Summary Heart Session
E Rene Rodriguez, M.D. and Carmela D. Tan, M.D.12th Banff Conference on Allograft Pathology
Comandatuba-Bahia, BrazilAugust 23, 2013
3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 yearsCarmela D. Tan, Cleveland Clinic
4:00 - 4:30 Update on the revised ISHLT AMR grading systemGerald Berry, Stanford University
4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHCMartin Goddard – Papworth Hospital, UK
5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspectiveMonica Colvin-Adams, University of Minnesota
6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosisDolly B. Tyan, Stanford University
6:30 - 7:00 AMR in the pediatric heart recipientsJanet Scheel, Johns Hopkins University
7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMRE Rene Rodriguez, Cleveland Clinic
Background - Clinical AMR
Tan et al, Am J Transplant. 2009 Sep;9(9):2075-84
Natural History of C4d deposition in Heart Allografts
Results
C4d+
C3d-48
C3d-40
C3d+8
C3d+16
Index biopsies
Follow-upbiopsies
Average time for conversion:13.5 (1.1-31.9) months
8/48 (17%) of patients progressed to C4d+C3d+
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 5 10 15 20 25 30 35 400.02.04.06.08.0
10.012.014.016.018.020.022.024.026.028.030.032.034.036.038.040.042.044.046.048.0
Time to first positive biopsy
C4d C4d converters C4dC3d
Mon
ths
postt
rans
plan
t
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.
Cox Proportional Hazard Survival Curves
Control
C4d
C4dConverter
C4dC3d
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.
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
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.
3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 yearsCarmela D. Tan, Cleveland Clinic
4:00 - 4:30 Update on the revised ISHLT AMR grading systemGerald Berry, Stanford University
4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHCMartin Goddard – Papworth Hospital, UK
5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspectiveMonica Colvin-Adams, University of Minnesota
6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosisDolly B. Tyan, Stanford University
6:30 - 7:00 AMR in the pediatric heart recipientsJanet Scheel, Johns Hopkins University
7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMRE Rene Rodriguez, Cleveland Clinic
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
• 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
3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 yearsCarmela D. Tan, Cleveland Clinic
4:00 - 4:30 Update on the revised ISHLT AMR grading systemGerald Berry, Stanford University
4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHCMartin Goddard – Papworth Hospital, UK
5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspectiveMonica Colvin-Adams, University of Minnesota
6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosisDolly B. Tyan, Stanford University
6:30 - 7:00 AMR in the pediatric heart recipientsJanet Scheel, Johns Hopkins University
7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMRE Rene Rodriguez, Cleveland Clinic
•Many examples of Histologic pAMR H+
•Technical challenges of C4d by IHC
For EMB:
Assess Reproducibility of interpretation amongst centers
Quality Assurance / Control (technical (virtual and non-virtual))
Refining and improving criteria ISHLT & Banff synergy
3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 yearsCarmela D. Tan, Cleveland Clinic
4:00 - 4:30 Update on the revised ISHLT AMR grading systemGerald Berry, Stanford University
4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHCMartin Goddard – Papworth Hospital, UK
5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspectiveMonica Colvin-Adams, University of Minnesota
6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosisDolly B. Tyan, Stanford University
6:30 - 7:00 AMR in the pediatric heart recipientsJanet Scheel, Johns Hopkins University
7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMRE Rene Rodriguez, Cleveland Clinic
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
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
3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 yearsCarmela D. Tan, Cleveland Clinic
4:00 - 4:30 Update on the revised ISHLT AMR grading systemGerald Berry, Stanford University
4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHCMartin Goddard – Papworth Hospital, UK
5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspectiveMonica Colvin-Adams, University of Minnesota
6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosisDolly B. Tyan, Stanford University
6:30 - 7:00 AMR in the pediatric heart recipientsJanet Scheel, Johns Hopkins University
7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMRE Rene Rodriguez, Cleveland Clinic
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.
3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 yearsCarmela D. Tan, Cleveland Clinic
4:00 - 4:30 Update on the revised ISHLT AMR grading systemGerald Berry, Stanford University
4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHCMartin Goddard – Papworth Hospital, UK
5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspectiveMonica Colvin-Adams, University of Minnesota
6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosisDolly B. Tyan, Stanford University
6:30 - 7:00 AMR in the pediatric heart recipientsJanet Scheel, Johns Hopkins University
7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMRE Rene Rodriguez, Cleveland Clinic
• 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
3:30 - 4:00 The natural history of C4d vs. clinical AMR in a large cohort over 5 yearsCarmela D. Tan, Cleveland Clinic
4:00 - 4:30 Update on the revised ISHLT AMR grading systemGerald Berry, Stanford University
4:30 - 5:00 Practical approach, diagnostic issues and pitfalls in the pathologic diagnosis of AMR by IHCMartin Goddard – Papworth Hospital, UK
5:00 - 5:30 Pathologic diagnosis of AMR – The clinician’s perspectiveMonica Colvin-Adams, University of Minnesota
6:00 - 6:30 How is DSA monitored and, how will it complement pAMR diagnosisDolly B. Tyan, Stanford University
6:30 - 7:00 AMR in the pediatric heart recipientsJanet Scheel, Johns Hopkins University
7:00 – 7:30 Future directions and challenges in the diagnosis and management of AMRE Rene Rodriguez, Cleveland Clinic
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)
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
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
Endothelial lining in the heart
-Coronary arteriesEpicardialIntramural
-Coronary arterioles-Capillaries-Venules-Veins-Endocardium
AtrialValvularVentricular
Endothelial lining in the heart
-Coronary arteriesEpicardialIntramural
-Coronary arterioles-Capillaries-Venules-Veins-Endocardium
AtrialValvularVentricular
AMR
Endothelial lining in the heart
-Coronary arteriesEpicardialIntramural
-Coronary arterioles-Capillaries-Venules-Veins-Endocardium
AtrialValvularVentricular
AMR
AMR ?
Endothelial lining in the heart
-Coronary arteriesEpicardialIntramural
-Coronary arterioles-Capillaries-Venules-Veins-Endocardium
AtrialValvularVentricular
AMR
AMR ?
ADCC ?
Endothelial lining in the heart
-Coronary arteriesEpicardialIntramural
-Coronary arterioles-Capillaries-Venules-Veins-Endocardium
AtrialValvularVentricular
AMR
AMR ?
ADCC ?
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