METHOD Subject Population: Subjects for consideration in the study will be those referred
from the out-patient nephrology clinic at the University of Chicago or a dialysis unit
affiliated with DaVita Dialysis for a primary AVF. Eligible patients are those who are
evaluated at the University of Chicago by a transplant or vascular surgeon. If the
treating surgeon determines that the patient will have an attempted BCF, these patients
will be eligible to participate in this study. The research team will be notified of a
potential subject.
Clinical Protocol: After the patient is enrolled, pre-operative labs and work-up will be
at the discretion of the surgeon. At the time of the OR, if a BCF is placed, labs will be
drawn for viscosity, hematocrit, and ADMA. If it is determined at any time by the
treating surgeon that a subject is not a suitable surgical candidate for a fistula due to
underlying medical conditions, the subject will be withdrawn from the study. A venogram
and Doppler of the cephalic arch will be obtained prior to anastomosis creation. A
segment of the cephalic vein and arterial tissue will be collected from the excised
amount and sent to the Human Tissue Research Center to be preserved for future assay for
histology, cytokines, and growth factors as discussed below. The serum specimens for
viscosity, Hct, and ADMA will be transported on ice to IIT for assay. The patient will
then have follow up Doppler, venogram, and associated tests according to the same
procedure following the schedule provided in table \ref{protocol} for the large-scale
prospective study. The clinically obtained measurements of geometry, flow rate, and whole
blood viscosity will be used as input to the CFD model that will be used to compute the
WSS and other HDP throughout the arch. Patients who develop symptoms of stenosis between
protocol measurements will have a venogram performed at the time of diagnosis. These
venograms will be considered standard of care, although data may be used for study
analysis. In addition, excised tissue samples of the cephalic vein and arterial tissue
will be obtained when the access is placed and at each surgical revision and banked for
future studies.
A subset of ten subjects from the large-scale study will be invited for a sub study that
will involve: 1) more detailed three-dimensional imaging of the cephalic arch using IVUS,
and 2) blood flow monitoring via Doppler during dialysis. Subjects who have not undergone
previous dialysis treatment will be invited to participate in this optional sub-study.
Participation in this sub-study will not affect participation in the main study. The IVUS
imaging will provide a three-dimensional image of the vessel geometry and remodeling
characteristics of the vein upon which the remodeling index (RI) will be computed
[26,27]. Detailed CFD modeling will be carried out on these cephalic arch
reconstructions, which will be performed at 0 and 24 months after fistula insertion. This
will allow for a detailed prospective study of the evolution of IH, remodeling, and
stenosis in the cephalic arch.
For the same ten subjects in the small-scale study, actual venous blood flow will be
measured during hemodialysis treatment using a hand held Doppler device in the upper arm
cephalic vein as close to the cephalic arch inlet as possible. The Doppler readings will
be obtained at dialyzer blood flows of 300, 350, 400 and 450 mL/minute. Three
measurements will be obtained at each of four blood flows, and the average at each blood
flow calculated. These readings will be taken at 0, 6, 12, 18, and 24 months after
fistula insertion. The Doppler data obtained during hemodialysis will be used along with
recent clinical venograms and laboratory data outlined above to perform CFD modeling.
This data during dialysis treatment will be used to 1) quantify the differences in the
HDP for subjects pre-dialysis and while on dialysis, and 2) seek a correlation between
the Doppler readings at the various dialyzer flow rates and the onset of CAS. It is
expected that formation of stenosis would alter the resistance to blood flow through the
arch, thereby altering the flow rate in such a way that a unique signature will be
apparent in the Doppler data during the controlled dialysis process. If this is the case,
then additional surveillance techniques could be developed for identifying the onset of
CAS.
History and Physical: The history and physical will be focused on the dialysis access.
The history will include type and problems with cannulation, pain score with cannulation,
needle size used, and bleeding complications. The physical exam will include an extensive
examination of the access including pulse, description of anastomosis, any evidence of
aneurisms, hematoma, inflammation, edema, or swelling of the head and neck.
Venogram: The venogram is performed as follows with simultaneous blood flow measurements.
The patient will have their fistula punctured with a 21-gauge needle near the arterial
anastomosis directed toward the stenosis (either venous or arterial). The needle will be
exchanged for a 5 French dilator, and a digital subtraction venogram encompassing the
outflow from puncture site to the right heart will be performed. Any stenosis will be
measured using electronic calipers and defined. Any significant hemodynamic stenosis,
defined as greater than 50% narrowing of the expected luminal diameter, will be treated
with balloon angioplasty according to DOQI consensus from the International Society of
Interventional Radiology [36]. In addition to the baseline venogram at the time of BCF
placement, the venogram will include an image of the anastomosis and a measurement of the
length from the anastomosis to the inlet of the cephalic arch.
Intravenous Ultrasound (IVUS): The subset of patients for the small-scale study will have
a venogram performed as above and IVUS imaging in the Cardiac Catheterization Laboratory
at the University of Chicago. The IVUS catheter will be inserted after the venogram, and
images will be taken during pullback of the catheter at a set rate in order to provide
cross-sectional images of the intimal and lumen layers of the vein at preset intervals
along the cephalic arch [26,40].
Doppler: Doppler spectral analysis will be performed by an interventional radiologist at
the time of each venogram or IVUS to measure velocity in the cephalic vein prior to
entering the cephalic arch. The peak systolic velocity (PSV) at a 60-degree angle of
insonation will be measured in the straight portion of the cephalic vein between the
anastomosis and the arch as close to the arch as possible. The velocities in this
location will be measured over several heart cycles and the average calculated.
Whole Blood Viscosity (WBV), Hematocrit, and ADMA: WBV, Hematocrit, and ADMA will be
measured from serum samples obtained from patients pre-op or pre-dialysis. Blood samples
will be anti-coagulated with 3.2% buffered sodium citrate and transported on ice to IIT.
At IIT, WBV will be measured using a Brookfield Programmable DV-II+ cone plate
viscometer. ADMA will be measured using an ADMA ELISA kit from EUROIMU US or by HPLC. The
samples will be collected every 6 months on all subjects and frozen to be run in aliquots
of 50 at IIT.
Cephalic Vein and Arterial Tissue Samples:
During placement of BCF vein and arterial tissue are excised during anastomosis to create
the fistula. After the tissue is removed from the vein and artery a small portion of each
will be removed and collected for research from this discarded material. The cephalic
vein and arterial samples will be collected and preserved in a tissue bank for later
review by light and electron microscopy in a subsequent study. The sections will be
reviewed by the pathologist for: generalized wall thickness, fibrous tissue infiltration,
intimal hyperplasia, loss of endothelial cell layer, disruption of internal elastic
lamina, mural calcification, and inflammatory reaction in the wall with infiltration by
erythrocytes and/or histiocycyte. The changes that are present will be correlated with
the development of intimal hyperplasia as evident by CAS. Our hypothesis is that
histiopathic changes of intimal hyperplasia at baseline will correlate with the
development of an accelerated course to develop CAS and subsequent thrombosis.
End-Point: The end-point of a subject's enrollment in the study will occur if they
develop CAS of greater than 50%, transfer out of the DaVita dialysis program,
transplantation, or death.