Number Of Human Leukocyte Antigen Mismatches Research Articles

Human leukocyte antigen mismatch and circulating donor-specific antibodies predict graft loss after kidney transplantation: A retrospective study from Campania region – Italy

Donor-specific antibodies (DSA) are an established biomarker predicting antibody-mediated rejection, as the leading cause of graft loss after kidney transplantation. Furthermore, human leukocyte antigen (HLA) matching offers a more precise assessment of donor-recipient HLA compatibility and may prevent more effectively sensitization against allograft tissue. Indeed, increased number of HLA mismatches (MM) is significantly associated with a higher risk of immunological rejection, de novo DSA (dnDSA) development, and graft failure. Over the last decade, a comprehensive approach to optimize kidney matching and monitor transplant recipients for acute and chronic graft dysfunction was the goal for the success of the kidney transplantation. In our long-term retrospective study, we have found that pre- and post-transplantation HLA antibodies were significantly associated with de novo dnDSA occurrence (pre-transplant HLA Class I antibodies p = 0.039p < 0.05; pre-transplant HLA Class II antibodies p = 0.011p < 0.05; post-transplant HLA Class I non-DSA antibodies p < 0.01; post-transplant HLA Class II non-DSA antibodies p < 0.01). In addition, HLA MM at locus A (hazard ratio (HR), 2.44; 95 % confidence interval (CI): 1.15–5.16; p = 0.01 hazard ratio (HR), 2.33; 95 % confidence interval (CI):1.132–4.805; p = 0.02) and DSA Class I (HR, 10.24; 95 % CI: 1.44–72.62; p = 0.02 HR, 5.539; 95 % CI: 1.264–24.272; p = 0.02) appeared to be significant predictors of poorer graft survival. Our investigation demonstrates the long medium-term experience of DSA development occurrence in patients with after kidney transplantation in Campania region – Italy.

O204: The influence of HLA matching on graft survival in lung transplant recipients is indication specific: An UNOS database analysis

Abstract Background and aims The importance of human leukocyte antigen (HLA) matching in lung transplantation remains unclear, and the influence of indication in HLA compatibility is unknown. This study aimed to determine the relationship between HLA matching and lung graft survival using a large-scale multi-center database (UNOS/OPTN) and multivariate logistic analysis. The secondary aim was to determine whether this relationship was influenced by transplant indication. Methods This retrospective observational analysis was performed using 26,312 lung transplant recipients from the UNOS/OPTN database. Patients were divided into two groups based on number of HLA mismatches (0-3 mismatches vs 4-6 mismatches) and then subcategorized by indication. Risk-adjusted outcomes were assessed by multivariate Cox analysis adjusting for donor and recipient characteristics and visualized using Kaplan-Meier survival curves. Results Increased HLA mismatch was associated with reduced allograft survival. Adjusted models found that the total HLA mismatch &amp;gt;3 increased the mortality hazard at 15 years (HR 1·05, p &amp;lt;0·05) and 20 years (HR 1·05, p&amp;lt;0·01). Pulmonary hypertension was the only indication with a statistically significant association between HLA mismatch and graft survival. Allografts in patients with 0-3 mismatches survived for 401 days longer than those with 4-6 mismatches (p=0·02). Conclusion Increased HLA mismatch reduced graft survival. When stratified by indication, this association was preserved exclusively in pulmonary hypertension. This finding is of potential clinical relevance to the management of this subsection of lung transplant recipients, impacting organ allocation, transplant surveillance and use of desensitisation and immunosuppression protocols.

O203: HLA Matching Between Donors and Recipients Improves Clinical Liver Transplant Graft Survival

Abstract Background and Aims The importance of human leukocyte antigen (HLA) matching between liver transplant donors and recipients on graft survival remains unclear and is not a clinical consideration in liver transplantation. This study aimed to determine the relationship between HLA matching and liver graft survival using a large-scale multi-center database (UNOS/OPTN) and multivariate logistic analysis. The secondary aim was to determine whether this relationship was influenced by transplant indication and donor status. Methods This retrospective observational analysis was performed using 22,702 liver transplant recipients from the UNOS/OPTN database. Patients were divided into two groups based on number of HLA mismatches (0-3 mismatches vs 4-6 mismatches), and then subcategorized by indication and donor status. Risk-adjusted outcomes were assessed by multivariate Cox analysis adjusting for donor and recipient characteristics and visualized using Kaplan-Meier survival curves. Results Allograft survival and risk of acute rejection were associated with degree of HLA mismatch. This association between HLA mismatch and graft survival persisted in individuals who underwent transplant for hepatitis, metabolic, drug toxicity and congenital indications. Donor status influenced the relationship between HLA mismatch and graft survival. Graft survival in DBD recipients was longer than in DCD in the 4-6 HLA mismatch group, whereas no significant difference was found in the 0-3 HLA mismatch group. Conclusion HLA mismatch significantly reduced graft survival and increased risk of acute rejection. This association was noted only in specific indications. These findings are of potential clinical relevance to organ allocation, allograft matching algorithms, immunosuppression protocols and transplant surveillance.

401.5: Development of High-Performing and Multicenter-Validated Dynamic Prediction Models With Longitudinal Measurements of Serum Creatinine and Proteinuria for Death-Censored Kidney Graft Failure

Introduction: Prediction models of graft survival in kidney transplantation allow risk stratification of kidney transplant recipients using big data and artificial intelligence. Many models require detailed information on allograft histology and presence of donor-specific antibodies which are not readily available in every transplant center. We developed a joint model using Bayesian estimation to correlate baseline transplant characteristics and longitudinal measurements of both serum creatinine (S-Cr) and urine protein-creatinine ratios (u-PCR) with death-censored graft failure (DCGF). Methods: 3596 kidney transplant recipients (KTRs) from four transplant centers in Europe were included with a total of 452.033 S-Cr and u-PCR measurements. Each KTR had a median of 112 (IQR: 52-163) consecutive measurements. The interval between measurements was 7 (IQR: 1-35) days. Median follow-up was 6 (IQR: 3-9) years. Model predictors included recipient and donor gender and age, total number of human leukocyte antigen-mismatches, donor type, pre-transplant DSAs, and dialysis vintage. Primary outcomes were DCGF six months after last S-Cr or u-PCR measurement and DCGF seven years post-transplantation. Two training and external validation methods have been used to assess best model performance: model 1; development in one center and validation in three remaining centers, and model 2; development on 80% of the total cohort and validation on the remaining 20% (Table 1). Results: A total of 549 (15%) out of 3596 KTRs experienced DCGF. Joint modeling revealed that recipient age, recipient gender, donor age, transplantation after dialysis initiation, and serial measurements of S-Cr and u-PCR were independent risk factors for DCGF. Our final joint models showed good calibration (prediction error: 0.01) and very high discrimination in the development and validation cohorts (6-months incident AUC 0.9 [95% CI: 0.87-0.93] and 7-years dynamic AUC 0.84 [95% CI: 0.81-0.87] for model 1, and 6-months incident AUC 0.98 [95% CI: 0.96-1.00] and 7-years dynamic AUC 0.85 [95% CI: 0.80-0.91] for model 2) (Table 1). Especially model 2 could be of interest as a personalized surveillance tool in clinical practice given its AUCs >0.95 from year 1 onwards.Conclusion: We developed a high performing and multicenter-validated, dynamic prediction model on death-censored allograft survival based on traditionally available baseline transplant characteristics and longitudinal measurements of S-Cr and u-PCR. This dynamic model can continuously be updated with new measurements and might enable personalized surveillance of kidney transplant recipients and objectify allograft prognosis (as illustrated in Figure 1). Of notice, our models can be extended with newly discovered dynamic biomarkers in the future if needed.

Evaluation of Deceased Donor Kidney Transplantation in the Eurotransplant Senior Program in Comparison to Standard Allocation.

BackgroundThe organ shortage and long waiting times have dramatically increased the age of potential kidney transplant recipients. The Eurotransplant Senior Program (ESP) was initiated to allocate kidneys from deceased donors aged ≥65 years to recipients with a comparable age independent of pre-transplant human leucocyte antigen (HLA) matching; however, parameters affecting the long-term benefits of this strategy remain poorly defined.Material/MethodsWe retrospectively evaluated outcome and risk factors for mortality in kidney recipients aged ≥65 years that were transplanted according to the ESP protocol relative to patients aged >50 years transplanted according to the Eurotransplant kidney allocation system (ETKAS) criteria at the University Freiburg Medical Center, Germany, between 2008 and 2018.ResultsGraft survival, graft function, the maintenance immunosuppressive therapy, and the incidence of rejections and infections did not differ between groups. Infectious diseases were the main cause of death in both groups; however, infection-associated mortality was more than double in the ESP group, and 5-year patient survival was 61.4% in the ESP group compared to 83.2% in the ETKAS group. Multivariate analysis identified age, the number of HLA mismatches, and the CMV serostatus with a seropositive donor and negative recipient as the main risk factors for mortality.ConclusionsA comparable immunosuppressive regimen used in ESP and ETKAS patients was associated with similar rejection rates and infectious disease complications, and infections were the most common cause of death in both groups. CMV-negative patients receiving an organ from a CMV-positive donor and patients with a high number of HLA mismatches require close follow-up to reduce mortality.

CAN EPITOPE MATCHING OUTMATCH TRADITIONAL HLA MATCHING?

Collaborative Transplant Study. Introduction: Pre-transplant presence and post-transplant development of alloantibodies against highly polymorphic human leukocyte antigen (HLA) allele mismatches (mm) play a major role in rejection of kidney allografts. However, antibodies recognize small sequences on HLA alleles called epitopes and the same epitope can be present on different alleles, impairing the precision of matching. Using the Collaborative Transplant Study database, we analyzed whether a T-cell epitope-based matching of donor-recipient pairs using the PIRCHE-II algorithm is a better predictor of graft survival than the currently applied allele group-based HLA-A, -B, -DR matching. Methods: 68,606 European deceased donor kidney-only transplantations during 1996–2016 were analyzed. PIRCHE-II mismatch score was calculated based on split typing using the 2007 NMDP haplotype frequency database and the PIRCHE matching service. Multivariable Cox regression analyses were performed to calculate hazard ratios (HRs) for death-censored graft loss. Correlation was analyzed with Spearman’s rank correlation. In order to achieve comparable HRs, a log-transformed PIRCHE-II score was used, followed by a linear transformation to match the value range of 0–6 HLA A+B+DR mm. Linear transformations in Cox regression analysis change the HR per point without changing the P- and Z-values. Results and Discussion: The HLA mismatch-derived PIRCHE-II score correlated strongly with the number of HLA mm (correlation coefficient ρ=0.65, P<0.001). Cox regression analyses revealed that Pirche II score and HLA mm are predictive confounders for death-censored graft loss at year 5 with highly significant prognostic power (Z-value for Pirche II: 9.8; for HLA: 11.2; P<0.001) (Table 1).The full Cox model per transformed PIRCHE-II score without HLA mm resulted in a hazard ratio (HR) for graft loss of 1.102 (95% CI=1.081–1.123; P<0.001). When HLA mm were added to the model, the HR per PIRCHE-II score decreased to 1.042 but remained statistically significant (95% CI=1.015–1.071; P=0.002) (Table 1). Overall, considering the HLA loci currently used for typing at split antigen level, HLA mm still had a higher predictive value than the PIRCHE-II score (11.2 vs. 9.8) regarding graft survival. As illustrated in Figure 1, the variance in PIRCHE-II score increased with higher number of HLA mm.Therefore, the possible clinical benefit of PIRCHE-II score matching improved with higher number of HLA mismatches. As demonstrated in Table 1, the risk of graft loss increases with each additional PIRCHE-II score. Conclusion: Our results indicate that PIRCHE-II score is useful and can be included into matching algorithms. However, it cannot fully replace traditional HLA matching. There seems to be information on immunological differences PIRCHE-II score cannot cover in its present form using HLA typing data at split level. This needs to be analyzed also for HLA matching at 4-digit molecular typing level.

Relating the number of human leucocytes antigen mismatches to pregnancy complications in oocyte donation pregnancies: study protocol for a prospective multicentre cohort study (DONOR study)

IntroductionOocyte donation (OD) enables women with reproductive failure to conceive. Compared with naturally conceived (NC) and in vitrofertilisation (IVF) pregnancies, OD pregnancies are associated with a higher risk of pregnancy...

Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression

Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.

245. The development of pre-eclampsia in oocyte donation pregnancies is related to the number of HLA class II mismatches

Introduction Oocyte donation pregnancies are associated with a higher incidence of pregnancy complications, such as pre-eclampsia. In OD pregnancies the fetus may be completely allogeneic to the mother, since the fetus carries paternal and donor derived Human Leukocyte Antigen (HLA) genes. The higher incidence of pregnancy complications might be related to the high level of immunogenetic dissimilarity, reflected by the number of HLA mismatches. Objective/hypothesis We studied the number of HLA mismatches in OD pregnancies in relation to pre-eclampsia. Methods In this retrospective study, HLA typing was performed in 99 women pregnant after OD and 118 children between 2004 and 2017. The HLA-genotype was determined for HLA-A, HLA-B, HLA-C (HLA class I), HLA-DR and HLA-DQ (HLA class II). The number of HLA mismatches of the child was calculated at the national reference laboratory for histocompatibility testing (LUMC). Results Twenty-two women developed preeclampsia in our group of 99 oocyte donation pregnancies. Maternal age and the frequency of twin pregnancies was significantly higher in the pre-eclampsia group, whereas gestational age was significantly lower in OD pregnancies complicated by pre-eclampsia. The number of HLA class II mismatches of the child was significantly higher in the cases with pre-eclampsia (n = 2.35 vs 3.15; p = 0.014; OR = 1.964 (95% CI = 1.149–3.355)), even after correction by logistic regression for maternal age and twin pregnancies. No significant effect of HLA class I mismatches was observed. Discussion This study showed that OD pregnancies with a higher level of HLA class II mismatches have a significantly higher chance to develop pre-eclampsia. Hence, HLA class II matching could be considered in OD pregnancies to decrease the risk of developing pre-eclampsia, and preventive pre-eclampsia treatment (aspirin) could be considered in OD pregnancies with a higher level of HLA class II mismatches.

Impact of human leukocyte antigen mismatch on lung transplant outcome.

Human leucocyte antigen (HLA) mismatch between donor and recipient has a differential impact on the outcome after transplant (Tx) among transplantable solid organs. Although the lung is considered a highly antigenic organ, the impact of HLA matching between the donor and the recipient has been shown to be heterogeneous on lung Tx outcome. To provide further evidence that HLA matching should be considered in the decision process prior to lung Tx, we evaluated the impact of donor/recipient HLA mismatch on the outcome after lung Tx at our institution. All patients who underwent lung Tx were analysed in this retrospective single-cohort study between 1994 and 2013 for HLA (-A, -B or -DR) matching between the donor and the recipient and their association with overall survival, the incidence of acute cellular rejection (ACR) and the development of chronic lung allograft dysfunction (CLAD). In total, 371 (197 men) patients were included. Of these, 117 patients had no HLA match (0/6), 143 had a 1/6 match, 77 had 2/6 matches, 28 had 3/6 matches and 6 had 4/6 matches. One hundred and twenty-two (33%) patients experienced at least 1 episode of ACR and 172 (46%) patients developed CLAD. Univariate analysis showed a significant correlation between HLA mismatch and the development of CLAD, whereas multivariate analysis revealed that the number of HLA matches (hazard ratio 0.76; P = 0.002), antibodies to cytomegalovirus in either donors or recipients (hazard ratio 1.52; P = 0.036) and donor age (hazard ratio 1.03; P < 0.001) were independent risk factors for the development of CLAD. On the other hand, HLA matches did not correlate with the incidence of ACR and with the overall survival rate. The number of HLA mismatches between donors and recipients after lung Tx did not correlate with ACR or with the overall survival. In contrast, HLA mismatch correlated with the development of CLAD and should therefore be considered a risk factor.

Transplantation Results of Completely HLA-Mismatched Living and Completely HLA-Matched Deceased-Donor Kidneys Are Comparable

Human leukocyte antigen (HLA) mismatches are known to influence graft survival in deceased-donor kidney transplantation. We studied the effect of HLA mismatches in a population of recipients of deceased-donor or living-donor kidney transplantations. All 1998 transplantations performed in our center between 1990 and 2011 were included in this retrospective cohort study. Four different multivariable Cox proportional hazard analyses were performed with HLA mismatches as continuous variable, as categorical variable (total number of HLA mismatches), as binary variable (zero vs. nonzero HLA mismatches), and HLA-A, -B, and -DR mismatches included separately. Nine hundred ninety-one patients received a deceased-donor kidney and 1007 received a living-donor kidney. In multivariable Cox analysis, HLA mismatches, recipient age, current panel-reactive antibodies, transplant year, donor age, calcineurin inhibitor treatment, and donor type were found to have a significant and independent influence on the risk of graft failure, censored for death. Variables representing the total number of HLA-A, -B, and -DR mismatches had a significant and comparable influence in all analyses. The influence of HLA mismatches on death-censored graft survival holds true for both deceased- and living-donor kidney transplantation. However, the relative risk of death-censored graft failure of a 2-2-2 mismatched living-donor kidney is comparable with that of a 0-0-0 mismatched deceased-donor kidney.

Haplotype-Based Banking of Human Pluripotent Stem Cells for Transplantation: Potential and Limitations

High expectations surround the area of stem cells therapeutics. However, the cells' source-adult or embryonic-and the cells' origin-patient-derived autologous or healthy donor genetically unrelated-remain subjects of debate. Autologous origins have the advantage of a theoretical absence of immune rejection by the recipient. However, this approach has several limitations with regard to the disease of the recipient and to potential problems with the generation, expansion, and manipulation of autologous induced pluripotent stem cells (iPS cells) preparation. An alternative to using autologous cells is the establishment of a bank of well-characterized adult cells that would be used to generate iPS cells and their derivatives. In the context of transplantation, such cells would come from genetically unrelated donors and the immune system of the recipient would reject the graft without immunosuppressive therapy. To minimize the risk of rejection, human leukocyte antigen (HLA) compatibility is certainly the best option, and the establishment of an HLA-organized bank would mean having a limited number of stem cells that would be sufficient for a large number of recipients. The concept of haplobanking with HLA homozygous cell lines would also limit the number of HLA mismatches, but such an approach will not necessarily be less immunogenic in terms of selection criteria, because of the limited number of HLA-compatible loci and the level of HLA typing resolution.

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA-loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.

Comparison of Unrelated Cord Blood Transplantation and HLA-Mismatched Unrelated Bone Marrow Transplantation for Adults with Leukemia

Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT.

Consideration of Donor Age and Human Leukocyte Antigen Matching in the Setting of Multiple Potential Living Kidney Donors

Defining living donor (LD)-related risk factors affecting kidney transplant outcome will allow better donor selection and more educated informed consent when there is more than one potential donor. We studied risk factors in a large cohort at a single institution. We reviewed 1632 recipients who underwent LD kidney transplantation at the University of Minnesota between January 1, 1990, and October 1, 2009. Using Cox regression, we studied the effect of donor and recipient risk factors on patient and graft survival. We specifically examined the effect of donor age and human leukocyte antigen (HLA) matching because these are variables that may help clinical decision making when multiple potential donors exist. Mean donor age was 40.6 years for all transplants; 180 (11%) donors were 55 years or older, and 24 (1.5%) donors were older than 65 years. Mean number of HLA mismatches (per transplant) was 2.9 (29.2% of recipients had one to two HLA mismatches, 39.8% had three to four HLA mismatches, and 25% had five to six HLA mismatches). Donor age more than 65 years, five to six HLA mismatches, delayed graft function, and acute rejection were independent predictors of decreased patient and graft survival. When controlling for recipient age, donor age more than 65 years remained a risk factor for worse outcome. Our data suggest that advanced donor age (>65 years) and degree of HLA mismatch (≥5) are independent donor-related risk factors associated with worse outcome. When multiple potential LDs exist, it may be ideal to attempt to use a donor younger than 65 years and with less than five HLA mismatches.

The effect of HLA mismatch on highly sensitized renal allograft recipients

We examined the effects of increasing human leukocyte antigen (HLA) mismatches (MM) on long-term graft outcomes in patients transplanted with a panel reactive antibody (PRA) >80% over a 10-yr period. A total of 142 recipients were divided into three groups based on the number of HLA MM with their allograft (0-2, 3-4 and 5-6 MM; Groups I, II and III). All patients received the same immunosuppression protocol. The higher MM groups had a higher incidence of rejection (4.4% vs. 11.4% vs. 31.3%, p < 0.01). A multivariate analysis showed that rejection was the only significant variable affecting graft loss (OR = 7.45, p = 0.01). There was a trend toward more CMV infection and worse graft function with higher MM. Kaplan-Meier five-yr graft survival estimates were 100% vs. 81% vs. 74% for Groups I, II and III, respectively (p = 0.14). In patients with PRA levels >80%, a higher HLA MM is associated with higher incidence of acute rejection. Acute rejection was the only significant variable affecting graft loss. We found a trend toward more CMV infections and worse graft outcomes with higher MM. Closer HLA matching and immunologic monitoring needs to be considered to improve graft outcomes among sensitized recipients.

Impact of HLA Compatibility on Lung Transplant Survival and Evidence for an HLA Restriction Phenomenon: A Collaborative Transplant Study Report

Data concerning the impact of human leukocyte antigen (HLA) compatibility on lung transplant survival rates are limited. Using the Collaborative Transplant Study database, 5-year graft outcome according to HLA mismatch was examined in 8020 deceased donor lung transplants performed during 1989 to 2009. Graft survival rates showed a stepwise decrease as the combined number of HLA-A+B+DR mismatches increased from one to six (P<0.001). Surprisingly, the 28 grafts with 0 mismatches at all 3 loci had a 1-year survival rate of only 49.7%, significantly lower than for 1, 2, 3, 4, 5, or 6 mismatches (P=0.002, <0.001, <0.001, <0.001, 0.002, and 0.003, respectively). Multivariate regression analysis confirmed that, paradoxically, transplantation of grafts with zero HLA-A+B+DR mismatches was associated with a 19% increase in relative risk of failure. Donor lung preservation for up to 12 hr was not associated with inferior graft survival versus shorter preservation times (P=0.60). Our data show that a high number of HLA mismatches or zero mismatches impacts unfavorably on lung transplant survival.

Comparable transplant outcomes between local and shipped deceased‐donor kidneys in Australia: Analysis of Australia and New Zealand Dialysis and Transplant Registry 1992–2007

Allocation of deceased-donor kidneys in Australia often involves the shipping of well-matched renal allografts across states. However, the impact of shipping on graft outcomes remains unclear. In this study, the effect of shipping of well-matched (0-2 human leucocyte antigen (HLA) mismatches) and poorer-matched (3-6 HLA mismatches) deceased-donor kidneys on transplant outcomes in Australia were examined. Using data from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), graft and patient outcomes were compared between shipped and locally transplanted allografts in Australia between 1992 and 2007 stratified by the number of HLA mismatches. Recipients receiving shipped renal allografts were more likely to be highly sensitized with previous grafts and/or higher panel reactive antibodies levels with significantly longer graft ischaemic time compared to local allografts. Regardless of the HLA mismatches, the risk of delayed graft function, acute rejection, 12 month serum creatinine, graft failure and patient survival was similar between shipped and locally transplanted renal allografts. Recipients of shipped renal allografts with 0-2 and 3-6 HLA mismatches have similar transplant outcomes to locally transplanted allografts.

Impact of human leukocyte antigen mismatching on outcomes of liver transplantation: A meta-analysis

To assess the effect of human leukocyte antigen (HLA) mismatching on liver graft outcome and acute rejection from a meta-analysis of available cohort studies. Articles in PubMed/MEDLINE, EMBASE and the Cochrane database from January 1970 to June 2009, including non-English literature identified in these databases, were searched. Only studies comparing HLA or sub-phenotype matching with mismatching were extracted. The percentage of graft survival was extracted by "Engauge Digitizer" from survival curves if the raw data were not displayed. A meta-analysis was performed when at least 3 studies provided data. Sixteen studies met the inclusion criteria. A lower number of HLA mismatches (0-2 vs 3-6) did reduce the incidence of acute rejection (relative risk: 0.77, P = 0.03). The degree of HLA mismatching (0-2 vs 3-6) had no significant effect on 1-year [hazard ratio (HR): 1.04, P = 0.68] and 5-year (HR: 1.09, P = 0.38) graft survival. In sub-phenotype analysis, the degree of HLA-A, B and DR mismatching (0 vs 1-2) had no significant effect on 1-year and 5-year graft survival, either. The HRs and P-values were 0.95, 0.71 (HLA-A, 1-year); 1.06, 0.60 (HLA-A, 5-year); 0.77, 0.16 (HLA-B, 1-year); 1.07, 0.56 (HLA-DR, 1-year); 1.18, 0.23 (HLA-DR, 5-year), respectively. The results of this systematic review imply that good HLA compatibility can reduce the incidence of acute rejection in spite of having no influence on graft outcomes. To obtain a short recovery time and minimize rejection post transplantation, HLA matching studies should be considered before the operation.

Soluble total human leukocyte antigen class I and human leukocyte antigen–G molecules in kidney and kidney/pancreas transplantation

The expression of human leukocyte antigen (HLA)–G, a nonclassical HLA class I molecule, and its soluble forms (sHLA-G) are found to improve graft acceptance. In this study we investigated whether sHLA-G is the most biologically relevant molecule among all types of soluble HLA class I molecules for graft acceptance. We addressed this question in kidney-transplanted ( n = 32) and kidney/pancreas-transplanted patients ( n = 29). To this end we analyzed the levels of total soluble HLA class I (sHLA-I) in comparison to sHLA-G in 488 plasma samples procured before and serial after transplantation by specific enzyme-linked immunoabsorbent assay. Samples from 126 healthy individuals served as controls. Pretransplantation sHLA-I levels were significantly increased in patients ( p < 0.001), whereas sHLA-G levels were in the range of those of healthy controls. Importantly, pretransplantation sHLA-I and sHLA-G levels did not differ between the two groups. Patients with biopsy-proven rejection ( n = 15) revealed significantly lower sHLA-G levels before transplantation (mean ± standard error of the mean, 12.9 ± 1.8 vs. 20.1 ± 1.9, p = 0.013) and after transplantation ( p = 0.006, two-way analysis of variance) than patients without rejection ( n = 46). In contrast, sHLA-I was slightly increased after but not before transplantation in patients with rejection ( p < 0.05, two-way analysis of variance). Nonparametric determination analysis showed that pretransplantation levels of sHLA-G < 11.5 ng/ml (sensitivity, 60%; specificity, 80.4%) were related to rejection. Regarding antibody status, retransplantation, number of HLA mismatches, recipient age, and recipient body mass index, multivariate analysis showed that sHLA-G but not sHLA-I is an independent risk factor for graft rejection. Thus high levels of sHLA-G but not of sHLA-I seem to contribute to better graft acceptance after kidney or kidney/pancreas transplantation.