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Management Brief No. 164

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Management eBriefs
Issue 164 December 2019

The report is a product of the VA/HSR Evidence Synthesis Program.

Risk of Nephrogenic Systemic Fibrosis after Exposure to Newer Gadolinium Agents

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. Over the last decade, the incidence of NSF dropped off dramatically after institution of formal restrictions that limit the use of older linear GBCAs, particularly in patients with advanced kidney disease who are at greatest risk for NSF. However, with the recent advent of newer and seemingly safer GBCAs, patients with chronic kidney disease (CKD) and their providers need contemporary evidence to guide shared decision-making about the use of the newer GBCA classes when MRIs are clinically warranted.

The MRI has become an essential tool in the diagnosis and management of a myriad of medical conditions, with 118 MRIs per 1,000 people conducted annually in the United States. Gadolinium is a heavy metal with paramagnetic properties that make it an optimal candidate for use as an MRI contrast agent. However, it is toxic in its free form and must be stabilized (e.g., by bonding) for human use. Newer GBCAs impart greater stability and are thought to be associated with lower, or potentially minimal, NSF risk.

The main objective of this systematic review was to assess the evidence on the risk of nephrogenic systemic fibrosis with use of newer GBCAs. A specific focus of the review was on American College of Radiology (ACR) group II and III agents, to inform the development of VA guidelines on their use. The secondary objective of the review was to identify the occurrence of NSF within specific subpopulations: all patients regardless of kidney function status; patients with CKD risk factors such as hypertension and diabetes; and patients with any degree of kidney disease. Investigators with VA’s Evidence-based Synthesis Program (ESP) Coordinating Center in Durham, NC searched MEDLINE® (via PubMed®), Embase, Cochrane Central Register of Controlled Trials, and Web of Science from inception through January 7, 2019 for relevant publications. After reviewing 1,150 citations, 314 were given a full-text review. Of these, 28 studies were retained for data abstraction, including 26 cohort studies (10 prospective and 16 retrospective), 1 case control study, and 1 non-randomized trial. Included studies were conducted across six continents, with most taking place in North America, Europe, and Asia.


Across all included studies, there were very few reports of cases of NSF after index exposures to newer gadolinium-based contrast agents (ACR group II and III agents). Moreover, there were uncertainties regarding most of the reported cases of NSF because they occurred in patients who also had been exposed to other—often older—GBCAs around the same time. Across the 12 included studies (188,819 patients) that examined patients exposed to ACR group II and patients exposed to ACR group I GBCA, 41 patients were found to have NSF. All but four of these 41 cases had some reported exposure to ACR group I agents (index or otherwise).  Of these four cases with exposure only to ACR group II GBCAs, three also had exposure to an unspecified GBCA. The degree of renal impairment was not clear across these four cases, but all had CKD of some stage.

Overall, most exposures occurred in patients with normal renal function. Investigators did not find any studies that assessed NSF risk in patients with key risk factors for CKD, such as diabetes and hypertension. Further, although several studies included individuals on dialysis, very few adequately provided information regarding acute kidney injury, yet it is a known NSF risk factor from prior studies.


This report is limited by the quality of the existing literature. Overall, the risk of bias for included studies was high or unclear primarily due to a few common issues, such as ethical barriers that prevented conduct of randomized controlled trials. Furthermore, assessment of gadolinium exposure was often incomplete due to lack of robust query regarding GBCA exposures outside of the healthcare setting from which the studies recruited patients.


Because the currently recognized major determining factors in the pathophysiology of nephrogenic systemic fibrosis are biological in nature, the results in this report are presumed to be readily applicable to the VA population. However, generally, investigators found little data to inform the care of patients who are at risk for developing CKD or those with acute kidney injury (AKI).

Future Research

Additional research on NSF should focus on patients who have known risk factors for CKD and AKI. To facilitate consistent and comparative findings across studies, future research should use standardized categorizations of CKD stages and diagnostic criteria for NSF. Inclusion of understudied GBCAs, such as gadoexetic acid (Eovist®) in future studies also would expand the evidence profile regarding GBCAs. Future studies of NSF occurrence after GBCA exposure should collect and report detailed exposure history at the individual level, including dose per scan and total cumulative dose per patient. GBCA use must be considered across healthcare systems to capture comprehensive exposure data. Large, comprehensive healthcare systems, like VA, are well-situated to conduct high-quality observational studies that could capture the majority or all GBCA exposures and cases of NSF. In particular, leveraging comprehensive electronic health record systems could support the examination of NSF risk among patients with risk factors for CKD – and those with AKI who have not been studied to date.

Goldstein KM, Lunyera J, Mohottige D, Amrhein TJ, Alexopoulos AS, Campbell H, Cameron CB, Sagalla N, Crowley MJ, Dietch JR, Gordon AM, Kosinski AS, Cantrell S, Williams JW Jr, Gierisch JM. Risk of Nephrogenic Systemic Fibrosis After Exposure to Newer Gadolinium Agents. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #09-010; 2019.

To view the full report, go to (Intranet only; copy and paste the URL into your browser if you have intranet access.)

ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.


This report is a product of VA/HSR&D's Evidence Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers –; and to disseminate these reports throughout VA.

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