Gadodiamide-Associated Nephrogenic Systemic Fibrosis: Why Radiologists Should Be Concerned (Omniscan). This study has images of the systemic nature of this disease. Because it is a systemic disease the skin does not have to be affected.
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.
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.
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.
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.
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) . 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.
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.
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).
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.
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.
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.
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