Nephrogenic systemic fibrosis (NSF) is a debilitating, and in most cases fatal, condition that currently has no definitive treatment. This disease is associated with exposure to certain gadolinium-based contrast agents (GBCA) administered during magnetic resonance imaging (MRI) or angiography (MRA) scans.¹ The first reports of NSF occurred in the early 2000s, when it was originally termed nephrogenic fibrosing dermopathy (NFD) based on the impression that its lesions were limited to the skin.^2,3 Eventually, the term NSF replaced NFD when it became evident that the disease affects multiple organ systems; occurs conspicuously in persons with end-stage renal disease (ESRD); and manifests histologically as increased collagen deposition in superficial soft tissues and internal organs such as the heart, liver, and lungs.³ Subsequently, starting in 2007, the FDA released a series of warnings about the use of certain GBCAs recognized to be connected to the development of NSF (see Appendix A).⁴

As a diagnostic tool, depending on clinical indication, MRI is much more effective when administered with a contrast agent. Gadolinium is a heavy metal with paramagnetic properties that make it an optimal candidate for use as an MRI contrast agent.⁵ However, it is toxic in its free form,⁶ and must be stabilized by chelation, or bonding, to a ligand for human use.^3,6 GBCAs can be characterized by the structure of their individual chelate (macrocyclic/linear) and charge (ionic/nonionic),⁶ which in turn contribute to the stability of a given GBCA and how easily the gadolinium is disconnected from its ligand.^3,6 These differences in stability of the linkage of gadolinium to the chelate ligand are thought to be a key factor in the risk of NSF, as dissociation of the gadolinium complex releases the unbound gadolinium ion, which triggers a cascade of events in a subset of patients culminating in the histological manifestations of NSF.⁷ Newer GBCAs impart greater stability of the gadolinium-ligand bond⁵ and thus are thought to be associated with lower, or potentially minimal, NSF risk. Table 1 contains information about the FDA-approved gadolinium agents. An additional critical risk factor for the development of NSF is renal impairment.⁷ All GBCAs are cleared, at least in part, from the body by the kidneys, and almost all cases of NSF have occurred in individuals with advanced kidney disease (eGFR <30 mL/min/1.73m²). However, other patient-level risk factors have been proposed as well, including the severity and chronicity of kidney dysfunction and inflammation.^1,8

As newer GBCAs with greater chemical stability have become available, guidelines recommending safe and effective administration of these agents have evolved, and, in places, diverged. While some advisory boards recommend liberalized use of the newer classes of GBCAs, others warn against risk for NSF with all classes of GBCAs (see Appendix B for GBCA guidelines). These divergent positions reflect uncertainties regarding the relative safety of newer compared with older classes of GBCAs and the degree of kidney dysfunction that portends risk for NSF. Despite these uncertainties, few studies have assessed risk for NSF with GBCA exposure specifically in relation to newer agents; across the range of kidney function; and according to patients’ underlying profile on comorbid factors that might amplify NSF risk, including diabetes and hypertension. Thus, synthesizing the existing evidence about the safety profile of newer, and presumably more stable, GBCAs across the spectrum of kidney function will inform clinical policies. Evidence-based benefits and risks of contrasted MRIs across different patient populations can be weighed in order to limit excess risks for NSF relative to the general population, while not inadvertently restricting the use of GBCAs in patients who would otherwise benefit from them.

Table 1

FDA-Approved Gadolinium Agents^,.

The current review was completed at the request of the Veterans Affairs (VA) Nephrology Field Advisory Committee, which provides independent advice on clinical policy and programming to the VA Office of Specialty Care Services and the National VA Renal program. Due to uncertainty about the safety of certain GBCAs, the current use of gadolinium is restricted in Veterans with advanced kidney disease. These restrictions limit access to high-quality MRI for the diagnosis and management of numerous and potentially life-threatening diseases. The goal of this report is to provide a systematic review of the existing evidence on the risk of NSF with use of newer GBCAs, specifically American College of Radiology (ACR) group II and III agents,⁹ to inform the their use within the VA.