Clinical Outcomes With Negative MRA Examinations
Of 16 MRA examinations, 13 were negative for findings related to the renal graft vasculature (representative example shown in Fig. 3). In one case, the patient had extensive contralateral iliofemoral venous thrombosis (which was observed on the MRA) and pulmonary thromboembolism, and expired later during that hospitalization from complications of pulmonary embolism. In a second case, the cause of graft dysfunction was determined to be transplant ureteral stricture with obstruction (which was demonstrated by the MRA examination), and the patient was treated with percutaneous nephrostomy. In a third case, transplant biopsy demonstrated acute on chronic rejection, and the patient eventually went on to receive a transplant nephrectomy.
In the 10 remaining cases with a negative MRA examination, an alternative cause of graft dysfunction was eventually found, including prerenal azotemia caused by other acute illnesses (pancreatitis, n=3; overdiuresis, n=2; urinary tract infection, n=2; and vomiting related to gastrointestinal illness, n=2) and postoperative hypotension from surgery not involving the transplant organ (n=1). In six of these cases, MRA was performed more than 3 months after allograft placement (and therefore, a posttransplant, pre-MRA baseline creatinine level had been established); clinical follow-up data were available over a mean (SD) of 9 (3) months (range, 6–12 months). Renal function stabilized to a mean (SD) serum creatinine level of 1.8 (0.2) mg/dL (range, 1.6–2.0 mg/dL) compared with mean (SD) baseline serum creatinine levels of 1.7 (0.1) mg/dL (range, 1.6–1.9 mg/dL) with supportive therapy/volume expansion (and antibiotics in two cases) and no direct intervention on the renal allografts. In the remaining four patients with negative MRA examinations, MRA was performed less than 3 weeks after allograft placement (on postoperative days 1, 2, 12, and 17 days, respectively), and so, a baseline posttransplantation pre-MRA creatinine was not considered to have been confidently established. All four of these patients also did well, with follow-up data available for a mean (SD) period of 5 (4) months (range, 1–9 months) and a mean (SD) serum creatinine level of 1.2 (0.2) mg/dL (range, 1.0–1.4 mg/dL) at the last follow-up.
This study demonstrates the novel use of ferumoxytol as an intravenous contrast agent for MRA assessment of transplant vascular patency. In our small study, three significant transplant vascular abnormalities were detected, which were not definitively diagnosed by ultrasonography and could not safely or effectively be assessed with other imaging modalities. Among these, two transplant artery stenoses were detected by MRA, and catheter-based treatment resulted in the improvement in transplant function. In the case of complete arterial occlusion and transplant infarction, the allograft was definitively determined to be unsalvageable by imaging. As a result, unnecessary catheter-based evaluation and surgical exploration were avoided. In those cases where MRA did not demonstrate a vascular abnormality, other causes of graft dysfunction or AKI were identified, and the MRA examinations successfully eliminated the need for additional vascular evaluations.
In both the immediate perioperative and during long-term postoperative periods, the initial evaluation of patients presenting with acute graft dysfunction often includes noninvasive imaging to exclude urinary obstruction and vascular compromise. This is typically performed by Doppler ultrasound, although these examinations can be difficult to interpret because of patient and technologist factors (4–6). Even under the best of technical circumstances, ultrasound results are often equivocal and inadequate to guide decisions to pursue percutaneous or surgical interventions. Imaging methods using contrast agents are attractive techniques for evaluating vascular patency. However, typical contrast agents are contraindicated in the transplantation population, particularly in the setting of AKI or CKD. Specifically, iodinated contrast agents used in CT carry the risk of contrast-induced nephropathy and worsening renal function, whereas gadolinium-based agents used in MRI are associated with nephrogenic systemic fibrosis, a debilitating and sometimes fatal disease involving fibrosis of the skin, musculoskeletal system, and visceral organs (7–10, 16, 17). Although renal transplant MRA using gadolinium-based contrast agents has been described extensively, this is contraindicated in the setting of AKI (18–21). Iron-based agents are not associated with nephrogenic systemic fibrosis and appear to have few, if any, significant deleterious adverse effects, although more recently, some concerns about hypersensitivity reactions have been raised (22).
Recently, ferumoxytol, an iron-containing medication, received approval from the Food and Drug Administration for the treatment of iron deficiency in patients with CKD (11, 17). As a contrast agent, ferumoxytol causes shortening of the T1 relaxation time of its microenvironment and, at certain concentrations, appears similarly to gadolinium-based agents on many MRI pulse sequences (13, 15, 23). In addition, Sigovan et al. (24) found that ferumoxytol-enhanced MRA provided better image quality and reduced flow artifacts compared with noncontrast MRA in dialysis fistula evaluation, with a much shorter acquisition time (19 vs. 270 s). Because little free iron is present in the ferumoxytol preparation, it can be injected rapidly without causing the reactions typical of other intravenous iron preparations. Our initial experience in renal transplant MRA with ferumoxytol has demonstrated excellent depiction of the transplant vasculature, consistent with or better than other imaging modalities or direct clinical/surgical observations. Ferumoxytol-enhanced MRA allows for direct anatomic assessment for vascular stenosis/occlusion, rather than an inferred assessment based on Doppler waveform and velocity criteria, which can be particularly unreliable in the setting of vessel tortuosity and aortoiliac atherosclerotic disease. Because ferumoxytol is an iron-based agent designed specifically for use in patients with advanced CKD, its safety profile in the transplantation population is excellent, although the reported rate of serious hypersensitivity reactions is somewhat higher (0.2%) than that associated with gadolinium-based agents such as gadoteridol (0.03%) (25, 26). In addition, the amount of ferumoxytol administered for MRA is small relative to the therapeutic dose (in this study, it ranged from 17% to 34% of our routine therapeutic dose).
Because of its large molecular weight of approximately 750 kD, ferumoxytol is not filtered in the glomeruli and behaves as a blood pool contrast agent, with a long intravascular half-life of 14 to 15 hr (13, 27, 28). This property allows for extended “vascular steady state” imaging sessions when needed to ensure high-image quality, an advantage which has been demonstrated with the gadolinium-based blood pool agent gadofosveset (29). By comparison, the low-molecular weight (non–blood pool) gadolinium-based agents traditionally used in MRA are eliminated rapidly by the kidneys, with a plasma half-life of 10 to 15 min in the presence of normal renal function (30). Leakage of these non–blood pool agents into the extravascular space also prevents high-quality steady-state imaging caused by increased background signal that may obscure major vascular structures (29). Ferumoxytol appears to provide an excellent combination of high-quality steady-state MRA properties without the potentially deleterious effects of gadolinium-based agents.
In this study, MRA was performed exclusively in patients with a nondiagnostic initial ultrasound examination. These 16 patients represent a small subset of those evaluated for graft dysfunction. During this time, 101 kidney transplantations were performed, with 34 patients experiencing at least one episode of unexpected graft dysfunction during the follow-up period, necessitating at least one (but often multiple) ultrasound examinations. A total of 486 kidney transplant ultrasounds were performed during this period, for both patients with new allografts and more remote graft placement with unexpected graft dysfunction; relatively speaking, the number of cases in which MRA was performed was quite small relative to the total number of evaluations for graft dysfunction. In addition, the cost of MRA is considerably higher than that of ultrasound (∼$3600 vs. $1000), so it is currently used only as a second-line imaging when ultrasound is nondiagnostic. It is possible that MRA could be cost effective if it provided definitive guidance for management and obviated the need for additional testing/procedures, as in the case of the patient who presented with graft artery occlusion, where catheter angiography/surgical exploration was avoided. However, we were unable to assess the downstream effects on patient care costs in the context of this retrospective study.
This study has several notable strengths. First, despite being a case series, sequential enrollment minimized selection bias. In addition, differences in exposure to ferumoxytol were minimized by the use of a consistent clinical protocol across all patients that were determined a priori between our multidisciplinary transplantation team, including members from medicine, surgery, and radiology. To our knowledge, it is the first case series describing the use of ferumoxytol-enhanced MRA for kidney transplant evaluation. It demonstrates the use of the technique in a high-risk population with no clear alternatives that are low risk or effective. Despite these strengths, however, this study also has several limitations. First, it was a single-center retrospective review with a relatively small number of cases. Second, the dose and injection protocol for ferumoxytol have not been thoroughly optimized, and anecdotally, it may be possible to obtain imaging of similar quality with a lower dose of ferumoxytol. Third, catheter-based angiography, the reference standard for luminal stenosis, was only available in a few cases, and we were forced to rely on clinical follow-up data to exclude functionally significant stenosis in most subjects. However, the study does suggest that MRA with ferumoxytol can accurately detect renal transplant artery abnormalities, and the consistently high image quality across subjects suggests that it may be more robust than conventional Doppler ultrasound evaluation.
In conclusion, based on our initial experience, renal transplant MRA with ferumoxytol is a useful diagnostic test for evaluating transplant vessel patency in the setting of allograft dysfunction. It may be a useful adjunct test when ultrasound evaluation is nondiagnostic or equivocal, and represents a novel method for anatomic depiction of allograft vascular patency without the risks associated with conventional imaging contrast agents.
MATERIALS AND METHODS
The institutional review board approved this Health Insurance Portability and Accountability Act–compliant study and waived the requirement for informed consent because of its retrospective design.
The study population consisted of 16 consecutive patients with renal allografts who were imaged with MRA using ferumoxytol between October 1, 2011, and November 1, 2012. These included nine men and seven women, with a mean (SD) age of 54.4 (11.7) years (range, 36–73 years). Patients were imaged for unexpected kidney dysfunction, presenting as slow or delayed graft function immediately after allograft placement or AKI more than 1 week after transplantation. AKI was defined as an increase in the baseline creatinine of 30% or more above the nadir creatinine (the lowest measured creatinine on two or more consecutive occasions). All patients had ultrasound examinations before MRA, which were equivocal or nondiagnostic with regard to graft vessel patency.
Historical data relating to the patients’ original cause for renal transplantation, the perioperative and postoperative course of events, and the acute episode that led to the need for allograft vascular evaluation were collected.
Imaging and Statistical Analysis
All patients underwent MRA focused on their renal allograft on either 1.5- or 3-T clinical MRI systems. First, precontrast T1- and T2-weighted imaging was performed for morphologic assessment. Then, dynamic post–contrast imaging was performed using a time-resolved pulse sequence with a 3- to 4-s frame rate, during the intravenous bolus injection of 3 mg/kg of ferumoxytol diluted with normal saline to a total bolus volume of 30 mL through a peripheral intravenous angiocatheter. Finally, contrast-enhanced anatomic imaging was performed with high-resolution T1-weighted sequence covering the renal allograft and ipsilateral iliac vessels. When available, confirmatory catheter angiography images and transplant ultrasound examinations were also reviewed. The dose of ferumoxytol administered to subjects for their MRA was also collected.
Two fellowship-trained faculty abdominal radiologists independently assessed vascular patency based on contrast-enhanced images. They rated vessel visualization on a scale of 1 (vessels not seen) to 4 (excellent visualization). Vascular segments evaluated included the iliac artery, main renal artery, segmental renal arteries, second-order arterial branches, iliac vein, main renal vein, and segmental renal veins. Signal intensity ratios normalized to muscle from the MRI examinations were measured in the graft cortex and medulla as a semiquantitative measure of small parenchymal vessel enhancement. Normalized signal intensity ratios measured before and after ferumoxytol administration were compared using a paired Student t test, with a value of P<0.05 considered statistically significant.
Clinical Reference Standard
All available clinical follow-up data available at the time of medical record review were collected. For those patients in whom baseline posttransplantation creatinine levels were available (creatinine levels obtained >3 months after transplantation, but before MRA and not during a clinically reported episode of AKI), baseline creatinine levels were recorded. The most recent available creatinine levels were also recorded as a follow-up measure of graft function. Graft biopsy results and surgical reports were also reviewed.
1. Audard V, Matignon M, Hemery F, et al. Risk factors and long-term outcome of transplant renal artery stenosis in adult recipients after treatment by percutaneous transluminal angioplasty. Am J Transplant 2006; 6: 95.
2. Pouria S, State OI, Wong W, et al. CMV infection is associated with transplant renal artery stenosis. QJM 1998; 91: 185.
3. Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial 2005; 18: 505.
4. Bruno S, Remuzzi G, Ruggenenti P. Transplant renal artery stenosis. J Am Soc Nephrol 2004; 15: 134.
5. Loubeyre P, Abidi H, Cahen R, et al. Transplanted renal artery: detection of stenosis with color Doppler US. Radiology 1997; 203: 661.
6. Steubl D, Papachristou E, Wolf P, et al. Doppler-ultrasound measurements in renal allografts depend on the patient’s body position. Vasa 2012; 41: 114.
7. Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy. Kidney Int 2005; 68: 14.
8. Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356: 1000.
9. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21: 1104.
10. Rydahl C, Thomsen HS, Marckmann P. High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol 2008; 43: 141.
11. Lu M, Cohen MH, Rieves D, et al. FDA report: ferumoxytol
for intravenous iron therapy in adult patients with chronic kidney disease. Am J Hematol 2010; 85: 315.
12. Qiu D, Zaharchuk G, Christen T, et al. Contrast-enhanced functional blood volume imaging (CE-fBVI): enhanced sensitivity for brain activation in humans using the ultrasmall superparamagnetic iron oxide agent ferumoxytol
. Neuroimage 2012; 62: 1726.
13. Stabi KL, Bendz LM. Ferumoxytol
use as an intravenous contrast agent for magnetic resonance angiography
. Ann Pharmacother 2011; 45: 1571.
14. Hamilton BE, Nesbit GM, Dosa E, et al. Comparative analysis of ferumoxytol
and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging. AJR Am J Roentgenol 2011; 197: 981.
15. Li W, Tutton S, Vu AT, et al. First-pass contrast-enhanced magnetic resonance angiography
in humans using ferumoxytol
, a novel ultrasmall superparamagnetic iron oxide (USPIO)–based blood pool agent. J Magn Reson Imaging 2005; 21: 46.
17. Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrast-induced nephropathy. JAMA 2006; 295: 2765.
18. Gedroyc WM, Negus R, al-Kutoubi A, et al. Magnetic resonance angiography
of renal transplants. Lancet 1992; 339: 789.
19. Loubeyre P, Cahen R, Grozel F, et al. Transplant renal artery stenosis. Evaluation of diagnosis with magnetic resonance angiography
compared with color duplex sonography and arteriography. Transplantation 1996; 62: 446.
20. Leung DA, Hagspiel KD, Angle JF, et al. MR angiography of the renal arteries. Radiol Clin North Am 2002; 40: 847.
21. Luk SH, Chan JH, Kwan TH, et al. Breath-hold 3D gadolinium-enhanced subtraction MRA
in the detection of transplant renal artery stenosis. Clin Radiol 1999; 54: 651.
22. Pai AB, Garba AO. Ferumoxytol
: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud? J Blood Med 2012; 3: 77.
23. Qiu D, Zaharchuk G, Christen T, et al. Contrast-enhanced functional blood volume imaging (CE-fBVI): enhanced sensitivity for brain activation in humans using the ultrasmall superparamagnetic iron oxide agent ferumoxytol
. Neuroimage 2012; 62: 1726.
24. Sigovan M, Gasper W, Alley HF, et al. USPIO-enhanced MR angiography of arteriovenous fistulas in patients with renal failure. Radiology 2012; 265: 584.
26. Prince MR, Zhang H, Zou Z, et al. Incidence of immediate gadolinium contrast media reactions. AJR Am J Roentgenol 2011; 196: W138.
27. Weinstein JS, Varallyay CG, Dosa E, et al. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 2010; 30: 15.
28. McCullough BJ, Kolokythas O, Maki JH, et al. Ferumoxytol
in clinical practice: implications for MRI. J Magn Reson Imaging 2013; 37: 1476.
29. Bremerich J, Bilecen D, Reimer P. MR angiography with blood pool contrast agents. Eur Radiol 2007; 17: 3017.
30. Karabulut N, Elmas N. Contrast agents used in MR imaging of the liver. Diagn Interv Radiol 2006; 12: 22.
Keywords:© 2013 by Lippincott Williams & Wilkins
Kidney transplant; Magnetic resonance angiography; MRA; Ferumoxytol; Feraheme