<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/NCT02981992</url>
  </required_header>
  <id_info>
    <org_study_id>20100014090</org_study_id>
    <nct_id>NCT02981992</nct_id>
  </id_info>
  <brief_title>T Regulatory Cells in Hemodialysis Patients: Observational Study</brief_title>
  <official_title>Observational Study on T Regulatory Cells in Hemodialysis Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS Policlinico S. Matteo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IRCCS Policlinico S. Matteo</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this observational study, the investigators evaluated the Treg number and function in a&#xD;
      population of patients undergoing hemodialysis (HD).&#xD;
&#xD;
      In particular, the investigators considered the relationship of Treg cell status with the&#xD;
      different HD modalities and clinical parameters.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients on hemodialysis (HD) present an elevated risk of cardiovascular disease, cancer and&#xD;
      infectious events that may lead to the high morbidity and mortality rate characteristic of&#xD;
      this population. Many causes can explain this increased risk, including inflammation that, in&#xD;
      turn, might be secondary to dialysis-specific factors, such as contaminated water, dialysis&#xD;
      modality and dialysis membranes used for treatment.&#xD;
&#xD;
      In addition to chronic inflammatory, in HD patients is also present a significant alteration&#xD;
      of the immune system resulting in chronic lymphocytic infiltration, alteration of T-helper&#xD;
      balance (Th1/Th2) etc. The immune response is controlled by very complex mechanisms; it is&#xD;
      mediated by interaction between antigen-presenting cells (APC), CD4+ T helper (Th) and T&#xD;
      cells CD4+ CD25+ regulatory (Treg), a cell subpopulation of T CD4+ expressing the IL-2&#xD;
      receptor (CD25) and forkhead factor (foxp 3). Treg cells contribute to the maintenance of&#xD;
      peripheral tolerance by suppressing the immune response to self-normal or tumor antigens.&#xD;
      Treg cells control population's expansion of peripheral cells and suppress the proliferation&#xD;
      of Th activated cells. Accessory molecules such as CTLA-4 receptors, CD28 and IL-2 cytokines&#xD;
      and IL-6, contribute to the activation and proliferation of Treg cells.&#xD;
&#xD;
      The characterization by flow cytometry of Treg suffered for a lack of specific surface&#xD;
      markers. These cells are generally identified on the basis of contemporary expression of&#xD;
      molecules CD4 and CD25, but the specificity of these markers is limited, given that the CD25&#xD;
      is also expressed on activated lymphocytes. Recently it has been showed that the expression&#xD;
      of Foxp3 gene is a phenomenon strictly linked to the development of regulatory activity of&#xD;
      Treg, and so, the extent of the expression of this gene by Real Time PCR is currently&#xD;
      considered the most specific Treg marker. There is very poor data on Treg cells function in&#xD;
      HD. A recent study shows that in patients on chronic HD, the number of Treg is lower if&#xD;
      compared to healthy subjects. Moreover, the Treg cells of patients on HD would present a&#xD;
      significant impairment of their function, assessed as the ability to inhibit lymphocyte&#xD;
      proliferation.&#xD;
&#xD;
      Those results, however, are affected by the lack of data on the characteristics of the&#xD;
      studied patients and the type of dialysis treatment applied. In contrast, a recent study by&#xD;
      our group showed that patients on hemodialysis with poor biocompatible membranes have a&#xD;
      greater number of circulating Treg compared with healthy controls matched for age and sex.&#xD;
&#xD;
      Given the absence of other data, it still remains to investigate the actual significance and&#xD;
      function of Treg in HD, considering that Treg status might potentially affect the immune&#xD;
      response.&#xD;
&#xD;
      Therefore, the purpose of this study was to evaluate the structure and function of Treg cells&#xD;
      in patients undergoing HD, also considering their relationship with the different HD&#xD;
      modalities and clinical parameters.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>February 2011</start_date>
  <completion_date type="Actual">February 2016</completion_date>
  <primary_completion_date type="Actual">February 2014</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Treg number</measure>
    <time_frame>Assessment of Treg number at basal control and then every 3 months for a total study period of 12 months</time_frame>
    <description>Assessment of the number of Treg by flow cytometry.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treg function</measure>
    <time_frame>Assessment of Treg function at basal control and then every 3 months for a total study period of 12 months</time_frame>
    <description>Evaluation of Treg function by measuring the ability to inhibit cell proliferation in the context of a mixed lymphocyte reaction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of dialysis modality</measure>
    <time_frame>Analysis of the number and function of Treg cells in function of the type of dialysis treatment at basal control and then every 6 months for a total study period of 12 months</time_frame>
    <description>Evaluation of the number and function of Treg cells before and after dialysis (by flow cytometry and in vitro experiments), as a function of the type of dialysis treatment by use of multivariate regression models</description>
  </secondary_outcome>
  <enrollment type="Actual">30</enrollment>
  <condition>Haemodialysis Complication</condition>
  <condition>Immune Dysfunction</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Sample used to evaluate T cell subpopulations&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        A total number of 30 prevalent patients undergoing chronic renal replacement terapy with&#xD;
        hemodialysis (HD) has been included in the evaluation. The study duration was 12 months,&#xD;
        with a check of the number and function of Treg every 3 months.&#xD;
&#xD;
        During the study patients were subjected to dialysis and farmacology treatment as usual,&#xD;
        without any alteration linked specifically to this protocol. The number and function of&#xD;
        Treg were measured as a percentage of CD4+CD25bright+pre-dialysis in the last week of each&#xD;
        third month of the study.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with spKt/V ≥ 1,2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cancer&#xD;
&#xD;
          -  Pregnant or breastfeeding&#xD;
&#xD;
          -  Sepsis&#xD;
&#xD;
          -  Kidney or other organ transplant&#xD;
&#xD;
          -  Major cardiovascular events in the previous 3 months&#xD;
&#xD;
          -  Patients unable to understand or interdicted&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carmelo Libetta, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fondazione Policlinico &quot;San Matteo&quot;, Pavia- Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fondazione Policlinico &quot;San Matteo&quot;</name>
      <address>
        <city>Pavia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Hendrikx TK, van Gurp EA, Mol WM, Schoordijk W, Sewgobind VD, Ijzermans JN, Weimar W, Baan CC. End-stage renal failure and regulatory activities of CD4+CD25bright+FoxP3+ T-cells. Nephrol Dial Transplant. 2009 Jun;24(6):1969-78. doi: 10.1093/ndt/gfp005. Epub 2009 Feb 4.</citation>
    <PMID>19193737</PMID>
  </reference>
  <reference>
    <citation>Sewgobind VD, van der Laan LJ, Kho MM, Kraaijeveld R, Korevaar SS, van Dam T, Ijzermans JN, Weimar W, Baan CC. Characterization of rabbit antithymocyte globulins-induced CD25+ regulatory T cells from cells of patients with end-stage renal disease. Transplantation. 2010 Mar 27;89(6):655-66. doi: 10.1097/TP.0b013e3181c9cc7a.</citation>
    <PMID>20164820</PMID>
  </reference>
  <reference>
    <citation>Sharif MR, Chitsazian Z, Moosavian M, Raygan F, Nikoueinejad H, Sharif AR, Einollahi B. Immune disorders in hemodialysis patients. Iran J Kidney Dis. 2015 Mar;9(2):84-96.</citation>
    <PMID>25851286</PMID>
  </reference>
  <reference>
    <citation>Uda S, Mizobuchi M, Akizawa T. Biocompatible characteristics of high-performance membranes. Contrib Nephrol. 2011;173:23-29. doi: 10.1159/000328941. Epub 2011 Aug 8.</citation>
    <PMID>21865772</PMID>
  </reference>
  <results_reference>
    <citation>Libetta C, Esposito P, Sepe V, Portalupi V, Margiotta E, Canevari M, Dal Canton A. Dialysis treatment and regulatory T cells. Nephrol Dial Transplant. 2010 May;25(5):1723-7. doi: 10.1093/ndt/gfq055. Epub 2010 Feb 15. No abstract available.</citation>
    <PMID>20157169</PMID>
  </results_reference>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>November 26, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 5, 2016</study_first_posted>
  <last_update_submitted>December 2, 2016</last_update_submitted>
  <last_update_submitted_qc>December 2, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 5, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>IRCCS Policlinico S. Matteo</investigator_affiliation>
    <investigator_full_name>Carmelo Libetta</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immune System Diseases</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/NCT02981992
org study id: 20100014090
nct id: NCT02981992
lead sponsor: 
has dmc: No
In this observational study, the investigators evaluated the Treg number and function in a
      population of patients undergoing hemodialysis (HD).

      In particular, the investigators considered the relationship of Treg cell status with the
      different HD modalities and clinical parameters.
Patients on hemodialysis (HD) present an elevated risk of cardiovascular disease, cancer and
      infectious events that may lead to the high morbidity and mortality rate characteristic of
      this population. Many causes can explain this increased risk, including inflammation that, in
      turn, might be secondary to dialysis-specific factors, such as contaminated water, dialysis
      modality and dialysis membranes used for treatment.

      In addition to chronic inflammatory, in HD patients is also present a significant alteration
      of the immune system resulting in chronic lymphocytic infiltration, alteration of T-helper
      balance (Th1/Th2) etc. The immune response is controlled by very complex mechanisms; it is
      mediated by interaction between antigen-presenting cells (APC), CD4+ T helper (Th) and T
      cells CD4+ CD25+ regulatory (Treg), a cell subpopulation of T CD4+ expressing the IL-2
      receptor (CD25) and forkhead factor (foxp 3). Treg cells contribute to the maintenance of
      peripheral tolerance by suppressing the immune response to self-normal or tumor antigens.
      Treg cells control population's expansion of peripheral cells and suppress the proliferation
      of Th activated cells. Accessory molecules such as CTLA-4 receptors, CD28 and IL-2 cytokines
      and IL-6, contribute to the activation and proliferation of Treg cells.

      The characterization by flow cytometry of Treg suffered for a lack of specific surface
      markers. These cells are generally identified on the basis of contemporary expression of
      molecules CD4 and CD25, but the specificity of these markers is limited, given that the CD25
      is also expressed on activated lymphocytes. Recently it has been showed that the expression
      of Foxp3 gene is a phenomenon strictly linked to the development of regulatory activity of
      Treg, and so, the extent of the expression of this gene by Real Time PCR is currently
      considered the most specific Treg marker. There is very poor data on Treg cells function in
      HD. A recent study shows that in patients on chronic HD, the number of Treg is lower if
      compared to healthy subjects. Moreover, the Treg cells of patients on HD would present a
      significant impairment of their function, assessed as the ability to inhibit lymphocyte
      proliferation.

      Those results, however, are affected by the lack of data on the characteristics of the
      studied patients and the type of dialysis treatment applied. In contrast, a recent study by
      our group showed that patients on hemodialysis with poor biocompatible membranes have a
      greater number of circulating Treg compared with healthy controls matched for age and sex.

      Given the absence of other data, it still remains to investigate the actual significance and
      function of Treg in HD, considering that Treg status might potentially affect the immune
      response.

      Therefore, the purpose of this study was to evaluate the structure and function of Treg cells
      in patients undergoing HD, also considering their relationship with the different HD
      modalities and clinical parameters.
observational model: Cohort
time perspective: Prospective
measure: Treg number
time frame: Assessment of Treg number at basal control and then every 3 months for a total study period of 12 months
description: Assessment of the number of Treg by flow cytometry.
measure: Treg function
time frame: Assessment of Treg function at basal control and then every 3 months for a total study period of 12 months
description: Evaluation of Treg function by measuring the ability to inhibit cell proliferation in the context of a mixed lymphocyte reaction.
measure: Effect of dialysis modality
time frame: Analysis of the number and function of Treg cells in function of the type of dialysis treatment at basal control and then every 6 months for a total study period of 12 months
description: Evaluation of the number and function of Treg cells before and after dialysis (by flow cytometry and in vitro experiments), as a function of the type of dialysis treatment by use of multivariate regression models
Sample used to evaluate T cell subpopulations
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Carmelo Libetta, Prof
role: Principal Investigator
affiliation: Fondazione Policlinico "San Matteo", Pavia- Italy
facility: 
country: Italy
citation: Hendrikx TK, van Gurp EA, Mol WM, Schoordijk W, Sewgobind VD, Ijzermans JN, Weimar W, Baan CC. End-stage renal failure and regulatory activities of CD4+CD25bright+FoxP3+ T-cells. Nephrol Dial Transplant. 2009 Jun;24(6):1969-78. doi: 10.1093/ndt/gfp005. Epub 2009 Feb 4.
PMID: 19193737
citation: Sewgobind VD, van der Laan LJ, Kho MM, Kraaijeveld R, Korevaar SS, van Dam T, Ijzermans JN, Weimar W, Baan CC. Characterization of rabbit antithymocyte globulins-induced CD25+ regulatory T cells from cells of patients with end-stage renal disease. Transplantation. 2010 Mar 27;89(6):655-66. doi: 10.1097/TP.0b013e3181c9cc7a.
PMID: 20164820
citation: Sharif MR, Chitsazian Z, Moosavian M, Raygan F, Nikoueinejad H, Sharif AR, Einollahi B. Immune disorders in hemodialysis patients. Iran J Kidney Dis. 2015 Mar;9(2):84-96.
PMID: 25851286
citation: Uda S, Mizobuchi M, Akizawa T. Biocompatible characteristics of high-performance membranes. Contrib Nephrol. 2011;173:23-29. doi: 10.1159/000328941. Epub 2011 Aug 8.
PMID: 21865772
citation: Libetta C, Esposito P, Sepe V, Portalupi V, Margiotta E, Canevari M, Dal Canton A. Dialysis treatment and regulatory T cells. Nephrol Dial Transplant. 2010 May;25(5):1723-7. doi: 10.1093/ndt/gfq055. Epub 2010 Feb 15. No abstract available.
PMID: 20157169
responsible party type: Principal Investigator
investigator affiliation: IRCCS Policlinico S. Matteo
investigator full name: Carmelo Libetta
investigator title: Professor
mesh term: Immune System Diseases
sharing ipd: No