Cath Lab Digest

Physicians are constantly introduced to new diagnostic and therapeutic modalities developed to enhance patient care. However, adverse effects of these technological advances often come to light only when they are later widely employed in clinical practice. Gadolinium-based contrast agents are utilized with magnetic resonance (MR) imaging and have been considered generally safe when administered to most patients. With the exception of allergic type reactions, and perhaps the potential of nephrotoxicity in high-risk patients (renal insufficiency, diabetic nephropathy), they are well tolerated. Recently however, reports of a previously rare condition, nephrogenic systemic fibrosis, have surfaced at an alarming rate in patients with advanced kidney disease, and especially those already receiving dialysis, which has now been strongly linked with exposure to gadolinium. As gadolinium-based studies are widely used by physicians across many specialties, including interventional and diagnostic radiology, cardiology, and in particular vascular surgery, the goal of this editorial is to review this new concern for the readership of Vascular Disease Management.

In 1997, several renal transplant recipients with failed allografts requiring chronic maintenance dialysis were noted to develop a previously unrecognized fibrosing disorder of the skin.¹ This new disease entity was descriptively coined nephrogenic fibrosing dermopathy (NFD).¹ Following the subsequent recognition that fibrosis also occurred in systemic organs (in addition to skin), the name was changed to nephrogenic systemic fibrosis (NSF). Nephrogenic systemic fibrosis is an acquired condition that develops in patients with acute kidney injury (AKI), advanced chronic kidney disease (CKD) and dialysis-dependent end-stage renal disease (ESRD).^2,3 It is characterized by dermal fibrosis, which can cause severe joint contractures and limitations in mobility, often leading to a wheelchair-dependent or bed-bound state.² Involvement of systemic organs such as the liver, heart, lungs, diaphragm and skeletal muscle has also been described, sometimes with fatal consequences.^2,3 Since its initial description, over 215 cases have been collected in the NSF registry under the stewardship of Shawn Cowper.³ The vast majority of patients that develop NSF are dialysis-dependent (90%), although it has also been described in patients with advanced CKD not yet on dialysis and those with AKI.^2,3 Exposure to gadolinium following a magnetic resonance imaging (MRI) study in patients with kidney disease has been recently linked to the development of NSF.^4–8 Initially reported in 5 dialysis-dependent ESRD patients following gadolinium exposure,⁴ subsequent reports have confirmed this finding in another 35 patients.^5–9 Deo et al in a small population study noted a 2.4% risk of NSF with each gadolinium exposure.⁶

Another group reported 12 cases of NSF, of which 4 had AKI secondary to hepatorenal syndrome (2 were on renal replacement therapy).⁸ Gadolinium exposure in these patients was associated with an odds ratio of 22.3 for the development of this fibrosing disorder.⁸ Khurana and colleagues described NSF in 6 patients with underlying kidney disease who were exposed to gadolinium.⁹ Four patients were initiated on dialysis after gadolinium exposure, while one patient started dialysis the day prior to administration of gadolinium. The NSF registry confirms the association of gadolinium exposure to development of NSF as all patients with data available for analysis have received this contrast agent prior to development of the disease.³ The time from gadolinium exposure to diagnosis of NSF ranged from 2 to 8 weeks.³ Recently, the FDA has also linked NSF to gadolinium and has released two Public Health Advisories, one published in 6/06 reporting NSF in 25 ESRD patients after gadolinium exposure,¹⁰ and an update in 12/06 increasing this number to 90 patients.¹¹ Two recent studies document free gadolinium within the affected fibrotic tissues of 5 NSF patients, further incriminating gadolinium as the pathogenic trigger.^12,13

There appears to be a dose relationship in the development of NSF as higher doses of gadolinium increase the risk of NSF. Most cases occur in patients who have received > 0.1mmol/kg dose. This aspect of gadolinium exposure and development of NSF is very relevant to physicians who care for patients with vascular disease, who often have underlying kidney disease. MR angiograms are commonly employed to study the renal, peripheral, and carotid vascular beds. Higher doses of gadolinium are usually required to perform these studies, which likely increase the risk for NSF. The initial report by Grobner noted that all patients in his series underwent an MR angiogram, which employs gadolinium doses of 0.2–0.3 mmol/kg.⁴ The 13 cases from Denmark used an average gadolinium volume of 18.5 mmol, or 0.26 mmol/kg for a 70 kg individual.⁵ Broome et al noted an odds ratio of developing NSF equal to 12.1 when comparing a 0.2 mmol/kg dose to a 0.1 mmol/kg dose.⁸ Finally, the dose of gadolinium administered to the 6 patients with NSF ranged from 0.11 to 0.36 mmol/kg, higher than the routine non-angiogram dose of 0.1 mmol/kg.⁹ Thus, an MR angiogram, typically using 0.3 mmol/kg of gadolinium would carry a significantly higher risk for NSF than a non-vascular MRI study.