Impact of IgG3 Subclass and C1q-Fixing Donor-Specific HLA Alloantibodies on Rejection and Survival in Liver Transplantation

Recent literature confirms donor-specific HLA alloantibodies (DSA) impair 5-year survival in some but not all liver transplant recipients. In an effort to improve DSA testing's association with rejection and death, we retrospectively evaluated 1270 liver transplant recipients for the presence of IgG3 and C1q-fixing DSA. In patients with preformed DSA, 29 and 51% had IgG3 and C1q-fixing DSA, respectively. In patients with de novo DSA, 62% and 67% had IgG3 and C1q-fixing DSA, respectively. When different types of DSA positive patients were compared to DSA negative patients, multivariable analysis showed that IgG3 DSA positivity had the highest numerical hazard ratio for death (IgG3: HR = 2.4, p < 0.001; C1q: HR = 1.9, p < 0.001; standard DSA: HR = 1.6, p < 0.001). Similarly, multivariable analysis demonstrated de novo IgG3 DSA positivity compared to no DSA had the highest hazard ratio for death (IgG3: HR = 2.1, p = 0.004; C1q: HR = 1.9, p = 0.02; standard DSA: HR = 1.8, p = 0.007). Preformed C1q-fixing class II DSA showed the strongest correlation with early rejection. In conclusion, preformed and de novo IgG3 subclass DSA positive patients had the highest absolute HR for death in side-by-side comparison with C1q and standard DSA positive versus DSA negative patients; however, IgG3 negative DSA positive patients still had inferior outcomes compared to DSA negative patients (read more)

Equipoise: Ethical, Scientific, and Clinical Trial Design Considerations for Compatible Pair Participation in Kidney Exchange Programs

Compatible living donor/recipient pair participation (CPP) in kidney exchange (KE) transplantation may substantially increase transplant volumes and significantly mitigate the O blood group donor shortage in KE. Initial ethical analysis did not support CPP for two primary reasons: (1) KE would be “unbalanced,” and (2) the possibility of undue influence experienced by the compatible pair living donor. Recent developments with CPP (modeling studies and small clinical experiences), have demonstrated substantial potential for increasing KE volumes. This encouraged us to reconsider initial ethical concerns, with a focus on the potential for a design of a prospective CPP clinical trial. This ethical reconsideration led us to conclude that the concept of unbalanced kidney exchanges (manifested primarily by differential benefit between compatible and incompatible pairs) is no longer as clear cut as originally conceived. In addition, application of two concepts substantially diminishes ethical concerns including: (1) “quasi-compatible” pairs, and (2) a priori definition of mitigating factors. We conclude that genuine uncertainty exists regarding whether kidney exchange is best performed with or without compatible pair participation and that a clinical trial is therefore warranted (read more)

HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis

PROBLEM: The aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM).
METHOD OF STUDY: A systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated.
RESULTS: We included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05-1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15-2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20-1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45-0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31-0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11-1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10-1.25) were both associated with the occurrence of RM.
CONCLUSION: Although the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully (read more)

Biological significance of HLA locus matching in unrelated donor bone marrow transplantation

We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell–replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus-host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versus-leukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection (read more)

Graft and Patient Outcomes of Zero Human Leukocyte Antigen Mismatched Deceased and Live-Donor Kidney Transplant Recipients

Greater compatibility of human leukocyte antigen (HLA) alleles between kidney donors and recipients may lead to improved graft outcomes. This study aimed to compare the incidence of acute rejection and graft failure in zero HLA-mismatched recipients of living-related (LD) and deceased donor (DD) kidney transplants. Using data from the Australia and New Zealand Dialysis and Transplant Registry, we compared the risk of any and biopsy-proven acute rejection (BPAR) and graft failure in recipients of zero HLA-mismatched kidneys between LD and DD using logistic and Cox regression models. Of the 931 zero HLA-mismatched recipients transplanted between 1990-2012, 19 (2.0%) received kidneys from monozygotic/dizygotic twins (twin), 500 (53.7%) from non-twin LD and 412 (44.3%) from DD. Twin kidney transplant recipients did not experience rejection. Compared to DD transplant recipients, the risk of any acute rejection (adjusted odds ratio 0.52, 95%CI 0.34-0.79, p=0.002) and overall graft failure (adjusted hazard ratio 0.55, 95%CI 0.41-0.73, p<0.001) was significantly lower in LD recipients independent of initial immunosuppression, but not for BPAR (adjusted odds ratio 0.52, 95%CI 0.16-1.64, p=0.263). Zero HLA-mismatched DD kidney transplant recipients have a significantly higher risk of any acute rejection episodes and graft loss compared to zero HLA mismatched LD kidney transplant recipients. A cautious and careful approach in reducing immunosuppression appears to be warranted in this group of transplant recipients (read more)

Anti-HLA Sensitization in Extensively Burned Patients: Extent, Associated Factors, and Reduction in Potential Access to Vascularized Composite Allotransplantation

Background : Extensively burned patients receive iterative blood transfusions and skin allografts that often lead to HLA sensitization, and potentially impede access to vascularized composite allotransplantation (VCA).
Methods : In this retrospective, single center study, anti-HLA sensitization was measured by single-antigen-flow-bead analysis in patients with deep, second and third degree burns over ≥40% total body surface area (TBSA). Association of HLA-sensitization with blood transfusions, skin allografts, and pregnancies was analyzed by bivariate analysis. The eligibility for transplantation was assessed using calculated panel reactive antibodies (cPRA).
Results : Twenty-nine patients aged 32±14 years, including 11 women, presented with a mean burned TBSA of 54±11%. Fifteen patients received skin allografts, comprising those who received cryopreserved (n=3) or glycerol preserved (n=7) allografts, or both (n=5). An average 36±13 packed red blood cell (PRBC) units were transfused per patient. In sera samples collected 38±13 months after the burns, all patients except one presented with anti-HLA antibodies, of which 13 patients (45%) had complement-fixing antibodies. Eighteen patients (62%) were considered highly sensitized (cPRA≥85%). Cryopreserved, but not glycerol preserved skin allografts, history of pregnancy, and number of PRBC units were associated with HLA-sensitization.
Conclusions : Extensively burned patients may become highly HLA sensitized during acute care, and hence not qualify for VCA. Alternatives to skin allografts might help preserve their later access to VCA (read more)

Clinical Impact of Preformed Donor Specific Denatured Class I HLA Antibodies after Kidney Transplantation

Class I single antigen flow beads (SAFB) carry native and denatured HLA molecules. Using a cohort of 179 class I HLA sensitised kidney recipients, we described incidence and clinical relevance of preformed denatured HLA Donor Specific Antibodies (DSA) using two different assays: an acid-treated SAFB assay (anti-dHLA DSA) and the iBeads assays (SAFB+/iBeads- DSA). Eighty-five class I DSA were found in 67 patients [median mean fluorescence intensity (MFI) of 1729 (range 520-13882)]. Anti-dHLA and SAFB+/iBeads- DSA represented 11% and 18% of class I DSA and were mainly low MFI DSA (500-1000 MFI). Concordance between these two assays was good (90%). None of the patients with only class I anti-dHLA DSA or only SAFB+/iBeads- DSA developed acute clinical AMR in the first year post-transplantation, and their 5-year DCGS was similar to that of patients without DSA. Moreover, all these patients displayed a negative current T-cell flow cytometry crossmatch. Therefore, both anti-dHLA DSA and SAFB+/iBeads- DSA appear irrelevant, which could explain the good outcome observed in some patients with preformed class I DSA (read more)