A commonly used system to classify MR contrast agents is by the contrast generating moiety. Clinically approved currently used contrast agents contain either iron (Fe3+) or gadolinium (Gd3+). Iron-based contrast agents are divided in the categories of superparamagnetic iron oxide agents (SPIO; diameter typically around 150 nm) or ultra-small superparamagnetic iron oxide particles (USPIO; diameter less than 50 nm). Iron oxide agents are true 'blood pool' or 'intravascular' agents due to their slow clearance from the blood (hours to days). Gadolinium-based agents on the other hand are cleared much quicker from the blood (seconds to minutes) and are commonly characterized as either a) extracellular, b) intravascular, and c) 'specific' contrast agents. An overview of this classification is given in figure 1.

In clinical practice two agents are used:

1) Gadofosveset trisodium (Ablavar, Lantheus, Billerica, MA). This a gadolinium based contrast agent of intermediate stability that reversibly binds to albumin. The binding fraction is around 85%, and the intravascular half-life is approximately 25-30 minutes. The r1 relaxivity of this FDA-approved MR contrast agent at body temperature in blood plasma is 23 mM-1s-1 (1).

2) Ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA). This is a superparamagnetic iron oxide coated with polyglucose sorbitol carboxymethylether. The r1 relaxivity of ferumoxytol is 15 mM-1s-1 (2).

It is important note that:

a) Ferumoxytol is not an FDA approved MR contrast agent; it is a drug used for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). Thus, its use in imaging remains off-label and investigational.

b) The U.S. Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal allergic reactions can occur when ferumoxytol is injected. The FDA has changed the prescribing instructions and approved a Boxed Warning, FDA’s strongest type of warning, regarding these serious risks (3). Also added is a new Contraindication, a strong recommendation against use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.

The much higher relaxivity of intravascular agents yields several possibilities for improvement of MR angiography:

1) it is possible to get a similar signal-to-noise ratio at lower contrast agent dose, or conversely,

2) it is possible to obtain higher spatial and/or temporal resolution images with similar signal-to-noise ratio (using for instance highly accelerated sequences), and

3) it is possible to extend the imaging window greatly compared to extracellular contrast agents which have an intravascular half-life of approximately 90 seconds (figure 2).

The use of intravascular contrast agents can be advantageous in a number of clinical scenarios whenever higher relaxivity or a prolonged intravascular residence time is desired, or when use of a non-gadolinium containing contrast agent is desired, such as in patient with impaired renal function.

Clinical applications include - but are not limited to - the following:

1) ultrahigh spatial resolution imaging of the arterial system to improve the sensitivity and specificity of stenosis detection in small peripheral arteries such as the upper and lower extremities.

2) imaging of the venous system throughout the body.

3) imaging of the chest vasculature using ECG-synchronized and respiratory-compensated sequences. These sequences typically take much longer to acquire compared to traditional first-pass MR angiography.

4) MR lymphangiography.

5) use of ferumoxytol in patients with severely impaired renal function or known allergies to gadolinium-based contast agents.

In the presentation clinical examples will be shown of all of these applications.

Gadofosveset is typically administered in lower doses compared to conventional extracellular contrast agents (0.025 mmol/kg versus 0.1 mmol/kg for a single-dose administration).

Ferumoxytol is packaged in a 17-mL vial containing 510 mg (concentration of 30 mg/mL). In a recent study patients typically received doses of ferumoxytol ranging from 1.25 to 2 mg/kg for studies of the aorta and doses of from 1 to 1.6 mg/kg for all other studies (4).

Readers are referred to either the ACR Manual on Contrast Media, Version 10 (5) or the European Society of Urogenital Radiology (ESUR) guidelines om Contrast Media, Version 9 (6) for further information on safety issues. These guidelines contain extensive details on the use of contrast agents in a variety of clinical conditions. The guidelines also contain recommendations with regard to the use of contrast agents in patients with impaired renal function. They provide a detailed discussion of which contrast agents may be used as a function of estimated GFR, and how often these agents can be administered without the risk for causing serious harm to patients with impaired renal function. It is important to note that guidelines are different for the USA and Europe.