Rene Rodriguez Heart Summary Banff 2013 Meeting in Brazil

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.








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








•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








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








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.








• 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








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




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





AMR





AMR

AMR ?





AMR

AMR ?

ADCC ?





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

Health & Medicine

Rene Rodriguez Heart Summary Banff 2013 Meeting in Brazil