MRI with Contrast (Gadolinium-Containing) Policy

The administration of intravenous gadolinium-containing contrast media was historically considered safe in patients with impaired renal function. This changed in 2006 when the FDA first reported the association between nephrogenic systemic fibrosis (NSF) and intravenous gadolinium administration. This rare but serious systemic disease is characterized by fibrosis of the skin and other tissues throughout the body. NSF is generally seen in the middle-aged, but has also been reported in the elderly and in children.

The exact etiology of NSF is unclear but most reported cases have been documented in patients with severe acute or chronic renal failure, with a glomerular filtration rate (GFR) < 30. Only two cases of NSF have been reported in patients with a GFR > 30¹. In 2009, the FDA determined that moderate renal impairment (eGFR of 30-60) was NOT a risk factor for NSF, reversing the position it had taken in December 2006, and stated² “The December information was based upon reports of NSF among patients with purportedly moderate renal insufficiency.  Since issuing the information in December 2006, FDA has received new information regarding these patients.  Additional details have clarified that the patients actually were in acute renal failure at the time they received a gadolinium based contrast agent. Considering this clarification, FDA has not received reports of NSF among patients with normal renal function or moderate renal insufficiency”.

Many of the reported cases of NSF have been in patients before or after liver transplant. Other comorbidities have been described in patients who developed NSF, including acute pro-inflammatory states, metabolic acidosis, increased iron, calcium or phosphate levels, immunosuppression, vasculopathy, high dose erythropoietin therapy and infection³. Many published series have suggested an increased risk of NSF development in patients exposed to high doses and multiple doses of gadolinium, however cases with single doses (0.1 mmol/kg) have also been reported. One meta-analysis including the seven large series of patients with NSF reported an odds ratio of 26.7 (95% CI = 10.3-69.4) for development of NSF after gadolinium administration in patients with impaired renal function (GFR < 30)⁴. The incidence of NSF in patients with severe renal dysfunction (GFR < 30) varies from 0.19 to 4%^5-7. As of October 2007, of the 431 of the cases reported from the FDA Freedom of Information system to the authors of a review paper in the topic, 283 were associated with Omniscan, 125 were associated with Magnevist, 20 were associated with Opti-MARK, 9 were associated with ProHance (8 of which were also exposed to other agents), and 10 were associated with MultiHance (8 of which were also exposed to other agents)⁸. A recent publication from a single institution has recently demonstrated a positive impact of screening for NSF risk factors prior to administration of gadolinium. After guidelines based on ACR/FDA recommendations where applied, the incidence of the disease fell from 36.5/100,000 patients to 4/100,000 patients⁹. Importantly, there have been no reported cases of NSF in the literature since 2009 with broader community use of macrocyclic GBCAs.

Recent data suggests that the risk of NSF is linked to the gadolinium binding strength of the chelates that form GBCAs, with most cases associated with weaker, linear chelates. As stated in the 2017 ACR guidelines: “It is now known that there are differences in the likelihood of a patient developing NSF after exposure to different formulations of GBCAs. Almost all unconfounded cases have been reported after exposure to gadodiamide [Omniscan], gadopentetate dimeglumine [Magnevist], and/or gadoversetamide [OptiMARK], while some GBCAs have been associated with few, if any, confirmed unconfounded cases of NSF. If the prevailing hypothesis is true—that the development of NSF is related to the release of gadolinium from the chelates that constitute GBCAs—the differences in number of reported cases may, in part, be explained by differences in the chemical properties of different GBCAs.” Stable macrocyclic agents such as Gadoterate acid (Dotarem®) and Gadobutrol (Gadavist®) are thought to minimize the risk of NSF.

Key points: Nephrogenic systemic fibrosis (NSF) is associated with the administration of intravenous GBCAs, particularly those with relatively weak gadolinium binding. The primary risk factor is acute or chronic renal failure (especially dialysis dependence and/or estimated GFR < 30). The theoretical risk of NSF with macrocyclic (group II) contrast agents is extremely low.

1. ACR Manual on Contrast Media Version 10.3, 2017. ACR Committee on Drugs and Contrast Media.
2. Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007; 243:148-157.
3. FDA Drug Safety Newsletter. Updated 8/13/2009.
4. ACR Manual on Contrast Media Version 7, 2010. ACR Committee on Drugs and Contrast Media.
5. Agarwal R, Brunelli SM, Williams K, Mitchell MD, Feldman HI, Umscheid CA. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis. Nephrol Dial Transplant 2009;24: 856-863.
6. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol 2007;188: 586-592.
7. Hope TA, Herfkens RJ, Denianke KS, Leboit PE, Hung YY, Weil E. Nephrogenic Systemic Fibrosis in Patients With Chronic Kidney Disease Who Received Gadopentetate Dimeglumine. Invest Radiol 2009.
8. Shabana WM, Cohan RH, Ellis JH, et al. Nephrogenic systemic fibrosis: a report of 29 cases. AJR Am J Roentgenol 2008;190:736-741.
9. Penfield JG, Reilly RF. Nephrogenic systemic fibrosis risk: is there a difference between gadolinium-based contrast agents? Semin Dial 2008; 21:129-134.
10. Perez-Rodriguez J, Lai S, Ehst BD, Fine DM, Bluemke DA. Nephrogenic systemic fibrosis: incidence, associations, and effect of risk factor assessment--report of 33 cases. Radiology 2009;250: 371-377.

The ACR recognizes three categories of GCBAs with respect to risk of NSF.¹ These are listed below (for simplicity, only agents approved for use in the United States by the FDA are included):

Group I agents are no longer used at UCSF. Group II agents are thought to have “very low, if any, risk of NSF development” per the latest ACR guidelines.¹ Based on this and our departmental experience, we use the group II agent Gadobutrol (Gadavist) as our routine gadolinium containing contrast medium.

Key point: Gadobutrol (Gadavist®) is the standard gadolinium containing contrast medium used at UCSF for all patients, including those that are deemed high risk for nephrogenic systemic fibrosis.

1. ACR Manual on Contrast Media Version 10.3, 2017. ACR Committee on Drugs and Contrast Media.
2. FDA Drug Safety Newsletter. Updated 8/13/2009.
3. FDA Drug Safety Newsletter, 9/13/2010. Available at https://www.fda.gov/Drugs/DrugSafety/ucm223966.htm

The relative risk to benefit of intravenous gadolinium in patients with severely impaired kidney function should be carefully considered by the referring physician and radiologist, with input from a nephrologist if necessary. Particular caution should be considered in patients with acute renal failure or evidence of co-existing severe liver disease. No patient should be denied any imaging investigation that is critical to clinical management.

No informed consent is required for outpatient administration of group II agents, regardless of eGFR. As stated by the ACR: “Given the very low, if any, risk of NSF development with group II agents, regardless of renal function or dialysis status, informed consent is not recommended prior to GBCA group II injection . . .” If there is known renal failure with an eGFR < 30 in an inpatient, a radiologist must confirm the need for GBCAs before proceeding with MRI. There is no contraindication to the use of multiple doses of GBCAs in a short time-period if deemed necessary for clinical management, although group II agents are strongly recommended in patients at risk for NSF.

If no alternative imaging technique is possible in a patient with an eGFR < 30, and a contrast enhanced MRI with a group III agent is considered critical to patient care, informed consent should be obtained by the attending radiologist using the green surgical procedure form (number 862-001Z).  

Key point: Gadolinium should only be given to an inpatient with GFR < 30 if MRI if contrast is considered necessary for clinical management

1. ACR Manual on Contrast Media Version 10.3, 2017. ACR Committee on Drugs and Contrast Media.

The risk of NSF is extremely low when group II agents are used in the setting of dialysis.¹ Dialysis after GBCA administration, however, does not protect patients from developing NSF.² Studies have shown that the serum concentration of gadolinium is significantly decreased after hemodialysis, but there is no information regarding residual tissue amounts.² Theoretically, the sooner the dialysis session is performed the less amount of contrast agent is deposited in the tissues. Therefore, all patients already receiving dialysis treatment should be scheduled for hemodialysis as soon as practical following the gadolinium-enhanced MRI and preferably within 24 hours. Patients receiving peritoneal dialysis do not need to be switched to hemodialysis.

This should be arranged by the requesting physician in consultation with the patient’s outpatient nephrologist and dialysis unit. Routine MRI studies should be scheduled in the morning and dialysis scheduled in the afternoon following the study; radiology scheduling staff will give morning slot priority to dialysis patients. Administration of dialysis promptly after gadolinium may require altering the patient’s regular outpatient dialysis schedule and advance communication several days in advance with the nephrologist and dialysis unit. There is general consensus that a patient with chronic kidney disease who is not already dialysis dependent should not be started on dialysis after administration of gadolinium for precautionary purposes only, since there is no data to support the benefits of this intervention.

Key point: Dialysis should preferably be performed within 24 hours of gadolinium administration to patients already on dialysis. The institution of dialysis is not required in patients with severe renal impairment who are not already on dialysis after gadolinium administration.

1. ACR Manual on Contrast Media Version 10.3, 2017. ACR Committee on Drugs and Contrast Media.
2. Broome DR, Cottrell AC, Kanal E. Response to "Will dialysis prevent the development of nephrogenic systemic fibrosis after gadolinium-based contrast administration?" AJR Am J Roentgenol 2007;189: W234-235.
3. Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998; 5: 491-502.

Group II Agents

For Group II agents (e.g. Gadavist®), screening for renal failure and laboratory testing of eGFR will no longer be routinely performed for outpatients. This reflects recent data and the latest ACR Manual on Contrast Media (version 10.3), which states that “the risk of NSF among patients exposed to standard or lower than standard doses of group II gadolinium-based contrast agents is sufficiently low or possibly nonexistent such that assessment of renal function with a questionnaire or laboratory testing is optional prior to intravenous administration.”

Group I and Group III Agents

Group I agents are no longer used at UCSF. For group III agents (e.g., Eovist®), laboratory results should be checked for the most recent serum creatinine (by the technologist performing the study). For patients with the following risk factors, serum creatinine with calculation of eGFR should be performed within 6 weeks of the MRI study:

Estimated Glomerular Filtration Rate (eGFR) is calculated using the serum creatinine. In those patients who have known CKD or other risk factors for CIN as noted above, the referring provider should place a new order for serum creatinine at the time the examination is ordered if the most recent creatinine will be greater than 6 weeks old on the date of the examination. Other patients will have point-of-care creatinine values drawn at the time of the examination using the i-STAT® system.

For consistency, eGFR calculation should be performed with the CKD-EPI equation, which is reported on APeX. See reference: https://www.kidney.org/content/ckd-epi-creatinine-equation-2009)

Note that eGFR of 30 is the single threshold in the latest ACR guidelines with specific recommendations for GBCA administration.¹ For eGFR 30-59, the ACR advises “No special precautions are necessary in this group.” For eGFR 60-119, “Any GBCA can be administered safely to these patients.”

*If no alternative imaging technique is possible and an enhanced MRI with a group III agent is considered critical to patient care, informed consent should be obtained by an attending radiologist using the green surgical procedure form (number 862-001Z). Annotation must be made in Radiant by the radiologist obtaining consent. The informed consent should also be documented in the dictated report.

1. ACR Manual on Contrast Media Version 10.3, 2017. ACR Committee on Drugs and Contrast Media.
2. Kidney International Supplements (2012) 2, 19–36; doi:10.1038/kisup.2011.32.

According to the National Kidney Disease Education Program, the best equation for estimating glomerular filtration rate (GFR) from serum creatinine in children is the Bedside Isotope Dilution Mass Spectrometry (IDMS)-traceable Schwartz equation:

https://www.niddk.nih.gov/health-information/communication-programs/nkdep​

Bedside IDMS-traceable Schwartz Equation for Children
GFR (mL/min/1.73 m2) = (0.41 x Height in cm) / Creatinine in mg/dL)

Excerpt from the ACR Manual on contrast media¹: “Radiologists commonly use contrast media for clinical purpose not contained in the labeling, i.e. off label use. By definition such usage is not FDA approved and the legal ramifications are unclear. Physicians have some latitude in using gadolinium chelates off label as guided by clinical circumstances but must be prepared to justify such usage in individual cases e.g. MR angiography, cardiac applications and pediatric applications in patients younger than 2 years. No gadolinium chelate is approved in the United States for use in a power injector.” Although gadolinium administration via a power injector is a commonly accepted practice, it is technically an off-label use of the power injector.

1. ACR Manual on Contrast Media Version 7, 2010. ACR Committee on Drugs and Contrast Media. 

Deposition of gadolinium in the brain has been increasingly reported in recent years. First described by Kanda et al. in 2014, high signal in the dentate nucleus and globus pallidus after prior gadolinium administration has now been documented in over 20 studies. The clinical significance of this brain deposition, however, is unknown.

Brain deposition is related to the strength of gadolinium binding by different gadolinium compounds. Less stable compounds (linear agents) are more strongly linked to brain deposition than more stable compounds (macrocyclic agents). Because of this, the stable macrocyclic agent Gadavist (Gadobutrol) is the preferred agent at UCSF. For certain specialized liver imaging applications, a second agent called Eovist (Gadoxetate) is used. Although not a macrocyclic agent like Gadavist, Eovist has unique properties that are sometimes required when imaging the liver.

Gadolinium as an MRI contrast agent should only be used when diagnostically necessary. When it is indicated, we believe that the clear benefits of gadolinium for imaging outweigh the unknown risks of brain deposition, which we have minimized with our use of a stable agent (Gadavist) that has resulted in few, if any, clear cases of brain deposition.

1. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body#:~:text=This%20is%20an%20update%20to,issued%20on%20May%2022%2C%202017
2. Kanda T et al. High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material. Radiology 2014; 270:834-841.
3. Olchowy C et al. The presence of the gadolinium-based contrast agent depositions in the brain and symptoms of gadolinium neurotoxicity – A systematic review. PLoS One. 2017 Feb 10;12(2):e0171704.