1. Marc Halushka MD, PhD Johns Hopkins University SOM 10 th Banff Conference on Allograft Pathology August 12, 2009

2. No Relevant Financial Relationships with Commercial Interests & No Reference to an Unlabeled or Unapproved use of a Drug or Product Marc Halushka, MD, PhD

3.  To understand the range of methods different institutions use to evaluate AMR.  To recognize the range of protocols different institutions have regarding evaluating AMR.  To realize that the time is upon us to develop a consensus guideline for AMR.

4.  Implementation of the ISHLT 2004 criteria  What centers doing regarding the evaluation of antibody-mediated (AMR/ humoral) rejection? (How much AMR are different groups reporting?)

5.  Survey of pathologists at US and Canadian heart transplantation centers  Queried about use and comfort with the ISHLT 2004 criteria & AMR-related practices

6.  Identified 113 US Centers and 9 Canadian Centers that performed heart transplantations in 2008 (UNOS and Dr. Veinot – U of Ottawa).  Identified one pathologist per institution who read cardiac transplantation biopsies (via websites, colleagues, phone calls to pathology departments/practices, etc).  Generated survey questions, placed these on SurveyMonkey and had the questions piloted by 4 cardiovascular pathology colleagues who assessed accuracy and coverage.  Survey was open from April 16, 2009 through May 20, 2009. Multiple reminder emails were sent, reminder phone calls were made and continuous updates made to reach the appropriate pathologists and maximize inclusion.

7.  94 Respondents 78% of transplant centers 82% of all transplants in 2008  Represents a good cross-section of US and Canadian centers

8.  90% of centers reported evaluating for AMR.  Centers that did not evaluate tended to perform fewer biopsies per year but were otherwise similar to other centers.

9. Count of Centers 1%40%40%18%2% ~20%~80%

10. % of Centers >5% AMR levels 0% 8% 19% 30-35% 60% No data from AK, DL, HI, ID, ME, MS, MT, ND, NH, NM, NV, RI, SD, UT, VT, WV, WY

11. 25% Count of Centers 75%

12. 62%13% 4%4% 39% 3%1%

14. Centers reporting >5% AMR * *OR = 3.15 p=0.05

15. “It would be good to know what the standard is for screening for AMR. It seems that by the time we are seeing positive IF (done only by request based on clinical suspicion), the clinical picture is so dire that the patients do not do well.” “Criteria on when to automatically test for humoral rejection would be useful. We occasionally see staining of only a few capillaries or blood vessels with C4d. We comment on it, but it would be nice to have a standardized way of grading / handling C4d staining.” “I have tried to assess humoral rejection and have found it impossible to interpret.”

16. “The aspect of biopsy grading that needs further standardization is AMR. When you talk to colleagues at other institutions, everyone is doing something different - different indications, different techniques, different interpretation. The clinical side needs to be addressed as well. If we have positive C4d staining and the patient is fine, no one knows what to do.”

17.  Prevalence of AMR: ~20% of centers report >5% of all biopsies have AMR. This varies regionally.  Evaluation of AMR: 90% of transplant centers do evaluate – nearing consensus  Protocol for AMR: 25% of centers evaluate every biopsy for AMR. Numerous other limited protocols exist. – need for consensus  Staining for AMR: Wide variability in C4d staining protocols (IF, IHC, both). 60% of centers also stain for other proteins (immunoglobulins, etc) – need for consensus

18. Johns Hopkins University SOM Lauren Kucirka Joseph Maleszewski Dorry Segev 94 Survey Respondents Chi Lai Dylan Miller Charles Steenbergen Carmela Tan John Veinot