Changing patterns of clinical decision making: are falling numbers of antibody incompatible transplants related to the increasing success of the UK Living Kidney Sharing Scheme? A national cohort study.

Antibody incompatibility is a barrier to living kidney transplantation; antibody incompatible transplantation (AIT) is an accepted treatment modality, albeit higher risk. This study aims to determine changes to clinical decision making and access to AIT in the UK. An electronic survey was sent to all UK renal transplant centres (n = 24), in 2014, and again in 2018. Questions focused on entry & duration in the UKLKSS for HLA and ABO-incompatible pairs, Can and provision of direct AIT transplantation within those centres. Between 2014 & 2018, the duration recommended for patients in the UKLKSS increased. In 2014, 34.8% of centres reported leaving HLA-i pairs in the UKLKSS indefinitely, or reviewing on a case by case basis, by 2018 this increased to 61%. Centres offering direct HLA-i transplantation reduced from 58% to 37%. For low titre (1:8) ABO-i recipients, 66% of centres recommended at least 9 months (3 matching runs) in the UKLKSS scheme in 2018, compared to 47% in 2014, 50% fewer units consider direct ABO-i transplantation for unsuccessful pairs with high ABO titres (>1:512). Over time, clinicians appear to be facilitating more conservative management of AIT patients, potentially limiting access to living donor transplantation.

Does HLA matching matter in the modern era of renal transplantation?

Children with end-stage kidney disease should be offered the best chance for future survival which ideally would be a well-matched pre-emptive kidney transplant. Paediatric and adult practice varies around the world depending on geography, transplant allocation schemes and different emphases on living (versus deceased) donor renal transplantation. Internationally, paediatric patients often have priority in allocation schemes and younger donors are preferentially allocated to paediatric recipients. HLA matching can be difficult and may result in longer waiting times. Additionally, with improved surgical techniques and modern immunosuppressive regimens, how important is the contribution of HLA matching to graft longevity? In this review, we discuss the relative importance of HLA matching compared with donor quality; and long-term patient outcomes including re-transplantation rates. We share empirical evidence that will be useful for clinicians and families to make decisions about best donor options. We discuss why living donation still provides the best allograft survival outcomes and what to do in the scenario of a highly mismatched living donor.

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

De novo donor-specific HLA antibodies after combined intestinal and vascularized composite allotransplantation - a retrospective study.

Combining vascularized composite allotransplantation (VCA) with intestinal transplantation to achieve primary abdominal closure has become a feasible procedure. Besides facilitating closure, the abdominal wall can be used to monitor intestinal rejection. As the inclusion of a VCA raises the possibility of an enhanced alloimmune response, we investigated the incidence and clinical effect of de novo donor-specific HLA antibodies (dnDSA) in a cohort of patients receiving an intestinal transplant with or without a VCA. The sequential clinical study includes 32 recipients of deceased donor intestinal and VCA transplants performed between 2008 and 2015; eight (25%) modified multivisceral transplants and 24 (75%) isolated small bowel transplants. A VCA was used in 18 (56.3%) cases. There were no episodes of intestinal rejection without VCA rejection. Fourteen patients (14 of 29; 48.3%) developed dnDSA. In the VCA group, fewer patients developed dnDSA; six of 16 (37.5%) VCA vs. eight of 13 (61.5%) non-VCA. There was no statistically significant difference in one- and 3-year overall graft survival stratified for the presence of dnDSA; P = 0.286. In the study, there is no evidence that the addition of a VCA increases the incidence of dnDSA formation compared to transplantation of the intestine alone.

Vessel rejection secondary to human leucocyte antigen antibodies directed against the arterial conduit following pancreas transplantation from a separate donor.

Whole-organ pancreas transplantation is typically carried out using a Y-graft derived from the donor iliac vessels. We describe a case in which a 31-year-old male underwent a simultaneous pancreas-kidney transplant, but in which vessels from a different donor were used for the arterial anastomosis of the pancreas graft. Although initially there was good function, 18 months post-transplant the patient was admitted with diabetic ketoacidosis secondary to pancreas graft failure. Radiological investigations revealed complete occlusion of the vascular Y-graft, and laboratory investigations demonstrated donor-specific human leucocyte antigen (HLA) antibodies directed against HLA mismatches of the vessel donor. This case highlights the risks of using allogeneic vascular material for surgical anastomoses.

Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study.

BACKGROUND: A third of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns have been raised about the long-term outcome of such transplants. We aimed to establish these outcomes for kidneys donated after controlled cardiac death versus brain death, and to identify the factors that affect graft survival and function. METHODS: We used data from the UK transplant registry to select a cohort of deceased kidney donors and the corresponding transplant recipients (aged ≥18 years) for transplantations done between Jan 1, 2000, and Dec 31, 2007. Kaplan-Meier estimates were used to assess graft survival, and multivariate analyses were used to identify factors associated with graft survival and with long-term renal function, which was measured from estimated glomerular filtration rate (eGFR). FINDINGS: 9134 kidney transplants were done in 23 centres; 8289 kidneys were donated after brain death and 845 after controlled cardiac death. First-time recipients of kidneys from cardiac-death donors (n=739) or brain-death donors (n=6759) showed no difference in graft survival up to 5 years (hazard ratio 1·01, 95% CI 0·83 to 1·19, p=0·97), or in eGFR at 1-5 years after transplantation (at 12 months -0·36 mL/min per 1·73 m(2), 95% CI -2·00 to 1·27, p=0·66). For recipients of kidneys from cardiac-death donors, increasing age of donor and recipient, repeat transplantation, and cold ischaemic time of more than 12 h were associated with worse graft survival; grafts from cardiac-death donors that were poorly matched for HLA had an association with inferior outcome that was not significant, and delayed graft function and warm ischaemic time had no effect on outcome. INTERPRETATION: Kidneys from controlled cardiac-death donors provide good graft survival and function up to 5 years in first-time recipients, and are equivalent to kidneys from brain-death donors. Allocation policy for kidneys from cardiac-death donors should reduce cold ischaemic time, avoid large age mismatches between donors and recipients, and restrict use of kidneys poorly matched for HLA in young recipients. FUNDING: UK National Health Service Blood and Transplant, and Cambridge National Institute for Health Research Biomedical Research Centre.

Baculovirus as delivery system for gene transfer during hypothermic organ preservation.

Concerns over the safety of conventional viral vectors have limited the translation of gene transfer from an exciting experimental procedure to a successful clinical therapy in transplantation. Baculoviruses are insect viruses, but have the ability to enter mammalian cells and deliver potential therapeutic molecules with no evidence of viral replication. This study provides evidence of the ability of recombinant baculovirus to enter mammalian kidneys and livers during cold preservation. Six kidneys and six liver lobules retrieved from large pigs were perfused with University of Wisconsin (UW) solution containing a baculovirus tagged with green fluorescent protein and preserved for 8 h. In addition, six kidneys were perfused with UW containing a baculovirus expressing red fluorescent protein and preserved for 24 h. Green fluorescent virus particles were detected within transduced kidneys and livers after 8 h standard cold storage and red fluorescent protein mRNA was detected in kidneys after 24 h of cold preservation. There were no significant differences in tissue architecture, cell morphology or ATP content between experimental organs and their controls. Ex vivo transduction of organs with recombinant baculovirus during conventional cold preservation was demonstrated with no evidence of additional injury or reduction in cell viability.

A Europe wide acceptable mismatch program will enable transplantation of long waiting highly sensitised patients with a compatible donor.

Immunisation against Human Leucocyte Antigens (HLA) can be caused by pregnancy, blood transfusion, or organ transplants. The HLA antibody status of a given patient significantly influences their access and waiting time to transplant. For some highly sensitised patients (HSP) there is hardly any suitable donor available in the deceased donor pool of their allocation organisation and therefore they wait a very long time before being offered a kidney for transplant. Especially patients with rare HLA phenotypes in relation to the actual donor pool are waiting extremely long. As HLA phenotypes are different in the various European populations, we hypothesized that extension of the donor pool outside the respective allocation system will increase the chance of receiving a compatible transplant for this subgroup of highly sensitised patients. One of the objectives of the EUROSTAM project, (a Europe-wide Strategy to enhance Transplantation of highly sensitised patients on the basis of Acceptable HLA Mismatches) was to develop a tool to compare the chance of transplanting HSP in different European populations with donor organs from within and outside their own donor pool. Information on the HLA type and ABO blood group of the actual donor population, as well as the acceptable mismatches of long waiting HSP were obtained from the EUROSTAM partner organizations i.e. Eurotransplant (ET), UK National Health Service Blood and Transplant (NHSBT), Barcelona, Prague and Athens. Results from simulations using the newly developed tool shows that 195 (27%) of the 724 long waiting highly sensitised patients registered at each partner organisation have increased chances of transplant in a different European donor pool. This makes a strong case for sharing kidneys between European countries for selected difficult to transplant patients.

The deceased donor score system in kidney transplants from deceased donors after cardiac death.

SUMMARY: A clinical score to identify kidneys from donors after cardiac death (DCD) with a high risk of dysfunction following transplantation could be a useful tool to guide the introduction of new algorithms for the preservation of these organs and improve their outcome after transplantation. We investigated whether the deceased donor score (DDS) system could identify DCD kidneys with higher risk of early post-transplant dysfunction. The DDS was validated in a cohort of 168 kidney transplants from donors after brain death (DBD) and then applied to a cohort of 56 kidney transplants from DCD. In the DBD cohort, the DDS grade predicted the incidence of delayed graft function (DGF) and levels of serum creatinine at 3 and 12 months post-transplant. Similarly, in the DCD cohort, the DDS grade correlated with DGF and also predicted the levels of serum creatinine at 3 and 12 months. Interestingly, the DDS identified a subgroup of marginal DCD kidneys in which minimization of cold ischemia time produced better early clinical outcome. These results highlight the impact of early interventions on clinical outcome of marginal DCD kidneys and open the possibility of using the DDS to identify those kidneys that may benefit most from therapeutic interventions before transplantation.

Effect of ischemic preconditioning on the genomic response to reperfusion injury in deceased donor liver transplantation.

Ischemic preconditioning (IP) is an effective method for protecting organs from ischemia/reperfusion (IR) injury; however, the molecular basis of this protective effect is poorly understood. This study assessed the gene expression profile in liver allografts during transplantation and evaluated the impact of IP. Prereperfusion and postreperfusion biopsy specimens from livers subjected to IP (n = 19) or no preconditioning (the IR group; n = 16) were obtained. Total RNA was extracted and hybridized to GeneChip microarrays, and the findings were validated with real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). IP livers showed less of an increase in aspartate aminotransferase after transplantation. A microarray analysis of the IR group showed increased expression of 57 genes mainly involved in cell death, inflammation and immune response, stress, and modulation of the cell cycle. The IP group showed attenuation of the expression of these genes after reperfusion. Additionally, IP led to increased expression of 43 genes involved in growth and maintenance, cell-cycle regulation, proliferation, and development. The expression of the 12 most significant genes was validated in all patients with real-time qRT-PCR, and the fold changes of a number of genes correlated with clinical parameters and graft outcomes. IP protection of liver allografts was associated with a reduction in the expression of immune response genes and promotion of those involved in protection and repair.

Towards uniformity in the definition of acceptable mismatches for highly sensitized patients.

The Eurotransplant (The Eurotransplant International Foundation) acceptable mismatch programme has been shown to be a successful tool to enhance transplantation of highly sensitized patients(HSPs). However, patients with rare HLA phenotypes in relation to the Eurotransplant donor population remain on the waiting list. EUROSTAM is an European Union funded project to explore the feasibility of a Europe-wide acceptable mismatch programme enabling transplantation of HSPs with rare HLA phenotypes within their own organ exchange organization. The present study, which forms part of the EUROSTAM project, assesses the differences in the practices of the laboratories in different countries with respect to their HLA antibody profiling and risk adverseness. In the serum exchange exercises of 18 samples, a high level of variability has been shown in both assays and interpretation of results. In the data exchange exercise when all participants were given the same Luminex raw data for analysis, a high degree of consensus was reached where the median fluorescent intensity values of beads were <500 and >2000 for standard single antigen bead assays, or <500 and >5000 for assignment of acceptable mismatches. The risk adverseness analysis has showed distinct patterns of attitudes towards the perceived risks based on HLA antibody assay results, most probably influenced by the local protocols of the clinical transplant programme of each laboratory. In order to ensure fairness and maintain consistencies of organ exchange among partner transplant centres, a centralized facility will be instrumental for a uniform definition of acceptable mismatches.

Tools for human leukocyte antigen antibody detection and their application to transplanting sensitized patients.

In recent years there have been major advances in the technology for the detection and definition of human leukocyte antigen antibodies. In this overview we describe the evolution in laboratory technology, the techniques currently available and consider their application in antibody specificity definition and in understanding a patient's sensitization profile. We discuss the importance of antibody specificity definition in facilitating efficient national organ allocation and informing clinical discussion regarding the appropriate pathway for sensitized patients awaiting renal transplantation.

Renal transplantation in the United Kingdom for patients from ethnic minorities.

BACKGROUND: To investigate any differences in access to transplant and post-transplant outcomes for ethnic minority patients in the United Kingdom, national data on ethnicity of patients on the waiting list, those receiving a transplant, and deceased donors were analyzed. METHODS: Adult patients and donors were included. Ethnic origin was classified as white, Asian, black, or "other." National data were analyzed, and 2001 U.K. National census data were used for comparative purposes. Median waiting times to transplant were obtained from Kaplan-Meier estimates for patients registered 1998-2000. Transplant survival was estimated for patients transplanted from 1998 to 2003. RESULTS: A total of 92% of the U.K. population was white, compared with 77% of waiting list patients, 88% of transplant recipients, and 97% of deceased donors. Median waiting time to transplantation for white patients was 719 days (95% confidence interval 680-758) compared with 1368 (1131-1605) days for Asian patients and 1419 (1165-1673) days for black patients. The degree of human leukocyte antigen matching achieved was inferior for Asian and black patients. There is some evidence of inferior 3-year transplant survival for black patients compared with white and Asian patients (P=0.03). CONCLUSIONS: There are imbalances in the ethnic make up of the waiting list, the donor pool, and renal transplant recipients. There are significant differences in both post-transplant outcomes and time to transplantation between patients of different ethnic origin. Waiting times are influenced by allocation schemes, and the 2006 U.K. National Kidney Allocation Scheme is designed to achieve greater equity of access to transplant for all patients, regardless of geography, blood group, or ethnicity.

The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants.

BACKGROUND: ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. METHODS: The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. RESULTS: For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. CONCLUSIONS: Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy.

Replication of the association of HLA-B7 with Alzheimer's disease: a role for homozygosity?

BACKGROUND: There are reasons to expect an association with Alzheimer's disease (AD) within the HLA region. The HLA-B & C genes have, however, been relatively understudied. A geographically specific association with HLA-B7 & HLA-Cw*0702 had been suggested by our previous, small study. METHODS: We studied the HLA-B & C alleles in 196 cases of 'definite' or 'probable' AD and 199 elderly controls of the OPTIMA cohort, the largest full study of these alleles in AD to date. RESULTS: We replicated the association of HLA-B7 with AD (overall, adjusted odds ratio = 2.3, 95% confidence interval = 1.4-3.7, p = 0.001), but not the previously suggested interaction with the epsilon4 allele of apolipoprotein E. Results for HLA-Cw*0702, which is in tight linkage disequilibrium with HLA-B7, were consistent with those for the latter. Homozygotes of both alleles appeared to be at particularly high risk of AD. CONCLUSION: HLA-B7 and HLA-Cw*0702 are associated with AD in the Oxford population. Because of the contradictions between cohorts in our previous study, we suggest that these results may be geographically specific. This might be because of differences between populations in the structure of linkage disequilibrium or in interactions with environmental, genetic or epigenetic factors. A much larger study will be needed to clarify the role of homozygosity of HLA alleles in AD risk.

Ischemic preconditioning of cadaver donor livers protects allografts following transplantation.

BACKGROUND: Ischemic preconditioning (IP) has been shown in animal models to protect livers against ischemia/reperfusion injury. The aim of this clinical study is to investigate whether IP of cadaver livers prior to retrieval confers protection on the allografts. METHODS: Cadaveric donor livers were subjected to IP prior to retrieval by clamping of the hepatic pedicle for 10 min followed by reperfusion. Biopsies were obtained from the preconditioned (n=9) and control nonpreconditioned (n=14) liver transplants prior to and 2 hr following reperfusion. Cryosections were stained with antibodies against neutrophils and platelets. RESULTS: IP livers were associated with significantly lower serum levels of aspartate aminotransferase (240+/-98 IU/L vs. 382+/-163 IU/L; P>0.016) and lactate (0.81+/-0.07 mmol/L vs. 1.58+/-0.9 mmol/L; P>0.018) 24 hr following transplantation. Furthermore, recipients of IP livers spent a significantly shorter time in the intensive care unit following transplantation compared to those given nonpreconditioned allografts (1 vs. 2.8+/-1.6 days; P=0.0008). Increases in neutrophil infiltration were detected in 6/14 (43%; P=0.022) and in CD41 deposition in 5/14 (36%; P=0.042) of nonpreconditioned livers. However, none of the IP allografts showed any change in the levels of platelets or neutrophil infiltration following transplantation. CONCLUSION: IP is an effective method of protecting cadaver donor allografts from cold ischemia and subsequent reperfusion injury. IP is also associated with a reduction in the nonspecific inflammatory response.

Expression of MHC class I-related Chain B (MICB) molecules on renal transplant biopsies.

BACKGROUND: MICA and MICB (MHC class I-related chain A and B) are polymorphic genes that encode molecules related to MHC class I and are expressed on epithelial cells in response to stress. Incompatible donor MIC antigens can stimulate antibody production in transplant recipients. This study was designed to determine MICB expression in kidney pretransplant and any subsequent changes in expression following transplantation and to correlate changes with inflammatory markers and clinical events. METHODS: Paired renal biopsies obtained from living donor (n=10) and cadaveric allografts (n=50) before and 7 days posttransplant were stained for MICB, leukocytic infiltration, and HLA class II antigens. RESULTS: Variable tubular MICB expression was evident in donor biopsies [high 6/60 (10%), low/negative 13/60 (22%), intermediate 41/60 (68%)]. Following transplantation, MICB was up-regulated on renal tubules of 17/60 (28%) biopsies and was associated with MHC class II antigen induction (P=0.02) and leukocyte infiltration (P=0.01). Acute tubular necrosis leading to delayed graft function (DGF) and acute rejection (AR) cause cellular stress within the transplanted kidney. We found a strong association between up-regulation of MICB and cellular stress, 15/17 biopsies with up-regulated MICB expression had AR and/or DGF (P=0.003). CONCLUSIONS: This is the first study demonstrating variable levels of MICB expression in kidneys before transplantation and induction of MICB expression following renal transplantation. MICB expression is associated with HLA class II antigen induction, leukocytic infiltration of the graft and cellular stress in the transplanted kidney. Expression of MICB could contribute significantly to the alloimmune response in mismatched donors and recipients.

Living Donation Has a Greater Impact on Renal Allograft Survival Than HLA Matching in Pediatric Renal Transplant Recipients.

BACKGROUND: Living donor (LD) kidney transplantation accounts for around half of all pediatric renal transplant recipients and results in improved renal allograft survival. The aim of this study was to determine the effect of HLA matching on deceased and LD renal allograft outcomes in pediatric recipients. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant on all children who received a donation after brain death (DBD) or LD kidney-only transplant between 2000 and 2011. HLA-A, HLA-B and HLA-DR mismatches were categorized into 4 levels and 2 groups. Data were fully anonymized. RESULTS: One thousand three hundred seventy-eight pediatric renal transplant recipients were analyzed; 804 (58%) received a DBD donor kidney, 574 (42%) received an LD kidney. Five-year renal allograft survival was superior for children receiving a poorly HLA-matched LD kidney transplant (88%, 95% confidence interval [95% CI], 84-91%) compared with children receiving a well HLA-matched DBD kidney transplant (83%, 95% CI, 80-86%, log rank test P = 0.03). Five-year renal allograft survival was superior for children receiving an LD kidney with 1 or 2 HLA-DR mismatches (88%, 95% CI, 84-91%) compared with children receiving a DBD kidney with 0 HLA-DR mismatches (83%, 95% CI, 80-86%, log rank test P = 0.03). CONCLUSIONS: In children, poorly HLA-matched LD renal transplant outcomes are not inferior when compared with well HLA-matched DBD renal transplants. It is difficult to justify preferentially waiting for an improved HLA-matched DBD kidney when a poorer HLA-matched LD kidney transplant is available.

The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors.

BACKGROUND AND AIMS: The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD). The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD), we aimed to understand how ischemia/reperfusion (I/R) injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration. METHODS: Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13) and DBD (n = 10) livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22) and DBD (n = 13) livers. RESULTS: When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05) and C22 ceramide (p<0.05) were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST) of DCD allografts had significantly increased. CONCLUSION: These data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation.

The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/DQB10201/02/03 haplotype protects from vulval lichen sclerosus.

Lichen sclerosus (LS) is considered to have an immunogenetic background. Several small studies, using serological typing, have reported that HLA-DR11, DR12, and DQ7 were increased in LS, with DR17 less frequent. This study aimed to validate and detect new HLA-DR and DQ associations with LS in females and its characteristic clinical parameters. The cases, 187 female LS patients, and 354 healthy controls were all UK North Europeans. PCR-sequence specific primers method was applied to genotype the HLA-DR, DQ polymorphisms that correspond to 17 serologically defined DR and seven DQ antigens. Statistical analysis was performed with two-tailed Fisher's exact test with Bonferroni adjustment (p value after Bonferrroni adjustment, Pc). We found increased frequency of DRB1*12 (DR12) (11.2%vs 2.5%, pc < 0.01) and the haplotype DRB1*12/DQB1*0301/04/09/010 (11.2%vs 2.5%, p < 0.001, pc < 0.05), and a lower frequency of DRB1*0301/04 (DR17) (11.8%vs 25.8%, pc < 0.01) and the haplotype DRB1*03/DQB1*02DRB1*0301/DQB1*0201/02/03 (11.2%vs 24.6%, pc < 0.0001) in patients compared with controls. HLA DR and DQ antigens were not associated with time of onset of disease, site of involvement, structural changes of genitals, and response to treatment with potent topical steroids. In conclusion, HLA-DR and DQ antigens or their haplotypes appear to be involved in both susceptibility to and protection from LS.