Comparison of dynamic susceptibility contrast (DSC) using gadolinium and iron-based contrast agents in high-grade glioma at high-field MRI.

PURPOSE: To compare DSC-MRI using Gadolinium (GBCA) and Ferumoxytol (FBCA) in high-grade glioma at 3T and 7T MRI field strengths. We hypothesized that using FBCA at 7T would enhance the performance of DSC, as measured by contrast-to-noise ratio (CNR). METHODS: Ten patients (13 lesions) were assigned to 3T (6 patients, 6 lesions) or 7T (4 patients, 7 lesions). All lesions received 0.1 mmol/kg of GBCA on day 1. Ten lesions (4 at 3T and 6 at 7T) received a lower dose (0.6 mg/kg) of FBCA, followed by a higher dose (1.0-1.2 mg/kg), while 3 lesions (2 at 3T and 1 at 7T) received only a higher dose on Day 2. CBV maps with leakage correction for GBCA but not for FBCA were generated. The CNR and normalized CBV (nCBV) were analyzed on enhancing and non-enhancing high T2W lesions. RESULTS: Regardless of FBCA dose, GBCA showed higher CNR than FBCA at 7T, which was significant for high-dose FBCA (p < .05). Comparable CNR between GBCA and high-dose FBCA was observed at 3T. There was a trend toward higher CNR for FBCA at 3T than 7T. GBCA also showed nCBV twice that of FBCA at both MRI field strengths with significance at 7T. CONCLUSION: GBCA demonstrated higher image conspicuity, as measured by CNR, than FBCA on 7T. The stronger T2* weighting realized with higher magnetic field strength, combined with FBCA, likely results in more signal loss rather than enhanced performance on DSC. However, at clinical 3T, both GBCA and FBCA, particularly a dosage of 1.0-1.2 mg/kg (optimal for perfusion imaging), yielded comparable CNR.

Cardiothoracic Magnetic Resonance Angiography.

Catheter-based angiography is regarded as the clinical reference imaging technique for vessel imaging; however, it is invasive and is currently used for intervention or physiologic measurements. Contrast enhanced magnetic resonance angiography (MRA) with gadolinium-based contrast agents can be performed as a three-dimensional (3D) MRA or as a time resolved 3D (4D) MRA without physiologic synchronization, in which case cardiac and respiratory motion may blur the edges of the vessels and cardiac chambers. Ferumoxytol has recently been a popular contrast agent for MRA in patients with chronic renal failure. Noncontrast 3D MRA with ECG gating and respiratory navigation are safe and accurate noninvasive cross-sectional imaging techniques for the visualization of great vessels of the heart and coronary arteries in a variety of cardiovascular disorders including complex congenital heart diseases. Noncontrast flow dependent MRA techniques such as time of flight, phase contrast, and black-blood MRA techniques can be used as complementary or primary techniques. Here we review both conventional and relatively new contrast enhanced and non-contrast enhanced MRA techniques including ferumoxytol enhanced MRA, and bright-blood and water-fat separation based noncontrast 3D MRA techniques.

Translatable Drug-Loaded Iron Oxide Nanophore Sensitizes Murine Melanoma Tumors to Monoclonal Antibody Immunotherapy.

Macrophages comprise a significant portion of the immune cell compartment within tumors and are known contributors to tumor pathology; however, cancer immunotherapies targeting these cells are not clinically available. The iron oxide nanoparticle, ferumoxytol (FH), may be utilized as a nanophore for drug delivery to tumor-associated macrophages. We have demonstrated that a vaccine adjuvant, monophosphoryl lipid A (MPLA), can be stably captured within the carbohydrate shell of ferumoxytol without chemical modification of either the drug or the nanophore. This drug-nanoparticle combination (FH-MPLA) activated macrophages to an antitumorigenic phenotype at clinically relevant concentrations. In the immunotherapy-resistant B16-F10 model of murine melanoma, FH-MPLA treatment induced tumor necrosis and regression in combination with agonistic α-CD40 monoclonal antibody therapy. FH-MPLA, composed of clinically approved nanoparticle and drug payload, represents a potential cancer immunotherapy with translational relevance. FH-MPLA may be useful as an adjunctive therapy to existing antibody-based cancer immunotherapies which target only lymphocytic cells, reshaping the tumor immune environment.

Pulmonary MRA During Pregnancy: Early Experience With Ferumoxytol.

BACKGROUND: Ferumoxytol, an intravenous iron supplement, is commonly used to treat anemia in pregnancy. Ferumoxytol-enhanced magnetic resonance angiography (Fe-MRA) is a viable off-label alternative to gadolinium-enhanced MRA for assessment of pulmonary embolism (PE) in pregnancy. PURPOSE: To describe our clinical experience with Fe-MRA in pregnant women with suspected PE. STUDY TYPE: Retrospective, observational, cohort. POPULATION: A total of 98 Fe-MRA exams (consecutive sample) performed in 94 pregnant women. FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T, 3D T1-weighted MRA. ASSESSMENT: After IRB approval including a waiver of informed consent, electronic health records were reviewed retrospectively for all Fe-MRA exams performed at our institution in pregnant between January, 2017 and March, 2022. The Fe-MRA protocol included 3D-MRA for assessment of pulmonary arteries, and T1-weighted imaging for ancillary findings. Fe-MRA exam duration was measured from image time stamps. Fe-MRA exams were reviewed by three cardiovascular imagers using a 4-point Likert scale for image quality and confidence for PE diagnosis (score 4 = best, 1 = worst), and tabulation of ancillary findings. STATISTICAL TESTS: Continuous data are presented as mean ± standard deviation. The overall image quality and confidence score is given as the mean of three readers. RESULTS: The 98 Fe-MRA exams were performed in 94 pregnant women (age 30 ± 6, range 19-48 years, gestational week 23 ± 10, range 3-38 weeks), with four undergoing two Fe-MRA exams during their pregnancy. Median Fe-MRA exam durration was 8 minutes (interquantile range 6 minutes). Overall image quality score was 3.3 ± 0.9. Confidence score for diagnosing PE was 3.5 ± 0.8. One subject was positive for PE (1/94, 1%); 42 of the 94 (45%) subjects Fe-MRA had ancillary findings including hydronephrosis or pneumonia. CONCLUSION: Ferumoxytol enhanced MRA is a radiation- and gadolinium-free alternative for diagnosis of PE during pregancy. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.

Utility of combined gadoxetic acid and ferumoxytol-enhanced liver MRI for preoperative detection of colorectal cancer liver metastases: a pilot study.

BACKGROUND: Colorectal cancer (CRC) is the second-leading cause of cancer-related death worldwide and resection of CRC metastases confined to the liver is the treatment of choice when feasible. Ferumoxytol is an off-label contrast agent that opacifies vasculature and may be helpful in distinguishing metastases from small hemangiomas and blood vessels on gadoxetic acid-enhanced magnetic resonance imaging (MRI). PURPOSE: To compare the diagnostic accuracy of MRI using a standard gadoxetic acid protocol and a combined gadoxetic acid/ferumoxytol protocol in patients with suspected colorectal hepatic metastases. MATERIAL AND METHODS: In this institutional review board-approved, single-institution, retrospective study, eight patients underwent gadoxetic acid-enhanced liver MRI, supplemented with additional T1-weighted ferumoxytol enhanced sequences. Two radiologists in consensus identified all metastases using all available sequences, which served as the reference standard. Two different radiologists reviewed each exam twice, once using the standard protocol and once with additional ferumoxytol sequences. The detection rate was estimated as the predicted probability of a metastasis along with the 95% confidence interval (CI) using hierarchical logistic regression models. RESULTS: A total of 49 metastases were identified. The mean diameter was 10 mm, measured in greatest axial dimension (median=7 mm; range=2-70 mm). Readers 1 and 2 had detection rates of 69.6% (95% CI = 48.2-85.0) and 53.1% (95% CI = 35.2-70.3) for gadoxetic acid alone and 98.0% (95% CI = 86.3-99.7) and 83.5% (95% CI = 59.3-94.7) for combined protocol. CONCLUSION: In this preliminary investigation, adding ferumoxytol-enhanced sequences to gadoxetic acid liver MRI protocol increased the detection rate of CRC hepatic metastases and may aid in preoperative decision making.

Undesired impact of iron supplement on MRI assessment of post-treatment glioblastoma.

Glioblastoma (GBM) is the most common malignant adult brain and has a poor prognosis. Routine post-treatment MRI evaluations are required to assess treatment response and disease progression. We present a case of an 83-year-old female who underwent MRI assessment of post-treatment GBM after intravenous iron replacement therapy, ferumoxytol. The brain MRI revealed unintended alteration of MRI signal characteristics from the iron containing agent which confounded diagnostic interpretation and subsequently, the treatment planning. Ferumoxytol injection prior to contrast enhanced MRI must be screened in post-treatment GBM patients to accurately evaluate tumor activity.

Oxidation of ferumoxytol by ionizing radiation releases iron. An electron paramagnetic resonance study.

Ferumoxytol (FMX) is an iron oxide nanoparticle that is FDA approved for the treatment of iron deficiency anemia. FMX contains an Fe3O4 core. Currently, the redox chemistry of Fe3O4 nanoparticles remains relatively unexplored. FMX has recently gained interest as an anti-cancer agent. Ionizing radiation (IR) is a treatment modality employed to treat several types of cancer. Utilizing electron paramagnetic resonance (EPR) spectroscopy, we found that the products produced from the radiolysis of water can oxidize the Fe3O4 core of FMX. Because of the limited diffusion of the HO2• and HO• produced, these highly oxidizing species have little direct effect on FMX oxidation. We have determined that H2O2 is the primary oxidant of FMX. In the presence of labile Fe2+, we found that reducing species generated from the radiolysis of H2O are able to reduce the Fe3+ sites of the Fe3O4 core. Importantly, we also have shown that IR stimulates the release of ferric iron from FMX. Because of its release of iron, FMX may serve as an adjuvant to enhance radiotherapy.

How to stop using gadolinium chelates for magnetic resonance imaging: clinical-translational experiences with ferumoxytol.

Gadolinium chelates have been used as standard contrast agents for clinical MRI for several decades. However, several investigators recently reported that rare Earth metals such as gadolinium are deposited in the brain for months or years. This is particularly concerning for children, whose developing brain is more vulnerable to exogenous toxins compared to adults. Therefore, a search is under way for alternative MR imaging biomarkers. The United States Food and Drug Administration (FDA)-approved iron supplement ferumoxytol can solve this unmet clinical need: ferumoxytol consists of iron oxide nanoparticles that can be detected with MRI and provide significant T1- and T2-signal enhancement of vessels and soft tissues. Several investigators including our research group have started to use ferumoxytol off-label as a new contrast agent for MRI. This article reviews the existing literature on the biodistribution of ferumoxytol in children and compares the diagnostic accuracy of ferumoxytol- and gadolinium-chelate-enhanced MRI. Iron oxide nanoparticles represent a promising new class of contrast agents for pediatric MRI that can be metabolized and are not deposited in the brain.

USPIOs as targeted contrast agents in cardiovascular magnetic resonance imaging.

PURPOSE OF REVIEW: We aim to discuss the diagnostic use of ultra-small superparamagnetic iron oxide (USPIOs) including ferumoxytol in targeted cardiovascular magnetic resonance imaging (MRI). RECENT FINDINGS: Ferumoxytol is the only USPIO clinically available in the U.S. and is a negatively charged USPIO that has potential use for tracking and characterization of macrophage-infiltrated cardiovascular structures. As an iron supplement that is approved for treatment of iron deficiency anemia, the iron core of ferumoxytol is incorporated into the body once it is phagocytosed by macrophages. In organs or tissues with high inflammatory cellular infiltration, such as atherosclerotic plaques and myocardial infarction, localization of iron-laden macrophages can be visualized on delayed MRI. The iron core of ferumoxytol alters the magnetic susceptibility and results in shortening of T2* and T2 relaxation rates. Areas with high concentration appear hypointense (negative contrast) on T2 and T2* MRI. Recently, in vitro findings support the potential specificity of ferumoxytol interactions with macrophage subtypes, which has implications for therapeutic interventions. With increasing concerns about gadolinium retention in the brain and other tissues, the value of ferumoxytol-enhanced MR for targeted clinical imaging is aided by its positive safety profile in patients with impaired renal function. SUMMARY: This paper discusses pharmacokinetic properties of USPIOs with a focus on ferumoxytol, and summarizes relevant in vitro, animal, and human studies investigating the diagnostic use of USPIOs in targeted contrast-enhanced imaging. We also discuss future directions for USPIOs as targeted imaging agents and associated challenges.

DOX@Ferumoxytol-Medical Chitosan as magnetic hydrogel therapeutic system for effective magnetic hyperthermia and chemotherapy in vitro.

Magnetic fluid hyperthermia has been one clinical treatment method in malignancy on account of the sufficient heat generation, which originates from hysteresis loss of magnetic nanomedicine in alternating magnetic field. Magnetic nanomedicine can also be employed as drug carrier for chemotherapy. Nevertheless few magnetic nanocarries has been approved in clinic, owing to the high pharmaceutical demand. For broadening the clinical application of current magnetic nanomedicine, novel magnetic hydrogel complex (DOX@FMT-MC) constituted by Doxorubicin, Ferumoxytol and Medical Chitosan was produced for hyperthermia and chemo synergistic therapy. The three materials were approved in clinic. Heat induction in vitro and rheology mesurements suggested this complex succeed in transforming into physical hydrogel when reaching hyperthermia temperature in alternating magnetic field. Drug release experiment implied the complex has the temperature-dependent slow drug release behaviour. Cell apoptosis assay presented that DOX@FMT-MC complex gave enhanced synergistic efficacy with 32.4 % on colon carcinoma cell treatment in vitro, compared to other therapeutic groups. Heat induction in mice subcutaneous xenografted tumour demonstrated the better heating performance of the complex than that of DOX@FMT. The novel hydrogel complex incorporated with three clinical available drugs promises the great potential in tumour synergistic treatment, motivating the clinical indication development of magnetic nanomedicine.

Differentiation of benign and malignant lymph nodes in pediatric patients on ferumoxytol-enhanced PET/MRI.

The composition of lymph nodes in pediatric patients is different from that in adults. Most notably, normal lymph nodes in children contain less macrophages. Therefore, previously described biodistributions of iron oxide nanoparticles in benign and malignant lymph nodes of adult patients may not apply to children. The purpose of our study was to evaluate if the iron supplement ferumoxytol improves the differentiation of benign and malignant lymph nodes in pediatric cancer patients on 18F-FDG PET/MRI. Methods: We conducted a prospective clinical trial from May 2015 to December 2018 to investigate the value of ferumoxytol nanoparticles for staging of children with cancer with 18F-FDG PET/MRI. Ferumoxytol is an FDA-approved iron supplement for the treatment of anemia and has been used "off-label" as an MRI contrast agent in this study. Forty-two children (7-18 years, 29 male, 13 female) received a 18F-FDG PET/MRI at 2 (n=20) or 24 hours (h) (n=22) after intravenous injection of ferumoxytol (dose 5 mg Fe/kg). The morphology of benign and malignant lymph nodes on ferumoxytol-enhanced T2-FSE sequences at 2 and 24 h were compared using a linear regression analysis. In addition, ADCmean-values, SUV-ratio (SUVmax lesion/SUVmean liver) and R2*-relaxation rate of benign and malignant lymph nodes were compared with a Mann-Whitney-U test. The accuracy of different criteria was assessed with a receiver operating characteristics (ROC) curve. Follow-up imaging for at least 6 months served as the standard of reference. Results: We examined a total of 613 lymph nodes, of which 464 (75.7%) were benign and 149 (24.3%) were malignant. On ferumoxytol-enhanced T2-FSE images, benign lymph nodes showed a hypointense hilum and hyperintense parenchyma, while malignant lymph nodes showed no discernible hilum. This pattern was not significantly different at 2 h and 24 h postcontrast (p=0.82). Benign and malignant lymph nodes showed significantly different ferumoxytol enhancement patterns, ADCmean values of 1578 and 852 x10-6 mm2/s, mean SUV-ratios of 0.5 and 2.8, and mean R2*-relaxation rate of 127.8 and 84.4 Hertz (Hz), respectively (all p<0.001). The accuracy of ADCmean, SUV-ratio and pattern (area under the curve (AUC): 0.99; 0.98; 0.97, respectively) was not significantly different (p=0.07). Compared to these three parameters, the accuracy of R2* was significantly lower (AUC: 0.93; p=0.001). Conclusion: Lymph nodes in children show different ferumoxytol-enhancement patterns on MRI than previously reported for adult patients. We found high accuracy (>90%) of ADCmean, SUV-ratio, pattern, and R2* measurements for the characterization of benign and malignant lymph nodes in children. Ferumoxytol nanoparticle accumulation at the hilum can be used to diagnose a benign lymph node. In the future, the delivery of clinically applicable nanoparticles to the hilum of benign lymph nodes could be harnessed to deliver theranostic drugs for immune cell priming.

Intermodality feature fusion combining unenhanced computed tomography and ferumoxytol-enhanced magnetic resonance angiography for patient-specific vascular mapping in renal impairment.

OBJECTIVE: The purpose of this study was to establish the feasibility of fusing complementary, high-contrast features from unenhanced computed tomography (CT) and ferumoxytol-enhanced magnetic resonance angiography (FE-MRA) for preprocedural vascular mapping in patients with renal impairment. METHODS: In this Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study, 15 consecutive patients underwent both FE-MRA and unenhanced CT scanning, and the complementary high-contrast features from both modalities were fused to form an integrated, multifeature image. Source images from CT and MRA were segmented and registered. To validate the accuracy, precision, and concordance of fused images to source images, unambiguous landmarks, such as wires from implantable medical devices or indwelling catheters, were marked on three-dimensional (3D) models of the respective modalities, followed by rigid co-registration, interactive fusion, and fine adjustment. We then compared the positional offsets using pacing wires or catheters in the source FE-MRA (defined as points of interest [POIs]) and fused images (n = 5 patients, n = 247 points). Points within 3D image space were referenced to the respective modalities: x (right-left), y (anterior-posterior), and z (cranial-caudal). The respective 3D orthogonal reference axes from both image sets were aligned, such that with perfect registration, a given point would have the same (x, y, z) component values in both sets. The 3D offsets (Δx mm, Δy mm, Δz mm) for each of the corresponding POIs represent nonconcordance between the source FE-MRA and fused images. The offsets were compared using concordance correlation coefficients. Interobserver agreement was assessed using intraclass correlation coefficients and Bland-Altman analyses. RESULTS: Thirteen patients (aged 76 ± 12 years; seven female) with aortic valve stenosis and chronic kidney disease and two patients with thoracoabdominal vascular aneurysms and chronic kidney disease underwent FE-MRA for preprocedural vascular assessment, and unenhanced CT examinations were available in all patients. No ferumoxytol-related adverse events occurred. There were 247 matched POIs evaluated on the source FE-MRA and fused images. In patients with implantable medical devices, the mean offsets in spatial position were 0.31 ± 0.51 mm (ρ = 0.99; Cb = 1; 95% confidence interval [CI], 0.99-0.99) for Δx, 0.27 ± 0.69 mm (ρ = 0.99; Cb = 0.99; 95% CI, 0.99-0.99) for Δy, and 0.20 ± 0.59 mm (ρ = 1; Cb = 1; 95% CI, 0.99-1.00) for Δz. Interobserver agreement was excellent (intraclass correlation coefficient, >0.99). The mean difference in offset between readers was 1.5 mm. CONCLUSIONS: Accurate 3D feature fusion is feasible, combining luminal information from FE-MRA with vessel wall information on unenhanced CT. This framework holds promise for combining the complementary strengths of magnetic resonance imaging and CT to generate information-rich, multifeature composite vascular images while avoiding the respective risks and limitations of both modalities.

Matrix-dependent size modifications of iron oxide nanoparticles (Ferumoxytol) spiked into rat blood cells and plasma: Characterisation with TEM, AF4-UV-MALS-ICP-MS/MS and spICP-MS.

Engineered nanoparticles such as iron oxide (Fe3O4) nanoparticles (IONPs) offer several benefits in nanomedicine, notably as contrast agents in magnetic resonance imaging (MRI). Ferumoxytol, a suspension of IONPs (with a manufacturer's reported particle diameter of 27 nm-30 nm) was characterized as a standard by spiking into rat blood plasma and cell fractions. Nanoparticle separation, and characterisation was investigated with asymmetric flow field-flow fractionation (AF4) coupled online to ultraviolet-visible spectroscopy (UV-VIS), multi-angle light scattering (MALS) and inductively coupled plasma mass spectrometry (ICP-MS) detectors; also with single particle inductively coupled plasma mass spectrometry (spICP-MS) and transmission electron microscopy (TEM). MALS signal of pristine Ferumoxytol indicated radii of gyration (Rg) between 15 and 28 nm for the Fe-containing fraction and 30-75 nm for the non-Fe fraction. IONPs spiked into blood plasma indicated a polydisperse distribution between 40 nm - 120 nm suggesting matrix-induced size alterations. Spiking of the IONPs into cells showed a shift in ICP-MS Fe signal to 15 min, however the MALS signal was undetected within the Fe containing fraction of the IONPs suggesting NP loss due to membrane-particle attraction. spICP-MS analysis of IONPs spiked in rat plasma suggested the release of Fe-containing colloids into plasma causing an increase in diameter of IONPs to 52 ±â€¯0.8 nm; whereas no major variation in particle size and distribution of the IONPs spiked in cell fractions was observed (33.2 ±â€¯2.0 nm) suggesting non-alteration of the NP Fe core. A complementary application of microscopic, light scattering, and mass spectrometry techniques for the characterisation of NPs in challenging biological matrices like blood has been demonstrated.

Ferumoxytol for the treatment of iron deficiency anemia.

INTRODUCTION: Ferumoxytol is a superparamagnetic molecule originally developed as a contrast agent for magnetic resonance imaging. Elemental iron is contained within the carbohydrate core and is released slowly after infusion allowing a large dose of iron to be administered in a short period of time. Ferumoxytol, originally approved for iron deficiency in chronic kidney disease, received a broad label for any cause of iron deficiency after oral iron intolerance or in those circumstances when oral iron is ineffective or harmful. Areas covered: The chemistry, pharmacology and pharmacokinetics of ferumoxytol were reviewed. Retrospective, observational, and prospective phase II and III trials were reviewed. When appropriate, comparative safety and efficacy parameters were reported. Differentiation between minor infusion reactions and more severe hypersensitivity reactions that may lead to anaphylaxis is described. Expert commentary: Ferumoxytol is a safe and effective iron formulation providing a means of iron repletion in persons with iron deficiency with or without anemia. Relative to iron sucrose, ferric gluconate, and iron dextran and similar to ferric carboxymaltose and iron isomaltoside, ferumoxytol yields relatively low quantities of labile free iron. Hypersensitivity and anaphylaxis is extremely rare. Hypophosphatemia with ferumoxytol's administration is extremely rare. Optimal strategies for application of ferumoxytol-enhanced imaging and full replacement dosing in a single setting remain to be determined.

Blood volume measurement using cardiovascular magnetic resonance and ferumoxytol: preclinical validation.

BACKGROUND: The hallmark of heart failure is increased blood volume. Quantitative blood volume measures are not conveniently available and are not tested in heart failure management. We assess ferumoxytol, a marketed parenteral iron supplement having a long intravascular half-life, to measure the blood volume with cardiovascular magnetic resonance (CMR). METHODS: Swine were administered 0.7 mg/kg ferumoxytol and blood pool T1 was measured repeatedly for an hour to characterize contrast agent extraction and subsequent effect on Vblood estimates. We compared CMR blood volume with a standard carbon monoxide rebreathing method. We then evaluated three abbreviated acquisition protocols for bias and precision. RESULTS: Mean plasma volume estimated by ferumoxytol was 61.9 ± 4.3 ml/kg. After adjustment for hematocrit the resultant mean blood volume was 88.1 ± 9.4 ml/kg, which agreed with carbon monoxide measures (91.1 ± 18.9 ml/kg). Repeated measurements yielded a coefficient of variation of 6.9%, and Bland-Altman repeatability coefficient of 14%. The blood volume estimates with abbreviated protocols yielded small biases (mean differences between 0.01-0.06 L) and strong correlations (r2 between 0.97-0.99) to the reference values indicating clinical feasibility. CONCLUSIONS: In this swine model, ferumoxytol CMR accurately measures plasma volume, and with correction for hematocrit, blood volume. Abbreviated protocols can be added to diagnostic CMR examination for heart failure within 8 min.

Ferumoxytol enhanced black-blood cardiovascular magnetic resonance imaging.

BACKGROUND: Bright-blood and black-blood cardiovascular magnetic resonance (CMR) techniques are frequently employed together during a clinical exam because of their complementary features. While valuable, existing black-blood CMR approaches are flow dependent and prone to failure. We aim to assess the effectiveness and reliability of ferumoxytol enhanced (FE) Half-Fourier Single-shot Turbo Spin-echo (HASTE) imaging without magnetization preparation pulses to yield uniform intra-luminal blood signal suppression by comparing FE-HASTE with pre-ferumoxytol HASTE imaging. METHODS: This study was IRB-approved and HIPAA compliant. Consecutive patients who were referred for FE-CMR between June 2013 and February 2017 were enrolled. Qualitative image scores reflecting the degree and reliability of blood signal suppression were based on a 3-point Likert scale, with 3 reflecting perfect suppression. For quantitative evaluation, homogeneity indices (defined as standard deviation of the left atrial signal intensity) and signal-to-noise ratios (SNR) for vascular lumens and cardiac chambers were measured. RESULTS: Of the 340 unique patients who underwent FE-CMR, HASTE was performed in 257. Ninety-three patients had both pre-ferumoxytol HASTE and FE-HASTE, and were included in this analysis. Qualitative image scores reflecting the degree and reliability of blood signal suppression were significantly higher for FE-HASTE images (2.9 [IQR 2.8-3.0] vs 1.8 [IQR 1.6-2.1], p < 0.001). Inter-reader agreement was moderate (k = 0.50, 95% CI 0.45-0.55). Blood signal suppression was more complete on FE-HASTE images than on pre-ferumoxytol HASTE, as indicated by lower mean homogeneity indices (24.5 [IQR 18.0-32.8] vs 108.0 [IQR 65.0-170.4], p < 0.001) and lower blood pool SNR for all regions (5.6 [IQR 3.2-10.0] vs 21.5 [IQR 12.5-39.4], p < 0.001). CONCLUSION: FE-HASTE black-blood imaging offers an effective, reliable, and simple approach for flow independent blood signal suppression. The technique holds promise as a fast and routine complement to bright-blood cardiovascular imaging with ferumoxytol.

The Ferumoxytol for Anemia of CKD Trial (FACT)-a randomized controlled trial of repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis: background and rationale.

BACKGROUND: Iron deficiency anemia (IDA) is a common manifestation of chronic kidney disease (CKD), affecting most patients on hemodialysis and imposing a substantial clinical burden. Treatment with iron supplementation increases hemoglobin levels and can reduce the severity of anemia in patients with CKD. While correcting anemia in these patients is an important therapeutic goal, there is a lack of long-term trials directly comparing intravenous iron therapies in patients with CKD receiving hemodialysis. METHODS/DESIGN: The Ferumoxytol for Anemia of CKD Trial (FACT) is a 13-month, open-label, randomized, multicenter, international, prospective study with 2 substudies. Entry criteria for the main study include adults with IDA (defined as hemoglobin <11.5 g/dL [<115.0 g/L] and a transferrin saturation <30%), serum ferritin <800 ng/mL (<1798 pmol/L), and receiving hemodialysis for ≥3 months. Patients are randomized to receive ferumoxytol (1.02 g over 2 doses) or iron sucrose (1.0 g over 10 doses) during the initial 5-week treatment period. Those with persistent/recurrent IDA over the 11-month observation period will receive additional 5-week treatment periods, as appropriate. The primary efficacy endpoint of the main study is the mean change in hemoglobin from Baseline to Week 5 for each treatment period. The secondary efficacy endpoints include the mean change in transferrin saturation from Baseline to Week 5 and the proportion of patients with a hemoglobin increase of ≥1.0 g/dL at any time from Baseline to Week 5. Safety will be assessed through an examination of the adverse event profile over the course of the study. An "oxidative stress" substudy in approximately 100 patients will assess the effects of treatment on biomarkers of oxidative stress/inflammation during the initial 5-week treatment period, and a magnetic resonance imaging substudy in approximately 70 patients will assess the potential for iron deposition in target tissues over 24 months. DISCUSSION: FACT fulfills the need for a long-term comparative trial in patients with IDA and CKD receiving hemodialysis. The efficacy and safety results will provide useful information for guiding therapy in this population. Two hundred ninety-six patients have been enrolled, and completion of the main study is expected soon. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01227616 (registered October 22, 2010); EudraCT number: 2010-022133-28.

Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis.

BACKGROUND: Iron supplementation is crucial for the treatment of anemia of chronic kidney disease (CKD). Although intravenous (IV) iron is preferred for patients with CKD receiving dialysis (CKD stage 5D), the method of iron replacement for patients with CKD stages 3 to 5 is controversial. STUDY DESIGN: Systematic review and meta-analysis. A search was performed until October 2015 of MEDLINE, Cochrane Library, conference proceedings in nephrology, and reference lists of included trials. SETTING & POPULATION: Patients with CKD stages 3 to 5 or 5D. SELECTION CRITERIA FOR STUDIES: All randomized controlled trials, regardless of publication status or language. INTERVENTION: IV versus oral iron supplementation. OUTCOMES: The primary outcome was defined as percentage of patients reaching an elevation in hemoglobin (Hb) concentration > 1g/dL. Secondary end points included percentage of patients who reached Hb levels > 11g/dL, absolute Hb concentration, change in Hb concentration, transferrin saturation, ferritin levels, erythropoiesis-stimulating agents and blood transfusion requirement, and quality of life. Safety analysis included all-cause mortality and serious and all adverse events. RESULTS: 24 trials were identified, 13 including 2,369 patients with CKD stages 3 to 5 and 11 including 818 patients with CKD stage 5D. Patients treated with IV iron were more likely to reach an Hb response > 1g/dL (risk ratios [RRs] of 1.61 [95% CI, 1.39-1.87] for CKD stages 3-5 and 2.14 [95% CI, 1.68-2.72] for CKD stage 5D). Safety analysis showed similar rates of mortality and serious and any adverse effects. IV iron replacement was associated with higher risk for hypotension (RR, 3.71; 95% CI, 1.74-7.94) and fewer gastrointestinal adverse events (RR, 0.43; 95% CI, 0.28-0.67). LIMITATIONS: Significant heterogeneity between trials; follow-up was usually limited to 3 months. CONCLUSIONS: Our results agree with current recommendations for IV iron replacement for patients with CKD stage 5D and support increased use of IV iron for patients with CKD stages 3 to 5.

The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress.

Production of minute concentrations of superoxide (O2(*-)) and nitrogen monoxide (nitric oxide, NO*) plays important roles in several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur owing to redox imbalance-a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(*-), hydrogen peroxide (H2O2), and NO*. Iron is involved in both the formation and the scavenging of these species. Iron deficiency (anemia) (ID(A)) is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (iv) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation levels and, thus, formation of non-transferrin-bound iron, a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an iv iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for iv therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(*-), H2O2, NO*, and other more reactive compounds derived from these species, the potential of various iron therapies to induce oxidative and nitrosative stress is discussed and possible underlying mechanisms are proposed. Understanding the mechanisms, by which various iron formulations may induce oxidative and nitrosative stress, will help us develop better tolerated and more efficient therapies for various dysfunctions of iron metabolism.

Ferumoxytol: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud?

Intravenous iron therapy is pivotal in the treatment of anemia of chronic kidney disease to optimize the response of hemoglobin to erythropoiesis-stimulating agents. Intravenous iron use in patients with chronic kidney disease is on the rise. Recent clinical trial data prompting safety concerns regarding the use of erythropoiesis-stimulating agents has stimulated new US Food and Drug Administration label changes and restrictions for these agents, and has encouraged more aggressive use of intravenous iron. The currently available intravenous iron products differ with regard to the stability of the iron-carbohydrate complex and potential to induce hypersensitivity reactions. Ferumoxytol is a newer large molecular weight intravenous iron formulation that is a colloidal iron oxide nanoparticle suspension coated with polyglucose sorbitol carboxymethyl ether. Ferumoxytol has robust iron-carbohydrate complex stability with minimal dissociation or appearance of free iron in the serum, allowing the drug to be given in relatively large doses with a rapid rate of administration. Clinical trials have demonstrated the superior efficacy of ferumoxytol versus oral iron with minimal adverse effects. However, recent postmarketing data have demonstrated a risk of hypersensitivity that has prompted new changes to the product information mandated by the Food and Drug Administration. Additionally, the long-term safety of this agent has not been evaluated, and its place in the treatment of anemia of chronic kidney disease has not been fully elucidated.