Kidney Transplantation Clinical Trial
Official title:
Use of Ferumoxytol Enhanced Magnetic Resonance Angiography for Cardiovascular Assessment in Late-stage Chronic Kidney Disease
Conventional vascular imaging techniques are often either contra-indicated in chronic kidney
disease (CKD) patients due to their relative invasiveness, risks and cost. Computed
tomography angiography (CTA) requires radiation and nephrotoxic iodinated contrast which may
precipitate significant worsening of renal function and even prompt the need for institution
of dialysis. Magnetic resonance angiography (MRA) using gadolinium-based contrast agents has
been associated with the rare disease nephrogenic systemic fibrosis. Alternative imaging
methods also have drawbacks: for example, this frail patient group has a higher risk of
complications from conventional invasive catheter-based angiography, non-contrast-enhanced
MRA allows visualization of smaller arteries but is less accurate for larger vascular
structures, and ultrasound is often not appropriate for evaluation of the deep vessels of the
abdomen and pelvis.
Ferumoxytol is an ultrasmall superparamagnetic iron oxide particle encapsulated by a
semisynthetic carbohydrate, which was initially developed as a magnetic resonance imaging
(MRI) contrast agent in 2000. However, interest in ferumoxytol as a therapeutic agent for the
treatment of iron deficiency anaemia in the setting of CKD eclipsed its use as MRI contrast
agent. During the last decade, ferumoxytol has gained appeal as an MRI contrast agent in
patients with estimated glomerular filtration rates <30mL/min and there are reports in the
literature for its safe use and utility in both adult and pediatric patients with CKD.
Participants will be selected from those who have been referred for assessment prior to
kidney transplant or prior to vascular access creation for haemodialysis and will be divided
into three groups. The first group will include patients who will undergo a CTA of abdominal
and aortoiliac vasculature as part of their preparation for potential kidney transplantation.
The second and third groups will include patients who are having a fistula or a graft created
for dialysis, respectively. These patients are routinely having US vascular mapping to
visualise the blood vessels before a fistula or a graft is created. Additionally, patients
included in the second and third groups are routinely having surveillance scans of their
fistula or graft at 6 weeks following creation. Study participants undergoing standard
imaging tests as part of their clinical care will also have ferumoxytol-enhanced MRA (FeMRA).
This is a comparative study in a cohort of patients with significant renal impairment. Study
participants undergoing standard imaging tests as part of their clinical care will also have
FeMRA. The investigators will compare outcomes of interest including quality of image and
diagnostic accuracy in a head-to-head design.
These hypotheses will be tested:
1. FeMRA is superior to CTA for characterisation of abdominal and aortoiliac anatomy
(pre-transplant assessment) before implantation of a kidney graft as it can robustly
evaluate both arterial and venous anatomy.
2. FeMRA is superior to Doppler US for characterisation of vascular anatomy (vascular
mapping) before vascular access creation as it can robustly assess central vein patency.
3. FeMRA is superior to Doppler US for characterisation of fistula (or graft) arm vascular
anatomy (surveillance) at 6 weeks after fistula creation.
4. Integrated cardiac and vascular assessment using FeMRA before vascular access creation
can better predict outcomes.
Patients will be selected from those who have been referred for assessment prior to kidney
transplant or prior to vascular access creation for haemodialysis and will be divided into 3
different groups. The first group (group A) will include patients who are having CTA of
abdominal and aortoiliac vasculature performed for pre-transplant assessment. The other two
groups will include patients who are having US vascular mapping performed before
arteriovenous fistula (group B) or synthetic graft (group C) creation for haemodialysis.
These patients are routinely having US Doppler of their fistula arm at 6 weeks following
access creation for surveillance. FeMRA will be performed in addition to standard care, i.e.
patients in group A will have a single FeMRA at baseline while patients in groups B and C
will have a FeMRA at baseline and a second one at 6 weeks. All patients will undergo Cardiac
MR with Ferumoxytol at the same time. This is to assess whether cardiac parameters before
transplantation or access creation are associated with outcomes (baseline Cardiac MR). The
6-weeks Cardiac MR aims to assess cardiovascular functional parameters (blood flow, cardiac
output, systolic and diastolic function) after vascular access creation.
Imaging will be performed on a 3T Prisma (Siemens) MRI system. A total dose of 3mg of
Ferumoxytol/kg of patient weight will be delivered but not to exceed one vial (510mg). In all
cases Ferumoxytol will be diluted to a concentration no greater than 1 part Ferumoxytol to 4
parts 0.9% sodium chloride and will be administered with several spaced infusions of diluted
agent for the different imaging components. Ferumoxytol infusion is controlled by a
sophisticated MRI compatible infusion pump for precise control over infusion rate. This
procedure would take a minimum of 20 minutes before the full cumulative dose is administered
for a usual size patient and even longer for the maximum expected dose of 510 mg in a very
large patient. As such the investigators are anticipating that patients will be scheduled for
up to 45 minutes of imaging.
Small fractions of the dose will be administered initially as an infusion for myocardial
perfusion and first pass imaging with a dynamic contrast enhanced (DCE) technique. After the
full dose is administered, steady state high-resolution imaging will be undertaken using an
ultrafast spoiled gradient echo sequences. Cardiac MR consisting of cardiac output, end
systolic volume, end diastolic volume, aortic distensibility and flow Cardiac MR will be
performed. Images will be obtained for left ventricular and right ventricular mass and
function plus flow quantification.
The MRA will be reviewed by vascular radiology consultants (with between 6 and 20 years'
experience) and a standard clinical report issued on the findings. At the end of the study,
all imaging (US Doppler, CTA and investigatory MRA) will be jointly reviewed by the
radiologists and other investigators in the study team. An independent radiologist that is
not directly involved in the study will also review images. All discrepancies will be
resolved by mutual consensus between the radiologists.
The general analytical approach will be to estimate accuracy (95% CI), sensitivity (95% CI)
and specificity (95% CI) of FeMRA and standard imaging techniques. In addition, Cohen's κ
with 95% CI will be computed to quantify the agreement between the FeMRA and standard imaging
findings. A value of κ>0.7 indicates a high level of agreement. Because multiple image
locations from each patient will be used for the statistical evaluation (at least 20 vascular
cross sections from each scan), the interdependence of each location for a given patient
examination will be assessed by use of a κ statistic. A value of κ<0.4 indicates weak or no
interdependence. The investigators aim to recruit 20 patients in group A and 10 patients in
each of the other two groups. Assuming that FeMRA will identify 10% more clinically
significant vascular anatomic characteristics compared with CTA/US, then one would need to
study 180 vascular sections in total to show a significant difference between tests using
chi-squared test, assuming power of 80% and probability of type 1 error of 5%.
To evaluate associations between anatomical predictor variables and outcomes, multiple linear
and logistic mixed-effects regression models will be used. Associations of fistula and graft
outcomes with predictors will be treated as uniform across all anatomical configurations
unless there is strong statistical or biological evidence to suggest otherwise. Based on data
from a retrospective study performed at the same centre, the investigators assume a fistula
failure rate of 30%.
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