Removing Barriers and Mitigating Risk: The Case for Crossing Donor-specific Antibodies in Lung Transplantation With the Use of Perioperative Desensitization

Currently, there is a lack of consensus within the lung transplant community around the practice of accepting and managing donor-specific antibodies (DSAs) at the time of transplant. Although a minority of programs are willing to accept offers regardless of the presence of DSAs and utilize a variety of perioperative desensitization therapies to mitigate the risk of hyperacute or early antibody-mediated rejection (AMR), the majority of programs exclude offers that cross DSAs that they consider to be “high-risk.”1 The practice of avoiding DSAs at the time of transplant effectively restricts the donor pool for highly sensitized lung transplant candidates, the majority of whom are women and/or African American. As a result, these candidates are significantly less likely to undergo transplant and more likely to die on the waitlist than unsensitized candidates.2 Currently, this disadvantage is not being mitigated in the allocation process, although the forthcoming Composite Allocation Score in the United States may include points for sensitization status.3 The heterogeneity in our practices stems from a lack of evidence to adequately inform the definition of “high-risk DSA” and the most effective perioperative desensitization regimen to use when DSAs are present. To date, a few programs have published their data on outcomes of lung transplants performed in the presence of DSAs, the largest of which include the Toronto Lung Transplant Program,4,5 the Brigham and Women’s Hospital (BWH) Lung Transplant Program,6 and the Foch Hospital Lung Transplant Program.7 The studies from these programs have differed in the types of crossmatches accepted and the choice of antibody-depleting therapies used perioperatively, but all reported positive short- and long-term outcomes.4-7 In this issue of Transplantation, Wang et al significantly add to this area of research with a retrospective study of 313 lung transplant recipients, 30 of whom had DSAs at the time of transplant.8 They report that DSA-positive lung transplant recipients have similar allograft survival and chronic lung allograft dysfunction-free survival to other lung transplant recipients, which is consistent with the prior literature.4-7 However, they also found that DSAs at the time of transplant were associated with both severe primary graft dysfunction at 48–72 h and AMR, which has been variably reported in prior studies.4,6,7 This study’s conclusion that DSA-positive lung transplants are associated with a manageable risk of severe primary graft dysfunction and AMR that does not impact allograft or chronic lung allograft dysfunction-free survival certainly adds to the growing evidence that crossing DSAs at the time of transplant is a safe option to improve access to the donor pool for sensitized lung transplant candidates.4-7 Moreover, these positive outcomes were achieved using a protocol for accepting and managing DSAs at the time of transplant that does differ from other published protocols in specific aspects,4,6,7 and it is in from highlighting these differences that other important conclusions may be inferred. First, in this study, DSA-positive lung transplants were accepted regardless of the mean fluorescence intensity (MFI) of the DSA or the results of the cell-based crossmatch.8 The Toronto program also accepted the crossing of DSAs regardless of MFI and without a prospective cell-based crossmatch,4 but the BWH and Foch programs excluded DSA-positive transplants if the CDCXM was positive or if the MFI of the DSAs exceeded 5000.6,7 As expected, the interquartile range of MFI of the DSAs included in this study and in the Toronto study was larger than that in the BWH and Foch studies.4,6-8 Although MFI as a measure of DSA strength is semiquantitative at best and cannot necessarily be compared directly between centers,9 the inclusion of DSAs of MFI as high as 11 987 in this study at least indicates that higher immunological risk DSAs may also be crossed safely at the time of transplant with perioperative desensitization.8 Second, plasmapheresis was initiated postoperatively for DSA-positive transplants in this study,8 which differs from the Toronto study (started intraoperatively)4 and the Foch study (started preoperatively).7 The concerns expressed by Wang et al for increased bleeding with intraoperative plasmapheresis8 are shared by many programs and are currently a significant barrier to more programs accepting DSA-positive transplants.1 The fact that the outcomes of this study8 are aligned with others that used intraoperative4 and preoperative plasmapheresis7 for DSA-positive lung transplants indicates that the timing of plasmapheresis may be modified safely. This knowledge may encourage programs without access to intraoperative plasmapheresis or with concerns about intraoperative bleeding to utilize postoperative plasmapheresis to facilitate DSA-positive transplants. Finally, the majority of DSA-positive lung transplant recipients were treated with antithymocyte globulin (ATG) in this study (67%).8 This is similar to what DSA-positive lung transplant recipients received in the Toronto study,4 whereas the BWH and Foch studies both used rituximab.6,7 The risks and benefits of using ATG or rituximab for DSA-positive transplants cannot be inferred from any of these observational studies, but this study does provide further evidence that ATG is a valid choice. As were the prior studies,4-7 this study is also limited by its observational, retrospective, and single-center nature.8 As an increasing number of programs have liberalized their acceptance of crossing DSAs at the time of transplant, we now have the opportunity to compare outcomes of our various protocols for accepting and managing these types of transplants. A multicenter study is necessary to better address our knowledge gaps pertaining to “high-risk DSA” and the most effective perioperative desensitization regimen to use when DSAs are present so more sensitized candidates can benefit from increased access to lung transplants.

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