Outcomes after ABO-incompatible heart transplantation in adults: A registry study.

BACKGROUND: In the past, ABO incompatibility was considered an absolute contraindication to heart transplantation (HT) in adults. Advances in ABO-incompatible HT in pediatric patients and ABO-incompatible abdominal transplantation in adult patients have led to clinical exploration of intentional ABO-incompatible HT in adults. However, it is not well known how outcomes in ABO-incompatible adult heart transplant recipients compare with outcomes in ABO-compatible recipients. METHODS: We analyzed International Society for Heart and Lung Transplantation transplant registry data from heart donors and recipients ≥18 years old at the time of transplant for HT performed between 1988 and 2011. We compared baseline characteristics and post-transplant outcomes in ABO-incompatible and ABO-compatible HT. Death or retransplantation was the composite primary end-point. RESULTS: Among 76,663 adult patients undergoing HT between 1988 and June 30, 2011, 94 ABO-incompatible heart transplants were performed. The incidence of death or retransplantation in the ABO-incompatible group was higher than in the ABO-compatible group: 21% vs 9% at 30 days (hazard ratio = 2.38, p < 0.001) and 36% vs 19% at 1 year after transplant. However, ABO-incompatible grafts surviving past the first year after transplant had a similar incidence of failure compared with the ABO-compatible group. After 2005, the rate ABO-incompatible HT in adults increased, likely as a result of planned, intentional (rather than accidental) ABO-incompatible HT. In this group of patients, short-term and long-term incidence of death or retransplantation was similar to ABO-compatible recipients (p = 0.822): 7% at 30 days and 19% at 1 year after transplantation. CONCLUSIONS: We found no difference in incidence of death or retransplantation between ABO-compatible and ABO-incompatible HT in patients who underwent transplantation after 2005.

Analysis of the Influence of HLA-A Matching Relative to HLA-B and -DR Matching on Heart Transplant Outcomes.

BACKGROUND: There are conflicting reports on the effect of donor-recipient HLA matching on outcomes in heart transplantation. The objective of this study was to investigate the effects of HLA-A matching relative to HLA-B and -DR matching on long-term survival in heart transplantation. METHODS: A total of 25 583 patients transplanted between 1988 and 2011 were identified from the International Society for Heart and Lung Transplantation registry. Transplants were divided into 2 donor-recipient matching groups: HLA-A-compatible (no HLA-A mismatches) and HLA-A-incompatible (1-2 HLA-A mismatches). Primary outcome was all-cause mortality. Secondary outcomes were graft failure-, cardiovascular-, infection-, or malignancy-related deaths. RESULTS: The risk of all-cause mortality 15 years after transplantation was higher for HLA-A-compatible (vs HLA-A-incompatible) grafts in patients who had HLA-B-, HLA-DR-, or HLA-B,DR-incompatible grafts (P = 0.027, P = 0.007, and P = 0.002, respectively) but not in HLA-B- and/or HLA-DR-compatible grafts. This was confirmed in multivariable Cox regression analysis where HLA-A compatibility (vs HLA-A incompatibility) was associated with higher mortality in transplants incompatible for HLA-DR or HLA-B and -DR (hazard ratio [HR], 1.59; 95% confidence interval [95% CI], 1.11-2.28; P = 0.012 and HR, 1.69; 95% CI, 1.17-2.43; P = 0.005, respectively). In multivariable analysis, the largest compromise in survival for HLA-A compatibility (vs HLA-incompatibility) was for chronic rejection in HLA-B- and -DR-incompatible grafts (HR, 1.91; 95% CI, 1.22-3.01; P = 0.005). CONCLUSIONS: Decreased long-term survival in heart transplantation was associated with HLA-A compatibility in HLA-B,DR-incompatible grafts.

Human leukocyte antigen matching in heart transplantation: systematic review and meta-analysis.

Allocation of donors with regard to human leukocyte antigen (HLA) is controversial in heart transplantation. This paper is a systematic review and meta-analysis of the available evidence. PubMed, Embase, and the Cochrane Library were searched systematically for studies that addressed the effects of HLA matching on outcome after heart transplantation. Fifty-seven studies met the eligibility criteria. 34 studies had graft rejection as outcome, with 26 of the studies reporting a significant reduction in graft rejection with increasing degree of HLA matching. Thirteen of 18 articles that reported on graft failure found that it decreased significantly with increasing HLA match. Two multicenter studies and nine single-center studies provided sufficient data to provide summary estimates at 12 months. Pooled comparisons showed that graft survival increased with fewer HLA-DR mismatches [0-1 vs. 2 mismatches: risk ratio (RR) = 1.09 (95% confidence interval (CI): 1.01-1.19; P = 0.04)]. Having fewer HLA-DR mismatches (0-1 vs. 2) reduced the incidence of acute rejection [(RR = 0.81 (0.66-0.99; P = 0.04)]. Despite the considerable heterogeneity between studies, the short observation time, and older data, HLA matching improves graft survival in heart transplantation. Prospective HLA-DR matching is clinically feasible and should be considered as a major selection criterion.

Desensitization and heart transplantation of a patient with high levels of donor-reactive anti-human leukocyte antigen antibodies.

BACKGROUND: To prepare a highly immunized recipient for heart transplantation, reduction of high levels of cytotoxic antibodies against human leukocyte antigen (HLA) was deemed essential to prevent antibody-mediated graft failure. METHODS: Antibodies were analyzed by lymphocytotoxic and solid-phase assays. The pretransplant desensitization treatment protocol included daily tacrolimus and mycophenolate mofetil, weekly protein-A immunoadsorption (IA), intravenous immunoglobulin, and daclizumab. Posttransplant treatment consisted of tacrolimus, mycophenolate mofetil, prednisolone, IA, and daclizumab. RESULTS: During pretransplant desensitization, each of the weekly immunoadsorption treatments reduced anti-HLA antibody levels by 50% to 70%, but they returned to the pretreatment level within 1 week as measured by flow cytometry. Cytotoxic antibodies remained reduced. After perioperative immunoadsorption, the donor-reactive antibodies (DRAs) were reduced to low levels. The patient underwent successful heart transplantation after 6 weeks on a waiting list. During the first week posttransplant, DRAs remained low. However, after the first week, anti-HLA DRAs reappeared and increased slightly over a 3-week period and then decreased slowly. Cytotoxic crossmatches were negative before and 3 week after transplantation. No clinical rejection was encountered. The patient was doing well 3 years after transplantation, and yearly clinical cardiac investigations were all normal. Three hyperimmunized patients have now undergone successful heart transplantation at our center using this desensitization protocol. CONCLUSIONS: IA in combination with pretransplant immunosuppressive drug treatment temporarily reduces antibody levels. The therapeutic levels of drug treatment at the time of transplantation may be of crucial importance. The treatment protocol resulted in freedom from rejection and other clinical adverse events.

Heart transplantation across antibodies against human leukocyte antigen and ABO-post-transplant follow-up of donor reactive antibodies.

BACKGROUND: We have successfully performed heart transplantation despite the most unfavourable risk factors for graft and patient survival: the presence of a high level of antibodies (Abs) against the donor's human leukocyte antigens (HLA) class I/II and blood group A1 antigens. The present study concerns post-transplant follow-up and characterization of donor reactive antibodies (DRA). METHODS: Pre-transplant treatment consisted of mycophenolate mofetil (MMF), prednisolone, tacrolimus, intravenous immunoglobulin (IVIG), rituximab, protein-A immunoadsorption (PAIA) and per-operative plasma exchange. A standard triple-drug immunosuppressive protocol was used post-operatively. Abs were analyzed by the complement dependent cytotoxicity (CDC) test against donor and panel B/T cells and by flow cytometry (FlowPRA tests detecting isolated HLA class I/II antigens). Abs against the donor's erythrocytes were analyzed using a standard direct agglutination test for immunoglobulin M (IgM) Abs and a Bio-Rad AHG gel card test detecting IgG Abs and C3d. RESULTS: Pre-transplant treatment reduced Ab titers against the donor's lymphocytes from 128 to 16 and against the donor's blood group A1 antigen from 256 to 0. The patient was emergently transplanted with a heart from a blood group incompatible donor (A1 secretor to O). No hyperacute rejection was seen. DRA were present against all mismatched HLA class I and class II antigens at the time of transplantation; two of these DRA Abs disappeared within the first year post-transplant (anti-B62 and anti-DR4), one showed weakened reactivity (anti-A24) and one is still strongly reactive (anti-DQ3). The donor-specific CDC cross-match is still positive (titers 2 to 8). The level of panel reactive antibodies (PRA) remained unchanged from 6 months on post-transplant. Rising anti-A1 blood group Abs preceded the second rejection and were adsorbed by two blood group specific immunoadsorptions (Glycosorb)-ABO) and remained at a low level. IgM anti-A1 blood group Abs disappeared at 1 yr post-transplant and IgG Abs are still reactive with blood group A1 erythrocytes but at low titers (1 to 2). CONCLUSIONS: The patient is clinically well 2 years after heart transplantation despite the constant persistence of donor reactive IgG Abs against blood group A1 and HLA-DQ antigens. The reactivity of DRA against other mismatched HLA antigens disappeared or weakened during the follow-up period.

Heart transplantation across the antibodies against HLA and ABO.

We have intentionally performed heart transplantation in a 5-year-old child, despite the most unfavourable risk factors for patient survival; the presence of high level of antibodies against donor's human leucocyte antigen (HLA) class I/II and blood group antigens. Pretransplant treatment by mycophenolate mofetil, prednisolone, tacrolimus, intravenous immunoglobulin, rituximab, protein-A immunoadsorption (IA) and plasma exchange reduced antibody titres against the donor's lymphocytes from 128 to 16 and against the donor's blood group antigen from 256 to 0. The patient was urgently transplanted with a heart from an ABO incompatible donor (A(1) to O). A standard triple-drug immunosuppressive protocol was used. No hyperacute rejection was seen. Antibodies against the donor's HLA antigens remained at a low level despite three acute rejections. Rising anti-A(1) blood group antibodies preceded the second rejection and were reduced by two blood group-specific IAs and remained at a low level. The patient is doing well despite the persistence of donor-reactive antibodies.