Ferumoxytol-enhanced magnetic resonance angiography for the assessment of potential kidney transplant recipients

We applied an MRA technique using intravenous iron as ferumoxytol to assess vessel characteristics, patency and course in a series of patients with severely impaired renal function or on dialysis whilst planning renal transplantation. Study participants underwent FeMRA as part of their clinical care instead of or in addition to standard imaging tests. We administered a total of 4 mg/kg of diluted ferumoxytol in divided infusions and achieved good signal intensity and image quality with absence of any adverse events. The information gained from synchronous depiction of arterial and venous compartments using a single investigation is essential when planning kidney transplantation. In a subgroup of patients who had both FeMRA and CTA performed, FeMRA was not limited by calcification in assessing the arterial lumen and it was better for venous evaluation compared to CTA.

Vascular disease is almost universal in potential kidney transplant recipients, the evaluation of which is important in planning transplantation. Doppler US is often not appropriate for evaluation of the deep vessels of the abdomen and pelvis and calcification further interferes with US assessment of the arterial vasculature. CTA of the aorto-iliac vasculature has been shown to allow better recipient selection and accurate planning for the arterial anastomosis [7], but is limited by calcification and also does not robustly evaluate venous anatomy. This latter limitation is of particular importance as frequently indwelling femoral vein catheters will have been employed and may have resulted in venous stenosis. MRI is limited by the concerns around potential development of NSF when high-risk linear chelate GBCAs are used. Practitioners are advised against the use of all linear GBCAs in patients with acute kidney injury or CKD with an eGFR <30 ml/min/1.73 m². On the other hand, although NSF seems not to be a risk with more stable gadolinium agents such as the cyclic chelates, residual concerns have constrained use. Lastly, conventional invasive angiography is usually reserved for use in the setting of possible endovascular intervention or targeted angiography when lower volumes of iodine-based contrast medium can be used in patients with CKD.

The risks of post-contrast acute kidney injury (AKI) have been questioned in recent publications [8, 9], although this remains controversial. Notably, in a series of similar design retrospective studies, McDonald and colleagues examined the rate of AKI in the 24–72 h after intravenous contrast-enhanced CT or non-contrast-enhanced CT imaging [10‐13]. Although diminished eGFR was associated with an increased risk of AKI and patients who developed AKI had higher rates of dialysis and mortality, the occurrence of these outcomes did not differ significantly between the contrast and non-contrast group in these studies. Nevertheless, these studies should be interpreted with caution as despite matching, in a retrospective study there may have been bias present in selection of the controls, which may erroneously underestimate or even obscure the real effects of contrast medium. Because of its large molecular weight of approximately 750 kD, ferumoxytol is not filtered by the glomerulus, but rather is removed from the circulation via phagocytosis by macrophages, and subsequently broken down. Following macrophage breakdown, the remaining iron oxide particles are taken up by the reticuloendothelial system, in particular the liver, spleen and bone marrow. The distribution of USPIO and conventional GBCAs is different, with the former remaining in the blood pool prior to largely redistributing to the reticuloendothelial system, whereas the latter distributes into the extracellular space after a relatively short time within the blood pool. With ferumoxytol, arteries and veins can be selectively depicted in a single examination. Additionally, the prolonged intravascular half-life (>14 h) of ferumoxytol allows for a longer time window for data acquisition, higher spatial resolution during the equilibrium phase and repeat imaging, if necessary, with negligible loss of intravascular signal intensity [14‐16]. On the downside, the agent can be present in the blood pool for weeks following administration and months in the reticuloendothelial system, potentially complicating the appearance of follow-up studies [17]. A previously described susceptibility artefact mimicking vascular thrombosis [18] related to higher concentrations of ferumoxytol was not observed in our study. In that study the authors used imaging sequences primarily intended for parenchymal evaluation rather than MR angiography, higher concentrations of ferumoxytol (up to 0.43 vs. 0.2 ml/ml total volume), longer echo times (1.8 vs. 1.0 ms) and slower infusion rates (2 vs. 1 ml/s), all potentially associated with susceptibility artefact.

Ferumoxytol has a good safety profile and no known long-term toxicity [19]. Adverse events with regard to cardiovascular, infectious and mortality outcomes have been shown to be similar compared with the more commonly used intravenous iron formulations (iron sucrose and ferric gluconate) [20]. Although the reported incidence of adverse reactions is higher with ferumoxytol than with GBCAs, the rates of these in clinical trials and post-marketing safety data on therapeutic use of ferumoxytol are very low [5, 21‐23]. Most reported adverse events were mild, transient and typically associated with the infusion process, although mild arthralgia/myalgia and headaches occurred up to 48 h post-infusion in one study [23], where 1.02 g of ferumoxytol was administered over 15 min. Serious adverse events included hypersensitivity [22, 24] and hypotension [24] with a pooled aggregate rate of anaphylaxis of 0.03% (3/10,425) based on published studies [5, 21, 22, 24]. The main concern has been reported cases of anaphylactic-type reactions with therapeutic bolus injections of undiluted compound leading to the recent recommendations for controlled infusion of dilute ferumoxytol. Rather than true allergy it is thought this is a chemotoxic phenomenon related to high concentrations of the iron compound when infused rapidly interacting with mast cells in the vascular wall [25]. Since 2009, approximately 1.2 million therapeutic doses of ferumoxytol have been administered. In March 2015, the US Food and Drug Administration (FDA) Adverse Event Reporting System reported 79 anaphylactic reactions, of which 18 were fatal. These deaths resulted in a boxed warning in March 2015 (http://​www.​fda.​gov/​Drugs/​DrugSafety/​ucm440138.​htm). Twenty-four percent of these patients had multiple drug allergies, and nearly half of these anaphylactic reactions occurred within 5 min of administration. This rate of adverse events is lower than the rates initially reported in Phase II–III clinical trials. When given for treatment of IDA, the licensed dose of ferumoxytol is an initial 510-mg dose administered as an intravenous infusion, followed by a second 510-mg dose 3–8 days later. We used only a fraction of the therapeutic dose (approximately a quarter of the full dose for a 70-kg adult), much-diluted and slowly infused (in 5-min intervals between pulsed infusions) to minimise the risk of reaction, and this was proven more than adequate for vascular imaging. It is important to note that the above risks have parity with the other commonly administered intravenous radiological contrast media (whether iodine or gadolinium-based), therefore patients were not exposed to disproportionate risk. Hence, ferumoxytol has the potential to be used for clinical vascular imaging beyond investigational use in patients with contraindications to GBCAs, such as renal failure and known GBCAs allergies.

Dose-related efficacy studies are lacking, hence different doses have been reported in the literature, ranging from 120 mg of elemental iron in a bolus solution for angiographic assessment of arteriovenous fistulae [26] to 6 mg/kg for kidney mapping [27]. We used a comprehensive protocol administering a total of 4 mg/kg of ferumoxytol diluted fourfold with normal saline and delivered in four equally divided infusions over a minimum of 20 min and we observed no significant blunting in signal intensity.

Others have studied MRA using ferumoxytol as contrast in patients with kidney disease. Sigovan et al. [26] found that FeMRA provided better image quality and reduced flow artefacts compared to non-contrast MRA in dialysis fistula evaluation, with a much shorter acquisition time (19 vs. 270 s). FeMRA has been used in kidney transplant recipients with graft dysfunction, where steady-state imaging was better for evaluation of transplant vasculature compared to first-pass imaging [28] and better for detection of graft artery abnormalities compared to US [29]. When compared with digital subtraction angiography (DSA), FeMRA was similarly sensitive and accurate in assessing the severity of transplant renal artery stenosis [30]. In a comparative study of ferumoxytol-enhanced versus gadofosveset-enhanced MR venography for abdominopelvic and lower extremity venous assessment, there was no difference in signal intensity between the two techniques [31]. In two paediatric cohorts of 30 children with CKD who needed detailed vascular mapping for various indications (i.e. vascular access planning or complication, pre- or post-kidney transplant evaluation), FeMRA examinations were reported to be diagnostic and safe [32, 33]. Apart from vascular imaging, ferumoxytol-based imaging has been successfully used for the delineation of primary pancreatic tumours [34] and as an ionising radiation-free staging method in children and young adults with malignant lymphomas and sarcomas [35]. In our study, ferumoxytol-enhancing complex renal cysts were detected in two patients; both proved to be renal cell carcinomas.

The main limitations of this study are the single-centre design with a relatively small number of patients and lack of consistent reference standard. However, the purpose of this study was to address the technical feasibility of acquiring adequate abdominal and aorto-iliac vascular enhancement with a non-nephrotoxic, high relaxivity contrast agent in patients before wait-listing for kidney transplantation. Four patients had both CTA and FeMRA performed and although some comparisons were made, the study was not designed to estimate accuracy, sensitivity and specificity of the two different imaging techniques. A formal prospective study directly comparing the diagnostic accuracy of FeMRA versus CTA is currently recruiting in our centre (Clinicaltrials.gov identifier: NCT02997046).

High concentrations of the agent can cause artefacts because of signal loss through T2* shortening, and care must be taken to inject a low enough concentration to avoid this pitfall. Therefore, we used small cumulative increments of ferumoxytol but in this preliminary report on 20 subjects the number of patients was not large enough to establish the definitive optimal (minimum) dose required to achieve adequate diagnostic accuracy. However, our preliminary findings indicate that the administration of doses >3 mg/kg does not improve image quality (unpublished data). Despite being a case series, sequential enrolment minimised selection bias. In addition, differences in exposure to ferumoxytol were minimised by the use of a consistent protocol with standardised infusion rates and imaging parameters. Using a consistent dosing regimen for contrast administration, we have shown that ferumoxytol-based vascular imaging has the potential to offer a clinically useful and reliable alternative in renal patients in whom standard imaging methods cannot be used.