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Alloantibodies & Graft Failure: A Challenge to Improve Transplant Outcomes

Understanding the impact of alloantibodies on graft failure and exploring management strategies for patients with de novo DSA. Learn about predictors, survival rates, and treatment approaches to enhance long-term transplant success.

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Alloantibodies & Graft Failure: A Challenge to Improve Transplant Outcomes

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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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