<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03231410</url>
  </required_header>
  <id_info>
    <org_study_id>WroclawMU</org_study_id>
    <nct_id>NCT03231410</nct_id>
  </id_info>
  <brief_title>Role of Monocytes Adhesion and Vascular Lesions in Vascular Access Success or Failure in Uremic Patients</brief_title>
  <acronym>ROMAVAS</acronym>
  <official_title>Role of Monocytes Adhesion and Vascular Lesions in Vascular Access Success or Failure in Uremic Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wroclaw Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Universitätsklinikum Halle</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Wroclaw Medical University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is designed to identify novel predictors of vascular access success or failure in&#xD;
      chronic kidney disease patients. Despite efforts to improve placement of arteriovenous&#xD;
      fistula (AVF) the primary failure rates are reported as high as 20-50%, but standard tools&#xD;
      like ultrasound cannot inform the clinician sufficiently to accurately predict success or&#xD;
      failure.&#xD;
&#xD;
      The aim of this study is to perform enhanced assessments of arterial health preoperatively&#xD;
      and correlate these measurements with vascular lesions (microscopic tissue changes and&#xD;
      monocyte infiltration) and early AVF outcome.&#xD;
&#xD;
      Activation of monocytes in uremia condition is responsible for endothelium dysfunction,&#xD;
      intimal hyperplasia and atherosclerosis. The investigators expect that stiff arteries caused&#xD;
      by monocyte dysfunction refer to the poor distensability and probably longer maturation time.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Research Project Objectives&#xD;
&#xD;
      For patients with progressive chronic kidney disease the definitive treatment is a renal&#xD;
      replacement therapy. One of the methods is hemodialysis, which is frequently chosen in&#xD;
      patients above 65y. of age. Several clinical practice guidelines recommend an arteriovenous&#xD;
      fistula (AVF), rather than a central venous catheter or arteriovenous graft, as the preferred&#xD;
      access for maintenance hemodialysis (HD) therapy. Despite efforts to improve placement of AVF&#xD;
      in both the hemodialysis incident and prevalent population, many patients continue dialysis&#xD;
      through a central venous catheter, exposing them to higher risks of infection, co-morbidity&#xD;
      and mortality in comparison to use an AVF for HD. Furthermore, AVF primary failure rates are&#xD;
      reportedly as high in 20-50% in published series confirming that ultrasound cannot&#xD;
      sufficiently inform the clinician to accurately predict success or failure. Because of higher&#xD;
      risk of early AVF failure offering this type of access is questionable in diabetics,&#xD;
      unfavorable artery/vein diameter and elderly people. To perform hemodialysis vascular access&#xD;
      ensuring adequate blood flow is required. Such access is most commonly obtained by the&#xD;
      creation of the vascular connection between an artery and a vein on the upper limb. Recent&#xD;
      data from European and National registries clearly indicate huge increase of incident&#xD;
      dialysis patients above 65y. In older patients with many co-morbidities and limited&#xD;
      predictive survival decision whether to start dialysis, when and how should be cautious. When&#xD;
      choosing vascular access fistula non-maturation problem must be taken into account. The&#xD;
      successful creation of a permanent vascular access depends on vessel health, patient&#xD;
      characteristics and possibly genetic factors. In patients with end stage renal disease&#xD;
      circulating monocytes are activated and proinflammatory monocytes are expanded. Recent data&#xD;
      indicates that uremic conditions drive monocytes to differentiate and interact with artery&#xD;
      wall promoting atherosclerosis. This interaction can be studied in the laboratory by testing&#xD;
      inﬂammatory activity of THP-1 monocytes and by checking proatherosclerotic and calcification&#xD;
      markers in the artery specimen (taken during AVF creation).&#xD;
&#xD;
      Research hypothesis: monocytes activation and advancement of vascular lesions affect the&#xD;
      process of remodeling (maturation) of arteriovenous fistula, determines its usability&#xD;
      (functionality). The investigators also hypothesize that an increase in the collagen content&#xD;
      of the vascular media (medial fibrosis) preoperatively would impair vascular dilation and&#xD;
      thereby, limit the postoperative increase in arteriovenous fistula diameter, blood flow and&#xD;
      finally AVF maturation.&#xD;
&#xD;
      Working second hypothesis: the metrical age of patient with mild to moderate vascular lesions&#xD;
      is not limiting factor in AVF success rate and maturation.&#xD;
&#xD;
      The main aim of the study is assessment of changes in the vessels and monocyte activation and&#xD;
      its impact on the ability to create AVF and its usability for hemodialysis. Secondary&#xD;
      objective of this study is to perform enhanced assessments of arterial health preoperatively&#xD;
      and correlate these measurements with vascular lesions. The investigators intend to perform&#xD;
      preoperative vascular mapping, flow mediated dilatation (FMD) and assess endothelial&#xD;
      function. These non invasive measurements will provide a more accurate picture of overall&#xD;
      vascular health prior to AVF formation with the ultimate intention of informing the clinician&#xD;
      as to the likelihood of success or failure.&#xD;
&#xD;
      Work plan&#xD;
&#xD;
      Participants will be subjects of a thorough evaluation of the morphological and functional&#xD;
      state of upper limb vessels by the techniques presented in the methodology of the study. The&#xD;
      study plan foresees the recruitment of patients, whose will have their vessels of the upper&#xD;
      limbs carried out in-depth assessment. Then creation of the vascular access - arteriovenous&#xD;
      fistula for dialysis, will be performed. Arterial and venous specimens will be sampled during&#xD;
      arteriovenous fistula surgery. Its maturation will be evaluated in a conventional manner&#xD;
      (functional fistula allowing delivery of adequate dialysis dose) as well as using criteria&#xD;
      mentioned in the publications.&#xD;
&#xD;
      Study design Prospective study with recruitment of consecutive approximately 30 patients with&#xD;
      chronic kidney disease stage 4 or 5, who will be referred for vascular access creation for&#xD;
      hemodialysis.&#xD;
&#xD;
      Inclusion: (1) Aged &gt;18 years, (2) Has chronic kidney disease with estimated glomerular&#xD;
      filtration rate (eGFR) &lt;20 mL/min/1.73 m2 , (3) Is undergoing AVF creation with venous&#xD;
      end-to-arterial side anastomosis in the upper extremity.&#xD;
&#xD;
      Exclusion: (1) Heart failure of New York Heart Association functional class III or IV, and&#xD;
      (2) Episode of cardio- or cerebrovascular event or receiving intervention therapy within 3&#xD;
      months prior to screening. The need for any interventional procedure (surgery or angioplasty)&#xD;
      to correct an occlusive or malfunctioning fistula.&#xD;
&#xD;
      After obtaining an informed consent to participate in the study each participant will be&#xD;
      tested with followed measures.&#xD;
&#xD;
      Study measures&#xD;
&#xD;
      Demographic and clinical characteristic will be collected during interview (family longevity,&#xD;
      hospitalizations, history of vein cannulation) and based on medical records (cardiac events&#xD;
      including angiographic studies, cancer, diabetes, peripheral artery diseases, dementia and&#xD;
      other co-morbidities. Physical examination focused on heart function (blood pressure in two&#xD;
      positions, heart rate, congestion in auscultation and chest as well as vascular anatomy&#xD;
      examination with Allen test (patency of palmar arch), pulse presence, veins patency with and&#xD;
      without stasis.&#xD;
&#xD;
      Imaging studies&#xD;
&#xD;
      Ultrasound condition of vessel will be evaluated prior AVF creation (upper arms flow,&#xD;
      diameter of arteries and veins, possible stenosis, etc) and in follow up period (day 1, 14,&#xD;
      30). In selected cases (history of previous subclavian vein catheterization, collateral&#xD;
      circulation developed) venography will be performed.&#xD;
&#xD;
      Histomorphology and immunomorphology of the vessels&#xD;
&#xD;
      Arterial and venous specimens will be stained. Following markers will be used for&#xD;
      immunomorphology assessment. Pro-atherosclerotic molecules (ACE/ACE2, VCAM-1, ICAM-1)&#xD;
      expression in artery and vein (1-2mm section taken during surgery) which undergo immediate&#xD;
      freezing. Masson's trichrome-staining of samples will be used to quantify medial fibrosis&#xD;
      (collagen) both the artery and the vein.&#xD;
&#xD;
      Whole blood parameters for circulating molecules/cells&#xD;
&#xD;
      Blood samples will be taken at routine control, or before routine dialysis session in HD&#xD;
      patients (referred for AVF placement). Samples will be collected and stored before the AVF.&#xD;
      Following vascular biomarkers will be assessed by enzyme-linked immunosorbent assays:ADMA and&#xD;
      sICAM1, sVCAM1. For HO-1 gene polymorphism genotyping blood sample will be collected ones. It&#xD;
      will be evaluated by Real Time PCR (frozen DNA samples).&#xD;
&#xD;
      Leukocytic RNA, serum and isolation of primary human monocytes&#xD;
&#xD;
      Blood samples for RNA and serum isolation will be obtained from ESRD/HD patients. Blood&#xD;
      samples for leukocytic RNA isolation will be drawn into Tempus Blood RNA Tubes (Life&#xD;
      Technologies). Total RNA is isolated with Tempus Spin RNA Isolation Kits according to the&#xD;
      manufacturer's instructions (Life Technologies). Transcripts of genes related to&#xD;
      calcification (osteopontin, osteokalcin, RunX2), inflammation (TNFa, IL6) and atherosclerosis&#xD;
      (ACE/ACE2, VCAM-1, ICAM-1) processes will be assessed.&#xD;
&#xD;
      Adhesion and transmigration assays&#xD;
&#xD;
      Another in vitro test is designed for adhesion/invasion of THP-1 monocytes. It will test&#xD;
      aggressive properties of monocytes infiltration endothelium. Adhesion of THP-1 monocytes to&#xD;
      endothelial HUVEC monolayers and all transmigration assays will be performed.&#xD;
&#xD;
      Vascular Functional tests&#xD;
&#xD;
      A number of measures are available to assess vascular function (and predict cardiovascular&#xD;
      risk) such as flow mediated dilation (FMD) or peak blood flow (PBF) of the brachial artery.&#xD;
      FMD provides an assessment of macrovascular endothelial cell function. Healthy endothelium&#xD;
      releases a potent vasodilator (nitric oxide, NO) in response to ischemic stress such as cuff&#xD;
      occlusion of the brachial artery. FMD is a measure of the change in the brachial artery&#xD;
      diameter in response to cuff occlusion and subsequent NO release. Whereas FMD reflects the&#xD;
      ability of a large artery to vasodilate, the subsequent change in blood flow that ensues&#xD;
      represents the health of the peripheral resistance vessels or microvascular function.&#xD;
&#xD;
      Above mentioned vascular tests will be conducted to assess endothelial dysfunction. The&#xD;
      absolute increase in diameter after ischemia (BAD, brachial artery diameter), peak blood flow&#xD;
      (PBF) and flow-mediated dilation (FMD) will be performed on both arms at day 0 (pre AVF&#xD;
      creation), and then at day 1, 14-28 (opposite to AVF arm). The measurement will be performed&#xD;
      according to published standard protocol for FMD measurement using Aloka alpha 7 USG device&#xD;
      with Doppler linear probe.&#xD;
&#xD;
      Routine laboratory parameters collected at baseline and during follow-up (14-28, 56-60, 90&#xD;
      day): Complete blood counts with focus on neutrophil-lymphocyte ratio (NLR), phosphorus,&#xD;
      calcium, PTH, C-reactive protein (CRP), urea acid, lipids (cholesterol fractions,&#xD;
      triglycerides).&#xD;
&#xD;
      Statistical analysis&#xD;
&#xD;
      All participants data from recruitment and follow up will be collected in special designed&#xD;
      computer program. The primary outcome of this study is AVF success (patent and mature) at 8&#xD;
      and 14 weeks post creation. Baseline patient characteristics including age, gender and&#xD;
      co-morbidities will be compared between the patients with successful AVF and those with&#xD;
      unsuccessful AVF. Categorical variables will be presented by frequency (percentage) and&#xD;
      comparisons will be made via the Chi-square or Fisher's Exact test. Underlying distributions&#xD;
      of continuous variables will be tested for normality using the Shapiro-Wilk test and then&#xD;
      analyzed with appropriate tests. All analyses will be performed by external statistical&#xD;
      laboratory with high references. The professional statistical expertise is planned (PREST&#xD;
      laboratory at Mathematical Institute in Wroclaw) with utilization of R package and STATISTICA&#xD;
      10 software.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Anticipated">August 2019</completion_date>
  <primary_completion_date type="Anticipated">June 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Primary patency rate</measure>
    <time_frame>Baseline to 12 months after AVF creation</time_frame>
    <description>Primary patency rate</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hemodialysis AVF blood flow</measure>
    <time_frame>Baseline to 12 months after AVF creation</time_frame>
    <description>Blood flow by Doppler ultrasound on brachial artery (ml/min.)</description>
  </secondary_outcome>
  <enrollment type="Anticipated">30</enrollment>
  <condition>End Stage Renal Disease</condition>
  <condition>Arteriovenous Fistula</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Transcripts of genes related to calcification (osteopontin, osteokalcin, RunX2), inflammation&#xD;
      (TNFa, IL6) and atherosclerosis (ACE/ACE2, VCAM-1, ICAM-1) processes will be assessed.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Prospective study with recruitment of consecutive 30 patients with chronic kidney disease&#xD;
        stage 4 or 5, who will be referred for vascular access creation for hemodialysis.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  aged &gt;18 years,&#xD;
&#xD;
          -  chronic kidney disease with estimated glomerular filtration rate (eGFR) &lt;20&#xD;
             mL/min/1.73 m2,&#xD;
&#xD;
          -  undergoing AVF creation with venous end-to-arterial side anastomosis in the upper&#xD;
             extremity.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Heart failure of New York Heart Association functional class III or IV,&#xD;
&#xD;
          -  Episode of cardio- or cerebrovascular event or receiving intervention therapy within 3&#xD;
             months prior to screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tomasz Gołębiowski, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Nephrology and Transplantation Medicine, Wroclaw Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mariusz Kusztal, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Department of Nephrology and Transplantation Medicine, Wroclaw Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Krzysztof Letachowicz, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Nephrology and Transplantation Medicine, Wroclaw Medical University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Tomasz Gołębiowski, MD, PhD</last_name>
    <phone>+48 71 7332546</phone>
    <email>tgolebiowski@op.pl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mariusz Kusztal, MD, PhD</last_name>
    <phone>+48 71 7332500</phone>
    <email>mariok@o2.pl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Department of Nephrology and Transplantation Medicine</name>
      <address>
        <city>Wrocław</city>
        <zip>50-556</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tomasz Gołębiowski, MD, PhD</last_name>
      <phone>+48 71 7332546</phone>
      <email>tgolebiowski@op.pl</email>
    </contact>
    <contact_backup>
      <last_name>Mariusz Kusztal, MD, PhD</last_name>
      <phone>+48 71 7332500</phone>
      <email>mariok@o2.pl</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <reference>
    <citation>Tordoir J, Canaud B, Haage P, Konner K, Basci A, Fouque D, Kooman J, Martin-Malo A, Pedrini L, Pizzarelli F, Tattersall J, Vennegoor M, Wanner C, ter Wee P, Vanholder R. EBPG on Vascular Access. Nephrol Dial Transplant. 2007 May;22 Suppl 2:ii88-117. doi: 10.1093/ndt/gfm021. No abstract available.</citation>
    <PMID>17507428</PMID>
  </reference>
  <reference>
    <citation>Roy-Chaudhury P, Kelly BS, Melhem M, Zhang J, Li J, Desai P, Munda R, Heffelfinger SC. Vascular access in hemodialysis: issues, management, and emerging concepts. Cardiol Clin. 2005 Aug;23(3):249-73. doi: 10.1016/j.ccl.2005.04.004.</citation>
    <PMID>16084276</PMID>
  </reference>
  <reference>
    <citation>Trojanowicz B, Ulrich C, Seibert E, Fiedler R, Girndt M. Uremic conditions drive human monocytes to pro-atherogenic differentiation via an angiotensin-dependent mechanism. PLoS One. 2014 Jul 8;9(7):e102137. doi: 10.1371/journal.pone.0102137. eCollection 2014.</citation>
    <PMID>25003524</PMID>
  </reference>
  <reference>
    <citation>Himmelfarb J. Uremic toxicity, oxidative stress, and hemodialysis as renal replacement therapy. Semin Dial. 2009 Nov-Dec;22(6):636-43. doi: 10.1111/j.1525-139X.2009.00659.x.</citation>
    <PMID>20017834</PMID>
  </reference>
  <reference>
    <citation>Zickler D, Willy K, Girndt M, Fiedler R, Martus P, Storr M, Schindler R. High cut-off dialysis in chronic haemodialysis patients reduces serum procalcific activity. Nephrol Dial Transplant. 2016 Oct;31(10):1706-12. doi: 10.1093/ndt/gfw293. Epub 2016 Jul 20.</citation>
    <PMID>27445317</PMID>
  </reference>
  <reference>
    <citation>Stoner L, Sabatier MJ. Use of ultrasound for non-invasive assessment of flow-mediated dilation. J Atheroscler Thromb. 2012;19(5):407-21. doi: 10.5551/jat.11395. Epub 2012 Mar 1.</citation>
    <PMID>22659525</PMID>
  </reference>
  <reference>
    <citation>Yilmaz MI, Stenvinkel P, Sonmez A, Saglam M, Yaman H, Kilic S, Eyileten T, Caglar K, Oguz Y, Vural A, Cakar M, Altun B, Yenicesu M, Carrero JJ. Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes. Nephrol Dial Transplant. 2011 Nov;26(11):3537-43. doi: 10.1093/ndt/gfr081. Epub 2011 Mar 4.</citation>
    <PMID>21378154</PMID>
  </reference>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>July 16, 2017</study_first_submitted>
  <study_first_submitted_qc>July 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2017</study_first_posted>
  <last_update_submitted>May 20, 2018</last_update_submitted>
  <last_update_submitted_qc>May 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 22, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Wroclaw Medical University</investigator_affiliation>
    <investigator_full_name>Tomasz Gołębiowski</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>arteriovenous fistula</keyword>
  <keyword>maturation</keyword>
  <keyword>monocyte adhesion</keyword>
  <keyword>vascular access</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Failure, Chronic</mesh_term>
    <mesh_term>Arteriovenous Fistula</mesh_term>
    <mesh_term>Fistula</mesh_term>
    <mesh_term>Tissue Adhesions</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03231410
org study id: WroclawMU
nct id: NCT03231410
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study is designed to identify novel predictors of vascular access success or failure in
      chronic kidney disease patients. Despite efforts to improve placement of arteriovenous
      fistula (AVF) the primary failure rates are reported as high as 20-50%, but standard tools
      like ultrasound cannot inform the clinician sufficiently to accurately predict success or
      failure.

      The aim of this study is to perform enhanced assessments of arterial health preoperatively
      and correlate these measurements with vascular lesions (microscopic tissue changes and
      monocyte infiltration) and early AVF outcome.

      Activation of monocytes in uremia condition is responsible for endothelium dysfunction,
      intimal hyperplasia and atherosclerosis. The investigators expect that stiff arteries caused
      by monocyte dysfunction refer to the poor distensability and probably longer maturation time.
Research Project Objectives

      For patients with progressive chronic kidney disease the definitive treatment is a renal
      replacement therapy. One of the methods is hemodialysis, which is frequently chosen in
      patients above 65y. of age. Several clinical practice guidelines recommend an arteriovenous
      fistula (AVF), rather than a central venous catheter or arteriovenous graft, as the preferred
      access for maintenance hemodialysis (HD) therapy. Despite efforts to improve placement of AVF
      in both the hemodialysis incident and prevalent population, many patients continue dialysis
      through a central venous catheter, exposing them to higher risks of infection, co-morbidity
      and mortality in comparison to use an AVF for HD. Furthermore, AVF primary failure rates are
      reportedly as high in 20-50% in published series confirming that ultrasound cannot
      sufficiently inform the clinician to accurately predict success or failure. Because of higher
      risk of early AVF failure offering this type of access is questionable in diabetics,
      unfavorable artery/vein diameter and elderly people. To perform hemodialysis vascular access
      ensuring adequate blood flow is required. Such access is most commonly obtained by the
      creation of the vascular connection between an artery and a vein on the upper limb. Recent
      data from European and National registries clearly indicate huge increase of incident
      dialysis patients above 65y. In older patients with many co-morbidities and limited
      predictive survival decision whether to start dialysis, when and how should be cautious. When
      choosing vascular access fistula non-maturation problem must be taken into account. The
      successful creation of a permanent vascular access depends on vessel health, patient
      characteristics and possibly genetic factors. In patients with end stage renal disease
      circulating monocytes are activated and proinflammatory monocytes are expanded. Recent data
      indicates that uremic conditions drive monocytes to differentiate and interact with artery
      wall promoting atherosclerosis. This interaction can be studied in the laboratory by testing
      inﬂammatory activity of THP-1 monocytes and by checking proatherosclerotic and calcification
      markers in the artery specimen (taken during AVF creation).

      Research hypothesis: monocytes activation and advancement of vascular lesions affect the
      process of remodeling (maturation) of arteriovenous fistula, determines its usability
      (functionality). The investigators also hypothesize that an increase in the collagen content
      of the vascular media (medial fibrosis) preoperatively would impair vascular dilation and
      thereby, limit the postoperative increase in arteriovenous fistula diameter, blood flow and
      finally AVF maturation.

      Working second hypothesis: the metrical age of patient with mild to moderate vascular lesions
      is not limiting factor in AVF success rate and maturation.

      The main aim of the study is assessment of changes in the vessels and monocyte activation and
      its impact on the ability to create AVF and its usability for hemodialysis. Secondary
      objective of this study is to perform enhanced assessments of arterial health preoperatively
      and correlate these measurements with vascular lesions. The investigators intend to perform
      preoperative vascular mapping, flow mediated dilatation (FMD) and assess endothelial
      function. These non invasive measurements will provide a more accurate picture of overall
      vascular health prior to AVF formation with the ultimate intention of informing the clinician
      as to the likelihood of success or failure.

      Work plan

      Participants will be subjects of a thorough evaluation of the morphological and functional
      state of upper limb vessels by the techniques presented in the methodology of the study. The
      study plan foresees the recruitment of patients, whose will have their vessels of the upper
      limbs carried out in-depth assessment. Then creation of the vascular access - arteriovenous
      fistula for dialysis, will be performed. Arterial and venous specimens will be sampled during
      arteriovenous fistula surgery. Its maturation will be evaluated in a conventional manner
      (functional fistula allowing delivery of adequate dialysis dose) as well as using criteria
      mentioned in the publications.

      Study design Prospective study with recruitment of consecutive approximately 30 patients with
      chronic kidney disease stage 4 or 5, who will be referred for vascular access creation for
      hemodialysis.

      Inclusion: (1) Aged >18 years, (2) Has chronic kidney disease with estimated glomerular
      filtration rate (eGFR) <20 mL/min/1.73 m2 , (3) Is undergoing AVF creation with venous
      end-to-arterial side anastomosis in the upper extremity.

      Exclusion: (1) Heart failure of New York Heart Association functional class III or IV, and
      (2) Episode of cardio- or cerebrovascular event or receiving intervention therapy within 3
      months prior to screening. The need for any interventional procedure (surgery or angioplasty)
      to correct an occlusive or malfunctioning fistula.

      After obtaining an informed consent to participate in the study each participant will be
      tested with followed measures.

      Study measures

      Demographic and clinical characteristic will be collected during interview (family longevity,
      hospitalizations, history of vein cannulation) and based on medical records (cardiac events
      including angiographic studies, cancer, diabetes, peripheral artery diseases, dementia and
      other co-morbidities. Physical examination focused on heart function (blood pressure in two
      positions, heart rate, congestion in auscultation and chest as well as vascular anatomy
      examination with Allen test (patency of palmar arch), pulse presence, veins patency with and
      without stasis.

      Imaging studies

      Ultrasound condition of vessel will be evaluated prior AVF creation (upper arms flow,
      diameter of arteries and veins, possible stenosis, etc) and in follow up period (day 1, 14,
      30). In selected cases (history of previous subclavian vein catheterization, collateral
      circulation developed) venography will be performed.

      Histomorphology and immunomorphology of the vessels

      Arterial and venous specimens will be stained. Following markers will be used for
      immunomorphology assessment. Pro-atherosclerotic molecules (ACE/ACE2, VCAM-1, ICAM-1)
      expression in artery and vein (1-2mm section taken during surgery) which undergo immediate
      freezing. Masson's trichrome-staining of samples will be used to quantify medial fibrosis
      (collagen) both the artery and the vein.

      Whole blood parameters for circulating molecules/cells

      Blood samples will be taken at routine control, or before routine dialysis session in HD
      patients (referred for AVF placement). Samples will be collected and stored before the AVF.
      Following vascular biomarkers will be assessed by enzyme-linked immunosorbent assays:ADMA and
      sICAM1, sVCAM1. For HO-1 gene polymorphism genotyping blood sample will be collected ones. It
      will be evaluated by Real Time PCR (frozen DNA samples).

      Leukocytic RNA, serum and isolation of primary human monocytes

      Blood samples for RNA and serum isolation will be obtained from ESRD/HD patients. Blood
      samples for leukocytic RNA isolation will be drawn into Tempus Blood RNA Tubes (Life
      Technologies). Total RNA is isolated with Tempus Spin RNA Isolation Kits according to the
      manufacturer's instructions (Life Technologies). Transcripts of genes related to
      calcification (osteopontin, osteokalcin, RunX2), inflammation (TNFa, IL6) and atherosclerosis
      (ACE/ACE2, VCAM-1, ICAM-1) processes will be assessed.

      Adhesion and transmigration assays

      Another in vitro test is designed for adhesion/invasion of THP-1 monocytes. It will test
      aggressive properties of monocytes infiltration endothelium. Adhesion of THP-1 monocytes to
      endothelial HUVEC monolayers and all transmigration assays will be performed.

      Vascular Functional tests

      A number of measures are available to assess vascular function (and predict cardiovascular
      risk) such as flow mediated dilation (FMD) or peak blood flow (PBF) of the brachial artery.
      FMD provides an assessment of macrovascular endothelial cell function. Healthy endothelium
      releases a potent vasodilator (nitric oxide, NO) in response to ischemic stress such as cuff
      occlusion of the brachial artery. FMD is a measure of the change in the brachial artery
      diameter in response to cuff occlusion and subsequent NO release. Whereas FMD reflects the
      ability of a large artery to vasodilate, the subsequent change in blood flow that ensues
      represents the health of the peripheral resistance vessels or microvascular function.

      Above mentioned vascular tests will be conducted to assess endothelial dysfunction. The
      absolute increase in diameter after ischemia (BAD, brachial artery diameter), peak blood flow
      (PBF) and flow-mediated dilation (FMD) will be performed on both arms at day 0 (pre AVF
      creation), and then at day 1, 14-28 (opposite to AVF arm). The measurement will be performed
      according to published standard protocol for FMD measurement using Aloka alpha 7 USG device
      with Doppler linear probe.

      Routine laboratory parameters collected at baseline and during follow-up (14-28, 56-60, 90
      day): Complete blood counts with focus on neutrophil-lymphocyte ratio (NLR), phosphorus,
      calcium, PTH, C-reactive protein (CRP), urea acid, lipids (cholesterol fractions,
      triglycerides).

      Statistical analysis

      All participants data from recruitment and follow up will be collected in special designed
      computer program. The primary outcome of this study is AVF success (patent and mature) at 8
      and 14 weeks post creation. Baseline patient characteristics including age, gender and
      co-morbidities will be compared between the patients with successful AVF and those with
      unsuccessful AVF. Categorical variables will be presented by frequency (percentage) and
      comparisons will be made via the Chi-square or Fisher's Exact test. Underlying distributions
      of continuous variables will be tested for normality using the Shapiro-Wilk test and then
      analyzed with appropriate tests. All analyses will be performed by external statistical
      laboratory with high references. The professional statistical expertise is planned (PREST
      laboratory at Mathematical Institute in Wroclaw) with utilization of R package and STATISTICA
      10 software.
observational model: Case-Control
time perspective: Prospective
measure: Primary patency rate
time frame: Baseline to 12 months after AVF creation
description: Primary patency rate
measure: Hemodialysis AVF blood flow
time frame: Baseline to 12 months after AVF creation
description: Blood flow by Doppler ultrasound on brachial artery (ml/min.)
Transcripts of genes related to calcification (osteopontin, osteokalcin, RunX2), inflammation
      (TNFa, IL6) and atherosclerosis (ACE/ACE2, VCAM-1, ICAM-1) processes will be assessed.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Tomasz Gołębiowski, MD, PhD
role: Principal Investigator
affiliation: Department of Nephrology and Transplantation Medicine, Wroclaw Medical University
last name: Mariusz Kusztal, MD, PhD
role: Study Director
affiliation: Department of Nephrology and Transplantation Medicine, Wroclaw Medical University
last name: Krzysztof Letachowicz, MD, PhD
role: Study Chair
affiliation: Department of Nephrology and Transplantation Medicine, Wroclaw Medical University
last name: Tomasz Gołębiowski, MD, PhD
phone: +48 71 7332546
email: tgolebiowski@op.pl
last name: Mariusz Kusztal, MD, PhD
phone: +48 71 7332500
email: mariok@o2.pl
facility: 
status: Recruiting
contact: 
contact backup: 
country: Poland
citation: Tordoir J, Canaud B, Haage P, Konner K, Basci A, Fouque D, Kooman J, Martin-Malo A, Pedrini L, Pizzarelli F, Tattersall J, Vennegoor M, Wanner C, ter Wee P, Vanholder R. EBPG on Vascular Access. Nephrol Dial Transplant. 2007 May;22 Suppl 2:ii88-117. doi: 10.1093/ndt/gfm021. No abstract available.
PMID: 17507428
citation: Roy-Chaudhury P, Kelly BS, Melhem M, Zhang J, Li J, Desai P, Munda R, Heffelfinger SC. Vascular access in hemodialysis: issues, management, and emerging concepts. Cardiol Clin. 2005 Aug;23(3):249-73. doi: 10.1016/j.ccl.2005.04.004.
PMID: 16084276
citation: Trojanowicz B, Ulrich C, Seibert E, Fiedler R, Girndt M. Uremic conditions drive human monocytes to pro-atherogenic differentiation via an angiotensin-dependent mechanism. PLoS One. 2014 Jul 8;9(7):e102137. doi: 10.1371/journal.pone.0102137. eCollection 2014.
PMID: 25003524
citation: Himmelfarb J. Uremic toxicity, oxidative stress, and hemodialysis as renal replacement therapy. Semin Dial. 2009 Nov-Dec;22(6):636-43. doi: 10.1111/j.1525-139X.2009.00659.x.
PMID: 20017834
citation: Zickler D, Willy K, Girndt M, Fiedler R, Martus P, Storr M, Schindler R. High cut-off dialysis in chronic haemodialysis patients reduces serum procalcific activity. Nephrol Dial Transplant. 2016 Oct;31(10):1706-12. doi: 10.1093/ndt/gfw293. Epub 2016 Jul 20.
PMID: 27445317
citation: Stoner L, Sabatier MJ. Use of ultrasound for non-invasive assessment of flow-mediated dilation. J Atheroscler Thromb. 2012;19(5):407-21. doi: 10.5551/jat.11395. Epub 2012 Mar 1.
PMID: 22659525
citation: Yilmaz MI, Stenvinkel P, Sonmez A, Saglam M, Yaman H, Kilic S, Eyileten T, Caglar K, Oguz Y, Vural A, Cakar M, Altun B, Yenicesu M, Carrero JJ. Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes. Nephrol Dial Transplant. 2011 Nov;26(11):3537-43. doi: 10.1093/ndt/gfr081. Epub 2011 Mar 4.
PMID: 21378154
responsible party type: Principal Investigator
investigator affiliation: Wroclaw Medical University
investigator full name: Tomasz Gołębiowski
investigator title: MD, PhD
mesh term: Kidney Failure, Chronic
mesh term: Arteriovenous Fistula
mesh term: Fistula
mesh term: Tissue Adhesions
sharing ipd: No