Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01011985 |
| Other study ID # |
06-07-336E |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 2006 |
| Est. completion date |
June 2008 |
Study information
| Verified date |
July 2018 |
| Source |
Montefiore Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
To determine if the type of hemodialysis vascular access correlates with markers of
inflammation, namely C-reactive protein and interleukin-6, and with both access and patient
survival in the end stage renal disease population.
Description:
A Study Of The Effect Of Hemodialysis Vascular Access Type On Markers Of Inflammation PI:
Michele H. Mokrzycki MD, MS
Introduction/Background: The prevalence of chronic inflammation is high (35-65%) in end stage
renal disease (ESRD) patients and is associated with an increased risk of atherosclerosis,
and overall and cardiovascular mortality in this population.(1-4) Stenvinkel et al observed
that a pre-HD C-reactive protein (CRP) level of >10 was associated with a higher prevalence
of carotid plaques (p<0.01), and clinical manifestations atherosclerotic cardiovascular
disease (MI, CVA, PVD) (p<0.05) in the ESRD population. (1) Zimmerman et al report a 2.7-fold
and 4.6-fold higher risk of 2 yr all-cause mortality associated with a CRP level between
7.5-15.7. and >15.7, respectively. The cardiovascular mortality was similar (2.9-fold, and
5.5-fold). A single elevated CRP level has been shown to be a powerful indicator of mortality
in ESRD patients, even after 4-5 years of follow-up. (3).
CRP is a sensitive major acute phase protein, synthesized by hepatocytes under
transcriptional control by IL-6. In the presence of human serum, CRP induces the expression
of MCP-1, VCAM-1, ICAM-1, and E-selectin. (5). The interaction of CRP with monocytes in vitro
results in the release of IL-1 β, IL-6, TNF-α, and tissue factor.(6)
The origin of inflammation in the ESRD population is unclear, although the HD session per se
has been implicated. Korevaar et al studied the effect of the HD session on CRP level and
mortality in 186 pts. (7) Thirty-eight % of patients had a CRP level below detection (<3
mg/L), and in those patients with detectable CRP levels pre-HD 37% had no increase with HD,
and 25% of patients had an increase (mean +2.3 (0.6-9.2)) in CRP level (adjusted for change
in blood volume) during HD. There was no difference in pre-HD CRP level between the latter 2
groups. A lower 2 yr survival was observed in the group in which CRP increased during HD, (44
vs. 66%, p=0.09). After adjusting for nutritional factors, age, comorbidity and primary
kidney disease, a rise of 1 mg/dl in CRP during a HD session, was associated with an increase
in mortality risk of 9% (Adjusted hazard ratio 1.09, 95%CI=1.09-1.16) Independent predictors
of high CRP levels during HD include patient age (β=0.07, p=0.05), pre-HD CRP (β=0.95,
p<0.01), 2 needle dialysis (β=2.39, p=0.05, and cholesterol ((β= -0.92, p=0.04).
Additional possible reasons for increased markers of inflammation in the ESRD population
include 1) uremia-related alterations in immune/host defense systems, specifically increased
cytokine production, 2) increased oxidative stress (oxidized-LDL), advanced glycation end
products (AGEs) 3) the dialysis membrane (IL-6 and IL-1 β production by certain membranes),
4) contaminated dialysate, [ultrapure dialysate reduces CRP levels],5) intercurrent clinical
events, 6) and occult arteriovenous graft infection, 7) protein-energy malnutrition, and 8)
shorter time on hemodialysis (HD). (8-13). None of the above CRP associated mortality studies
controlled for type of vascular access. There are reports of an association of vascular
access type with other markers of inflammation. Kaysen et al report an association between
low levels of serum albumin with presence of an AVG, and Thadani et al recently reported
elevated WBC count and hemocatheters (14,15).
Polkinghorne et al studied the effect of vascular access in incident hemodialysis patients on
all-cause mortality using multivariate analysis.(16) In this adjusted analysis, catheter use
and AVGs were associated with significant excess mortality. Compared to AVFs, catheters were
associated with a 3.3-fold higher and AVGs with a 1.6-fold higher all-cause mortality after
120 days. However, the authors speculate that, in part, this may due to the higher risk of
infections. In fact the risk of infectious death was 1.7-fold higher with AVGs, and 2.7 fold
higher with catheters. The risk of the type of vascular access with inflammation, independent
of infection, is unknown.
Research Question/Objective: To determine if the type of HD vascular access correlates with
markers of inflammation, namely CRP and IL-6, and with both access and patient survival in
the ESRD population.
Study Design: A prospective study using a multiple group design.
Subjects: Incident ESRD patients. Patients with Stage IV and V (GFR <30 ml/min using MDRD mod
equation) will be recruited from the renal clinics and private practices. Sites include both
the Moses and Weiler campuses of the Montefiore Medical Center in Bronx, NY. Type of vascular
access to be inserted will be determined on clinical grounds by the patient's nephrologist
and access surgeon, these include hemocatheter, arteriovenous graft, and arteriovenous
fistula.
Study Procedures: Blood samples (10 cc) will be drawn immediately (within 24 hours) prior to
access surgery, and 1 week, and 1, 3, 6 and 12 months, and upon dialysis initiation.(6
samples per subject over 1 year) Once the patient is on hemodialysis the blood samples will
be drawn pre-HD via the access. Samples will be centrifuged immediately (3000 rpm x 10
minutes), cooled within 1 hour, and stored at -80 degrees C. Pre-dialysis samples will be
tested for high-sensitivity C-Reactive Protein (hsCRP) TNF-α and IL-6 (both ELISA assay,
plasma by sandwich-type immunoassay) levels. Patient demographic and other clinical data will
be recorded, This includes age, race, sex, body surface area, DM, SLE and other connective
tissue diseases, malignancy, history of atherosclerotic diseases (CAD, PVD, CVA), active
infection, history of viral infection with hepatitis B or C, human immunodeficiency virus.
Routine monthly lab results drawn pre-dialysis as part of clinical practice will be recorded,
these include serum albumin, complete blood count, electrolytes, blood urea nitrogen,
creatinine, liver function tests, and lipid profile. Medications will be reviewed for the
presence of ACE-Inhibitors, ARBs, aspirin, NSAIDS, statins. A subjective global assessment
score (SGA) and comorbidity risk score will be performed. (17,18) Date of HD initiation, and
type of HD membrane will be recorded. Clinical events after vascular access surgery will be
monitored, including infection, hospitalization (reason), MI, CVA. Outcomes to be recorded
will include access survival (primary and secondary patency), patient mortality (all-cause,
infectious and cardiovascular).
Data Management and Analysis: Differences in hs-CRP, TNF-α and IL-6 levels between the 3
vascular access groups for all time periods (baseline, 1 week, 1, 3, 6,12 months) will be
analyzed using a random effects (mixed) model, with time as a random effect. A Power analysis
was performed by Kathrine Freeman, PhD in the Department of Biostatistics and Epidemiology at
Montefiore Medical Center, using multiple comparisons between groups. We hypothesize a 100%
increase in hsCRP level from baseline in the catheter group and a 10% increase in the AVF
group. We predict that the AVG group will have an increase in hs CRP between 10-100%. The
initial power analysis (80%, 2-tailed α=0.05) predicted that 51 subjects per group would be
needed. Anticipating a 20% dropout rate per year, we will recruit 61 subjects will be
required in each group. All hsCRP data will be transformed, most likely using a log scale, as
per prior studies and upon review of the distribution of the data. Dunnett's multiple
comparison procedure will be performed for the 2 contrasts (each group, ie. the AVF and AVG
groups, compared with the tunneled catheter group. A multivariate analysis using a mixed
effects model will be performed to determine the factors related to a change in CRP level at
baseline and at 1 week, 3, 6, 12 months. Patient and access survival will be analyzed using
Kaplan-Meier method and Cox proportional hazards regression analysis.
Blood specimens will be stored in a -70 freezer in Dr. Joel Neugarten's lab, Moses 6th floor
laboratories. Patient charts will be coded and stored in a locked file cabinet in Dr.
Mokrzycki's office, Centennial 4th floor at Montefiore Medical Center. One of the
co-investigators will perform the sandwich immunoassays for hsCRP, TNF-α and IL-6 in Dr.
Victor Schuster's lab, Ullman Building 6th floor.
Implementation plan/timetable: Enrollment of subjects by Dr. Mala Sachdeva, and Peter Durkin,
PA will begin once the protocol has been approved by the IRB. The sites of patient
identification and enrollment, and baseline specimens will be the Renal Clinics at Montefiore
and Weiler Hospitals, and from the Renal Faculty practices. Follow-up specimens will be drawn
at the above sites, while the patients are pre-hemodialysis, and will be drawn before the
dialysis session for patients already receiving hemodialysis. Both preliminary and follow-up
data entry will be performed by Dr. Mala Sachdeva using SPSS. Patient charts/records and
specimens will be coded to ensure confidentiality. Specimens and charts will be stored as
described above. Data analysis will be performed by Dr. Mokrzycki, Dr. Sachdeva and Dr
Kathrine Freeman. The anticipated duration of the study is 3 years: approximately 2 years for
patient enrollment and 1 year of follow-up data and time for data analysis.
