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).

A Phase I/II Placebo-Controlled Trial of C1-Inhibitor for Prevention of Antibody-Mediated Rejection in HLA Sensitized Patients

Background: Antibody-mediated rejection (AMR) is a severe form of rejection, mediated primarily by antibody-dependent complement (C) activation. C1 inhibitor (C1-INH, Berinert) inhibits the classical and lectin pathways of C activation. We performed a randomized, placebo-controlled study using C1-INH in highly sensitized renal transplant recipients for prevention of AMR. 

Methods: Twenty highly sensitized patients desensitized with IVIG + rituximab ± plasma exchange were enrolled and randomized 1:1 to receive plasma-derived human C1-INH (20 IU/kg/dose) versus placebo intraoperatively, then twice weekly for 7 doses. Renal function, adverse events (AEs)/serious AEs, C3, C4, and C1-INH levels were monitored and C1q+ HLA antibodies were also blindly assessed.

Results: One patient in the C1-INH group versus 2 patients in the placebo group developed serious AEs, but none were related to study drug. Delayed graft function developed in 1 C1-INH subject and 4 in the placebo. The C1-INH trough levels increased with C1-INH treatment. C3 and C4 levels also increased significantly in the C1-INH group compared to placebo. No C1-INH patient developed AMR during the study. Two patients developed AMR after the study. Three placebo patients developed AMR, one during the study. C1q+ donor specific antibodies were reduced in 2 C1-INH treated patients tested, while immunoglobulin G DSA levels showed decreased binding for both groups. 

Conclusions: The C1-INH appears safe in the posttransplant period. The C1-INH treatment may reduce ischemia-reperfusion injury. The C1-INH also resulted in significant elevations of C1-INH levels, C3, C4, and reduced C1q+ HLA antibodies. Taken together, the combination of antibody reduction and C1-INH may prove useful in prevention of AMR. Further controlled studies are warranted (read more)

A closer look at rituximab induction on HLA antibody rebound following HLA-incompatible kidney transplantation

Rituximab has been used to increase the efficacy of desensitization protocols for human leukocyte antigen (HLA)-incompatible kidney transplantation; however, controlled comparisons have not been reported. Here we examined 256 post-transplant HLA antibody levels in 25 recipients desensitized with and 25 without rituximab induction, to determine the impact of B-cell depletion. We found significantly less HLA antibody rebound in the rituximab-treated patients (7% of donor-specific antibodies (DSAs) and 33% of non-DSAs) compared with a control cohort desensitized and transplanted without rituximab (32% DSAs and 55% non-DSAs). The magnitude of the increase was significantly larger among patients who did not receive rituximab. Interestingly, in rituximab-treated patients, of the 39 HLA antibodies that increased post transplant, 34 were specific for HLA mismatches present in previous allografts or pregnancies, implying limited efficacy in memory B-cell depletion. Compared with controls, rituximab-treated patients had a significantly greater mean reduction in DSA (−2505 vs. −292 mean fluorescence intensity), but a similar rate of DSA persistence (52% in rituximab treated-and 40% in non-treated recipients). Thus, rituximab induction in HLA-incompatible recipients reduced the incidence and magnitude of HLA antibody rebound, but did not affect DSA elimination, antibody-mediated rejection, or 5-year allograft survival when compared with recipients desensitized and transplanted without rituximab (read more)

Pre-transplant Virtual PRA and Long-term Outcomes of Kidney Transplant Recipients

Virtual Panel Reactive Antibodies (vPRA) has been implemented to gauge sensitization worldwide. It is unclear how it associates with long-term outcomes, and its correlation with peak (pPRA) or actual (aPRA) has not been studied. We retrospectively reviewed data from 18-65 year-old kidney-only transplant patients during 1.1.1996–31.7.2011 in our centre. PRAs were calculated based on solid-phase techniques. Of the 726 qualified cases, regardless of the PRA type, sensitized patients (PRA>5%) had more females and previous transplant. Highly sensitized (HS, PRA>50%) had longer waiting time, lower transplant rate, less living donor, more delayed graft function and acute rejection. The conformity between vPRA and pPRA in HS were 75%, 57% between pPRA and aPRA. Forty-three percent (61/142) patients whose pPRA was >5% had no detectable aPRA and maintained similar outcomes as sensitized patients. Multivariate analysis showed consistently lower death-censored graft survival in HS defined by vPRA [HR 2.086 (95% CI 1.078-4.037), P<0.05] and pPRA [HR 2.139 (95% CI 1.024-4.487), P<0.05]. Both vPRA and pPRA provided reliable way estimating sensitization and predicting long-term graft survival, while aPRA might underestimate true sensitization. vPRA might be the most objective parameter to gauge sensitization (read more)