Identification of risk epitope mismatches associated with de novo donor-specific HLA antibody development in cardiothoracic transplantation.

The development of de novo donor-specific HLA antibodies (dnDSA) after transplantation is associated with graft failure, mortality, and cost. There is no effective therapeutic intervention to prevent dnDSA or ameliorate associated injury. The aims of this study were to identify specific HLA factors associated with dnDSA development and to propose primary prevention strategies that could reduce the incidence of dnDSA without prohibitively limiting access to transplant. The investigation cohort included heart transplant recipients from 2008 to 2015 (n = 265). HLA typing was performed and HLA antibody testing was undertaken before and after transplantation. HLAMatchmaker analysis was performed for persistent dnDSA to identify potentially more immunogenic eplet differences. Validation was performed in recipients of lung transplants from 2008 to 2013 (n = 433). The majority of recipients with dnDSA had antibodies to identical eplet positions on DQ2 and DQ7. A high-risk epitope mismatch (found in DQA1*05 +  DQB1*02/DQB1*03:01(7)) was associated with a 4.2- and 4.9-fold increased risk of dnDSA in heart and lung recipients respectively. HLA electrostatic potential modeling provided a plausible explanation for this observed immunogenicity. A theoretical allocation algorithm avoiding high-risk epitope mismatches was generated and predicted to reduce dnDSA by up to 72% without additional testing, eplet analysis, or cost.

Survival Analysis in the Presence of Competing Risks: The Example of Waitlisted Kidney Transplant Candidates.

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long-term mortality. In a typical analysis of time-to-event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of "independent censoring," which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause-specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation.

cPRA Increases With DQA, DPA, and DPB Unacceptable Antigens in the Canadian cPRA Calculator.

A calculated panel reactive antibody (cPRA) estimates the percentage of donors with unacceptable antigens (UA) for a recipient. cPRA may be underestimated in transplant candidates with UA to DQA, DPA, and DPB if these are not included in the calculation program. To serve the National Canadian Transplant Programs, a cPRA calculator was developed with complete molecular typing for all donors at HLA-A, B, C, DRB1, DRB3/4/5, DQA1, DQB1, DPA1, and DPB1, all resolved to serologic equivalents. The prevalence of UA at DQA, DPA and DPB was evaluated in a sensitized regional population. The impact of adding these additional UA to cPRA was calculated alone and in combination, and compared to the baseline cPRA for UA at A, B, C, DR, DR51/52/53, and DQ. Of 740 sensitized transplant candidates, 18% of total and 32% with cPRA≥95% had DQA UA. Twenty-seven percent of total and 54% with cPRA≥95% had DPB UA. Of 280/740 subjects with these UA, 36/280 (13%) had cPRA increase of >20% when they were included, 7% increased cPRA to ≥80% and 6% to ≥95%. Inclusion of DQA, DPA, and DPB UA in Canadian cPRA calculations improves the accuracy of cPRA where these are relevant in allocation.

Survival in sensitized lung transplant recipients with perioperative desensitization.

Donor-specific HLA antibodies (DSA) have an adverse effect on short-term and long-term lung transplant outcomes. We implemented a perioperative strategy to treat DSA-positive recipients, leading to equivalent rejection and graft survival outcomes. Pretransplant DSA were identified to HLA-A, B, C, DR and DQ antigens. DSA-positive patients were transplanted if panel reactive antibody (PRA) ≥30% or medically urgent and desensitized with perioperative plasma exchange, intravenous immune globulin, antithymocyte globulin (ATG), and mycophenolic acid (MPA). PRA-positive/DSA-negative recipients received MPA. Unsensitized patients received routine cyclosporine, azathioprine and prednisone without ATG. From 2008-2011, 340 lung-only first transplants were performed: 53 DSA-positive, 93 PRA-positive/DSA-negative and 194 unsensitized. Thirty-day survival was 96 %/99%/96% in the three groups, respectively. One-year graft survival was 89%/88%/86% (p = 0.47). DSA-positive and PRA-positive/DSA-negative patients were less likely to experience any ≥ grade 2 acute rejection (9% and 9% vs. 18% unsensitized p = 0.04). Maximum predicted forced expiratory volume (1 s) (81%/74%/76%, p = NS) and predicted forced vital capacity (81%/77%/78%, respectively, p = NS) were equivalent between groups. With the application of this perioperative treatment protocol, lung transplantation can be safely performed in DSA/PRA-positive patients, with similar outcomes to unsensitized recipients.

The role of donor-specific HLA alloantibodies in liver transplantation.

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

A survey of current practice for antibody-mediated rejection in heart transplantation.

No evidence based management guidelines exist for antibody mediated rejection (AMR) in heart transplantation. The International Society for Heart and Lung Transplantation (ISHLT) recently introduced standardized pathologic based diagnostic criteria for AMR (pAMR 0-3). We evaluated international practice for the management of AMR focusing on pAMR grade, donor specific antibody (DSA) and allograft function. On-line survey data were analyzed from 184 ISHLT members (physicians-78%, surgeons-20%). The majority were from adult-transplant (84%), medium-large volume centres (transplants/year: 10-25, 61%; 25-50, 19%) across North America (60%) and Europe (26%). Irrespective of pAMR grade and DSA, 83-90% treated a drop in ejection fraction (EF≤45% or >25% decrease). In the presence of stable EF, an increasing number elected treatment for progressively severe pAMR grade (p<0.001) and for accompanying DSA (p<0.05, pAMR 1-3). Intravenous steroid was the most commonly used therapy followed by intravenous immunoglobulin (IVIG) or plasmapheresis, rituximab and thymoglobulin. Plasmapheresis and rituximab were favored for positive versus negative DSA (p<0.05). Using a threshold of ≥70% consensus among respondents, treatment for AMR may be considered for a drop in EF, asymptomatic pAMR 3 or asymptomatic pAMR 2 with DSA. Combination steroid, IVIG and plasmapheresis are suggested as initial therapies.