HLA Mismatch Research Articles

Impact of HLA eplet mismatch load in immunological outcomes after living donor kidney transplantation

IntroductionHLA eplets mismatches (eMM) have been associated with negative kidney outcomes after transplantation, such as the development of de novo donor-specific antibody (dnDSA), antibody-mediated rejection (ABMR), and early graft loss. This study aimed to evaluate the clinical effects of the HLA eMM load on dnDSA development, ABMR, renal function, allograft survival and graft loss. Material and methodsThis retrospective study involved 159 living donor kidney transplant patients categorized into groups based on antigen HLA mismatches assessed traditionally and HLA eMM load. Patients had followed for at least one year. The EpViX online program was used to evaluate the HLA eMM load. Cox models were constructed to assess the risk of graft loss. Kaplan-Meier survival curves were carried out. The analyses had performed using the R program and p < 0.05 was considered significant. ResultsFrom all 159 patients, 28 (17.6%) lost their allografts. Rejection episodes occurred in 37.1% of patients, 13.6% of whom were ABMR. Patients with rejection episodes had higher HLA-AB (p = 0.032) and HLA-DR (p = 0.008) HLA eMM load, HLA-AB (p = 0.006) and HLA-DR (p = 0.009) antigens mismatches, and higher proportions of the following eMM in the HLA-DR locus: 70R eMM (p = 0.015), 70RE (p = 0.015), 74E (p = 0.015) and 48Q (p = 0.047). In multiple models, the presence of HLA-DR 70qq eMM (HR 3.75, 95% CI 1.47; 9.55) add an increase in creatinine levels at 1-year (HR 3.87, 95% CI 2.30, 6.53) were associated with the risk of graft loss. ConclusionThe HLA eMM load was related to episodes of rejection and allograft loss. The HLA-DR eMM was most strongly associated with a worse immunologic outcome than eMM mismatches for HLA-AB.

Selection of Cord Blood Unit by CD34+ Cell and GM-CFU Numbers and Allele-Level HLA Matching in Single Cord Blood Transplantation

In Japan, only single-unit cord blood transplantations (CBTs) are typically performed, and their number has increased over the last 23 years, with ongoing improvement in results. In most cases, CBTs with multiple HLA mismatches are used, owing to a low HLA barrier, and lower engraftment rate is a problem that must be overcome. Here, as part of an effort to improve guidelines for the selection and processing of CB units for transplantation, we sought to assess the present status of CBT in Japan and to elucidate factors contributing to the favorable outcomes, focusing in particular on selection by cell components of CB unit and HLA allele matching. We conducted a nationwide study analyzing 13,443 patients who underwent first CBT between in Japan between December 1997 and December 2019 using multivariate regression analysis. Both patient- and transplantation-related variables, such as age and Hematopoietic Cell Transplantation Comorbidity Index, as well as selected CB unit characteristics, were included in the analysis. The interaction analysis elucidated that CB unit selection favoring higher counts of CD34+ cells and granulocyte macrophage colony-forming units (GM-CFU)/kg, but not of total nucleated cells, contributed to improved engraftment after transplantation. Moreover, a higher CD34+ cell dose was associated with improved overall survival (OS). Distinctive HLA allele matching was observed. A 0 or 1 HLA allele mismatch between patient and donor had favorable engraftment and carried significantly lower risks of acute GVHD and chronic GVHD but had a significantly higher leukemia relapse rate, compared with a 3-HLA allele mismatch. HLA-DRB1 mismatches were associated with reduced risk of leukemia relapse. Notably, the number of HLA allele mismatches had no incremental effect on engraftment, acute and chronic GVHD, or relapse incidence. As a result, 5-year overall survival did not differ significantly among patients receiving CB units with 0 to 7 HLA allele mismatches. The main points of CB unit selection are as follows. First, selection according to a higher number of CD34+ cells/kg and then of CFU-GM/kg is recommended to obtain favorable engraftment. A unit with .5 × 105 CD34+ cells/kg is minimally acceptable. For units with a CD34+ cell dose of .5 to 1.0 × 105 cells/kg, applying the parameter of ≥20 to 50 × 103 GM-CFU/kg (66.5% of transplanted CB units in this cohort) is associated with a neutrophil engraftment rate of approximately 90%. A unit with ≥1.0 × 105 CD34+ cells/kg can achieve a ≥90% mean neutrophil engraftment rate. Subsequently, HLA allele matching of HLA-A, -B, -C, and -DRB1 at the 2-field level should be searched for units with 0 or 1 HLA allele mismatch in the host-versus-graft direction for favorable engraftment. Units with 2 to 6 HLA allele mismatches are acceptable in patients age ≥15 years and units with 2 to 4 HLA allele mismatches are acceptable in patients age ≤14 years. Units with HLA-DRB1 and/or -B allele mismatch(es) might not be preferable owing to an increased GVHD risk. Our analysis demonstrates that single-unit CBT with the selection of adequate CD34+/kg and GM-CFU/kg and HLA allele matching showed favorable outcomes in both pediatric and adult patients.

Ureterovesical Leak Following Renal Transplant and Effects of Acute Rejection and Antirejection Therapy: A Nested Case-Control Analysis and Outcome of 1102 Consecutive Renal Transplant Recipients.

Studies on nontechnical risk factors for ureterovesical leak after renal transplant are scarce. This study aimed to report the possible pre- and postoperative risk factors and the role of acute rejection and antirejection therapies for urine leak after transplant and its effect on graft and patient survival. We conducted a retrospective analysis of 13 patients (1.17%) with urine leak (case group) and 52 patients without leak (control group) (case-to-control ratio of 1:4) from 1102 living related (first degree) renal transplant recipients seen between January 2012 and December 2021. We analyzed demographic and clinical details and biochemical and outcome parameters using a nested case-control design. Cases were olderthan controls (P = .018), were more ABO incompatible (P = .009), and had more 6/6 HLA mismatch transplants (P = .047). Donors of cases were older than donors of controls (P = .049). The rate of postoperative hypoalbuminemia was greaterin the case group (P = .050). Rates of acute rejection (P = .012) and plasmapheresis (P = .003) were greaterin the case group than in the control group. On multivariate logistic regression analysis, recipient age, 6/6 HLA mismatch, and plasmapheresis were found to independently associated with urine leak. None ofthe patient required surgical repair, as all responded to conservative therapy. Urine leak did not affect graft outcomes (P = .324), but overall survival was less in cases than in controls. Nontechnical risk factors that cause posttransplant ureteric leak include older donor and recipient age and ABO incompatible and 6/6 HLA mismatch transplants. Acute rejection and plasmapheresis predispose leak, and an indwelling double J stent can allow adequate healing of the anastomosis. High index of suspicion and prompt management are imperative to preserve graft and patient outcome.

Single-cell transcriptomic analysis of renal allograft rejection reveals insights into intragraft TCR clonality.

Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.

Time-dependent analysis of the impact on early cytomegalovirus reactivation of HLA mismatch and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation from related donors in acquired aplastic anemia.

Cytomegalovirus (CMV) reactivation is an important issue in allogeneic hematopoietic cell transplantation (HCT). The incidence of early CMV reactivation is notably high in HLA-mismatched HCT. However, the interactions between HLA mismatch and acute graft-versus-host disease (aGvHD), a time-dependent event, make it methodologically challenging to evaluate the independent impact on CMV reactivation of the two variables. We retrospectively analyzed 355 patients with acquired aplastic anemia who received related donor transplants using a unified antithymocyte globulin-based platform. Patients were divided into group 1 (6/6 HLA match), group 2 (1-2/6 HLA allelic mismatch), and group 3 (3/6 HLA allelic mismatch). The impact of covariates was analyzed through two models: (1) time-dependent Cox and (2) dynamic landmarking analysis. The time-dependent Cox model showed that the HLA mismatch of 3/6 alleles (hazard ratio (HR) =1.852, P = .004) and aGvHD (HR = 1.009, P = .019) were independent risk factors for CMV reactivation. With the dynamic landmarking analysis, a higher HLA disparity correlated to increased early CMV reactivation (HR = 1.606, P = .001) at all time points. Developing aGvHD following HCT was generally associated with a higher incidence of CMV reactivation (HR = 1.623, P = .013), though its impact decreased with successive later landmark time points. In conclusion, our data suggest that the higher HLA disparity and aGvHD increases susceptibility to early CMV reactivation. In particular, the dynamic landmarking analysis demonstrated the time-varying effect of aGvHD on CMV reactivation, and HLA mismatch showed a profound impact over time following HCT.

Pediatric Kidney Transplantation—Living or Deceased Donor?

Kidney transplantation is ideal for children and adolescents with chronic end-stage renal disease because it offers better growth, development, and quality of life. Donor choice is vitally important in this age group, given the long life expectancy of these patients. A retrospective analysis of pediatric patients (<18 years) who underwent kidney transplantation from January 1999 to December/2018 was performed. Short- and long-term outcomes were compared between living and deceased donor transplants. We included 59 pediatric kidney transplant recipients, 12 from a living donor and 47 from a deceased donor. Thirty-six (61.0%) patients were boys, and 5 (8.5%) had a retransplant. There were no differences between groups on sex, race, and weight of the recipient and donor, as well as the age and the etiology of the recipient's primary disease. Most recipients received induction immunosuppression with basiliximab and maintenance with triple therapy, with no differences between groups. Living donor transplants were mostly pre-emptive (58.3% vs 4.3%, P < .001) and had fewer HLA mismatches (≤3: 90.9% vs 13.0%, P < .001), older donors (38.4 vs 24.3 years, P < .001) and shorter hospital stays (8.8 vs 14.1 days, P=.004). There were no statistically significant differences regarding medical-surgical complications and graft or patient survival. However, we found that at 13 years post-transplant 91.7% of the living donor grafts were functioning vs 72.3% of the deceased donor grafts. Our experience points out that a living donor graft in pediatric patients is associated with a higher probability of pre-emptive transplant, shorter hospital stay, greater HLA compatibility, and increased graft survival.

Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation

BackgroundHuman leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). MethodsIn a secondary analysis from a previous study, 166,256 adult KTRs in 2000–2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1–3, and 4–6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. ResultsCompared with 0 HLA-mm, 1–3 HLA-mm was not associated, and 4–6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94–1.17 and HR = 1.11, 95% CI = 1.00–1.34, respectively]. Both 1–3 HLA-mm and 4–6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08–1.18) and (HR = 1.16, 95% CI = 1.09–1.22), respectively]. KTR's history of pre-transplant cancer, age 50–64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1–3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1–3 and 4–6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. ConclusionDirect association between SOM and the degree of HLA mismatching is equivocal and limited to the 4–6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.

Differences between Kidney Transplant Recipients from Deceased Donors with Diabetes Mellitus as Identified by Machine Learning Consensus Clustering.

Clinical outcomes of deceased donor kidney transplants coming from diabetic donors currently remain inconsistent, possibly due to high heterogeneities in this population. Our study aimed to cluster recipients of diabetic deceased donor kidney transplants using an unsupervised machine learning approach in order to identify subgroups with high risk of inferior outcomes and potential variables associated with these outcomes. Consensus cluster analysis was performed based on recipient-, donor-, and transplant-related characteristics in 7876 recipients of diabetic deceased donor kidney transplants from 2010 to 2019 in the OPTN/UNOS database. We determined the important characteristics of each assigned cluster and compared the post-transplant outcomes between the clusters. Consensus cluster analysis identified three clinically distinct clusters. Recipients in cluster 1 (n = 2903) were characterized by oldest age (64 ± 8 years), highest rate of comorbid diabetes mellitus (55%). They were more likely to receive kidney allografts from donors that were older (58 ± 6.3 years), had hypertension (89%), met expanded criteria donor (ECD) status (78%), had a high rate of cerebrovascular death (63%), and carried a high kidney donor profile index (KDPI). Recipients in cluster 2 (n = 687) were younger (49 ± 13 years) and all were re-transplant patients with higher panel reactive antibodies (PRA) (88 [IQR 46, 98]) who received kidneys from younger (44 ± 11 years), non-ECD deceased donors (88%) with low numbers of HLA mismatch (4 [IQR 2, 5]). The cluster 3 cohort was characterized by first-time kidney transplant recipients (100%) who received kidney allografts from younger (42 ± 11 years), non-ECD deceased donors (98%). Compared to cluster 3, cluster 1 had higher incidence of primary non-function, delayed graft function, patient death and death-censored graft failure, whereas cluster 2 had higher incidence of delayed graft function and death-censored graft failure but comparable primary non-function and patient death. An unsupervised machine learning approach characterized diabetic donor kidney transplant patients into three clinically distinct clusters with differing outcomes. Our data highlight opportunities to improve utilization of high KDPI kidneys coming from diabetic donors in recipients with survival-limiting comorbidities such as those observed in cluster 1.

DQA1 Eplet Mismatch Load As an Independent Risk Factor of CLAD After Lung Transplantation.

Based on clinical data, 240 lung transplant recipients were eligible for CLAD, and HLA and eplet mismatch was analyzed using the HLAMatchmaker 3.1 software. A total of 92 (38.3%) lung transplant recipients developed CLAD. The time free-of-CLAD was significantly decreased in patients with presence of DQA1 eplet mismatches (P = 0.015). Furthermore, when other previously described CLAD risk factors were studied in a multivariate analysis, the presence of DQA1 eplet mismatches was found to be independently associated with the early onset of CLAD. The concept of epitope load has arisen as a new tool to better define donor-recipient immunologic compatibility. The presence of DQA1 eplet mismatches potentially would increase the likelihood of developing CLAD.

Investigation of KIR/HLA relationship and other clinical variables after T-cell-replete haploidentical bone marrow transplantation in patients with acute myeloid leukemia (AML)

BackgroundKIR/HLA mismatch in hematopoietic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia (AML), was related to decreased recurrence rates, improved engraftment, and a reduction in graft-versus-host disease, according to recent research (GVHD). Uncertainty exists about the impact of KIR/HLA mismatch on haploidentical-HSCTs treated with post-transplant cyclophosphamide (PTCy). We attempted to analyze the effects of KIR/HLA mismatch on clinical outcomes on transplant outcomes using the cohort of 54 AML patients who received a haplo-HSCT with PTCy.ResultsIn contrast to KIR/HLA match, our findings showed that donor KIR/HLA mismatch was substantially associated with superior OS (HR, 2.92; (P = 0.04)). Moreover, donor KIR/HLA mismatch (KIR2DS1D/C2+R and KIR2DS2D/C1+R mismatch versus KIR2DL1D/C2−R mm, KIR2DL2/3D/C1−R mm and KIR3DL1D/Bw4− mm) was correlated with the improvements in OS (HR, 0.74; P = 0.085) and activating. KIR/HLA mismatch versus KIR/HLA match was significantly correlated with improvements in OS (HR, .46; P = 0.03) and inhibitory. KIR/HLA mismatch versus KIR/HLA match was enhancement in the OS (HR, .93; P = 0.06). Despite a higher rate of aGvHD (grade I-IV) in the patients with KIR/HLA mismatch compared to KIR/HLA matched (57% vs. 33% (p = 0.04). However, the KIR/HLA mismatch group saw a decreased relapse rate (3.2% vs. 23%, p = 0.04).ConclusionThis analysis shows the significance of KIR/HLA Incompatibility, other clinical variables like CMV, the relationship between donor/recipient and donor age, and the relationship between donor/recipient and donor age in the haplo-donor selection process. It also suggests that KIR and HLA mismatching between donor and recipient could be routinely performed for haplo-donor selection and may improve clinical outcomes after haplo-HSCTs with PTCy.

#4769 EFFECT OF EXTREMELY LONG DIALYSIS VINTAGE ON RENAL ALLOGRAFT SURVIVAL: A SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Dialysis vintage is long in kidney transplant recipients (KTRs) due to the donor shortage in Turkey. We assessed the effect of pre-transplant dialysis duration (more than 10 years) on the outcomes of renal allografts. Method We retrospectively evaluated 480 KTRs who were grafted between January 2009 and October 2020 at Ankara University School of Medicine, Ibni Sina Hospital. KTRs were divided into two groups according to the duration of pre-transplant dialysis treatment: Group A, ≥10 years and Group B, &amp;lt;10 years. Data on demographics, comorbidities, immunologic properties and graft survivals were compared between the two groups. Results Group A included 60 patients and dialysis vintage was 288±60 months (Table 1). 420 patients in Group B had an average of 19 months period of dialysis treatment. While cadaveric transplantation was 78.3% in Group A, it was much lower in Group B (11.2%, p&amp;lt;0.001). Most of the patients were on hemodialysis treatment (95.0% vs. 58.3%, respectively, P = .001). Recipients’ age (P = .001), HLA mismatch number (P = .008) and PRA positivity (P = .001) were significantly higher in Group A. Although anti-human T-thymocyte globulin had been mostly chosen for induction therapy in Group A (p&amp;lt;0.001); almost all patients were under standard triple maintenance immunosuppression therapy. First year and late acute rejection rates were similar between two groups (p=1.000 and P = .407, respectively). Clinically important difference was demonstrated in graft loss, which was mostly seen in the ≥10 years dialysis group (Group A, 18.3% vs. Group B, 8.3%, P = .014). The 1-, and 5- years graft survival rates were 91.4%, and 81.3%, respectively, in Group A and 97.4%, and 93.4%, respectively, in Group B (P = .034 and P = .029, respectively). Patient loss was significantly higher in Group A (Group A, 28.3% vs. Group B, 14.3%, P = .018). Conclusion We demonstrated that pre-transplant dialysis duration for more than 10 years has adverse effects on post-transplant graft and patient outcomes, accompanied by high immunological risk. Updates of organ allocation system considering sensitized candidates and strategies to expand donor pool and donation rates are needed to reduce waiting times on dialysis.

#3770 EBV-NEGATIVE KIDNEY TRANSPLANT RECIPIENTS AND PTLD: THE IMPACT OF INDUCTION THERAPY

Abstract Background and Aims Individuals who are most susceptible to developing PTLD are those who are EBV-negative and receive organs from EBV-positive donors (EBV R-/D+). The evidence regarding the connection between ATG induction therapy and PTLD is inconsistent. No studies have specifically examined the relationship between ATG use and PTLD in subgroups of EBV-negative transplant recipients (EBV R-). Using the UNOS database, we studied the association between the use of induction agents and PTLD in EBV R- patients. Method We analyzed data from 2007 to 2022 of EBV R- patients who underwent their first kidney-only transplant and excluded those who received induction agents other than ATG, basiliximab, or alemtuzumab. We used logistic regression to evaluate the association between induction agents and PTLD. Results Of 20,531 recipients, 50.7% received ATG, 19.13% received basiliximab, 13.42% received alemtuzumab, and 16.75% received no induction. The overall PTLD incidence was 2.14%. ATG recipients had higher rates of deceased donor transplants, higher degree of HLA mismatch, longer dialysis vintage, and were less likely to be white, compared to non-ATG recipients. Multivariate analysis showed ATG recipients had a higher risk of PTLD compared to non-ATG (odds ratio = 1.47, p&amp;lt;0.001). After excluding recipients who did not receive induction, ATG remained a significant independent risk factor for PTLD when compared to recipients who received either basiliximab or alemtuzumab (odds ratio = 1.35, p = 0.007). There was no statistically significant difference in PTLD risk among patients treated with basiliximab, alemtuzumab, or no induction (refer to Table 1). Conclusion The use of ATG induction in EBV-negative kidney transplant recipients is associated with a higher risk of PTLD compared to basiliximab, alemtuzumab, and no induction. The risk of PTLD should be considered when choosing induction therapy for this patient population.

#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.

HLA mismatch is important for 20-year graft survival in kidney transplant patients

BackgroundHuman leukocyte antigens (HLA) matching is gradually being omitted from clinical practice in evaluation for renal allograft transplant. While such practices may yield shorter wait times and adequate short-term outcomes, graft longevity in HLA mismatched patients remains unclear. This study aims to demonstrate that HLA matching may still play an important role in long-term graft survival. MethodsWe identified patients undergoing an index kidney transplant in the United Network for Organ Sharing (UNOS) data from 1990 to 1999, with one-year graft survival. The primary outcome of the analysis was graft survival beyond 10 years. We explored the long-lasting impact of HLA mismatches by landmarking the analysis at established time points. ResultsWe identified 76,530 patients receiving renal transplants in the time frame, 23,914 from living donors and 52,616 from deceased donors. On multivariate analysis, more HLA mismatches were associated with worse graft survival beyond 10 years for both living and deceased donor allografts. HLA mismatch continued to remain an essential factor in the long term. ConclusionsA greater number of HLA mismatches was associated with progressively worse long-term graft survival for patients. Our analysis reinforces the importance of HLA matching in the preoperative evaluation of renal allografts.

The effect of donor dominant one-way hla mismatch on liver transplantation outcomes: An analysis of Korean organ transplantation registry (KOTRY) database

The effect of donor dominant one-way hla mismatch on liver transplantation outcomes: An analysis of Korean organ transplantation registry (KOTRY) database

The UK kidney donor risk index poorly predicts long-term transplant survival in paediatric kidney transplant recipients.

The UK kidney offering scheme introduced a kidney donor risk index (UK-KDRI) to improve the utility of deceased-donor kidney allocations. The UK-KDRI was derived using adult donor and recipient data. We assessed this in a paediatric cohort from the UK transplant registry. We performed Cox survival analysis on first kidney-only deceased brain-dead transplants in paediatric (<18 years) recipients from 2000-2014. The primary outcome was death-censored allograft survival >30 days post-transplant. The main study variable was UK-KDRI derived from seven donor risk-factors, categorised into four groups (D1-low risk, D2, D3 and D4-highest risk). Follow-up ended on 31-December-2021. 319/908 patients experienced transplant loss with rejection as the main cause (55%). The majority of paediatric patients received donors from D1 donors (64%). There was an increase in D2-4 donors during the study period, whilst the level of HLA mismatching improved. The KDRI was not associated with allograft failure. In multi-variate analysis, increasing recipient age [adjusted HR and 95%CI: 1.05(1.03-1.08) per-year, p<0.001], recipient minority ethnic group [1.28(1.01-1.63), p<0.05), dialysis before transplant [1.38(1.04-1.81), p<0.005], donor height [0.99 (0.98-1.00) per centimetre, p<0.05] and level of HLA mismatch [Level 3: 1.92(1.19-3.11); Level 4: 2.40(1.26-4.58) versus Level 1, p<0.01] were associated with worse outcomes. Patients with Level 1 and 2 HLA mismatches (0 DR +0/1 B mismatch) had median graft survival >17 years regardless of UK-KDRI groups. Increasing donor age was marginally associated with worse allograft survival [1.01 (1.00-1.01) per year, p=0.05]. Adult donor risk scores were not associated with long-term allograft survival in paediatric patients. The level of HLA mismatch had the most profound effect on survival. Risk models based on adult data alone may not have the same validity for paediatric patients and therefore all age-groups should be included in future risk prediction models.

Renal Transplantation in the Elderly: Are They All the Same? A Multicenter, Comorbidity-Based Study

Introduction: The age for kidney transplantation (KT) is no longer a limitation and several studies have shown benefits in the survival of elderly patients. The aim of this study was to examine the relationship of the baseline Charlson comorbidity index (CCI) score to morbidity and mortality after transplantation. Methods: In this multicentric observational retrospective cohort study, we included patients older than 60 years admitted on the waiting list (WL) for deceased donor KT from January 01, 2006, to December 31, 2016. The CCI score was calculated for each patient at inclusion on the WL. Results: Data for analysis were available of 387 patients. The patients were divided in tertiles of CCI: group 1 (CCI: 1-2) n = 117, group 2 (CCI: 3-4) n = 158, and group 3 (CCI: ≥5) n = 112. Patient survival was significantly different between CCI groups at 1, 3, and 5 years, respectively: 90%, 88%, and 84% for group 1, 88%, 80%, and 72% for group 2, and 87%, 75%, and 63% for group 3 (p < 0.0001). Variables associated with mortality were CCI score (p < 0.0001), HLA mismatch (p = 0.014), length of hospital stay (p < 0.0001), surgical complications (p = 0.048). Conclusion: Individualized strategies to modify these variables may improve patient’s morbidity and mortality after KT.

P477 PIRCHE (PREDICTED INDIRECTLY RECOGNIZABLE HLA EPITOPES) ALGORITHM AS A POSSIBLE PREDICTOR OF AMR (ANTIBODY MEDIATED REJECTION) FOLLOWING HEART TRANSPLANT, FROM LAB EXPERIENCE TO CLINICAL PRACTICE: A CASE REPORT

Abstract PIRCHE–II is an algorithm used to estimate the risk for developing alloreactivity towards HLA mismatches. A 35–year–old man with idiopathic dilated cardiomyopathy with several previous hospitalizations for heart failure is admitted to our unit for a new episode in August 2021. After evaluation, the patient was placed on the waiting list for transplant. The following month the patient underwent heart transplant. The donor had a compatible CDC crossmatch and was negative for anti–HLA antibodies. After 46 days, the patient was discharged at home in stable conditions after 2 negative endomyocardial biopsies (EMB): ISHLT’04 0. In January 2021, the patient was newly admitted for dyspnea and oliguria. Imaging revealed bilateral severe pleural effusion, biventricular cardiac disfunction; EMB showed acute rejection (ISHLT’04 3R). Panel–reactive antibody (PRA) screening found 93 % of class I PRA, 3 % of class II PRA with IgM and IgG donor–specific antibodies (DSA), C1q–positive. After 2 months, the patient was placed again on the transplant waitlist for a persistent severe biventricular disfunction, massive tricuspid regurgitation and diffuse myocardial fibrosis; class I PRA was decreasing (41 % in March 2022, 31 % in April 2022). Unfortunately, the patient died of infection before re–transplantation. After the event, which was recognized as AMR caused by class I DSA, a form rarely described in literature, we employed the PIRCHE (Predicted Indirectly Recognizable HLA Epitopes) algorithm to predict indirect donor–recipient alloreactivity: PIRCHE–II was 54. Is a high PIRCHE–II score a reliable predictor of AMR following heart transplant? More data and deeper understanding is surely needed. A correct after–transplant serologic monitoring is definitely needed to search for de–novo DSA.

Transoperative Hemodynamic Status and Delayed Graft Function: Analysis of 42 Consecutive Renal Transplantation

Objective: Evaluate the correlation between transoperative hemodynamic status and development of delayed graft function (DGF) in patients undergoing kidney transplantation. Methods: We analyzed 42 consecutive renal transplants between May 2021 and May 2022 in a University Hospital. Four kinds of variables were assessed. Recipients variables: age, gender, race, type of dialysis, dialysis time before transplantation and residual diuresis. Donor variables: age, serum creatinine level, death cause, race, laterality of the kidney (right or left kidney), perfusion solution and Kidney Donor Profile Index (KDPI). Surgical variables: cold Ischemia time (CIT), vascular multiplicity, the surgeon, duration of surgery and blood pressure during the procedure. Immunological variables: Panel reactive antibodies (PRA), HLA mismatches and the need of induction therapy with antithymocyte globulin. Results: In univariate analysis, regarding recipients’ factors, type of dialysis (hemodyalisis) (p=0.004) and absence of residual diuresis (p=0.011) were significant on the development of DGF. Among the donors, only the laterality of the kidney (right kidney) was statiscally significant (p=0.005). The cold ischemia time higher than 24 hours (p=0.022), systolic blood pressure (SBP) less than 130 mmHg at reperfusion (p&lt;0.001), Mean Arterial Pressure (MAP) less than 80 mmHg at the reperfusion (p&lt;0.001), and mean MAP post-reperfusion (p=0.049) were the significant surgical factors for DGF. Among immunological factors, the patients that received antithymocyte globulin as induction therapy more frequently developed DGF (p=0.036). Only MAP &lt; 80 mmHg (p=0.004) and SBP &lt; 130m mmHg (p=0.005) were independent risk factors for DGF. Conclusion: In this survey, optimal renal perfusion, avoiding fall in blood pressure in the transoperative period, especially after graft reperfusion, is crucial for the immediate functioning of the kidney

O001 A novel molecular HLA mismatch algorithm to identify transplant patients at low risk of primary alloimmunity

Abstract Introduction There is an unmet need for prognostic biomarkers for alloimmune risk stratification to guide personalised recipient care kidney transplantation. Methods We used three molecular Mismatch (molMM) algorithms - Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and NetMHCIIpan in a dataset of patients receiving standardised donor lymphocyte injections to predict de-novo donor-specific-antibody (dnDSA) at the individual HLA level (n=665). Risk thresholds were derived for HLA-DR/DQ mismatch and algorithms combined. External validation was performed in two extensively-phenotyped kidney transplant cohorts (Manitoba, n=856, Denver n=404) and in the NHSBT kidney transplant registry (2000–2020, n=27,028). Results External validation (Manitoba cohort, 10-year follow-up) showed all algorithms predicted dnDSA development using experimentally derived HLA-DR/DQ molMM risk thresholds (HLA-DQ AUC: 0.78-0.80; HLA-DR AUC:0.76-0.81). AAMS and EMS3D had improved risk stratification (low-medium-high risk groups for HLA-DR+DQ dnDSA) vs NetMHCIIpan (p=NS). A combined AAMS+EMS3D molMM algorithm further improved discrimination and identified a large patient cohort (15.4% patients) at very-low risk of Class-II dnDSA (1.3% at 10 years). Multivariate analysis confirmed correlation with primary alloimmune events (dnDSA p&amp;lt;0.001, TCMR p&amp;lt;0.001, ABMR p=0.0049) and all-cause graft loss (p=0.0038). Further external validation of the combined molMM algorithm in an ethnically diverse cohort (Denver) confirmed the dnDSA risk association (p&amp;lt;0.0001), and in the UK registry cohort confirmed significant association with all-cause graft loss (p&amp;lt;0.001). Conclusion We developed and validated a novel molMM algorithm, incorporating information from HLA amino-acid sequence and tertiary structurebthat may be used as a prognostic biomarker of primary alloimmunity risk and to enrich prospective clinical trials in kidney transplantation.