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ISHLT Summary


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David Nelson, MD
Integris Baptist Medical Center
Oklahoma City, OK, USA
David.nelson@integrisok.com



The week in Washington provided outstanding information for heart transplanters starting with Jon Kobashigawa's Palomar Conference. The 2016 ISHLT meeting produced similarly great content via pre-meeting symposia, the Heart Allocation meeting and the concurrent sessions. This brief review does not cover the Academies.

PALOMAR

The conference can be summarized by the message given in Kathryn Tinckam's pre-meeting symposium presentation: those choices made regarding thresholds for "avoids", desensitization and treatment of DSA were decisions not to be made based on a single test result, but should include consideration of:

  1. Multiple types of tests
  2. Trends of the test results
  3. Risk of delaying transplant
  4. Consultation with the HLA lab professionals

It was noted, both on the pre-meeting survey as well as the consensus session near the end of the conference, that there was a wide spectrum of opinion regarding MFI thresholds to desensitize, which probably reflects the multifactorial decision to desensitize as described by Dr. Tinckam. It was generally accepted that the existence of DSA alone post-transplant was not justification to treat, but factors to treat post-transplant DSA include:

  1. Increasing strength of MFI
  2. Recurrent cellular rejection, without AMR but wiht DSA with graft dysfunction
  3. Graft dysfunction
  4. Epitope spreading (broader DSA)

Additional factoids from the conference include:

  1. Recommendation for protocol DSA monitoring at 2 weeks; 1, 3, 6, and 12 months; and annually thereafter. There was discussion about how this frequency might be altered by "high risk" versus "low risk" recipients.
  2. Dolly Tyan of Stanford noted that you cannot predict C1q by MFI, and that commercial C1q kits currently are less sensitive than the C1q monitoring at Stanford.
  3. Dr. Nancy Reinsmoen reiterated Cedars Sinai JHLTX report (Reinsmoen et al, 2016; 35:165-172) that 23% of their transplants had DSA at transplant, but only half of these had a positive flow crossmatch.
  4. At Cleveland Clinic C4d and C3 positive biopsy correlates with both DSA and graft dysfunction. We were reminded that Utah has previously shown increased mortality with DSA, and an abstract from Utah on Friday showed that C3 cleared faster than C4d from positive biopsies.
  5. Dr. René Rodriguez from Cleveland Clinic noted that it takes an experienced pathologist to diagnose C4d negative AMR by CD68 (macrophages).
  6. Dr. Randy Starling stated that "Only 50% of IVUS studies everywhere are really adequate quality, so this compromises studies."
  7. Dr. Andreas Zuckermann asked the group, "How do we measure success--survival, all the rest is accessory," and then cited Loupy's 2016 AJT study, which reported failed cardiac grafts commonly showed asymptomatic AMR 4.5 plus or minus 2.5 years before failure.
  8. Dr. Zuckermann rhetorically asked, "What MFI threshold to treat--we don't know, there is a very wide spectrum of emotional opinion."
  9. Dr. Randy Starling recommended post-transplant "avoiding toxic treatment unless there is graft dysfunction, but if C4d, C3 are positive, then maximize maintenance immunosuppression and monitor carefully." Somewhat in contrast to this, Elaine Reed (UCLA) noted that if you treat DSA early you get a better response. This same comment was made later during the conference regarding the use of Bortezomib ("If it's going to help, use it early").
  10. Useful guidance from Dr. Dolly Tyan at Stanford was that they will not transplant over a current C1q positive antibody, and their flow crossmatch must have a mean channel shift less than 200 for both class I and for class II.

PRE-MEETING SYMPOSIA

A few highlights of the outstanding pre-meeting symposium were:

  1. Kiran Khush presented a review of the heart allocation section at CEOT, reported her new NIH-funded Donor Heart Study, which will involve 9 OPOs, and reported on the September 2015 European Consensus Conference related to donation/procurement.
  2. Excellent preliminary results on DCD heart donation was presented by Dr. Kumud Dhital from Saint Vincent's in Australia. He provided the insightful advice that the ideal planning to develop a DCD heart program should follow 3 stages: Live animals, un-utilized hearts, and finally, marginal hearts. His message was, "This is a big deal, you can't just have a meeting and then start doing them." It was noteworthy that he "expects better results with young DCD than with VAD."
  3. Jignesh Patel editorialized that one is best using Rituxan and Velcade together, because "neither works well without the other." Understanding the mechanism of both treatments makes this insight intuitively practical.
  4. Kathryn Tinckam said that non-HLA antibody "may not mean as much if not in association with HLA antibody." During Palomar, the non-HLA receiving the most attention was AT1R, which was cited a number of times as demonstrating synergistic adverse impact in conjunction with anti-HLA antibodies.

HEART ALLOCATION MEETING

Monica Colvin and the Scientific Council leadership convened a meeting on Wednesday and Thursday, divided into 3 workgroups, addressing broader sharing, ECMO, and prioritization statuses of I and II. Highlights of meeting recommendations to UNOS include that broader sharing should be 500 miles but restricted to the highest status, and that ECMO would have a time cap of 7 days as status I and then drop to status III, but they have the option to appeal for extended status I via the "exception" pathway. Special consideration regarding pediatric patients was recommended, so that the new allocation policy would not adversely affect this important and vulnerable population. The importance of PRA was, as usual, acknowledged, but with no practical way of incorporating it to everyone's satisfaction in an evidence-based way could be determined.

ISHLT / CONCURRENT SESSIONS (abstracts)

A few abstracts from the outstanding selection included the following:

  1. "Molecular correlates of endothelial mTOR activation in heart transplant recipients," from Paris and Edmonton. (Abstract 25)
  2. "The timeline of DSA after cardiac transplantation," from Pittsburgh, showing that 23% developed DSA with 3% class I, approximately 6% class I and class II, and 12% class II, with both class I and class II presenting at approximately 1100 days (about 3-1/2 years). Approximately half of the class II were DQ and half were DR. (Abstract 88)
  3. "De Novo DQ donor-specific antibodies are associated with worse outcomes compared to non-DQ DSA following heart transplantation," from Emory. This showed approximately half were DQ and half were non-DQ, with the non-DQ showing benign outcomes but the DQ showing a fivefold increased risk of death or graft dysfunction. (Abstract 91)
  4. "Prolonged cardiac allograft donor distance does not impact long-term survival," by Gaffey, et al, from the University of Pennsylvania. This was a UNOS data study. (Abstract 135)
  5. "The overall concept of bridging to transplantation by a ventricular assist device in comparison to bridging by conservative treatment--results using the United Network for Organ Sharing database," by Bernhardt, et al, from Hamburg and Columbia, showed better outcomes, including posttransplant survival, in the conservative non-LVAD cohort. (Abstract 139)
  6. "Incremental value to coronary angiography by optical coherence tomography for detection and interpretation of cardiac allograft vasculopathy," by Clemmensen, et al, from Denmark and The Netherlands. OCT is a "novel high-resolution intravascular imaging modality" that classified plaques as lipid, calcifications, or layered complex plaques. The study provided "important information on pathogenesis and enables detection of plaque compositions associated with CAD and increasing severity of CAD before detectable by angiography." (Abstract 246)
  7. "PU.1 and CD34 immunohistochemistry for the diagnosis of antibody-mediated rejection in the heart," by Fishbein, et al, from The Brigham. This study noted that macrophages can be seen in a variety of settings, such as "ischemic injury, acute cellular rejection, Quilty effect, and old biopsy sites," and that only macrophages within capillaries and small venules are considered diagnostic of antibody-mediated rejection; however, distinguishing between intra- and extra-vascular location is challenging, and this study used the PU.1 double stained with vascular marker CD34 as a substitute for CD68, with good results. This study received accolades from the room, which included Dr. Elizabeth Hammond and the 2 chairs of the session. During the Palomar conference, Dr. René Rodriguez from Cleveland Clinic noted that macrophages were "scavengers" that showed up late, in AMR and were not of major interest at his center, but he posited that macrophages could be used to diagnose AMR in a C4d/C3 negative biopsy, but only by "a very experienced pathologist." (Abstract 268)

Disclosure Statement: The author has no conflicts of interest to disclose.




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