A Study Evaluating the Association of Inflammation With Hemodialysis Access Type
Condition: End Stage Renal Disease; Inflammation
MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Inflammation
Study type: Observational

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.
    

Detailed 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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Incident stage 4 and 5 chronic kidney disease patients receiving their first dialysis
        access.
      
Biospecimen description: 
      serum
    
Keywords: end stage renal disease; inflammation; vascular access; hemodialysis