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Fda Iri Dgf Workshop 09 Sep2011 W Irish
 

Fda Iri Dgf Workshop 09 Sep2011 W Irish

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Impact of preservation method on delayed graft function

Impact of preservation method on delayed graft function

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    Fda Iri Dgf Workshop 09 Sep2011 W Irish Fda Iri Dgf Workshop 09 Sep2011 W Irish Presentation Transcript

    • Cold Machine Perfusion versus Static Cold Storage for SCD, ECD and DCD Kidneys
      Session 6: Devices for Kidney Flushing, Transport and Preservation
      William Irish, PhD
      CTI Clinical Trial and Consulting Services
      September 9, 2011
    • Disclosure
      Consultant: Y’s Therapeutics
    • Outline
      Delayed graft function
      Incidence and clinical impact
      Risk factors – role of ischemia time
      Kidney preservation
      Preservation solutions
      Storage modalities – cold storage vs. machine perfusion
      Outcomes
      Cost-effectiveness
      Sources of variability
      Unanswered questions/unresolved issues
      Approaching resolution
    • Delayed Graft Function by Donor Status
      Donation after cardiac death
      ECD deceased donors
      All deceased donors
      SCD deceased donors
      Living donors
      U.S. Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2010.
    • Endpoint
      With DGF
      No DGF
      (N=203)
      (N=298)
      % AR by 6 months post
      -
      33.5
      20.1
      transplant
      Odds Ratio* (95% CI)
      1.9 (1.2

      2.8)
      1.0
      AR, Graft failure or death**
      Hazard rate ratio* (95% CI)
      2.1 (1.5

      3.1)
      1.0
      Graft failure**
      Hazard rate ratio
      * (95% CI)
      3.1 (1.5

      6.5)
      1.0
      * Adjusted for MMF vs. no MMF, Europe vs. North America and ANTILFA vs. placebo
      ** Excludes patients who failed within the first 7 days post-transplant
      Clinical Impact of Delayed Graft Function
      Danovich G and Irish W for the DGF Study Group. Program and Abstract from the American Society of Nephrology 2000, October 11-16, Toronto, Canada
    • Clinical Impact of Delayed Graft Function continued
      Systematic Review and Meta Analysis
      Pooled estimates using random effects model
      Yarlagadda et al. Nephol Dial Transplant 24: 1039-1047, 2009
    • Clinical Impact of Delayed Graft Function by Donor Type
      0.5
      ECD DGF %
      Yes Yes 5.3
      Yes No 9.6
      No Yes 19.4
      No No 65.7
      0.4
      0.3
      Hazards of Graft Failure
      0.2
      0.1
      0.0
      0
      1
      2
      3
      4
      5
      Years Post-Transplant
      Source: UNOS/OPTN data as of April 29, 2011
    • 0
      10
      20
      30
      40
      50
      60
      70
      80
      90
      100
      Continuous Variables
      Peak PRA (%)
      0
      60
      Duration Dialysis (days)
      0
      1000
      2000
      3000
      4000
      5000
      6000
      7000
      8000
      Duration Dialysis Squared
      8000
      7000
      6000
      5000
      4000
      3000
      1000
      Recipient BMI (kg/m2)
      0
      5
      10
      15
      20
      25
      30
      35
      40
      45
      1
      5
      HLA Mismatch
      0
      4
      CIT (hours)
      0
      5
      10
      15
      20
      25
      30
      35
      40
      45
      WIT (minutes)
      0
      30
      60
      90
      Donor Terminal Creatinine (mg/dL)
      0
      0.5
      1
      1.5
      2
      2.5
      3
      3.5
      4
      Donor Age (years)
      0
      10
      25
      40
      55
      Donor Weight (kg)
      200
      160
      120
      80
      40
      0
      Donor Weight Squared
      0
      60
      80
      100
      120
      140
      Comprehensive Risk Model to Predict Risk of DGF
      Points
      Points
      Categorical Variables
      6
      Black Recipient
      9
      Male Recipient
      5
      Previous Transplant
      8
      Recipient Diabetes
      6
      Recipient Pre
      -transplant Transfusion
      27
      Donation after Cardiac Death
      6
      Donor History of Hypertension
      6
      Donor Cause of Death
      -Anoxia
      6
      Donor Cause of Death
      -Cardiovascular
      160
      180
      200
      Total Points
      0
      50
      100
      150
      200
      250
      300
      350
      Risk of DGF
      0.10
      0.20
      0.50
      0.70
      0.90
      Irish et al. Am J Transplant 2010;10(10):2279-2286
    • Cold Ischemia Time and Probabilityof Delayed Graft Function
      Slope = 0.0084 risk of DGF per 1 hr increase in CIT
      Irish et al. Am J Transplant 2010;10(10):2279-2286
    • Potential Role of Warm Ischemia Timeas a Risk Factor for DGF
      Warm ischemic time associated with DCD transplants
      *Time from circulatory arrest until start of cold perfusion and grouped by 10 minute intervals with <10 minutes as reference
      # Adjusted for donor - and recipient characteristics and type of preservation method (machine perfusion versus static cold storage)
      Jochmans et al. Ann Surg 2010; 252:756-764
    • Kidney Preservation Modalities
      Static Cold Storage1:
      US: 80%
      Eurotransplant: 100%
      LifePort™ Kidney Transporter
      for hypothermic machine perfusion
      1Hartono C, Suthanthiran M Nat Rev Nephr 2009; 5:433-434
    • Static Cold Storage
    • Clinical Trials Comparing UW and HTK Solutionsin Deceased Donor Kidney Transplantation
      de Boer et al. Transpll Int. 1999;12(6):447-53.
      Klaus et al. Transplant Proc 2007; 39(2):353-54.
    • Prolonged Cold Ischemia Time: UW versus HTK in Deceased Donor Kidney Transplantation
      Roels et al. Transplantation. 1998; 66(12): 1660-64
      Agarwal et al. Transplantation 2006; 81(3): 480-82
      Lynch et al. Am J Transplant 2008; 8: 567-73
    • Impact of HTK on Long-term Graft Survival Following Deceased Donor Kidney Transplantation
      Stewart et al. Am J Transplant 2009; 9:1048-54
    • What Does the Evidence Suggest?
      Results are mixed: no clear evidence to discriminate either preservation method
      Conflicting results, due in part, to:
      Insufficient sample size
      Non-randomized comparisons subject to:
      Confounding by indication
      Selection and reporting biases
      Differential center-effects
      Changing patient management practices
      Prospective, randomized, adequately powered studies are still needed; especially in “at-risk” study populations (e.g., ECD, prolonged CIT)
    • Machine Pulsatile Perfusion
      Taylor and Baicu. Cryobiology 2010; 60(3S): S20-S35
      Sung et al. Am J Transplant 2008; 8(Part 2): 922-34
    • Influence of Machine Perfusion on Risk of DGF: Meta-analysis Results#
      *Relative risk (MP vs. CS) of DGF (DerSimonian and Laird random effects model)
      # Included studies in which kidney pairs were allocated between the two preservation methods
      Wight et al Clin Transplant 2003; 17:293-307
    • Clinical Trial Comparing Static versus Active Perfusion in Deceased Donor Kidney Transplantation
      *Defined as the absence of a decrease in the serum creatinine level of at least 10% per day for at least 3 consecutive days
      in the first week after transplantation. This category did not include patients in whom acute rejection, CNI toxicity, or both
      developed in the first week.
      Moers C et al N Engl J Med 2009; 360:7-19
    • Impact of Machine Perfusion on Risk of DGF by Donor Risk Category
      Moers C et al N Engl J Med 2009; 360:7-19
    • Clinical Trial Comparing Static versus Active Perfusion in DCD Kidney Transplantation
      Watson et al Am J Transplant 2010; 10:1991-1999
    • Unanswered Questions
    • Does Machine Perfusion Make a Difference Following DCD Only in Older Recipients?
      • OPTN database analysis; N=6,057 DCD recipients transplanted between 1993-2008
      • Mean follow up: 2.2±2.6 years
      Cantafio et al Clin Transplant 2011; DOI: 10.1111/j.1399-0012.2011.01477.x
    • Does Preservation Modality Affect Outcomes Following Transplantation of ECD Kidneys?
      UNOS database analysis of ECD kidneys transplanted between 2000 and 2003
      Matsuoka Am J Transplant 2006; 6:1473-1478;
    • Does Preservation Modality AffectLong-Term Graft Survival?
      Results of a Meta-analysis
      MP CS
      DBD
      DCD
      CS – cold storage; DBD – donation after brain death; DCD – donation after cardiac death; MP – machine perfusion
      Wight et al Clin Transplant 2003; 17:293-307
    • What About Cost-Effectiveness?
      • Modeling inputs based mostly on the European Machine Preservation Trial
      • Assumes a higher utilization of machine perfusion (80%) for ECD kidneys than for SCD kidneys (20%)
      • Cost drivers: DGF, dialysis, acquisition cost, transplant hospitalization, transplant maintenance
      • Primary clinical endpoint (utility) is graft survival at one-year post-transplant
      Garfield et al. Transplant Proceedings 2009; 41:3531-36
    • Approaching Resolution
    • Sources of Variability
      Definitions of DGF1
      Lack of a standardized definition
      Dialysis-dependent: requirement within 7-10 days
      Creatinine-dependent: increase/insufficient reduction within 3 days
      Study design
      Randomized vs. non-randomized comparison
      Insufficient sample size
      Center effects
      Kidney discard rate
      Staff resources and experience
      Patient management strategies
      Donor type
      SCD vs. ECD
      DBD vs. DCD
      Organ treatment
      Variable cold ischemia time
      Warm ischemia time (sp. uncontrolled DCD) not adequately studied
      Early exposure to calcineurin inhibitors
      1Yarlagadda SG et al Nephrol Dial Transplant 2008; 23:2995-3003
    • Accounting for Variability
      How it:
      Affects outcome
      Choice of preservation modality
      Type of donor organ