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Donor Management Research Update and Double Randomization

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David Nelson, MD
Integris Baptist Medical Center
Oklahoma City, OK, USA

Donor management research is critical to transplant recipients. Immunomodulating effects of pre-procurement injury not only affects the incidence and severity of primary graft dysfunction but also could promote antibody-mediated rejection. Donor management meaningfully influences organ utilization, early graft function, and long-term graft survival. It therefore directly affects wait-list deaths, costs (postop ICU care), and transplant benefits (quality of life and graft longevity).

As previously reported in Links, two HRSA funded consensus conferences were held (Donor Intervention Research Expert Panel November 2014, Crystal City and May 2015, Philadelphia) to define barriers to donor management research and explore their possible solutions.

Two of several conclusions of these conferences were:

  1. Need for a national oversight board to vet for scientific merit, provide safety monitoring and facilitate transplant center IRB approval analogous to existing national IRBs.
  2. Recognition that the existing network of regulations which safeguards us from human research abuse is a misfit for donor-related research in the complex context of organ allocation.

As a result, the IOM (now National Academy of Medicine) plans a study of donor management research which will result in recommendations addressing the barriers impeding this important research. Highlighting the importance and momentum of this issue was the announcement at the June White House Summit on Transplantation of a 4.2 million dollar grant to the new Donor Management Research Institute generously provided by the Arnold Foundation.

During the two DIREP conferences, at least one solution surfaced for almost every barrier explored, except one: double randomization.

Double randomization occurs if an organ from a donor in a randomized study is transplanted into a recipient also enrolled in another randomized study. Generally, this event can result in disqualification of the recipient from their trial.

Double randomization is the one issue for which my DIREP notes come up blank over and over again. It was the one issue habitually moved to the "parking lot."

However, two other clinical phenomena disturbingly broaden our consideration of donor-related double randomization. First, donor management is not uniform between OPOs. Steroid, hormonal, and other therapies that vary across OPOs are commonly not reported in transplant studies that have recruited donors from multiple OPOs and from which intra-OPO protocols may have changed over the course of the recipient study. Secondly, donors may already be in a randomized study before they are donors. Pre-brain death (pre-donor) randomized interventions are actions about which transplant teams and their "randomized" recipients are generally unaware. Until the New England Journal's publication of the Hypothermia Trial (Niemann CV et al, NEJM 2015;373:405-414), disclosure of donor randomization had never, to my knowledge, been provided on DonorNet offers associated with a randomized donor intervention. The hypothermia disclosure occurred only because of the foresight and rigorous efforts of the authors, recognized leaders in donor management research.

Double randomization applied to the donor-recipient relationship is unique in its application of the concept, and its harmonization is necessary to increase the number and quality of organs and standardize the reporting of pre- and post-brain death pre-procurement donor interventions. ■

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

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