Outcome of BCF Access in Hemodialysis Patients

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conditions, the subject will be withdrawn from the study.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.

Inclusion Criteria:

- Subjects enrolled in the study will include patients with irreversible chronic renal
failure; either those receiving chronic hemodialysis or anticipation that hemodialysis
will be required.

- Subjects for consideration in the study will be referred from the out-patient
nephrology clinic at the University of Chicago or a dialysis unit affiliated with
DaVita Dialysis for a primary AVF. The patient will be referred for AVF placement and
evaluated at the University of Chicago by a transplant or vascular surgeon. If it is
determined that the patient is a candidate for fistula placement, the surgeon will
decide based on physical exam, the best location for the access. If the optimal
location is a proposed BCF, a research coordinator will be notified and the patient
will be enrolled by written consent approved by the IRB from the University of
Chicago.

- Subjects who can provide consent or consent of a surrogate through proxy

Exclusion Criteria:

- Patients will be excluded if they are less than 21 years of age

- Pregnant females will be excluded. A careful history will be taken and women who are
pregnant or have a clinical indication will have a serum pregnancy test with a
positive result will be excluded.

- Those with a known history of anaphylaxis from contrast

- Those who are found to be ineligible to have a surgical placement of a BCF as
determined by the surgeon

Additional Criteria for the sub-study

Inclusion Criteria:

- No history of hemodialysis prior to BCF access placement

Exclusion Criteria:

- History of hemodialysis prior to BCF access placement