title: Studies of the vasculopathy of Chronic Kidney Disease using iron-enhanced and cardiac Magnetic Resonance Imaging
Creators: name: Stoumpos, Sokratis
Publisher: name: University of Glasgow
Year: 2021
Subjects: subject: vascular, ferumoxytol, imaging, cardiovascular, MRI, Duplex ultrasound, angiogram, transplantation, renal, kidney, chronic kidney disease, haemodialysis.

description: Use of conventional contrast agents, both iodinated or gadolinium-based, in patients with late-stage chronic kidney disease (CKD) are limited by the risks for additional acute kidney injury and nephrogenic systemic fibrosis (NSF), respectively, that must be balanced by the critical nature of the radiologic study for the well being of the patient. In addition, current techniques have reduced accuracy for arterial diagnosis in the presence of arteriosclerotic calcification or have limitations in assessing peripheral and central vein patency. To overcome these challenges we examined whether ferumoxytol-based vascular magnetic resonance imaging (MRI) can offer a practical solution to both gadolinium-based and iodinated contrast agents when assessing vessel anatomy. We focused on two district groups of patients: a) kidney transplant candidates and b) patients requiring vascular access creation for haemodialysis. Kidney transplantation is the treatment of choice for suitable patients with end-stage renal disease (ESRD) with around 90 000 kidney transplants performed every year worldwide. Approximately 25% of patients with CKD have evidence of peripheral arterial disease (PAD) on non-invasive studies. Even though PAD does not preclude transplantation, revascularisation procedures may be required before listing. Characterisation of PAD in kidney transplant candidates relies on history, physical examination and imaging studies. Imaging studies with vascular mapping, including computed tomography angiography (CTA), provide precise preoperative anatomy of vascular and extravascular systems allowing the surgeon to determine if kidney transplantation is possible, whether presurgical procedures are necessary, and the best surgical technique for each candidate. Until now the widespread use of CTA in the workup of potential kidney transplant recipients has been limited because of the perceived increased risk of nephrotoxicity in patients with residual renal function. Preoperative sonographic mapping of arm vessels is essential for creating permanent haemodialysis access and used for arterial and venous evaluation to optimise arteriovenous fistula (AVF) placement. But Duplex ultrasound (US) is limited by an inherent operator-dependence, the inability to provide direct evidence of central stenosis and the lack of image manipulation and reconstruction to inform the surgeon about vascular anatomical course and tortuosity. Contrast-enhanced MR angiography provides excellent visualisation of both central and upper extremity vessels. However, the risk of NSF in advanced CKD has curtailed its use in arteriovenous access planning. The alternative option of traditional iodinated contrast-based CT angiography risks nephrotoxicity in patients with residual renal function. Arteriovenous fistula is considered the preferred type of access for maintenance haemodialysis, however it may contribute to maladaptive cardiovascular remodelling. The creation of an AVF leads to a localised area of high flow shunting of blood from the arterial to venous circulation, and exposes the low pressure, high capacitance venous system to the high pressure, low capacitance arterial system. Immediately following creation, AVF is associated with an increase in cardiac output, predominantly as a consequence of reduced systemic vascular resistance, increased myocardial contractility, and an increase in stroke volume and heart rate. Over time, because of the increase in blood volume, the right atrial pressure, pulmonary artery pressure, and left ventricular (LV) end-diastolic pressure gradually increase until the myocardium decompensates, the LV dilates, the ejection fraction declines, and the patient has symptoms of heart failure. Ferumoxytol has been increasingly used for MR angiography, particularly for patients with CKD. Ferumoxytol is a carbohydrate-coated ultra-small paramagnetic iron oxide approved for intravenous treatment of iron deficiency anaemia. However, ferumoxytol was originally designed as an intravascular contrast agent for MRI, and therefore, has powerful imaging attributes not present in other intravenous iron products nor the extracellular gadolinium-based contrast agents. A large molecular weight of 750 kD for ferumoxytol delays contrast extravasation, allowing slow administration or application before the patient is transferred to the MRI suite. The glomerulus does not filter ferumoxytol. Removal of ferumoxytol occurs via circulating macrophages with the remaining iron oxide particles taken up by the reticuloendothelial system of the liver, spleen and bone marrow. Given its half-life of approximately 15 hours, ferumoxytol allows enhancement of both the arterial and venous vasculature without the need for bolus timing. As part of this thesis, we have applied novel techniques using ferumoxytol-enhanced MR angiography (FeMRA) whilst planning transplantation or haemodialysis in two comparative cohort studies. To optimise our MRI protocol and ferumoxytol dosing regime, we also performed preliminary feasibility and dose-finding studies. The first cohort included patients undergoing CTA of iliac vasculature prior to listing for kidney transplantation. The second cohort included patients undergoing US vascular mapping prior to upper limb AVF creation for haemodialysis. A third cohort consisted of study participants in the second cohort who underwent cardiac magnetic resonance imaging (CMR) at baseline and 6 weeks after AVF surgery to assess changes in cardiovascular anatomical and functional parameters. We compared outcomes of interest including quality of image and diagnostic accuracy in a head-to-head design between CTA or Duplex US and FeMRA. For the CMR study, changes in outcomes of interest from baseline to follow-up scans were assessed. All three studies are briefly discussed below. In a prospective study of 36 kidney transplant candidates, FeMRA was compared with CTA for assessment of arterial and vein diameter, calcification, and signal. FeMRA was comparable to CTA for evaluating arterial diameter and calcification and offered improved venous depiction. Two transplant surgeons identified vein abnormalities critical to venous anastomosis planning in 11% of patients with FeMRA. These findings favor FeMRA and could improve clinical practice. In a prospective study of 59 participants with CKD requiring upper limb vascular mapping, FeMRA identified 15 central vessel stenoses and characterised 37% of arterial sections as unsuitable for AVF creation compared with 26% for Duplex US (p = 0.01). Ferumoxytol-enhanced MR angiography independently predicted successful fistula outcome for models including and excluding central vasculature. Compared with Duplex US, FeMRA had superior detection of central vein stenosis and arterial disease that correlated with outcomes of arteriovenous fistula surgery for haemodialysis. In a prospective study of 40 participants who underwent CMR imaging before and an average time of 6.4 weeks after AVF creation, a mean increase of 7.4 g (p = 0.02) was observed in LV myocardial mass. The changes were more pronounced in high blood flow arteriovenous fistulas (15.5 g, p = 0.003). Significant increases in LV end-diastolic volumes, cardiac output, and cardiac index were also seen after AVF creation (p &lt; 0.04). These data support further investigation of the impact of routine AVF creation in CKD patients on clinical outcomes. Our results demonstrate that ferumoxytol-enhanced MR angiography is a robust method for vascular mapping of patients with advanced CKD with similar or higher yield compared with the currently employed imaging techniques. Ferumoxytol’s favorable pharmacodynamics allows imaging of predialysis patients without concerns for iodine or gadolinium contrast toxicity.