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lloantibodies & llograft Failure

lloantibodies & llograft Failure. A. A. Challenge to improve transplant outcomes. Matthew Everly Terasaki Foundation. Dr. Paul Terasaki . Always leading the way . 10 years ago. cause allograft failure. Antibodies. Natural History of Antibody-Mediated Allograft Deterioration.

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lloantibodies & llograft Failure

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  1. lloantibodies & llograft Failure A A Challenge to improve transplant outcomes Matthew Everly Terasaki Foundation

  2. Dr. Paul Terasaki Always leading the way

  3. 10 years ago cause allograft failure Antibodies

  4. Natural History of Antibody-Mediated Allograft Deterioration Loupy et al. Nat Rev Nephrol 2012;8:348

  5. Today 2014 How do we manage patients with Alloantibodies?

  6. Scope of the de novo DSA problem 1 Incidence of de novo DSA Temporal Relationship Actual risk of de novo DSA

  7. East Carolina University & Terasaki Foundation Collaboration 0.50 0.40 0.30 0.20 0.10 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 Years Post-Transplant 6 188 21 Number at risk 168 159 145 138 131 120 89 67 50 39 (n=189) 10% de novo DSA (IgG) Incidence 2-6% Everly, Rebellato, …, Terasaki. Transplantation 2013;95:410

  8. MULTIVARIATE ANALYSIS FOR De Novo IgGDSA Predictors (n=189) Everly et al. Transplantation 2013;95:410

  9. De novo DSA (IgG) by Mismatch (n=189) Everly et al. Transplantation 2013;95:410

  10. 1 .9 .8 .7 .6 Probability of Allograft Survival .5 .4 .3 .2 .1 0 0 1 2 3 4 5 Years after DSA Appearance 59 53 45 33 29 22 Number at risk 5-Year Actual Post- de novo DSA Survival (n=47) Post- IgGDSA Year 1: 9% Failed 18 Grafts Lost by 5 years post-DSA 31% Failure Everly et al. Transplantation 2013;95:410

  11. IgG3+ & IgM persistent DSA has the worst prognosis 1.00 0.90 0.80 0.70 0.60 Probability of Allograft Survival 0.50 0.40 0.30 0.20 0.10 0.00 0 1 2 3 4 5 Years after DSA Appearance Number at risk Group 1 27 25 25 17 17 11 Group 2 20 17 13 10 7 6 IgG DSA Group 1: with IgG3+ alone, IgM alone, OR neither (n=47) IgG DSA Group 2: with Persistent IgM+ AND IgG3+ Everly et al. Transplantation 2014; In press

  12. Antibodies Temporal Relationship Allograft Failure

  13. Looked at Graft Function 1-year after de novo DSA appearance 1. 2. 3. Wu P, Everly M, et al. Transplantation 2013; 96:919

  14. Stable patients with DSA n=30 Glomerular Filtration Rate 68% Of patients have stable function 1- year post DSA Early allograft dysfunction and early failure patients with DSA Glomerular Filtration Rate n=8 Wu P, Everly M, et al. Transplantation 2013; 96:919

  15. We have a window of opportunity (1-year?) to treat in most cases.

  16. All DSA positive patients 1 year dysfunction predictsfailure at 2-3 years post-DSA. All AMR Cases Wu P, Everly M, et al. Transplantation 2013; 96:919

  17. 2 Treating de novo DSA * Antibody Reduction In Rejection and Preemptive Treatment Improves Survival

  18. Reduction of Donor Specific Antibody Levels Prevents Renal Allograft Loss 100 Antibody Reduction Responders (n=7, NO Allograft Loss) 90 80 70 Log-rank p=0.033 60 Percent Allograft Survival 50 40 30 20 Antibody Reduction Non-Responders (n=23, 12 Allografts Lost) 10 0 0 12 24 36 48 60 72 84 96 Months after Transplantation Brody Medical School at East Carolina University, Greenville, NC Everly, et al. Transplantation. University of Cincinnati, Cincinnati, OH Everly et al. Am J Transplant 2009;9:1-9 Log Rank p=0.021 p = 0.043 (Log-Rank) Statistically significant at the α = 0.05 level

  19. 100 75 50 25 0 Cleared DSA Persisted DSA Survival Log rank p<0.01 0 365 730 1095 Time after DSA identification, days Hachem et al. J Heart Lung Transplant 2010;29:973

  20. We don’t have the best approach to treatment yet.

  21. IVIg reduces Class I DSA but Class II DSA is resistant 28 patients with Acute and Chronic Rejections treated with 6 months IVIg ( 5g/kg total) Cooper et al. Transplantation 2014;In press

  22. Rituximab Fails to Reduce DSA NoChange in DSA levels following Rituximab Zarkhin et al. Am J Transplant 2008;8:2607

  23. n=26 Everly et al. Transplantation 2012;93:572 96% of patients with a Partial Response (50% reduction) 69% of patients with a Complete Response (removal of DSA)

  24. High Rate of DSA RELAPSE after remission in bortezomib protocol Everly et al. Transplantation 2012;93:572

  25. Mean Serum Creatinine Change from Antibody Positive to last follow-up 9% Scr Increase Remission (n=8) 41% Scr Increase Relapsed (n=10) 46% Scr Increase Partial/No Response (n=8) (only a 50% reduction) Everly et al. Transplantation 2012;93:572

  26. Today Summarizing what we know 2014

  27. 20% of patients develop de novo DSA in first 5 years post transplant

  28. 5 years post DSA development 31% of patients will lose their allograft

  29. We have a window of opportunity to treat patients More aggressive treatment in those with AMR, rising DSA, and IgG3+ DSA

  30. Removal of DSA is the goal of treatment

  31. Looking at the Next 10 years

  32. Study and develop a long term management plan for DSA Clinical Trials for Treatment Prevention of DSA Continued documentation of Antibody data outside of trials

  33. You Thank meverly@terasakilab.org

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