Use of GBCA in MRIs for High-Risk Patients

To the Editor:

We read with interest the case report of nephrogenic systemic fibrosis (NSF) by Chuang, Kaneshiro, and Betancourt in the June 2018 issue of Federal Practitioner.¹ It was reported that a 61-year-old Hispanic male patient with a history of IV heroin abuse with end-stage renal disease (ESRD) secondary to membranous glomerulonephritis on hemodialysis and chronic hepatitis C infection received 15 mL gadoversetamide, a linear gadolinium-based contrast agent (GBCA) during magnetic resonance imaging (MRI) of the brain. Hemodialysis was performed 18 hours after the contrast administration.

Eight weeks after his initial presentation, the patient developed pyoderma gangrenosum on his right forearm, which was treated with high-dose steroids. He then developed thickening and induration of his bilateral forearm skin with peau d’orange appearance. NSF was confirmed by a skin biopsy. The patient developed contractures of his upper and lower extremities and was finally wheelchair bound.

This case is very concerning since no NSF cases in patients receiving GBCA have been published since 2009. Unfortunately, the authors give no information on the occurrence of this particular case. Thus, it is unclear whether this case was observed before or after the switch to macrocyclic agents in patients with reduced renal function. The reported patient with ESRD was on hemodialysis and received 15 mL gadoversetamide during MRI of the brain. In 2007 the ESUR (European Society of Urogenital Radiology) published guidelines indicating linear GBCA (gadodiamide, gadoversetamide, gadopentetate dimeglumine) as high-risk agents that may not be used in patients with eGFR < 30 mL/min/1.73 m².^2,3

Consequently in 2007, the European Medicines Agency contraindicated these linear GBCA in patients with chronic kidney disease grades 4 and 5. Also in 2007 the US Food and Drug Administration (FDA) requested a revision of the prescribing information for all 5 GBCA approved in the US.⁴ In response to accumulating more informative data, in 2010 the FDA again used this class labeling approach to more explicitly describe differences in NSF risks among the agents.⁴ FDA regulation and contraindication of the use of low-stability GBCA in patients with advanced renal impairment and robust local policies on the safe use of these agents have resulted in marked reduction in the prevalence of NSF in the US. This case report needs to clarify why a high-risk linear agent was administered to a patient with ESRD.

In 2006 Grobner and Marckmann and colleagues reported their observations of a previously unrecognized link between exposure to gadodiamide and the development of NSF.^5,6 It soon became clear that NSF is a delayed adverse contrast reaction that may cause severe disability and even death. Advanced renal disease and high-risk linear GBCA are the main factors in the pathogenesis of NSF. Additionally, the dose of the agent may play a role. NSF can occur from hours to years after exposure to GBCA. Not all patients with severe kidney disease exposed to high-risk agents developed NSF. Thus, additional factors were proposed to play a role in the pathogenesis of NSF. Among those factors were erythropoietin, metabolic acidosis, anion gap, iron, increased phosphate, zinc loss, proinflammatory conditions/inflammation and angiotensin-converting enzyme (ACE) inhibitors.⁷ Although there is little proof with these assumptions, special care must be taken as shown by this reported patient with multiple inflammatory disorders.

- Gertraud Heinz, MD, MBA; Aart van der Molen, MD; and Giles Roditi, MD; on behalf of the ESUR Contrast Media Safety Committee

Author affiliations: Gertraud Heinz is former President ESUR and Head of the Department of Radiology, Diagnostics and Intervention University Hospital St. Pölten Karl Landsteiner University of Health Sciences.

Correspondence: Gertraud Heinz (gertraud.heinz@stpoelten .lknoe.at)

Disclosures: The authors report no conflict of interest with regard to this article.

References
1. Chuang K, Kaneshiro C, Betancourt J. Nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders. Fed Pract. 2018;35(6):40-43.
2. Thomsen HS; European Society of Urogenital Radiology (ESUR). ESUR guideline: gadolinium based contrast media and nephrogenic systemic fibrosis. Eur Radiol. 2007;17(10):2692-2696.
3. Thomsen HS, Morcos SK, Almén T, et al; ESUR Contrast Medium Safety Committee. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Media Safety Committee guidelines. Eur Radiol. 2013;23(2):307-318
4. Yang L, Krefting I, Gorovets A, et al. Nephrogenic systemic fibrosis and class labeling of gadolinium-based agents by the Food and Drug Administration. Radiology. 2012;265(1):248-253.
5. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108.
6. Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17(9):2359-2362.
7. Thomsen HS, Bennett CL. Six years after. Acta Radiol. 2012;53(8):827-829.