HLA-B Mismatches Research Articles

HLA evolutionary divergence (HED) informs the effect of HLA-B mismatch on outcomes after haploidentical transplantation.

Graft versus tumor relies on tumor-associated antigens (TAAs) that are presented to donor T cells via human leukocyte antigens (HLAs). The HLA evolutionary divergence (HED) between alleles of a single individual can dictate the ability to present TAAs. The impact of HED in haploidentical donor transplantation (HIDT) has not been studied. We studied the effect of HED on transplant outcomes following HIDT. We analyzed 322 consecutive recipient/donor pairs with a median follow-up of 57.2 months. Pairwise divergence of HLA class I and II showed that HLA-B, -DRB1, and -DQB1 contributing most to mean HED. The mean HED was class I 6.85 (HLA-A 7.08, -B 8.24, and -C 5.07), class II 8.58 (HLA-DRB1 10.97, -DQB1 10.06 and -DPB1 4.06). A high HED in class I mismatched recipient/donor haplotype (RD MM) was significant for worse DFS (HR 1.11, p = 0.020), and relapse (HR 1.11, p = 0.02). Also, a high HED in RD MM HLA-B haplotype had worse OS (HR 1.07, p = 0.02), DFS (HR 1.09, p = 0.002), higher relapse (HR 1.10, p = 0.003), and similar NRM to low HED. The multivariate analysis showed that high HED in RD MM HLA-B (≥7.8 vs <7.8) had worse DFS (HR 1.53, p = 0.01), higher relapse (HR 1.61, p = 0.024), and similar NRM and OS.

The impact of MICB mismatches in unrelated haematopoietic stem cell transplantation.

MICA polymorphisms have been associated with increased incidence of acute GvHD and adverse outcome in allogeneic haematopoietic stem cell transplantation (HSCT). MICB is another expressed member of MHC class I-related chain genes and its impact on HSCT outcome is yet to be fully defined. We typed a large cohort of patients and donors for MICB polymorphisms and investigated the impact of MICB matching on outcome after unrelated HSCT. 69.2% of the patients were 10/10 human leukocyte antigen (HLA) matched and 30.8% were 9/10 HLA matched. MICB typing was performed using a short amplicon-based NGS typing assay on the Illumina MiSeq platform. Differences in proteins were considered as mismatches. MICA polymorphisms were identified as possible confounder and were therefore included as parameter in the multivariate analyses. Due to the strong linkage disequilibrium with the classical HLA-genes, sub-stratification for HLA matching status was necessary, and no effect of MICB mismatches was seen in the 10/10 HLA matched group when compared to the MICB matched cases. However, in the 9/10 HLA matched group, MICB mismatched cases showed significantly worse disease free survival (DFS), GvHD and relapse free survival (GRFS) compared to the MICB matched cases (DFS: HR 1.24, p = 0.011; GRFS: HR 1.26, p = 0.002). MICA mismatches had no impact on any outcome parameter. According to our findings, effects previously attributed to MICA differences may have been confounded by MICB polymorphisms. We show that MICB differences contribute a small but relevant effect in 9/10 HLA-matched transplantations, which in turn highlights the possible usefulness of MICB typing in donor selection among similarly suitable 9/10 matched donors, especially when HLA-B mismatches have to be accepted.

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&lt;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&lt;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.

HLA Evolutionary Divergence (HED) Informs the Effect of HLA-B-Loci Mismatch on Relapse and Disease Free Survival after Haploidentical Hematopoietic Cell Transplantation (Haplo) with Post-Transplant Cyclophosphamide (PTCY)

The Success of allogeneic Hematopoietic cell transplantation (HCT) is dependent on a potent graft versus tumor (GVT) benefit. GVT relies on tumor-associated antigens TAAs that are presented to donor T cells via human leukocyte antigens HLAs. The high diversity of HLAs allows for presentation of immense repertoire of peptides including TAAs. HLAs are polymorphic and each allele presents a different repertoire of peptides referred to as the immunopeptidome. The HLA evolutionary divergence (HED) between alleles of a single individual can dictate the ability to present TAAs. Patients with higher HED can present a more diverse immunopeptidome, including TAAs and potentially have a benefit of higher GVT after allogeneic HCT. The effect of HED was studied among cancer patients receiving immune check point inhibitors where high HED diversity was associated with better survival. Low recipient HEDs in HLA class I and DR were strong predictors for worse overall survival after matched donor HCT. The effect of HED divergence among recipients of haplo HCT with PTCY has not been evaluated. Moreover, the mismatch between donor and recipient in haplo HCT allows for assessing the effect of HED divergence in the donor and in the donor/recipient mismatched haplotype. To study the effect of HED among recipients of haplo HCT, we analyzed 322 consecutive recipient/donor pairs who received their transplant at our center with a median follow up of 57.2 months (range 18-196). HED was calculated as pairwise differences using two methods: a Grantham distance metric using a perl Script ( https://sourceforge.net/projects/granthamdist/) and manual calculation of one random sample from each analysis to verity results. Data were collected from our database where it was prospectively entered. Patient diagnosis included AML (n=122), ALL (n=68), MDS (n=41), NHL (n=50), other (n=41). Baseline recipient characteristics included a median age of 50 years (19,80), 53% white, HCT-CI≥3 in 50%, Disease risk (intermediate 53%, high/very high 33%), PBSC graft 80% and myeloablative conditioning 49%. Donor characteristics were median age 37 years (13,73), CMV positive 61%, male 61% and female donor to male recipient 21%. Pairwise divergence of HLA class I and class II showed differences in values with HLA-B, DRB1 and DQB1 contributing most to mean HED class I and II. The HED values for recipient included mean HLA class I 6.85 (HLA-A 7.08, B 8.24 and C 3.47), class II 8.58 (DRB1 10.97, DQB1 10.06 and DPB1 4.06). Donor mean HED HLA-class I was 6.5 (HLA-A 6.43, B7.93 and C 4.61), mean HLA-class II was 8.84 (DRB1 10.93, DQB1 11.24 and DPB1 4.06). The mean HEDs for the mismatched haplotype between donor and recipient were class I 6.49 (A 6.43, B 7.8, C4.94) and Class II 8.74 (DRB1 10.48, DQB1 10.06, DPB1 4.06). Next, we performed a univariate Cox model to identify HED variables that are associated with OS, DFS, NRM and relapse. Based on continuous and dichotomized divergence (median cutoff) univariate cox, a high HED in class I mismatched donor-recipient haplotype was significant for worse DFS (HR 1.11, p=0.020), and relapse (HR 1.11, p=0.02). Also, high HED in HLA B in mismatched haplotype was significant for worse OS (HR 1.07, p=0.02), DFS (HR 1.09, p=0.002), higher relapse (HR 1.10, p=0.003) and similar NRM to low HED. AS HLA-B was the biggest contributor to class I HED mean and the only predictor of outcomes in a univariate cox, we evaluated HLA-B in mismatched haplotype ( donor-recipient) further in a Multivariate analysis using dichotomization based on median level. Variables in the analysis included were age (<55, ≥55), gender, race, diagnosis, cell source, regimen intensity, HCT-CI (0-2, ≥3), DRI (low/intermediate, high/very high), CMV status; donor age (<38, ≥38), donor gender, female-donor-to-male-recipient, donor CMV status, year of transplant. The multivariate cox analysis showed that high HED (≥7.8 vs <7.8) was significant for worse DFS ( HR 1.53, 95% CI 1.09-2.16; p=0.01), higher relapse (HR 1.61, CI 1.07-2.44, p=0.024) and similar NRM and OS (table 1) . The significance was reproduced in the lymphoid and myeloid lineages. In Summary, among patients receiving haplo with PTCY, a high divergence in HLA-B mismatch haplotype increases relapse risk and worsens DFS. In addition to this being the first analysis to assess HED in a large haplo cohort, the negative consequences of HED can be mitigated by selecting donors with lower HED in the mismatched haplotype at HLA-B. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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.

Effect of Multiple HLA Locus Mismatches on Outcomes after Single Cord Blood Transplantation

The effect of single or multiple mismatches at each HLA locus on outcomes after cord blood transplantation (CBT) is controversial. We analyzed the effects of single or multiple HLA locus mismatches on the outcomes after single CBT using Japanese registry data from the Japan Society for Hematopoietic Cell Transplantation. Patients age ≥16 years with acute leukemia and myelodysplastic syndromes who underwent their first CBT between 2003 and 2017 (n=4074) were included. The effect of the number of HLA locus mismatches (0, 1, or 2 for the HLA-A, -B, -C, and -DRB1 loci) on outcomes was analyzed after adjusting for other significant variables. The patient cohort had a median age of 54 years. The median total nucleated and CD34 cell doses were 2.6×107/kg and .8×105/kg, respectively. The number of CBTs with single or double mismatches were 2099 and 292, respectively, for the HLA-A locus, 2699 and 341 for the HLA-B locus, 2555 and 609 for the HLA-C locus, and 2593 and 571 for the HLA-DRB1 locus. Single and double HLA-DRB1 mismatches were associated with a higher risk of grade II-IV acute graft-versus-host disease (GVHD; single: hazard ratio [HR], 1.29, P < .001; double: HR, 1.49, P < .001; P for trend <.001). Single and double mismatches at HLA-DRB1 as well as single mismatches at HLA-A and HLA-B also were associated with grade III-IV acute GVHD. Single and double HLA-B mismatches and double HLA-DRB1 mismatches were associated with a high risk of nonrelapse mortality (NRM). On the other hand, double mismatches at HLA-A or HLA-DRB1 and single mismatches at HLA-B were associated with a lower risk of relapse. HLA-DRB1 double mismatch was associated with high risk of grade II-IV and grade III-IV acute GVHD and NRM but lower risk of relapse. Not only the locus mismatch, but also the number of mismatches, should be considered in cord blood unit selection.

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.

HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation

AbstractHematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B–mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1–mismatched MM patients compared with HLA-DQB1–mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1–mismatched MM or MT patients compared with HLA-DRB1–mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

ATG and Post-Transplant Cyclophosphamide Do Not Abrogate the Inferior Outcome Risk Conferred By HLA-Α and HLA-B Mismatched Unrelated Donors

Background Donor selection for allogeneic stem cell transplant is a complex process, where several factors are considered for potential impact on transplant outcome. Several publications have suggested that 9/10 mismatched unrelated donors (MMUD) may be equivalent to 10/10 MUDs. However, there is debate as to whether all 9/10 mismatches (MM) are equivalent. We sought to examine this in a single centre retrospective study using ATG followed by post transplant cyclophosphamide (ATG PTCy) as standard GvHD prophylaxis and correlated outcomes in terms of donor MM, donor age and CMV serostatus. Patients and methods A total of 414 patients who received HCT from unrelated donors between Jan 2015 and Dec 2019, at Princess Margaret Cancer Centre, Canada, were enrolled in the retrospective study. Patients and disease characteristics, and outcomes are detailed in Tables 1-3. The probability of overall survival (OS) was calculated using the Kaplan Meier product limit method and heterogeneity of time to event distribution functions was compared by the log rank test. The cumulative incidences of chronic and acute GvHD, relapse, and transplant related mortality (TRM) were estimated using the cumulative incidence method considering competing risk, and groups were compared using Gray's test. Death was considered a competing event for relapse, acute and cGvHD, and relapse was considered a competing event for NRM, acute and cGvHD. GvHD outcomes shown in Table 4. Results Median OS at 5y for the whole cohort (n=414) was 45.8% (38.2-53.0), and relapse free survival was 40.2% (32.9-47.4), with TRM at 1y 23.7% (19.6-28.0), Table 5. Compared to the whole cohort (median OS 38.8mo [21.6-NA]), patients who received grafts from MMUD (n=86) had median OS 9.2mo (6.0-17.3), p&amp;lt;0.001, in particular median OS for HLA-A MM was 8.1mo (5.3-18.4), HLA-B MM 5.9 (2.7-11.8) compared to other 9/10 MMUD (n=32) 18.8mo (5.7-NA), p&amp;lt;0.001. This was due to higher TRM at 1y, MMUD 39.1% (24.0-49.4) vs MUD (n=327) 19.2% (15.0-23.8) p&amp;lt;0.001 primarily due to HLA-A MM 39.6% (24.0-54.9) and HLA-B MM 35.7% (11.7-61.1), p=0.001. GVHD-Free Relapse free Survival (GRFS) at 5y for the whole cohort was 36.8% (29.7-43.9). GRFS At 2y for 9/10 MMUD was 25.2% (16.1-35.4), HLA-A MM 21.6% (9.9-36.2) HLA-B MM 15.4% (2.5-38.8) vs MUD 51.4% (45.3-57.2), p&amp;lt;0.001. Median OS for patients who received ATG PTCY (n=298) was 49.2mo (49.2-NA), for 9/10 (n=58) 10.2mo (6.1-19.6), with HLA-A MMUD (n=26) 9.6 mo (5.8-27.4), HLA-B MMUD (n=9) 4.6mo (1-11.8) (p&amp;lt;0.001), Figure. A number of donor factors significant by univariate analysis (incl. donor age, recipient/donor CMV, CD34 dose, presence of HLA MM, type of MM, female donor to male recipient), were selected to determine correlates with all mortality by multivariable analysis (MVA). The only significant factor was 9/10 MMUD HR 2.27 (1.65-3.14), p&amp;lt;0.0001, specifically HLA-A MM HR 2.69 (1.77-4.08), p&amp;lt;0.00001, HLA-B MM HR 3.14 (1.71-5.78) p=0.0002, Table 6. The same donor factors significant by univariate analysis were examined for correlation with TRM and significance was found for HLA MM HR 2.36 (1.57-3.55) p=0.00004, specifically HLA-A MM HR 2.44 (1.42-4.17), p=0.0012, HLA-B MM HR 2.39 (1.03-5.57) p=0.0034. Graft failure (GF) occurred in 4.6% of patients. Significant donor factors for GF were CD34 dose &amp;lt;4.0x106/kg, HR 5.28 (1.11-24.98) p=0.038; and HLA MM 2.78 (1.27-6.05) p=0.01. Of 414 patients, 395 patients (95.4%) received fresh stem cells and 19 (4.6%) received cryopreserved stem cells. Cryopreserved MUD grafts were associated with GF on MVA, HR 5.56 (1.75-17.4, p=0.0034), which may be due to several possible factors including the travel time prior to cryopreservation. Among AML patients, CMV negative patients in receipt of grafts from CMV negative donors (CMV-/-) (n=64) had worse survival (HR 2.05, 1.03-4.09, p=0.04) compared to recipient/donor pairs where any were CMV positive. There was a significantly higher relapse rate in the CMV-/- (15/64, 23.4%), compared to CMV positive (30/236, 12.2%, any combination), p=0.01 by Chi-squared test. Conclusions These data suggest that HLA-A and HLA-B mismatched donors confer a significantly inferior outcome despite the use of ATG PTCy. Cryopreserved stem cells from unrelated donors were associated with graft failure, and CMV-/- were associated with higher incidence of relapse. Further work is required to develop novel conditioning regimens and GvHD prophylaxis to mitigate these risks. Disclosures Lipton: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Mattsson:Gilead: Honoraria; ITB: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Mallinkrodt: Honoraria.

Use of the HLA-B leader to optimize cord blood transplantation

Cord blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4,822 transplants, 2,178 had one HLA-B mismatch of which 1,013 were HLAA and HLA-A and -DRB1 matched. The leader (methionine [M] or threonine [T]) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of graft-versus-host disease, relapse, non-relapse mortality and overall mortality were estimated for various leader-defined groups using multi-variable regression models. Among the 1,013 HLA-A and -DRB1-matched transplants with one HLA-B mismatch, increasing numbers of cord blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one Mleader allele 1.30, 95% Confidence Interval [CI]: 1.05-1.60, P=0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI: 0.23-0.81; P=0.009) relative to leader matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation

The Impact of Nationwide Allocation System on Kidney Transplantation: A Single-Center Experience

ObjectivesOrgan allocation is of decisive importance in the current situation of organ shortage. The aim of this study is to compare the long-term graft outcomes of deceased donor recipients before and after the new nationwide allocation system in Taiwan. MethodsFrom April 1, 2000 to March 31, 2010, 181 deceased kidney transplantations were reviewed retrospectively, and recipients were divided by the enforcement day (April 1, 2005) of nationwide allocation into group 1 (before) and group 2 (after). Baseline demographics were reviewed. Outcomes, including graft survival (GS) and patient survival, at 1-, 3-, 5-, and 10-years after transplantation were analyzed. ResultsThe baseline demography was similar between the 2 groups except that group 1 is younger. Group 2 has less HLA-B (P < .001) and HLA mismatches (P = .005). There were significantly more 0-mismatch recipients in group 2 (6 vs 27, P = .001), as well as extended criteria donor (ECD) recipients (0 vs 7). Group 2 has less optimal 1-year GS (95.6% vs 86.8%, Log-Rank P = .037), which becomes nonsignificant at 3-, 5-, and 10-years after transplantation. By excluding ECD recipients, the GS were similar at all time. There was no difference in patient survival between the 2 groups. ConclusionThe new nationwide allocation system provided us more 0-mismatch kidneys. The nationwide scheme remains beneficial to kidney recipients after the acute adverse effects of ECD and aging vanish.

IgA Nephropathy Recurrence after Kidney Transplantation: Role of Recipient Age and Human Leukocyte Antigen-B Mismatch

Background: Recurrence of immunoglobulin (Ig)A nephropathy (rIgAN) is a growing cause of kidney allograft dysfunction. This study was aimed at investigating factors associated with rIgAN and the subsequent progression to end-stage renal disease (ESRD). Methods: Retrospective study including consecutive patients with IgA nephropathy (IgAN) who received a kidney transplant in our center between 1992 and 2016 and had a renal biopsy by clinical indication. The date of detection of chronic kidney disease (CKD) 5 was used as renal outcome. Results: Eighty-six kidney transplants were performed in patients with IgAN, 38 (44%) were from living donors (related n = 26). rIgAN was diagnosed in 23 allografts (27%). Renal function and proteinuria at the end of the follow-up period were worst in the rIgAN patients compared to those without rIgAN (2.2 vs. 1.4 mg/dL, p = 0.014, and 1.16 vs. 0.49 g/day, p = 0.005, respectively). Risk of rIgAN and progression to CKD 5 decreased with patient’s age (hazard ratio [HR] 0.95, 95% CI 0.92–0.98, p = 0.002, and HR 0.97, 95% CI 0.83–0.97, p = 0.008 per year, respectively). Patients with rIgAN had a higher risk of progression to CKD 5 (HR 6.7, 95% CI 1.3–35.7, p = 0.025). Full donor-recipient mismatch in the human leukocyte antigen (HLA)-B loci decreased the risk of rIgAN (HR 0.22, 95% CI 0.06–0.76, p = 0.017). Conclusions: rIgAN was an independent risk factor for ESRD after renal allograft. Younger age increased the risk of rIgAN and CKD 5. Conversely, HLA-B mismatching was a potential protective factor for rIgAN of this glomerular disease.

Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study

The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. The National Institutes of Health, USA.

A donor risk index for graft loss in pediatric living donor kidney transplantation.

Pediatric kidney transplant candidates often have multiple potential living donors (LDs); no evidence-based tool exists to compare potential LDs, or to decide between marginal LDs and deceased donor (DD) kidney transplantation (KT). We developed a pediatric living kidney donor profile index (P-LKDPI) on the same scale as the DD KDPI by using Cox regression to model the risk of all-cause graft loss as a function of living donor characteristics and DD KDPI. HLA-B mismatch (adjusted hazard ratio [aHR] per mismatch=1.04 1.271.55 ), HLA-DR mismatch (aHR per mismatch=1.02 1.231.49 ), ABO incompatibility (aHR=1.20 3.268.81 ), donor systolic blood pressure (aHR per 10mm Hg=1.01 1.071.18 ), and donor estimated GFR (eGFR; aHR per 10mL/min/1.73m2 = 0.88 0.940.99 ) were associated with graft loss after LDKT. Median (interquartile range [IQR]) P-LKDPI was -25 (-56 to 12). 68% of donors had P-LKDPI <0 (less risk than any DD kidney) and 25% of donors had P-LKDPI >14 (more risk than median DD kidney among pediatric KT recipients during the study period). Strata of LDKT recipients of kidneys with higher P-LKDPI had a higher cumulative incidence of graft loss (39% at 10years for P-LDKPI ≥20, 28% for 20>P-LKDPI ≥-20, 23% for -20>P-LKDPI ≥-60, 19% for P-LKDPI <-60 [log rank P<.001]). The P-LKDPI can aid in organ selection for pediatric KT recipients by allowing comparison of potential LD and DD kidneys.

Association of HLA Antigen Mismatch With Risk of Developing Skin Cancer After Solid-Organ Transplant

Risk factors for the development of skin cancer after solid-organ transplant can inform clinical care, but data on these risk factors are limited. To study the association between HLA antigen mismatch and skin cancer incidence after solid-organ transplant. This retrospective cohort study is a secondary analysis of the multicenter Transplant Skin Cancer Network study of 10 649 adults who underwent a primary solid-organ transplant between January 1, 2003, and December 31, 2003, or between January 1, 2008, and December 31, 2008. These participants were identified through the Scientific Registry of Transplant Recipients standard analysis files, which contain data collected mostly by the Organ Procurement and Transplantation Network. Participants were matched to skin cancer outcomes by medical record review. This study was conducted from August 1, 2016, to July 31, 2017. The primary outcome was time to diagnosis of posttransplant skin cancer, including squamous cell carcinoma, melanoma, and Merkel cell carcinoma. The HLA antigen mismatch was calculated based on the 2016 Organ Procurement and Transplantation Network guidelines. Risk of skin cancer was analyzed using a multivariate Cox proportional hazards regression model. In total, 10 649 organ transplant recipients (6776 men [63.6%], with a mean [SD] age of 51 [12] years) contributed 59 923 years of follow-up. For each additional mismatched allele, a 7% to 8% reduction in skin cancer risk was found (adjusted hazard ratio [HR], 0.93; 95% CI, 0.87-0.99; P = .01). Subgroup analysis found the protective effect of HLA antigen mismatch to be statistically significant in lung (adjusted HR, 0.70; 95% CI, 0.56-0.87; P = .001) and heart (adjusted HR, 0.75; 95% CI, 0.60-0.93; P = .008) transplant recipients but not for recipients of liver, kidney, or pancreas. The degree of HLA-DR mismatch, but not HLA-A or HLA-B mismatch, was the most statistically significant for skin cancer risk (adjusted HR, 0.85; 95% CI, 0.74-0.97; P = .01). The HLA antigen mismatch appears to be associated with reductions in the risk of skin cancer after solid-organ transplant among heart and lung transplant recipients; this finding suggests that HLA antigen mismatch activates the tumor surveillance mechanisms that protect against skin cancer in transplant recipients and that skin cancer risk may be higher in patients who received a well-matched organ.

Risk Factors for Mortality among Kidney Transplant Recipients with Pneumocystis Jirovecii Infection

Infection by P. jirovecii (PCP) has been described with increased incidence among kidney transplant recipients (KTR) in the recent years and a high mortality rate was associated with these infections. The aim of this study was to analyze risk factor for mortality due to PCP infection in a cohort of KTR. We analyzed all KTR that developed PCP in a single center from January 2004 to December 2016. Case of PCP was defined based on a combination of clinical assessment, plus radiologic changes, and one confirmatory test (positive PCR or direct fluorescent-antibody test of respiratory specimens or histological exam of lung). We excluded combined transplant. Independent variables analyzed were related to donors’ aspects, receptor aspects, induction therapy, cold ischemia time, immunosuppression at time of PCP, previous CMV disease, acute cellular rejection and laboratory tests and clinical presentation of PCP at diagnosis. The outcome was death related to PCP, defined as persistence of signs and symptoms of PCP infection at the time of death, or death occurring within 30 days after the diagnosis of the infection with no other cause identified. All patients were followed for 60 days. Statistical analysis was performed through Cox regression, we included in initial model of multivariate analysis all variable with P <0.2 in univariate analysis. A total of 60 cases were identified during study period, the most common radiological features were ground-glass pattern in 48 (80%) cases, consolidation in 6 (10%) and small nodules and tree-in-bud opacities in 6 (10%), median lactate dehydrogenase dosage at diagnosis was 527.5 U/L, 46(76.7%) patients needed ICU stay, and 34 (56.6%) needed mechanical ventilation, five (8.3%) patients were under PCP prophylaxis, one patient died before received specific PCP treatment. Only 2 patients received another drug than Sulfamethoxazole -Trimethoprim due to toxicity. The death related mortality rate was 26.6%. Risk factor associated to increased mortality rate were KTR age at PCP diagnosis(p 0.05 HR 1.05 95%CI 1.01-1.10), previous hospital stays in the last 3 months (p0.05 HR 2.74 95%CI 1.20-7.49) and HLA-B mismatch (p0.04 HR2.40 95%CI1.06-5.46). In conclusion, any radiological or laboratory aspects at PCP diagnosis was associated to a worse outcome of PCP infection. Features that increased mortality were associated to KTR aspects and comorbidities.

Impact of HLA allele mismatch at HLA-A, -B, -C, -DRB1, and -DQB1 on outcomes in haploidentical stem cell transplantation.

The impact of human leukocyte antigen (HLA) allele mismatch on transplant outcomes in haploidentical stem cell transplantation (haplo-SCT) has not been established. We retrospectively studied 595 patients with hematologic malignancy who received haplo-SCT. The impact of multiple HLA allele mismatches (HLA-A, -B, -C, -DRB1, and -DQB1) and each HLA allele mismatch on transplant outcomes was analyzed. Greater number of HLA allele disparity does not appear worsen outcome. As for each HLA locus, HLA-A mismatch correlated with decreased rate of platelet engraftment (HR 0.740, P = .003); HLA-B mismatch independently correlated with decreased relapse rate (HR 0.494, P = .032) and improved disease-free survival and overall survival (HR 0.514, P = .003; HR 0.494, P = .002, respectively); HLA-C mismatch appeared to be protective for transplant-related mortality (TRM) (HR 0.567, P = .039); HLA-DRB1 mismatch was associated with increased cumulative incidence of grade II-IV acute graft-vs.-host disease (GVHD) (HR 1.942, P = .002). No associations of any HLA mismatch with delayed neutrophil engraftment or increased cumulative incidence of chronic GVHD were observed. Our data indicated that high degree of HLA allele mismatches did not adversely affect transplant outcomes in haplo-SCT and each HLA allele mismatch had different effect.

T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts.

Inflammation in fibrosis areas (i-IF/TA) of kidney allografts is associated with allograft loss; however, its diagnostic significance remains to be determined. We investigated the clinicohistologic phenotype and determinants of i-IF/TA in a prospective cohort of 1539 kidney recipients undergoing evaluation of i-IF/TA and tubulitis in atrophic tubules (t-IF/TA) on protocol allograft biopsies performed at 1 year posttransplantation. We considered donor, recipient, and transplant characteristics, immunosuppression, and histological diagnoses in 2260 indication biopsies performed within the first year posttransplantation. Nine hundred forty-six (61.5%) patients presented interstitial fibrosis/tubular atrophy (IF/TA Banff grade>0) at 1 year posttransplant, among whom 394 (41.6%) showed i-IF/TA. i-IF/TA correlated with concurrent t-IF/TA (P<.001), interstitial inflammation (P<.001), tubulitis (P<.001), total inflammation (P<.001), peritubular capillaritis (P<.001), interstitial fibrosis (P<.001), and tubular atrophy (P=.02). The independent determinants of i-IF/TA were previous T cell-mediated rejection (TCMR) (P<.001), BK virus nephropathy (P=.007), steroid therapy (P=.039), calcineurin inhibitor therapy (P=.011), inosine-5'-monophosphate dehydrogenase inhibitor therapy (P=.011), HLA-B mismatches (P=.012), and HLA-DR mismatches (P=.044). TCMR patients with i-IF/TA on posttreatment biopsy (N=83/136, 61.0%) exhibited accelerated progression of IF/TA over time (P=.01) and decreased 8-year allograft survival (70.8% vs 83.5%, P=.038) compared to those without posttreatment i-IF/TA. Our results support that i-IF/TA may represent a manifestation of chronic active TCMR.

P156 Allelic and epitope HLA mismatch analysis in lung transplant

Aim The urgent need for donor lungs and a shortage of suitable organs requires transplantation of HLA mismatched donor:recipient pairs. Post-transplant high resolution HLA typing of the donor and recipient, if available, presents a post hoc opportunity to investigate comparative allelic and epitope mismatch strategies to predict post-transplant events and optimize immunosuppressive therapy. Methods Thirty donor-recipient lung transplant pairs with available extracted DNA were studied (De Vlaminck et al. (2015)). High resolution NGS HLA typing required targeted sequencing and was performed according to Moonsamy et al. (2013). Respective two-region HLA types were assigned using Conexio ASSIGN ATF 454 software and compared to the catalog of common and well-documented HLA alleles. Epitope mismatches were determined using HLAMatchmaker. Prior transplant studies noted the importance of HLA-A, HLA-B and DRB1 for short and long term survival and therefore were selected for this study. Results Thirty lung transplant pairs had 3 (n = 1), 4 (5), 5 (10) and 6 (14) HLA-A, HLA-B and HLA DRB1 allelic mismatches. Epitope mismatches ranged from 16–51. The epitope mismatch extremes each had 6 allelic mismatches: 16: HLA-A,-B 9; DRB1 7 and 51: HLA-A,-B 19; DRB1 32. The single 3 allelic mismatch pair had 31 epitope mismatches: HLA-A,-B 10; DRB1 21. DRB1 epitope mismatch contribution to total epitope mismatches ranged from 19% to 63%. Conclusions Allelic (antigenic) mismatches have a more limited range than epitope (immunogenic) mismatches, and mismatch burdens using these two models varied considerably in lung transplants in this study. The relative contribution of epitope mismatches in HLA-A, HLA-B and DRB1 varies in transplant donor recipient pairs. Prognostic estimates of antibody mediated rejection to inform surveillance and increased risk of post-transplant malignancies and infection to inform long term immunosuppressive therapy merit investigation using epitope mismatch burden.