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出境医 / 临床实验 / The Renal Transplant Outcome Prediction and Validation Study (TOPVAS)

The Renal Transplant Outcome Prediction and Validation Study (TOPVAS)

Study Description
Brief Summary:

The number of patients with end stage renal disease is increasing continuously and kidney transplantation is the preferred treatment modality. Modern immunosuppressive therapy has reduced the number of acute rejection episodes and increased one year allograft survival dramatically. Nonetheless, 4% of allografts are lost beyond the first year annually due to a multifactorial process and the latter number has not changed for decades. One of the most important factors to determine long-term success after kidney transplantation is the quality of the donor organ. For example, transplantation of organs from elderly or extended criteria donors results in reduced allograft and patient survival.

In previous work, the investigators specifically focused on age-associated molecular signatures including telomere length and mRNA expression levels of the cell cycle inhibitors CDKN2A (p16INK4a) and CDKN1A (p21WAF1) and assessed these parameters in pre-implantation biopsies of 54 patients. In a linear regression analysis CDKN2A turned out to be the best single predictor for serum creatinine after 1 year followed by donor age and telomere length. A multiple linear regression analysis revealed that the combination of CDKN2A values and donor age yielded even higher predictive values. In another study the investigators were able to show an interaction between donor age and use of calcineurin inhibitors with regard to outcome after renal transplantation.

During these past activities an extensive set of whole genome transcriptomics profile information from zero hour biopsies and clinical follow-up data has been collected. In the TOPVAS study, existing data derived from 72 of the above mentioned set of biopsies (exclusion of live donor grafts) will be analysed with state of the art bioinformatical/system biology tools to derive a general (not purely age associated) prognostic biomarker panel for functional transplant outcome two years after transplantation. This marker panel will also be used to define organs preferentially suitable for MMF/tacrolimus based immunosuppression. Both panels will then be validated for their prognostic and predictive information on the long-term outcome after transplantation in a new independent patient population treated with tacrolimus and MMF. In addition to biomarker assessment and in pursue of identifying alternative and/or complementary parameters with predictive value , an advanced morphological investigation of tissue biopsy life stains will be performed employing an innovative cell viability staining technology ("BIOPSYCHRONOLOGY").


Condition or disease Intervention/treatment Phase
Ischemia Reperfusion Injury Diagnostic Test: Confocal microscopy Not Applicable

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 113 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Prospective, single-center pilot study
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: The Renal Transplant Outcome Prediction and Validation Study (TOPVAS)
Actual Study Start Date : June 11, 2015
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : March 31, 2020
Arms and Interventions
Outcome Measures
Primary Outcome Measures :
  1. The number of dialysis in the first 7 days post transplant [ Time Frame: 7 days ]
    The need of at least one dialysis within the first 7 days post transplant.

  2. Kidney parenchyma quality [ Time Frame: before transplant ]

    Live and dead cells in the kidney biopsy will be quantified using the dyes Syto-16/PI and WGA will be calculated as follows:

    Groups: The number of dead/live cells will be entered in the following groups

    1. Total count (irrespective of localization).
    2. Tubular area (cells from the tubular area)
    3. Glomerular area (cells from the glomerulus) For each group the number of viable cells will be divided by the number of dead cells.

    (+1) Using this approach we will obtain for highly viable biopsies/areas high numbers, bigger than (0) For biopsies/areas in which the number of viable cells equals the one of dead cells we will obtain 1.

    (-1) For those in which the number of dead cells outnumbers the one of live cells, numbers between 1 and 0 will be obtained.

    For each biopsy, a score will be calculated which will consist of the two tubular areas and the glomerular area. Therefore a maximum of +3 points can be achieved, or in the worst case -3.



Eligibility Criteria
Contacts and Locations
Tracking Information
First Submitted Date  ICMJE March 4, 2019
First Posted Date  ICMJE June 6, 2019
Last Update Posted Date July 26, 2019
Actual Study Start Date  ICMJE June 11, 2015
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 24, 2019)
  • The number of dialysis in the first 7 days post transplant [ Time Frame: 7 days ]
    The need of at least one dialysis within the first 7 days post transplant.
  • Kidney parenchyma quality [ Time Frame: before transplant ]
    Live and dead cells in the kidney biopsy will be quantified using the dyes Syto-16/PI and WGA will be calculated as follows: Groups: The number of dead/live cells will be entered in the following groups
    1. Total count (irrespective of localization).
    2. Tubular area (cells from the tubular area)
    3. Glomerular area (cells from the glomerulus) For each group the number of viable cells will be divided by the number of dead cells.
    (+1) Using this approach we will obtain for highly viable biopsies/areas high numbers, bigger than (0) For biopsies/areas in which the number of viable cells equals the one of dead cells we will obtain 1. (-1) For those in which the number of dead cells outnumbers the one of live cells, numbers between 1 and 0 will be obtained. For each biopsy, a score will be calculated which will consist of the two tubular areas and the glomerular area. Therefore a maximum of +3 points can be achieved, or in the worst case -3.
Original Primary Outcome Measures  ICMJE
 (submitted: June 5, 2019)
  • Delayed Graft Function [ Time Frame: 7 days ]
    The need of at least one dialysis within the first 7 days post transplant.
  • Kidney parenchyma quality [ Time Frame: before transplant ]
    Live and dead cells in the kidney biopsy will be quantified using the dyes Syto-16/PI and WGA will be calculated as follows: Groups: The number of dead/live cells will be entered in the following groups
    1. Total count (irrespective of localization).
    2. Tubular area (cells from the tubular area)
    3. Glomerular area (cells from the glomerulus) For each group the number of viable cells will be divided by the number of dead cells.
    (+1) Using this approach we will obtain for highly viable biopsies/areas high numbers, bigger than (0) For biopsies/areas in which the number of viable cells equals the one of dead cells we will obtain 1. (-1) For those in which the number of dead cells outnumbers the one of live cells, numbers between 1 and 0 will be obtained. For each biopsy, a score will be calculated which will consist of the two tubular areas and the glomerular area. Therefore a maximum of +3 points can be achieved, or in the worst case -3.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Renal Transplant Outcome Prediction and Validation Study
Official Title  ICMJE The Renal Transplant Outcome Prediction and Validation Study (TOPVAS)
Brief Summary

The number of patients with end stage renal disease is increasing continuously and kidney transplantation is the preferred treatment modality. Modern immunosuppressive therapy has reduced the number of acute rejection episodes and increased one year allograft survival dramatically. Nonetheless, 4% of allografts are lost beyond the first year annually due to a multifactorial process and the latter number has not changed for decades. One of the most important factors to determine long-term success after kidney transplantation is the quality of the donor organ. For example, transplantation of organs from elderly or extended criteria donors results in reduced allograft and patient survival.

In previous work, the investigators specifically focused on age-associated molecular signatures including telomere length and mRNA expression levels of the cell cycle inhibitors CDKN2A (p16INK4a) and CDKN1A (p21WAF1) and assessed these parameters in pre-implantation biopsies of 54 patients. In a linear regression analysis CDKN2A turned out to be the best single predictor for serum creatinine after 1 year followed by donor age and telomere length. A multiple linear regression analysis revealed that the combination of CDKN2A values and donor age yielded even higher predictive values. In another study the investigators were able to show an interaction between donor age and use of calcineurin inhibitors with regard to outcome after renal transplantation.

During these past activities an extensive set of whole genome transcriptomics profile information from zero hour biopsies and clinical follow-up data has been collected. In the TOPVAS study, existing data derived from 72 of the above mentioned set of biopsies (exclusion of live donor grafts) will be analysed with state of the art bioinformatical/system biology tools to derive a general (not purely age associated) prognostic biomarker panel for functional transplant outcome two years after transplantation. This marker panel will also be used to define organs preferentially suitable for MMF/tacrolimus based immunosuppression. Both panels will then be validated for their prognostic and predictive information on the long-term outcome after transplantation in a new independent patient population treated with tacrolimus and MMF. In addition to biomarker assessment and in pursue of identifying alternative and/or complementary parameters with predictive value , an advanced morphological investigation of tissue biopsy life stains will be performed employing an innovative cell viability staining technology ("BIOPSYCHRONOLOGY").
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Prospective, single-center pilot study
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Ischemia Reperfusion Injury
Intervention  ICMJE Diagnostic Test: Confocal microscopy

For this purpose "live stains" will be combined with a confocal imaging setup equipped with 6 laser lines. A major advantage of this technique is that tissue specimens do not need to be fixed prior to analysis. Such an approach does not only allow tissue viability and integrity assessment in an unprecedented speed and accuracy, but also promises to shed new light into quality assessment and prognosis in kidney transplantation. The investigators herein wish to establish the predictive values of this technology in kidney transplantation.

The methodology used in this trial is referred to as BIOPSYCHRONOLOGY - as a reference to dendrochronology, or tree ring dating. Leaving the biopsy sample intact facilitates its analysis, just as drills are used for tree-ring counting.
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: June 5, 2019) 		113
Original Actual Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2020
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent
  • Recipient age > 18 years
  • First or second deceased donor kidney transplantation
  • Panel reactive antibody frequency <50%

Exclusion Criteria:

  • Combined kidney transplantation with another organ
  • Living donor kidney transplantation
  • TOPVAS is a interventional prospective cohort study and participation of patients in other randomized prospective interventional trials does not per se violate the protocol
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03978065
Other Study ID Numbers  ICMJE Version 1.1
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Medical University Innsbruck
Study Sponsor  ICMJE Medical University Innsbruck
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Medical University Innsbruck
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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