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)

ABO-Incompatible Kidney Transplantation Is a Novel Risk Factor for BK Nephropathy

A link between ABO-incompatible kidney transplantation and the risk of BK virus allograft nephropathy (BKVAN) has been identified in a report from Johns Hopkins Hospital.1 The 11 (17.7%) of 62 cases of BKVAN were identified by protocol (n = 5) or indication (n = 6) biopsies. The incidence of BKVAN in HLA–incompatible allograft recipients (transplantation after the removal of donor-specific HLA antibodies) and compatible allograft recipients was 5.9% and 3.0%, respectively. In a multivariable analysis, ABO-incompatible kidney transplantation was identified as an independent risk factor for the development of BKVAN (read more)

Graft and Patient Survival Outcomes of a Third Kidney Transplant

Background: The waiting time for deceased donor renal transplantation in the United States continues to grow. Retransplant candidates make up a small but growing percentage of the overall transplant waiting list and raise questions about the stewardship of scarce resources. The utility of renal transplantation among individuals with two prior renal transplants is not described in the literature, and we thus sought to determine the survival benefit associated with a third kidney transplant (3KT). 

Methods: Multivariable Cox regression models were created to determine characteristics associated with 3KT outcomes and the survival benefit of 3KT among recipients wait listed and transplanted within the United States between 1995 and 2009. 

Results: A total of 4,334 patients were waitlisted for a 3KT and 2,492 patients received a 3KT. In a multivariate analysis, 3KT demonstrated an overall patient survival benefit compared to the waitlist (hazards ratio, 0.379; 95% confidence interval, 0.302-0.475; P < 0.001) for those awaiting their first, second, or third kidney transplants, although an inferior graft outcome compared to first kidney transplants. The time to survival benefit did not accrue until 8 months after transplantation. In addition, we found that the duration of second graft survival was predictive of third graft survival, such that second graft survival beyond 5 years is associated with superior 3KT graft survival. Second graft loss in 30 days or less was not associated with inferior 3KT graft survival. 

Conclusion: A 3KT achieves a survival benefit over remaining on the waitlist, although is associated with inferior graft outcomes compared to first kidney transplants. Graft survival of the second transplant beyond 5 years is associated with superior 3KT graft survival (read more).