Nephrogenic systemic fibrosis (NSF)
The risk of developing NSF with Gd, particularly in patients with severe AKI and CKD, is reviewed in detail in Appendix E. It should be noted here that the European Medicines Agency stated a contraindication for use of gadodiamide in patients with a GFR < 30 ml/min per 1.73m2, and issued a warning for its use in patients who have a GFR between 30 and 60 ml/min per 1.73 m2 (EMEA Public assessment report. http://www.esur.org/fileadmin/NSF/Public_Assessment_Report_NSF_Gadolinium_26_June_2007.pdf; last accessed January 5, 2012). The US FDA requested that vendors add warnings about the risk for developing NSF to the full prescribing information on the packaging for all Gd-containing contrast agents (gadopentetate dimeglumine, gadodiamide, gadoversetamide, gadoteridol, gadobenate dimeglumine).427 New labeling describes the risk for NSF following exposure to Gd in patients with a GFR < 30 ml/min per 1.73 m2 and in patients with AKI of any severity due to hepato-renal syndrome or in the perioperative liver transplantation period. Additional recommendations were recently proposed by Perazella420 and were endorsed by the Work Group:
- (a)
Use of a macrocyclic chelate (gadoteridol in the USA), is preferred over linear chelates. The risk associated with the various Gd-containing agents is likely different. Gadodiamide, the linear nonionic chelate–- based formulation, maintains the highest risk on the basis of epidemiologic data and animal studies. Gadopentetate, the linear ionic chelate–based product probably has a medium risk, less than the linear nonionic chelates but more than the macrocyclic chelates. Gadoteridol, the only FDA-approved macrocyclic chelate, maintains less risk. Clearly, high dosages and large cumulative dosages of all these agents will increase risk for NSF.
- (b)
Demonstration of significant quantities of insoluble Gd in the skin of NSF patients, months after exposure to Gd-based contrast material and after extensive tissue processing, suggests that Gd might have undergone transmetallation in vivo. Supporting the importance of transmetallation, all NSF cases reported before 2009 have been associated with linear MRI contrast agents (for a review, see Kay428) that have inferior thermodynamic stability and a kinetic or conditional stability that favors transmetallation. However, a recent case of NSF in a dialysis patient after exposure to a macrocyclic chelate has been described,429 and at least two additional cases are known.430
- (c)
Use the lowest dosage of the agent possible to achieve the image.
- (d)
Avoid repeat exposures with Gd.
- (e)
Consider performing IHD after the exposure (and the next 2 days) in patients who are already maintained on IHD, recognizing that there are no data that support prevention of NSF with this modality. This recommendation is based on the pharmacokinetics of Gd and the theoretical benefit of removing it with IHD ( > 95% plasma clearance). PD clears these agents rather poorly.