgia BLE and BUE swelling

None

None

46, M

40

CRF-SLE

HD 1 wk later

AV graft revision

Severe

10

32, F

Abd MRI Abd MRA Pelvic MRA

40

CRF-DM

HD 3/wk

RLE pain and and swelling Fatigue and BLE edema

None

Mild

11

38, F

40

CRF-DM HN

HD 3/wk

None

Worsening of prior severe disability None

12

59, M

Abd MRI Abd MRA

40

CRF-DM HN

HD 3/wk

Left thigh pain and swelling

None

NoteM = male, F = female, Abd = abdominal, ARF = acute renal failure, BLE = bilateral lower extremity, BUE = bilateral upper extremity, CRF = chronic renal failure, DM = diabetes mellitus, eCrCl = estimated creatinine clearance, HD = hemodialysis, HN = hypertensive nephropathy, HRS = hepatorenal syndrome, SLE = systemic lupus erythematosis, AV = arteriovenous.

Abnormal imaging findings on bone scintigraphy and extremity MRI would suggest that NSF is a systemic disorder of connective tissue involving skeletal muscle, skin, and tendons. Four patients underwent wholebody bone scans using 99mTc HDP (hydroxymethylene diphosphonate) performed 68 weeks after gadodiamide administration. The scans, obtained at 23 hours, showed symmetric increased uptake in the muscles,

tendons, and skin (Figs. 2A, 3A, and 3B). Peripheral upper-extremity uptake was noted in three patients. There was also abdominal wall uptake in one patient and chest wall uptake in another patient. These same four patients also had MRI examinations of the lower extremities that showed skin thickening and an edematous pattern of low T1 signal and high T2 signal throughout the skeletal muscle, intermuscular fascia, and skin (Figs. 2B and 2C).

The MRI findings were thought to represent a polymyositis process, although myonecrosis was found on four patients who underwent muscle biopsy. One patient developed such severe myositis and asymmetric swelling in the left thigh that a fasciotomy was performed for suspected necrotizing fasciitis. However, bacterial cultures of this region revealed no organism, and a muscle biopsy revealed severe myonecrosis. One day later the patient

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Gadodiamide-Associated Nephrogenic Systemic Fibrosis

Fig. 1Two patients with nephrogenic systemic fibrosis (NSF) that developed after gadodiamide injection. A, Photograph of 46-year-old man shows skin changes due to NSF, including slightly raised and erythematous nodular plaques, and linear and confluent regions of fibrosis. B, Photograph of 30-year-old woman with soft-tissue swelling and flexion contractures of hand (with fingers maximally extended) due to NSF.

Fig. 259-year-old man with nephrogenic systemic fibrosis (NSF) with both skeletal muscle and skin findings. A, Anteroposterior 99mTc HDP 3-hour bone scan shows symmetric increased radionuclide skin and muscle uptake in entire lower extremity and distal upper extremities. B and C, Axial T1- and fat-suppressed T2weighted images of thighs show symmetric skin thickening and edema in medial thighs. There is also marked edema in subcutaneous fat, intermuscular fascia, and thigh muscles with some sparing of posterior thigh muscles.

developed similar symptoms in the right thigh. Because of the bilateral involvement, negative cultures, and slow disease progression, this was felt to represent NSF with the

subsequent development of persistent skin fibrosis/thickening (Fig. 2). A total of 559 MRI examinations were performed on 168 dialysis patients at our institu-

tion between January 2000 and August 2006. This included 301 gadodiamide-enhanced and 258 unenhanced MRI examinations. From a 2 2 contingency table (12 NSF cases

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Broome et al.
Fig. 330-year-old woman with nephrogenic systemic fibrosis with predominant skin finding. A and B, Anteroposterior and lateral 99mTc HDP delayed bone scan shows extensive symmetric skin uptake in lower extremities and distal upper extremities. Uptake is also seen in calf muscles, Achilles tendon, and chest wall.

among 301 gadodiamide-exposed cases, zero NSF cases among the 258 gadodiamide-unexposed patients), the odds ratio (Haldanes estimator) was 22.3 (95% confidence interval, 1.3378.9) and the likelihood ratio was 1.89 (95% confidence interval, 1.752.05). The prevalence of NSF among the gadodiamideexposed dialysis patients was 4.0%. Of the 301 patients who underwent gadodiamide-enhanced MR examinations, 207 of the examinations were performed with 0.2 mmol/kg of gadodiamide (of which 12 patients later developed NSF), and 94 were performed with 0.1 mmol/kg (of which none developed NSF). Using a 2 2 contingency table (with all 12 NSF cases with double dosing and 195 double-dosed cases and 94 single-dosed cases without NSF) the odds ratio and likelihood ratio for development of NSF with double-dose compared with single-dose gadodiamide administration were 12.1 (95% confidence interval, 0.7206.2) and 1.48 (95% confidence interval, 1.361.61) patients, respectively. The clinical outcome of the 12 NSF patients included three patients with severe long-term inability to ambulate due to contractures and myopathytwo wheelchair-bound and the

third bedridden. The latter patient developed progressive severe skin ulcerations and died from liver failure from severe recurrent hepatitis C five months after the onset of NSF. One patient had worsening of a severe disability from limited to full-time wheelchair requirement. Four patients had mild disability and required a cane to ambulate for a short period of time. The remaining patients had no disability, although skin changes have persisted to variable degrees depending on therapy. Discussion NSF is a rare fibrosing disease occurring in renal insufficiency that has only been described since 1997. The exact cause of NSF has not been clearly proven. Multiple associations have been proposed including coagulation abnormalities and deep venous thrombosis, recent surgery (particularly vascular surgery) and recent failure of a transplanted kidney, and erythropoietin exposure [2, 8]. According to the International Center of Nephrogenic Fibrosing Dermopathy Research (ICNFDR), a voluntary NSF registry, there is no convincing evidence that it is caused by a medication, microorganism, or dialysis [4]. In May

2006, the Danish Medicines Agency reported 25 cases of NSF (including 20 cases from two Danish hospitals and five cases from an Austrian hospital) that occurred in patients who had received IV gadodiamide for MRI/MR angiography examinations within 2 months before development of the disease [9]. Grobner [10], who published the Austrian cases, found that five of nine dialysis patients who received IV gadodiamide for MR angiography subsequently developed NSF 24 weeks after the injection. The dialysis patients who developed NSF had metabolic acidosis but the four unaffected patients did not. He suggested that free gadolinium might serve as a trigger for the development of NSF in the setting of metabolic acidosis [10]. Marckmann et al. [11] recently reported 13 of the Danish NSF cases that developed following IV gadodiamide administration without any other common exposure or event between 2002 and 2005 at their institution. The ICNFDR also reports that all NSF cases for which records can be located (exact number not stated) have had at least one known exposure to gadolinium-based contrast within 28 weeks before the development of clinical symptoms [2]. Our study likewise found no common medications or medical or surgical events among our NSF patients except for IV gadodiamide administration in the setting of renal failure. All 12 of our patients had received double-dose (0.2 mmol/kg) IV gadodiamide for MRI examination in the setting of underlying renal disease, either acute renal failure or end-stage renal disease on dialysis. All our NSF cases developed within 28 weeks of gadodiamide administration except one patient who developed skin fibrosis at 11 weeks. One intriguing model for the pathogenesis of NSF has been proposed by Cowper et al. [12] and states that a combination of events leads to the development of NSF beginning with renal disease, followed by allergen deposition leading to circulating fibrocyte deposition, a dominant cell found in the histopathologic examination of skin in patients with NSF and considered to be a main actor in wound healing and fibrosis. The suggestion that endothelial damage and elevated levels of cytokines may lead to development of the disease is supported by the fact that eight of our 12 patients had either undergone vascular surgery, experienced deep venous thrombosis, or had coagulopathies within the interval between gadodiamide injection and development of skin fibrosis. The imaging findings of skin, muscle, and tendon uptake of bone scintigraphy agents in this study are likely due to the deposition

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Gadodiamide-Associated Nephrogenic Systemic Fibrosis and activity of fibrocytes within these tissues. The MRI findings of low T1 and T2 signal skin thickening are consistent with the dermal fibrosis noted on skin histology. Although the extremity MRI muscle findings of low T1 and high T2 signal may represent a myositis response, more likely they represent myonecrosis based on the few muscle biopsy results in this study. Although the bone scan and extremity MRI findings are nonspecific and were noted after the onset of skin fibrosis, they may be useful studies to confirm the development of NSF. However, the definitive method of diagnosis of NSF is clinical assessment and a deep skin biopsy sufficient to sample the dermis, subcutaneous fat, and fascia. Most of the dermal spindle cells will stain positive for CD34 and procollagen I. This profile is identical to the immunohistochemical profile of the circulating fibrocyte [13]. Five different gadolinium chelates have received U.S. Food and Drug Administration (FDA) approval as paramagnetic MR contrast agents for central nervous system and (in some cases) body imaging indications, but none specifically for MR angiography indications. IV gadolinium at standard doses of 0.1 mmol/kg has been shown to be a safe contrast agent with relatively few adverse reactions in healthy and renally impaired patientswith minor reactions in approximately 34% of patients and severe reactions (< 1% of patients) according to the package inserts. Double and even triple dosing of gadodiamide has been reported to be safe with a similar incidence of adverse reactions as the standard dose (0.1 mmol/kg) [14]. Gadoteridol (FDA approved in 1992) and gadodiamide (FDA approved in 1993) have subsequently received FDA approval for double and triple dosing, which has become increasingly popular for abdominal MRI and many MR angiography examinations. It is interesting to note that the onset of first reported cases of NSF in 1997 coincides closely with the rapid rise in the use of highdose gadolinium injection for MRI and MR angiography in the last decade. The first Medlineindexed article describing the use of gadolinium-enhanced MR angiography in renal patients was also published in 1997 [15]. To date, the only gadolinium-based contrast agent reported to be associated with NSF is gadodiamide. However, the reporting of this association is still quite immature and other gadolinium agents may be found to have a similar association. Marckmann et al. [11] have postulated that NSF may result from a toxic reaction from free gadolinium (Gd3+), liberated from the chelate but not adequately excreted due to impaired renal function. Transmetallation, the release of free gadolinium from the chelate and subsequent binding to endogenous ions, is dependent on the molecular conditional thermodynamic stability. Gadolinium contrast media with lower conditional stability constant values would be more likely to undergo transmetallation. The conditional stability constants (at a pH of 7.4) of the FDAapproved major contrast agents are: gadodiamide, 1014.9; gadoversetamide, 1015.0; gadoteridol, 1017.1; gadopentetate dimeglumine, 1018.1; and gadobenate dimeglumine, 1018.4 [16, 17]. If this postulate is true, contrast media such as gadodiamide and gadoversetamide, which have 1,000-fold lower conditional stability constants than the more stable gadolinium chelates, would be more likely to release free gadolinium and result in NSF. To minimize the risk of release of free gadolinium, contrast manufacturers have added additional chelate to bind the free gadolinium. The excess chelate content (according to the latest U.S. package inserts) of FDA-approved gadolinium contrast agents are as follows: gadodiamide (12 mg/mL), gadoversetamide (28.4 mg/mL), gadoteridol (0.23 mg/mL), gadopentetate (0.4 mg/mL), and gadobenate (0 mg/mL). Although some have theorized that the excess chelate with gadodiamide may contribute to the higher incidence of NSF [11], more likely the excess chelate has a protective effect in binding the free gadolinium. MRI and MR angiography examinations are commonly requested for patients with endstage liver and renal disease to evaluate for transplant eligibility, visualization of vascular anatomy, and posttransplant complications. Gadolinium-enhanced MRI traditionally has been preferred over contrast-enhanced CT because many of these patients have impaired renal function. Gadolinium-based contrast media (at doses of 0.10.2 mmol/kg) are considered less nephrotoxic than iodinated contrast agents [18], although there is considerable controversy in the literature regarding the safety of gadolinium-based contrast media administered to patients with renal failure [19]. Despite numerous studies on the safety of gadolinium-based contrast agents in renal insufficiency and dialysis patients, none has reported NSF as a complication before Grobners study [10]. Our study also confirmed that dialysis patients are at significant risk for the development of NSF when gadodiamide is administered: The prevalence rate is 4% and the odds ratio is 22.3. The risk was significantly higher when a 0.2 mmol/kg dose of gadodiamide was administered. Also, our study showed that NSF can develop when gadodiamide is administered in the setting of acute renal failure. All of our acute renal failure NSF patients had hepatorenal syndrome and subsequently underwent liver transplantation within a 17-day interval after gadodiamide administration. Several publications have confirmed that liver transplant patients are particularly prone to the development of NSF [5, 20]. For this reason, caution should be exercised in performing gadodiamide-enhanced MRI examinations in patients with acute hepatorenal syndrome in the immediate pre- or postliver transplant period. NSF is a disfiguring and potentially debilitating disease without a consistently effective treatment or prevention regimen. In the Danish study, seven of 13 patients were severely disabled and one died [11]. In our study, four of the 12 patients developed severe ambulatory disability and four patients developed short-term ambulatory disability. Plasmapheresis has been used with some success at our institution to treat NSF [5]. Other treatment options such as extracorporeal photopheresis, physical therapy, oral corticosteroids, oral pentoxifylline, and ultraviolet therapy have been tried with anecdotal success [2]. In the recent Public Health Advisory, the FDA stated that it may be prudent to institute prompt dialysis to prevent NSF in patients with advanced kidney dysfunction who receive gadolinium contrast [9]. Several reports have shown that 68% of gadolinium is eliminated after a 3-hour dialysis session and approximately 98% after three consecutive dialysis sessions [21]. In our study, three patients had received daily dialysis for three consecutive days starting on the day of gadodiamide administration. Theoretically the dialysis should have removed up to 98% of the injected gadodiamide in these patients, but dialysis did not prevent their developing NSF. It is probable that the gadodiamide-triggered event occurs quite rapidly in patients with renal insufficiency and is not reversed by hemodialysis. It is somewhat impractical to schedule patients for immediate dialysis after injection of gadodiamide to attempt to prevent this disorder. Further studies will need to be performed to study the efficacy of immediate dialysis in preventing NSF. In June 2006, the FDA issued a public health advisory concerning the use of highdose gadolinium-containing contrast agents in patients with advanced renal failure [9]. Because of the association of NSF with the use of IV gadodiamide, our institution has adopted a policy regarding the use of gadodiamide in renal insufficiency patients until

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Broome et al. more medical research becomes available: We are no longer administering IV gadodiamide to dialysis patients or end-stage renal disease patients with a creatinine clearance of < 15 mL/min. We also are avoiding double- or triple-dose injections of gadodiamide, and we are exercising caution in administering gadodiamide to patients with acute renal failure, particularly with hepatorenal syndrome. Our department has begun screening patients scheduled for contrast-enhanced MRI examinations by obtaining a recent serum creatinine level and calculated creatinine clearance if they have a history of kidney disease or diabetes mellitus. Inpatients older than 60 years also will have their serum creatinine and calculated creatinine clearance checked before gadodiamide administration. Given the limited reporting of the association of NSF with gadolinium-based contrast, a cause-and-effect linkage has not yet been proven. There will be a tremendous pressure among researchers to associate all cases of NSF with gadolinium-based contrast. This could inaccurately link specific MR contrast agents to NSF. Future reporting of this association should adhere to certain reasonable research criteria, as we have done. The diagnosis of NSF should be confirmed by skin biopsy and should not be based solely on clinical manifestations. The specific MR contrast agent should be documented in the contrast administration records and should not simply be inferred. The temporal relationship of contrast administration and development of NSF should be documented and should likely conform to the time period of 2 weeks to 3 months reported in this and other series. The possibility that patients may have been exposed to multiple MR contrast agents during the 3-month period should be verified, including those administered at other facilities. In conclusion, NSF is a disfiguring and potentially disabling or fatal disorder that appears to be strongly associated with or triggered by IV injection of double-dose gadodiamide for MRI and MR angiography examinations in patients with acute or chronic renal insufficiency who are usually, but not always, on dialysis. NSF can show abnormal soft uptake of bone scintigraphy agents and abnormal MR signal in the muscles and skin of the extremities and less commonly the torso. Dialysis following the administration of gadodiamide did not appear to prevent the development of NSF in our patients.
10. Grobner T. Gadoliniuma specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21:11041108 11. Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006; 17:23592362 12. Cowper SE, Bucala R, Leboit PE. Editorial: nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosissetting the record straight. Semin Arthritis Rheum 2006; 4:208210 13. DeHoratius DM, Cowper SE. Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial 2006; 19:191194 14. Svaland MG, Lundby B, Kristofferson DT. Comparison of the safety of the standard dose and a higher dose of gadodiamide injection for MR imaging of the central nervous system. J Magn Reson Imaging 1994; 4:419423 15. Johnson DB, Lerner CA, Prince MR, et al. Gadolinium-enhanced magnetic resonance angiography of renal transplants. Magn Reson Imaging 1997; 15:1320 16. Prince MR, Erel HE, Lent RW, et al. Gadodiamide administration causes spurious hypocalcemia. Radiology 2003; 227:639646 17. Uggeri F, Aime S, Anelli PL, et al. Novel contrast agents for magnetic resonance imaging. Synthesis and characterisation of the ligand BOPTA and its Ln(III) complexes. Inorg Chem 1995; 34:633642 18. Prince MR, Arnoldus C, Frisoli JK. Nephrotoxicity of high-dose gadolinium compared with iodinated contrast. J Magn Reson Imaging 1996; 6:162166 19. Thomsen HS. Gadolinium-based contrast media may be nephrotoxic even at approved doses. Eur Radiol 2004; 14:16541656 20. Maloo M, Abt P, Kashyap R, et al. Nephrogenic systemic fibrosis among liver transplant recipients: a single institution experience and topic update. Am J Transplant 2006; 6:22122217 21. Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acta Radiol 1998; 5:491502

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A Special Alert for this article from the AJR Editor in Chief can be viewed in the online version of the article at: www.ajronline.org.

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