Rejection and graft outcomes in kidney transplant recipients with and without angiotensin II receptor type 1 antibodies.

AIM: Angiotensin II type 1 receptor antibody (AT1R Ab) is a non-Human Leucocyte Antigen (HLA) antibody that is maybe associated with early severe kidney transplant rejection and worse graft outcomes. This study aimed to assess the association between AT1R Ab and kidney transplant rejection and graft outcomes. METHODS: We performed a retrospective analysis of all adult kidney transplant recipients in an Australian centre who had an AT1R Ab test between 1 January 2015 to 30 June 2020. AT1R Ab positive patients were compared to AT1R Ab negative patients. Primary outcomes were rejection risk, type and histopathological severity scores. Secondary outcomes were 8-week graft function and graft loss. RESULTS: Of 965 kidney transplants that were performed during the study period, 73 patients had AT1R Ab tested; 16 (22%) were positive and 57(78%) were negative. Positive patients were on average younger and had higher level of donor-specific HLA antibodies. Rejection occurred in 13 (81%) positive patients and 41 (72%) negative patients (P = 0.45). No significant differences in rejection type or severity were found. HLA mismatch and peak panel reactive antibody ≥80%, but not AT1R Ab, independently predicted rejection. Average (132 vs. 177 mmol/L, P = 0.302) and graft loss were not significantly different between groups. CONCLUSION: The study found no evidence that AT1R Ab is associated with rejection type, severity or worse graft function. Future studies should assess its relationship with graft outcomes to help complement immunological risk assessment and potentially provide therapeutic options to alter outcomes.

Pretransplant platelet transfusion refractoriness is not associated with platelet nonengraftment in T-replete hematopoietic progenitor cell transplantation for hematologic malignancies.

BACKGROUND: Cellular engraftment after allogeneic hematopoietic progenitor cell transplantation (HPCT) can be affected by pre-HPCT antibodies against donor human leukocyte antigen (HLA; donor-specific antibodies [DSAs]), which are commonly acquired by either pregnancy or transfusion. Issues regarding high assay sensitivity and variable interpretation limit routine screening for DSAs. Platelet (PLT) transfusion refractoriness (PTR) is relatively common in patients with hematologic malignancies, and anti-HLA alloantibodies can be identified in up to 20% of cases. For patients with PTR undergoing subsequent allogeneic HPCT, however, the effect if any on subsequent PLT nonengraftment is unknown. STUDY DESIGN AND METHODS: We conducted a retrospective study of 480 adults who underwent T-replete HPCT for hematologic malignancy and compared the posttransplantation clinical outcomes between patients who were PTR before HPCT and those who were not. RESULTS: Multivariate analysis demonstrated that PTR was not directly associated with PLT nonengraftment or graft failure, but did predict for early intensive care unit admission, which was the only variable associated with these outcomes (p < 0.0001). CONCLUSION: Our findings suggest that PTR before HPCT identifies patients at higher risk of early clinical rather than immunologic complications.

HLA class I associations with EBV+ post-transplant lymphoproliferative disorder.

Epstein-Barr virus (EBV) is frequently associated with post-transplant lymphoproliferative disorders (EBV(+) PTLD). In these cases, impaired Epstein-Barr virus (EBV)-specific CD8(+) T-cell immunity is strongly implicated and antigen presentation within the malignant B-cell is intact. Interestingly, several studies have reported HLA class I alleles with protective or susceptibility associations. However, results are conflicting, likely influenced by methodology including inconsistent use of multiple hypothesis testing. By contrast, HLA class I associations have been repeatedly reported for classical Hodgkin Lymphoma (cHL), in which EBV is also implicated in a proportion of cases. In contrast to EBV(+) PTLD which expresses the immunodominant EBV latency III EBNA3A/B/C proteins, EBV(+) cHL is restricted to the subdominant EBNA1/LMP1/LMP2 proteins. Herein, we report a study of HLA class I associations in EBV(+) PTLD, with 263 patients with lymphoma (cHL or PTLD) evaluated. Two Australian population cohorts, n = 23,736 and n = 891 were used for comparison. Contrary to previous reports, no HLA class I associations with EBV(+) PTLD were found, whereas for cHL known HLA class I associations were confirmed, with HLA-A*02 homozygous individuals having the lowest odds of developing EBV(+) cHL. Our results suggest that HLA class I does not influence susceptibility to the viral latency III expressing lymphoma, EBV(+) PTLD. Further studies are required for definitive confirmation.

High transplant rates of highly sensitized recipients with virtual crossmatching in kidney paired donation.

BACKGROUND: In kidney paired donation (KPD), flexibility in the allocation of incompatible pairs is required if a critical mass of pairs to efficiently find matches cannot be reached. METHODS: In the Australian KPD program, virtual crossmatch is used for the allocation of suitable donors to registered recipients. Matching is based on acceptable mismatches, and donors are excluded from matching to recipients with donor-specific antibodies (DSAs) greater than 2000 mean fluorescence intensity (MFI). Match and transplant rates in the first year of the program were reviewed with respect to recipient and donor characteristics, including blood group distribution, level of recipient's sensitization, and postallocation crossmatches. RESULTS: Four quarterly match runs were performed, which included 53 pairs and 2 altruistic donors. Human leukocyte antigen incompatibility accounted for 90% of the listed pairs. In the second run, the DSA threshold was increased to greater than 8000 MFI, because no matches were found with standard allocation. Optional ABO-incompatible matching was introduced from run 3. Matches were identified in 37 (70%) patients, of whom 92% had a negative crossmatch with their matched donor. Crossmatch positive results were found only in recipients with DSAs greater than 2000 MFI in the second run. In 4 cases immunological reasons and in 4 cases other reasons resulted in breakdown of chains and 17 patients not progressing to transplantation. Eventually, 20 (38%) patients received a KPD transplant, and 35% of these had a calculated panel-reactive antibody greater than 90%. CONCLUSIONS: KPD using virtual crossmatch is a valid and effective solution for patients with immunologically incompatible donors even in the context of highly sensitized recipients.

Aortic valve allograft structural deterioration is associated with a subset of antibodies to human leukocyte antigens.

BACKGROUND AND AIM OF THE STUDY: The association between aortic valve allograft dysfunction in patients with long-term follow up and human leukocyte class 2 antigen donor/recipient mismatch suggests that elements of the anti-donor immune response penetrate and damage the aortic valve allograft. An aortic valve allograft recipient cohort was studied to determine whether presence of recipient antibodies to donor human leukocyte class 1 or 2 antigen was associated with shorter time to aortic valve allograft dysfunction. METHODS: Both donor and recipient human leukocyte antigen (HLA) type, HLA antibody information and echocardiography data were available for 148 recipients of cryopreserved aortic valve allografts between 1986 and 1998. Structural deterioration of the aortic valve allograft was defined as at least moderate aortic stenosis or regurgitation by echocardiography. Recipient sera were assayed for anti-HLA (class 1 and 2) antibodies using three assays: complement-dependent cytotoxicity (CDC) on T- and B-lymphocyte panels (CDC PRA); flow cytometry using HLA-coated beads (Flow PRA); and an ELISA using HLA-coated microwells. The donor specificity of anti-class 1 and 2 HLA antibodies was determined on T- and B-cell panels using CDC. Associations between the results of the three assays and donor-specific class 1 and 2 antibodies and time to structural deterioration were analyzed using Kaplan-Meier curves of freedom from structural deterioration. Cox proportional-hazards were used to determine independent predictors of time to structural deterioration. RESULTS: Patients highly positive for HLA class 2 antibodies using an ELISA had a significant association (p = 0.007) with shorter time to aortic valve allograft structural deterioration using both a log rank test and Cox proportional-hazards analysis. Patients (n = 15) with donor-specific antibodies to class 2 antigen (DR antigens) had significantly more structural deterioration (p = 0.035) than those without specific antibodies. CONCLUSION: The association between aortic valve allograft structural deterioration and high titer human leukocyte class 2 antigen antibodies, a subset detected by ELISA adds further information about the link between HLA class 2 mismatch and structural deterioration. Further studies are needed to confirm the importance of class 2 antibodies on outcome, and to determine by which method these antibodies should be detected. Potential recipients with pre-existing antibodies of these specific types might be expected to sustain accelerated allograft damage.