DR Mismatches Research Articles

Report on post-transplantation cancer in southeast Asia from the Thai kidney transplantation cohort

Post-transplantation cancer is a significant cause of mortality among kidney transplant recipients (KTR). The incidence of post-transplantation cancer varies based on geographic region and ethnicity. However, data on KTR from South East Asia, where characteristics differ from other parts of Asia, is lacking. We conducted a retrospective cohort study at a transplant center in Thailand to investigate the incidence of post-transplantation cancer and mortality rates. Factors associated with post-transplantation cancer and patient outcomes were analyzed using competing-risks regression. The study included 1156 KTR with a post-transplant follow-up duration of 5.1 (2.7–9.4) years. The age- and sex-adjusted incidence rate of post-transplant cancer was highest for urothelial cancer (6.9 per 1000 person-years), which also resulted in the highest standardized incidence ratio (SIR) of 42.5 when compared to the general population. Kidney cancer had the second-highest SIR of 24.4. Increasing age was the factor associated with an increased risk of post-transplant cancer (SHR 1.03; 95% CI 1.01–1.05). Human leukocyte antigen (HLA) DR mismatch was associated with a decreased risk of post-transplant cancer (SHR 0.72; 95% CI 0.52–0.98). Post-transplantation cancer was significantly associated with patient mortality (HR 3.16; 95% CI 2.21–4.52). Cancer significantly contributes to KTR mortality, and the risk profile for cancer development in Thai KTRs differs from that of Western and most Asian counterparts. Further research is essential to explore appropriate screening protocols for countries with high rates of urothelial and kidney cancer, including Thailand.

Risk Factors for Adverse Outcomes in Kidney Transplants From Donors After Circulatory Death With Normothermic Regional Perfusion: A Systematic Analysis.

This study examined 1071 adult primary kidney transplants from the French-controlled donation after the circulatory determination of death (cDCD) program, which uses normothermic regional perfusion (NRP), and involves short cold ischemia times (CIT) and constrained asystole times differing by donor age. Logistic regression identified risk factors for primary nonfunction (PNF), delayed graft function (DGF), and graft failure. Risk factors for PNF included donor hypertension, admission for ischemic vascular stroke, and HLA DR mismatches. Risk factors for DGF included functional warm ischemia time >40 min, dialysis >2 y, recipient body mass index of 30 kg/m2 or higher, recipient diabetes, and CIT >10 h. Risk factors for 1-y graft failure included donor hypertension, donor lung recovery, ostial calcification, recipient cardiovascular comorbidities, and HLA DR mismatches. A high donor estimated glomerular filtration rate protected against DGF and graft failure at 1-y. After adjustment restricted to recipient and graft factors and donor age, the risks of PNF, DGF, and graft failure increased with donor age up to 65 y and then remained stable. The study suggests that cDCD kidney transplants are highly successful, but also that its outcomes are influenced by lung recovery, poor HLA DR matching, and warm ischemia times differing with donor age. Our study identified several risk factors for kidney transplantation failure after cDCD with systematic use of NRP and some of them seem as modifiable variables associated with cDCD transplant outcome.

#2468 2-Step-Scores with optional histopathology for the prediction of delayed graft function and 1-year transplant loss in Eurotransplant

Abstract Background and Aims The decision for acceptance or discard of the increasingly rare and marginal deceased donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores we call 2-Step Scores for the prognosis of delayed graft function (DGF) as 2-Step-DGF and one-year death-censored transplant loss (1y-tl) as 2-Step-1y, reflecting current practice of six ET countries including Croatia and Belgium. Method The training set was n = 620 for DGF and n = 711 for 1y-tl, with validation sets n = 158 and n = 162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. Results Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively). Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. Receiver operating characteristics of both 2-Step-DGF and 2-Step-1y compared to established scores are shown in Figs 1 and 2. Conclusion Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pumps use.

2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Role of HLA matching and donor specific antibody development in long-term survival, acute rejection and cardiac allograft vasculopathy

Although there are different data supporting benefits of HLA matching in kidney transplantation, its role in heart transplantation is still unclear. HLA mismatch (MM) between donor and recipient can lead to the development of donor-specific antibodies (DSA) which produces negative events on the outcome of heart transplantation. Moreover, DSAs are involved in the development of antibody-mediated rejection (AMR) and are associated with an increase in cardiac allograft vasculopathy (CAV). In this study it is analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, AMR and CAV in heart transplantation. For this retrospective study are recruited heart transplanted patients at the Cardiac Transplantation Centre of Naples between 2000 and 2019. Among the 155 heart transplant patients, the mean number of HLA-A, B, -DR MM (0 to 6) between donor and recipient was 4.5 ± 1.1. The results show a negative association between MM HLA-DR and survival (p = 0.01). Comparison of patients with 0–1 MM at each locus to all others with 2 MM, for both HLA class I and class II, has not showed significant differences in the development of CAV. Our analysis detected DSA in 38.1% of patients. The production of de novo DSA reveals that there is not an influence on survival (p = 0.72) and/or AMR (p = 0.39). Instead, there is an association between the production of DSA class II and the probability of CAV development (p = 0.03). Mean fluorescence intensity (MFI) values were significantly higher in CAV-positive patients that CAV-negative patients (p = 0.02). Prospective studies are needed to evaluate HLA class II matching as an additional parameter for heart allocation, especially considering the increment of waiting list time.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0–5%; PRA-0) and intermediately sensitized (PRA 6–84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

A Multi-Step Precision Pathway for Predicting Allograft Survival in Heterogeneous Cohorts of Kidney Transplant Recipients.

Accurate prediction of allograft survival after kidney transplantation allows early identification of at-risk recipients for adverse outcomes and initiation of preventive interventions to optimize post-transplant care. Many prediction algorithms do not model cohort heterogeneity and may lead to inaccurate assessment of longer-term graft outcomes among minority groups. Using data from a national Australian kidney transplant cohort (2008-2017) as the derivation set, we developed P-Cube, a multi-step precision prediction pathway model for predicting overall graft survival in three ethnic subgroups: European Australians, Asian Australians and Aboriginal and Torres Strait Islander Peoples. The concordance index for the European Australians, Asian Australians, and Aboriginal and Torres Strait Islander Peoples subpopulations were 0.99 (0.98-0.99), 0.93 (0.92-0.94) and 0.92 (0.91-0.93), respectively. Similar findings were observed when validating P-cube using an external dataset [Scientific Registry of Transplant Recipient Registry (2006-2020)]. Six sub-categories of recipients with distinct risk factor profiles were identified. Some factors such as blood group compatibility were considered important across the entire transplant population. Other factors such as human leukocyte antigen (HLA)-DR mismatches were unique to older recipients. The P-cube model identifies allograft survival specific risk factors within a heterogenous population and offers personalized survival predictions in a diverse cohort.

#5884 HLA COMPATIBILITY DOES NOT INFLUENCE KIDNEY GRAFT SURVIVAL AND DOES NOT IMPACT THE DEVELOPMENT OF POST-TRANSPLANT NEOPLASIA

Abstract Background and Aims HLA compatibility is a key issue in deceased and living kidney allocation, although the continuous improvement of immunosuppressive protocols might have reduced its relevance. However, an increased immunosuppression is associated with several adverse events, including the development of post-transplant neoplasia. Indeed, several reports demonstrated that the improvement in immunosuppressive drug efficiency corresponded to an increase incidence of malignancies after kidney transplantation. Thus, the aim of our study was to investigate the effect of HLA compatibility on kidney graft survival and incidence of post-transplant neoplasia. Method This is an observational, retrospective, multicenter center study including 1506 patients receiving a single kidney transplant at the Gemelli and Policlinico “Consorziale” kidney transplant centers from 1/1/2000 to 1/2/2022. The primary outcomes were death-censored graft survival and the development of post-transplant neoplasia. HLA compatibility was measured as the number of HLA mismatches (MM) at the three main class I (A and B) and class II (DR) loci. To this purpose, both donor and recipients were genotyped for HLA A, B and DR. We included in the analysis all deceased and living kidney donor transplants and excluded recipients from AB0 incompatible living kidney donors and with pre-transplant donor specific antibodies. Results Based on HLA compatibility, we divided our patients’ population in three groups (0-2 MM, 369 patients 3-4 MM, 856 patients and 5-6 MM, 281 patients). At univariate analysis (Kaplan-Meyer) number of MM were not associate with death-censored graft survival (Logrank p = 0.6) whereas we observed a significant association with the development of post-transplant neoplasia (Logrank p = 0.01). However, multivariate analysis (Cox model including recipient age, induction and maintenance immunosuppressive therapy) demonstrated that patients with 3-4 (HR 1.033, 95% CI 0.676-1.580, p = 0.9) and 5-6 MM (HR 1.342, 95% CI 0.853-2.111, p = 0.2) did not have any statistically significant increase in the risk to develop a post-transplant malignancy. Conclusion In this observational retrospective multicenter analysis, we demonstrated that HLA incompatibility, as indicated by the number of HLA A, B and DR MM, does not predict death-censored graft survival and does not impact the development of post-transplant neoplasia. Our observation would suggest that the missing effect of HLA compatibility on graft outcome is not associated with an increased long-term over-immunosuppression.

Unrelated versus related living-donor kidney transplantation is associated with higher acute rejection rate but similar graft survival Running title: Outcomes in living-donor kidney transplantation

Kidney transplantation (KT) from living donors has been shown to have multiple benefits compared with that from deceased donors. We sought to compare significant graft outcomes, namely acute rejection (AR), graft function, and survival, between transplant recipients who received a kidney from a living-related donor (LRD) and from a living unrelated donor (LURD). Our cohort comprised 198 donor and recipient pairs undergoing living-donor KT at our center over 10 years. LRD recipients were compared with LURD recipients according to demographic and clinical characteristics, transplant variables (including immunosuppression), graft function, survival, and AR rate. The estimated glomerular filtration rate (eGFR) was similar in both groups over the follow-up time, of 60-65 mL/min (p<0.05 over a 10-year period). Censored graft survival was similar between LRD and LURD recipients (96.9% vs. 98.0% at 5 years and 87.8% vs. 79.4% at 10 years, respectively; p=0.837). LURD recipients had a higher incidence of AR, although LURD recipient status was not an independent risk factor for AR. Multivariate analysis showed that human leukocyte antigen (HLA) -DR mismatch (MM) was an independent predictor of AR (hazard ratio [HR] 2.256, p<0.05). HLA-A and HLA-B MM did not affect the AR HR between the groups. Graft function and censored-death survival rates were similar between the LURD and LRD KT recipients. HLA-DR MM was an independent risk factor for AR.

Biologically Unrelated Living Donor for Kidney Transplantation Associated With Higher Acute Rejection Rate but With Similar Graft Survival of a Related Living Donor.

Kidney transplantation (KT) from living donors has been shown to have multiple benefits compared to those from deceased donors. We sought to compare significant graft outcomes, namely acute rejection (AR), graft function, and survival between transplant recipients who received a kidney from living related donor (LRD) and living unrelated donor (LURD). Our cohort comprised 198 donor and recipient pairs undergoing living-donor KT at our center over 10 years. The LRD recipients were compared with LURD recipients according to demographic and clinical characteristics, transplant variables (including immunosuppression), graft function, survival, and AR rate. The estimated glomerular filtration rate (eGFR) was similar in both groups over the follow-up time i.e.,60-65 mL/min (p>0.05 over 10 years). Censored graft survival was similar between LRD and LURD recipients (96.9% vs. 98.0% at five years and 87.8% vs. 79.4% at 10 years, respectively; p=0.837). The LURD recipients had a higher incidence of AR, although LURD recipient status was not an independent risk factor for AR.Multivariate analysis showed that human leukocyte antigen (HLA)-DR mismatch (MM) was an independent predictor of AR (hazard ratio (HR) 2.256, p<0.05). Both HLA-A and HLA-B MM did not affect the AR HR between the groups. Graft function and censored graft survival rates were similar between LURD and LRD KT recipients in our study. The AR was higher in LURD recipients, although the LURD recipient status was not an independent risk factor for AR. The HLA-DR MM was an independent predictor of AR, while HLA-A and HLA-B MM did not affect AR HR between groups of patients.

Significance of HLA-matching and anti-HLA antibodies in heart transplant patients receiving induction therapy?

ObjectivesThough Human Leukocyte Antigen (HLA) matching benefits are demonstrated in renal transplantation, evidence in heart transplantation is lacking, and its clinical feasibility is uncertain. Post-transplantation anti-HLA antibodies are being increasingly studied in organ transplantation, with diverging conclusions between transplantated organs. MethodsWe analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, acute rejection and chronic allograft vasculopathy in 309 patients receiving induction therapy and triple-drug immunosuppression. ResultsThe average number of HLA-A/B/DR mismatches between donor and recipient was 4.9 ± 1. The majority of mismatches was for Class I HLA-A/B with an average of 3.3, then for Class I HLA-DR with an average of 1.6. Overall, the HLA-A/-B/-DR mismatches had no influence on the cardiac allograft survival (p = 0.28). However, HLA-DR mismatches were negatively correlated to severe cellular and/or humoral allograft rejection (p = 0.04). Our analysis found anti-HLA antibodies in 27% of recipients, de novo anti-HLA antibodies in 16% of recipients, and donor-specific anti-HLA (DSA) antibodies in 8% of recipients. Furthermore, de novo DSA had no influence on the 5-year survival (78% with DSA vs. 92% without DSA; p = 0.49), which may be masked by the limited number of recipients in analysis By univariable analysis, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on severe cellular and/or humoral rejection or on chronic allograft vasculopathy. ConclusionsHLA-DR mismatch was negatively correlated to severe cellular and/or humoral allograft rejection but had no influence on cardiac allograft survival. In this study, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on cellular and/or humoral rejection or on chronic allograft vasculopathy. The results of this study add to the controversy on the impact of allo-antibodies in heart transplant recipients receiving induction therapy and contemporary immunosuppression.

416.3: Are HLA-A,B,DR and DQ-Mismatching Important for the Kidney Allocation Schemes?-UK Registry Data- an Artificial Intelligence Approach

Introduction: Currently, there is inconsistency among different kidney allocation systems for deceased donors and paired exchange schemes in terms of assessment for HLA-A,B,DR and DQ mismatch. The aim of our study is to assess the effect of HLA-A,B,DR and DQ mismatch on kidney transplant graft survival in the current era. Methodology: All renal transplant patients registered in the United Kingdom Transplant Registry database between January 2005 till January 2015 were retrospectively reviewed. Patients with complete data about HLA-A,D,DR and DQ mismatch were included. Follow up was till April 2021.Patient with complete dataset were included in the study. Recipients with multiple organ transplant, previous renal transplants, or those with missing data about HLA mismatch were excluded from the study. For survival analysis, we fit a penalised Cox model to the entire set of data. We obtained the estimated set of alphas using estimated cross-validated grid-search. The variables included in the penalised cox model donor, recipient and transplant factors in addition to the HLA mismatches. Then we determined the set of alpha for evaluation using optimized cross-validated grid-search. Moreover, we visualised how the coefficients changed for varying α using ridge regression model. The regression models were adjusted for recipient factors (age, sex, ethnicity, diabetes, body mass index), transplant factors (HLA mismatches, calculated reaction frequency, cold ischemia time, delayed graft function, induction, and maintenance immunotherapy) and donor factors (donor type, donor creatinine at time of retrieval, donor age). Results: Median follow-up was 7.5 years. Among living donor kidney transplant recipients (n=4782), Incremental increase in HLA-DR mismatch touched statistical significance and was associated with worse survival (Two HLA-DR: HR=1.31, P=0.05, 95%CI: 1.0-1.72; One HLA-DR mismatch: HR=1.21, P=0.05, 95%CI: 1.00-1.47). None of the other categories of HLA mismatches were associated with worse graft outcomes (P>0.05 for each category).Other factors that played an important role in determining graft survival were delayed graft function (P<0.01), black ethnicity (HR=1.88, 95%CI:1.45-2.51, p<0.01), and donor age (HR=1.02, P<0.01). Among deceased donor kidney transplant recipients (n=7996), None of the HLA mismatches were associated with worse graft survival (P>0.05 for each category of HLA mismatches). The factors that played an important role in determining graft survival were delayed graft function (HR=1.84, 95%CI: 1.67-2.03, P<0.01), black ethnicity (HR=1.42, 95%CI:1.21-1.65, p<0.01), donor age (HR=1.02, P<0.01), and recipient age (HR=0.99, P<0.01). Conclusion: In the current era, HLA-DR mismatches are associated with worse graft outcomes among living donor transplants. However, none of the HLA mismatches are associated with worse graft outcomes among deceased donor kidney transplant recipients. Other factors that play an important role in determining graft survival are delayed graft function, donor age and black ethnicity.

416.1: Impact of HLA-A,B DR and DQ on Deceased Kidney Transplant Outcomes in the Tacrolimus/MMF Era: An Artificial Intelligence Approach

Introduction: One of the biological barriers that can impact outcomes in kidney transplantation is HLA mismatch. Several immunotherapy protocols were implemented to reduce this detrimental effect. The aim of our study is to assess the effect of HLA mismatches on acute rejection rates and graft survival in the Tacrolimus era. Moreover, to determine the most important factors affecting survival. Methodology: All kidney transplant patients registered in UNOS database between 01/01 2005 and 01/12/2019 were retrospectively reviewed. Inclusion criteria: deceased donor transplants that were discharged on Tacrolimus/Mycophenolate Mofetil. Exclusion criteria: multiple organ transplants, previous kidney transplants, recipient age<18 years old, living donor transplants, missing data about induction therapy, missing HLA mismatch or ABO incompatible transplant. We used double-selection lasso (least absolute shrinkage and selection operator) logistic regression model to assess for the effect of HLA-A, B, DR, and DQ on acute rejection rates at one-year post-transplant. Variables of interest were HLA-A,B,DR and DQ mismatch. Variables Lasso selected from were: recipient characteristics (age, sex, BMI, ethnicity, diabetes, recipient/donor CMV status, pre-transplant dialysis), donor characteristics (KDPI score) and transplant characteristics (induction therapy, steroid intake, cold ischemia time, delayed graft function, PRA). Acute rejection was defined as biopsy proven or clinically suspected rejection. For survival analysis, we fit a penalised Cox model after choosing best alpha. Cross-validated grid-search was used to evaluate the best alpha. The variables included in the penalised cox model: donor, recipient and transplant factors. We visualised the coefficients variations across different α using ridge regression model in figure 1. Results: 66,021 were included. Worse acute rejection rates at one-year post-transplant were noted with incremental increase in HLA-DQ (Two HLA-DQ: OR=1.24, P=0.005,95%CI:1.10-1.40; One HLA DQ:OR=1.19,P=0.01,95%CI:1.06-1.33), HLA-DR mismatches (Two HLA-DR: OR=1.41, P<0.01, 95%CI:1.25-1.61; One HLA-DR: OR=1.27,p<0.01, 95%CI:1.13-1.43),Two HLA-B (OR=1.19,P=0.049) and HLA-A(Two HLA-A: OR=1.18, P=0.01; One HLA-A: OR=1.16,P=0.02). In the penalized cox regression model, only Two HLA-DR mismatch was associated with worse survival (HR=1.13, P<0.01, 95%CI: 1.05-1.21). KDPI was the most important factor affecting graft survival (KDPI>80%: HR=2.3, P<0.01; KDPI 60-80%: HR=1.57, P<0.01; KDPI 40-60%: HR=1.23, P<0.01). Delayed graft function affected graft survival by HR=1.50 (P<0.01). Mean follow-up time was 3.79 years. Conclusion: HLA-DQ, DR,B and A mismatches play a vital role in the occurrence of acute rejection in the Tacrolimus/MMF era. However, only 2-HLA-DR mismatch has significant effect on graft survival. KDPI>40% and delayed graft function play the most important role in determining graft survival.

401.1: Impact of HLA-A,B DR and DQ on Living Kidney Transplant Outcomes in the Tacrolimus/MMF Era: An Artificial Intelligence Approach

Introduction: One of the biological barriers that can impact outcomes among Living donor kidney transplantation is HLA mismatch. The aim of our study is to assess the effect of HLA mismatches on acute rejection rates and graft survival in the Tacrolimus era. Moreover, to assess factors affecting survival. Methodology: All Living donor kidney transplant patients registered in UNOS database between 01/01/2005 and 01/12/2019 were retrospectively reviewed. Inclusion criteria: Living donor transplant recipients that were discharged on Tacrolimus/Mycophenolate Mofetil. Exclusion criteria: multiple organ transplants, previous kidney transplants, recipient age<18 years old, deceased donor transplants, missing data about induction therapy, missing HLA mismatch or ABO incompatible transplant. We used double-selection lasso (least absolute shrinkage and selection operator) logistic regression model to assess for acute rejection rates at one-year post-transplant. Variables of interest were HLA-A,B,DR and DQ mismatch. Variables Lasso selected from were: recipient characteristics (age, sex, BMI, ethnicity, diabetes, recipient/donor CMV status, pre-transplant dialysis), donor characteristics (age,ethnicity, diabetes and hypertension) and transplant characteristics (induction therapy, steroid intake, cold ischemia time, delayed graft function, PRA). Acute rejection was defined as biopsy proven or clinically suspected rejection. For survival analysis, we fit a penalised Cox model after choosing best alpha. Cross-validated grid-search was used to evaluate the best alpha. The variables included in the penalised cox model donor, recipient and transplant factors plus HLA mismatches. Results: 28,736 patients were included in our study. Worse acute rejection rates at one-year post-transplant were noted with incremental increase in HLA-DQ (Two HLA-DQ: OR=1.29, P<0.01, 95%CI:1.08-1.54; One HLA DQ:OR=1.22,P=0.01, 95%CI:1.05-1.44), HLA-DR mismatches (Two HLA-DR: OR=1.85, P<0.01, 95%CI:1.48-2.31; One HLA-DR: OR=1.51,p<0.01, 95%CI:1.23-1.85),HLA-B mismatches(Two HLA-B OR=1.33, P=0.01,95%CI:1.05-1.69; One HLA-B mismatch: OR=1.21,P=0.09) and HLA-A mismatch (OR:1.19, P<0.01). In the penalized cox regression model, None of the HLA types (A,B,DR or DQ) were associated with worse graft survival (P>0.05 for every type). The factors that were associated with worse outcomes are: Recipient black ethnicity (HR 1.2, P<0.01, 95%CI:1.10-1.31); delayed graft function (HR=1.54, p<0.01, 95%CI:1.31-1.81), pre-transplant dialysis (HR=1.19,P<0.01, 95%CI:1.12-1.26) and donor Black ethnicity(HR=1.21, P<0.01, 95%CI:1.10-1.33). Conclusion: HLA-DQ, DR,B and A mismatches play a vital role in the occurrence of acute rejection among Living donor kidney transplant recipients. However, HLA mismatches have no significant effect on graft survival. Delayed graft function, pre-transplant dialysis recipient and donor black ethnicity, play an important role in determining graft survival.

The impact of human leukocyte antigen mismatch on recipient outcomes in living-donor liver transplantation.

Donor-recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990-2020). The primary and secondary endpoints were recipient survival and the incidence of T cell-mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0-10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p=0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21-5.87; p=0.02) and recipient survival (HR 2.44, 95% CI 1.11-5.35; p=0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor-recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.

MO994: Impact of Hla-A, B DR and DQ on renal transplant outcomes in the Tacrolimus/Mmf Era: An Artificial Intelligence Approach

Abstract BACKGROUND AND AIMS One of the biological barriers that can increase risk of acute rejection in kidney transplantation is HLA mismatch. Several immunotherapy protocols have been implemented to reduce the effect of HLA-mismatch and improve outcomes. The aim of our study is to assess the effect of HLA mismatches on acute rejection rates in the Tacrolimus era. METHOD All kidney transplant patients registered in UNOS database between 1 January 2005 and 1 December 2019 were retrospectively reviewed. Inclusion criteria: deceased donor transplants that were discharged on Tacrolimus/Mycophenolate Mofetil. Exclusion criteria: multiple organ transplants, previous kidney transplants, recipient age &amp;lt;18 years old, living donor transplants, patients not discharged on Tacrolimus/Mycophenolate Mofetil immunotherapy, missing HLA mismatch or ABO incompatible transplant. We used double-selection lasso (‘least absolute shrinkage and selection operator) logistic regression model to assess for the effect of HLA-A, B, DR and DQ on acute rejection rates at one-year post-transplant. We used square-root lassos for the variables of interest. Variables of interest were HLA-A, B, DR and DQ mismatch. Variables Lasso selected from were: recipient characteristics (age, sex, BMI, ethnicity, diabetes, recipient/donor CMV status, time on dialysis), donor characteristics (KDPI score) and transplant characteristics (type of induction therapy, steroid therapy at time of discharge, cold ischemia time, delayed graft function, PRA). For survival analysis, we fit a penalized Cox model to the entire set of data and obtained the estimated set of alphas. The variables included in the penalized cox model donor, recipient and transplant factors in addition to the HLA mismatches. Then we determined the set of alpha for evaluation using optimized cross-validated grid-search. Moreover, we visualized how the coefficients changed for varying α using ridge regression model. RESULTS About 73 910 were included in our study. Worse acute rejection rates at one-year post-transplant were noted with incremental increase in HLA-DQ (Two HLA-DQ: OR = 1.56, P = 0.005, 95%CI: 1.04–1.27; One HLA DQ: OR = 1.15, P = 0.01, 95%CI: 1.03–1.24), HLA-DR mismatches (two HLA-DR: HR = 1.46, P &amp;lt; 0.01, 95%CI: 1.31–1.62; One HLA-DR: OR = 1.29, P &amp;lt; 0.01, 95%CI: 1.16–1.43), and Two HLA-A (OR = 1.12, P = 0.049, 95%CI: 1.0006–1.26). However, the effect of different HLA-mismatches on death-censored graft survival were minimal (HLA-DQ coefficient: 0.003, HLA-DR coefficient: 0.05, HLA-A coefficient: 0.008 and HLA-B coefficient: 0.007). Mean follow-up time was 3.79 years. Figure 1 shows the visualisation of coefficients among different alphas for the ridge penalised cox regression model. CONCLUSION HLA-DQ, DR and A mismatches still play a vital role in the occurrence of acute rejection in the Tacrolimus/MMF era. However, the effect of HLA mismatches on the graft survival is minimal.

Development and Internal Validation of a Model to Predict Malignancy within a Year After Heart Transplantation in Adults

<h3>Purpose</h3> Malignancy after heart transplantation (HT) is associated with poor outcomes. A model to predict the risk of malignancy within the first year after HT is urgently required. <h3>Methods</h3> We included adults (>18 years of age) who underwent HT included in the Scientific Registry of Transplant Recipients (SRTR) between January 2000 and May 2021. Candidate predictors were identified based on their association with malignancy in literature, included recipient age, gender, race, height, weight, kidney function, heart failure etiology, prior history of hypertension, diabetes, and smoking, induction therapy use, various histocompatibility results (CMV, EBV, DR mismatches), and transplant year. A multivariable regression model for predicting malignancy development within a first year after HT was developed and internally validated via 500 bootstrapped samples to estimate the optimism-corrected measures of model accuracy and performance. <h3>Results</h3> Among the 47,212 HT recipients with a median (25^th, 75^th percentile) age of 56 (46, 62) years, 25.6% were female, 75.8% were White, and 7.2% had prior malignancy. 2.3% developed malignancy within the first year. Recipient age at transplant, history of malignancy, recipient White race, and heart failure etiology were the strongest predictors of malignancy. The optimism-corrected model had modest discrimination (C-statistic: 0.699, 95%CI 0.688-0.714) and good calibration and performance (calibration slope: 0.967; Nagelkerke R² 0.065), particularly at lower predicted risk (Figure). <h3>Conclusion</h3> Despite selecting variables previously linked to malignancy, our model was modestly predictive of the development of malignancy in the first year after heart transplantation. These findings highlight the importance of future work to identify factors that may increase prediction of malignancy and may benefit from incorporation of time-to-event data.

Management strategies and outcomes in renal transplant recipients recovering from COVID-19: A retrospective, multicentre, cohort study

SummaryBackgroundThere is an enormous knowledge gap on management strategies, clinical outcomes, and follow-up after kidney transplantation (KT) in recipients that have recovered from coronavirus disease (COVID-19).MethodsWe conducted a multi-center, retrospective analysis in 23 Indian transplant centres between June 26, 2020 to December 1, 2021 on KT recipients who recovered after COVID-19 infections. We analyzed clinical and biopsy-confirmed acute rejection (AR) incidence and used cox-proportional modeling to estimate multivariate-adjusted hazard ratios (HR) for predictors of AR. We also performed competing risk analysis. Additional outcome measures included graft loss, all-cause mortality, waiting time from a positive real-time polymerase test (RT-PCR) to KT, laboratory parameters, and quality of life in follow-up.FindingsAmong 372 KT which included 38(10·21%) ABO-incompatible, 12(3·22%) sensitized, 64(17·20%) coexisting donors with COVID-19 history and 20 (5·37%) recipients with residual radiographic abnormalities, the incidence of AR was 34 (9·1%) with 1(0·26%) death censored graft loss, and 4(1·07%) all-cause mortality over a median (interquartile range) follow-up of 241 (106–350) days. In our cox hazard proportional analysis, absence of oxygen requirement during COVID-19 compared to oxygen need [HR = 0·14(0·03–0·59); p-value = 0·0071], and use of thymoglobulin use compared to other induction strategies [HR = 0·17(0·03–0.95); p-value = 0·044] had a lower risk for AR. Degree of Human leukocyte antigen (HLA) DR mismatch had the highest risk of AR [HR = 10.2(1·74–65·83); p-value = 0·011]. With competing risk analysis, with death as a competing event, HLA DR mismatch, and oxygen requirement continued to be associated with AR. Age, gender, obesity, inflammatory markers, dialysis vintage, steroid use, sensitization and ABO-incompatibility have not been associated with a higher risk of AR. The median duration between COVID-19 real time polymerase test negativity to transplant was 88(40–145) days (overall), and ranged from 88(40–137), 65(42–120), 110(49–190), and 127(64–161) days in World Health Organization ordinal scale ≤ 3, 4, 5, and 6–7, respectively. There was no difference in quality of life, tacrolimus levels, blood counts, and mean serum creatinine assessed in patients with a past COVID-19 infection independent of severity.InterpretationOur findings support that the outcomes of KT after COVID-19 recovery are excellent with absence of COVID-19 sequelae during follow-up. Additionally, there does not seem to be a need for changes in the induction/immunosuppression regimen based on the severity of COVID-19.FundingSanofi

Human leukocyte antigen mismatch on lung transplantation outcomes.

Human leucocyte antigen (HLA) mismatch is a known risk factor for renal transplantation; however, there are conflicting and limited data on its ramifications within lung transplantation (LTx). Therefore, our study evaluated the effects of total HLA, HLA-A, -B and -DR mismatches on LTx outcomes. We retrospectively examined the United Network for Organ Sharing database for adult patients who had undergone LTx for the first time between January 2005 and July 2021. Total HLA mismatch (0-3, 4, 5 and 6) and HLA locus mismatch (0-1 and 2) were analysed, with the end points of interest being mortality and bronchiolitis obliterans syndrome (BOS) development. Kaplan-Meier curve analysis found a significant difference in both overall survival (n = 27 651; 11 830 events) and BOS development (n = 25 444; 8901 events) for the total number of HLA (P < 0.001, P < 0.001), HLA-A (P < 0.001, P = 0.006) and HLA-DR (P < 0.001, P < 0.001) mismatches. With reference to 0-3 total HLA mismatches, multivariable Cox regression model found that 6 mismatches had an increased risk of mortality (P = 0.002) while 4 (P = 0.010), 5 (P = 0.007) and 6 (P < 0.001) mismatches had an increased risk of BOS. HLA-B mismatch was not associated with an increased mortality (P = 0.975) or BOS risk (P = 0.512). This study demonstrates a significant relationship between increased HLA mismatches and BOS development, with decreased overall survival only apparent with 6 mismatches. HLA-A and -DR mismatches were associated with an increased risk of mortality and BOS development compared to groups with at least 1 locus match.

Graft Loss due to Chronic Rejection in Pancreas Transplantation: Impact of HLA Matching

Chronic rejection has remained the Achilles heel in improving the long-term graft survival in pancreas transplants. A single center retrospective analysis of outcomes was performed to determine if HLA mismatches were associated with graft loss due to chronic rejection. In this study, we analyzed all simultaneous kidney-pancreas transplants performed at our center between January 2000 to January 2011. Patients with functioning grafts (FG) were compared to those with grafts lost due to chronic rejection (CRG) with respect to their HLA A, B and DR matches and mismatches. Of the 112 kidney pancreas recipients, 72 recipients (64%) had functioning graft at more than 10 year follow up. 28 patients (25%) lost their graft to chronic rejection. Twelve recipients (11%) with failed grafts due to surgical or infectious complications were excluded from the study. The recipients with graft loss due to chronic rejection (CRG) were slightly younger (mean age 37 in comparison to 42) than recipients with functioning grafts (FG). Both groups had similar mean BMI of 25. Mean pancreas preservation time in FG and CRG groups were 12.5 and 12 hours respectively. The mean HLA A, B and DR mismatches in FG group (1.43,1.58,1.34) was comparable to those in CRG group (1.46,1.5,1.53). The mean total HLA mismatches in the FG and CRG groups were 4.36 and 4.5 respectively. Our data does not support the use of HLA matching to predict pancreas graft loss due to chronic rejection in simultaneous kidney pancreas transplant recipients.