Rene Rodriguez Heart Summary Banff 2013 Meeting in Brazil

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Heart summary from 12th Banff Conference on Transplant Pathology from the meeting in Comandatuba-Bahia, Brazil on August 23rd, 2013 http://cybernephrology.ualberta.ca/banff/2013

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  • An assessment of the data using exact methods of logistic regression relating CAV and patient type indicated there were no significant differences in CAV odds ratios as a function of patient group.
  • Rene Rodriguez Heart Summary Banff 2013 Meeting in Brazil

    1. 1. Summary Heart Session E Rene Rodriguez, M.D. and Carmela D. Tan, M.D. 12th Banff Conference on Allograft Pathology Comandatuba-Bahia, Brazil August 23, 2013
    2. 2. 3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 years Carmela D. Tan, Cleveland Clinic 4:00 - 4:30 Update on the revised ISHLT AMR grading system Gerald Berry, Stanford University 4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHC Martin Goddard – Papworth Hospital, UK 5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspective Monica Colvin-Adams, University of Minnesota 6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosis Dolly B. Tyan, Stanford University 6:30 - 7:00 AMR in the pediatric heart recipients Janet Scheel, Johns Hopkins University 7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMR E Rene Rodriguez, Cleveland Clinic
    3. 3. Background - Clinical AMR Tan et al, Am J Transplant. 2009 Sep;9(9):2075-84
    4. 4. Natural History of C4d deposition in Heart Allografts
    5. 5. Results C4d+ C3d- 48 C3d- 40 C3d+ 8 C3d+ 16 Index biopsies Follow-up biopsies Average time for conversion: 13.5 (1.1-31.9) months 8/48 (17%) of patients progressed to C4d+C3d+
    6. 6. C4d C4d converters C4dC3d P-value Average (months) 13.2 7.38 12.6 NS Range (months) 0.2-61.1 0.7-17.4 0.2-37.2 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 22.0 24.0 26.0 28.0 30.0 32.0 34.0 36.0 38.0 40.0 42.0 44.0 46.0 48.0 0 5 10 15 20 25 30 35 40 Time to first positive biopsy C4d C4d converters C4dC3d Monthsposttransplant
    7. 7. Assessment of mortality odds ratio Backward Logistic Regression Reduced Model Odds Ratio Estimates Odds 95% Wald Effect Ratio Confidence Limits P-Value C4d+ vs. Control 4.690 1.959 11.227 .0005 (40 vs.232) C4d+ converters vs. Control 5.824 1.221 27.775 .027 (8 vs. 232) C4d+C3d+ vs. Control 6.166 1.844 20.615 .003 (16 vs.232) The odds ratio for mortality in the three patient groups were significant compared against the control group.
    8. 8. Cox Proportional Hazard Survival Curves Control C4d C4d Converter C4dC3d
    9. 9. Assessment of Odds ratios for CAV Exact Odds Ratios Odds 95% Confidence Parameter Ratio Limits p-Value C4d+ vs. Control 2.611 0.228 19.006 0.5141 C4d+ converters vs. Control 5.324* 0 47.623 1.0000 C4d+C3d+ vs. Control 2.438* 0 20.529 1.0000 *Indicates a median unbiased estimate There were no significant differences in CAV odds ratios as a function of patient groupings.
    10. 10. Conclusions I • C4d+ C3d+ capillary –> AMR with DSA and Dysfunction • Majority of C4d+ only episodes are single occurrences (60%) and subclinical (85%). • Some patients with C4d staining alone (8 of 48, 17%) will develop AMR (Convert to C4d+ C3d+) on follow-up. Control C4d+ C4d+ Converters C4d+C3d+ P-Value Patient Gender Male 176 33 7 8 0.08 Female 56 7 1 8 232 40 8 16
    11. 11. Conclusions II • There is no increased risk for CAV associated with complement deposition (C4d+ only or C4d+ C3d+). • Cardiovascular mortality is increased in patients with complement deposition relative to controls.
    12. 12. 3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 years Carmela D. Tan, Cleveland Clinic 4:00 - 4:30 Update on the revised ISHLT AMR grading system Gerald Berry, Stanford University 4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHC Martin Goddard – Papworth Hospital, UK 5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspective Monica Colvin-Adams, University of Minnesota 6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosis Dolly B. Tyan, Stanford University 6:30 - 7:00 AMR in the pediatric heart recipients Janet Scheel, Johns Hopkins University 7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMR E Rene Rodriguez, Cleveland Clinic
    13. 13. 2011 GRADING SCHEME now accepted by ISHLT as the new Working Formulation for AMR 2013 • pAMR 0: Negative for pathologic AMR: both histological and immunopathological studies are negative • pAMR 1 (H+): Histopathological AMR alone: histopathological findings present and immunopathological findings absent • pAMR 1 (I+): Immunopathologic AMR alone: Immunopathological findings present and histological findings absent • pAMR 2: Pathologic AMR: both histological and immunopathological findings present • pAMR 3: Severe pathologic AMR: Rare cases of severe AMR with histopathological findings of IS hemorrhage, capillary fragmentation, mixed inflammation, endothelial cells pyknosis, karyorrhexis, marked edema
    14. 14. • Since this grading has been in use for two years as of this Banff meeting it will be imperative to evaluate its accuracy in order to refine or revise criteria. • Usefulness of C4d and CD68 by IHC and how it correlates with DSA and dysfunction • Great goal for Banff 2015
    15. 15. 3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 years Carmela D. Tan, Cleveland Clinic 4:00 - 4:30 Update on the revised ISHLT AMR grading system Gerald Berry, Stanford University 4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHC Martin Goddard – Papworth Hospital, UK 5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspective Monica Colvin-Adams, University of Minnesota 6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosis Dolly B. Tyan, Stanford University 6:30 - 7:00 AMR in the pediatric heart recipients Janet Scheel, Johns Hopkins University 7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMR E Rene Rodriguez, Cleveland Clinic
    16. 16. •Many examples of Histologic pAMR H+ •Technical challenges of C4d by IHC
    17. 17. For EMB: Assess Reproducibility of interpretation amongst centers Quality Assurance / Control (technical (virtual and non- virtual)) Refining and improving criteria ISHLT & Banff synergy
    18. 18. 3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 years Carmela D. Tan, Cleveland Clinic 4:00 - 4:30 Update on the revised ISHLT AMR grading system Gerald Berry, Stanford University 4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHC Martin Goddard – Papworth Hospital, UK 5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspective Monica Colvin-Adams, University of Minnesota 6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosis Dolly B. Tyan, Stanford University 6:30 - 7:00 AMR in the pediatric heart recipients Janet Scheel, Johns Hopkins University 7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMR E Rene Rodriguez, Cleveland Clinic
    19. 19. Clinical Cardiologists Need • Consistency on interpretation • Guidance on interpretation and correlation of DSA and Bx with clinical AMR • Validation through clicical trials • Studies that correlate with outcomes • AHA Scientific Statement on AMR in the process of being published • Expectation is to validate
    20. 20. Clinical Cardiologists Need • Consistency on interpretation • Guidance on interpretation and correlation of DSA and Bx with clinical AMR • Validation through clicical trials • Studies that correlate with outcomes • AHA Scientific Statement on AMR in the process of being published • Expectation is to validate
    21. 21. 3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 years Carmela D. Tan, Cleveland Clinic 4:00 - 4:30 Update on the revised ISHLT AMR grading system Gerald Berry, Stanford University 4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHC Martin Goddard – Papworth Hospital, UK 5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspective Monica Colvin-Adams, University of Minnesota 6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosis Dolly B. Tyan, Stanford University 6:30 - 7:00 AMR in the pediatric heart recipients Janet Scheel, Johns Hopkins University 7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMR E Rene Rodriguez, Cleveland Clinic
    22. 22. Wisdom on interpreting DSA in cardiac AMR • Whether and which kind of DSA should be considered in diagnosis AMR • Discussion of value of C1q assay (pre- post- transplant) • Kinds of non HLA DSA in heart transplant discussed with new information from Cedars Sinai – AT1 receptor, MICA • The must be a STRONG recommendation somewhere about utilization of monitoring DSA. This will help hospital administrators and 3rd party payers to make up their minds and pay for useful tests.
    23. 23. 3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 years Carmela D. Tan, Cleveland Clinic 4:00 - 4:30 Update on the revised ISHLT AMR grading system Gerald Berry, Stanford University 4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHC Martin Goddard – Papworth Hospital, UK 5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspective Monica Colvin-Adams, University of Minnesota 6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosis Dolly B. Tyan, Stanford University 6:30 - 7:00 AMR in the pediatric heart recipients Janet Scheel, Johns Hopkins University 7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMR E Rene Rodriguez, Cleveland Clinic
    24. 24. •For the pediatric cardiologist •Highly sensitized patients, common •Monitoring DSA already being done. But… •How often? How long? •Better defined role of non HLA antibodies in the pediatric patients •Definitions of dysfunction not standardized, which makes difficult to utilize ISHLT working formulation for AMR •How to address AMR without dysfunction if just a pathologic diagnosis
    25. 25. 3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 years Carmela D. Tan, Cleveland Clinic 4:00 - 4:30 Update on the revised ISHLT AMR grading system Gerald Berry, Stanford University 4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHC Martin Goddard – Papworth Hospital, UK 5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspective Monica Colvin-Adams, University of Minnesota 6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosis Dolly B. Tyan, Stanford University 6:30 - 7:00 AMR in the pediatric heart recipients Janet Scheel, Johns Hopkins University 7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMR E Rene Rodriguez, Cleveland Clinic
    26. 26. Antibodies in Heart Allograft Rejection • Antibody mediated rejection -> Capillary deposition -> Complement activation and deposition • Antibody dependent cellular cytotoxicity -> Mediated by Cells (NK cells, eosinophils, neutrophils)
    27. 27. Antibodies in Heart Allograft Rejection • Antibody mediated rejection -> Capillary deposition -> Complement activation and deposition • Antibody dependent cellular cytotoxicity -> Mediated by Cells (NK cells, eosinophils, neutrophils) Acute process – Devastating if not treated – May recur
    28. 28. Antibodies in Heart Allograft Rejection • Antibody mediated rejection -> Capillary deposition -> Complement activation and deposition • Antibody dependent cellular cytotoxicity -> Mediated by Cells (NK cells, eosinophils, neutrophils) Acute process – Devastating if not treated – May recur Slow (smoldering / chronic) process – Eventually devastating – Not amenable to effective treatment of prevention
    29. 29. Endothelial lining in the heart -Coronary arteries Epicardial Intramural -Coronary arterioles -Capillaries -Venules -Veins -Endocardium Atrial Valvular Ventricular
    30. 30. Endothelial lining in the heart -Coronary arteries Epicardial Intramural -Coronary arterioles -Capillaries -Venules -Veins -Endocardium Atrial Valvular Ventricular AMR
    31. 31. Endothelial lining in the heart -Coronary arteries Epicardial Intramural -Coronary arterioles -Capillaries -Venules -Veins -Endocardium Atrial Valvular Ventricular AMR
    32. 32. Endothelial lining in the heart -Coronary arteries Epicardial Intramural -Coronary arterioles -Capillaries -Venules -Veins -Endocardium Atrial Valvular Ventricular AMR
    33. 33. Endothelial lining in the heart -Coronary arteries Epicardial Intramural -Coronary arterioles -Capillaries -Venules -Veins -Endocardium Atrial Valvular Ventricular AMR Can we really assume that these are two related processes? They may share one thing.. Antibody But… The antibodies can produce allograft injury (CAV) by a different pathogenetic mechanism

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