Pretransplant Panel Reactive Antibody Research Articles

Impact of HLA Eplet Mismatch on De Novo Donor Specific Antibody Formation After Kidney Transplantation

HLA eplet mismatching is an alternative approach to assess the risk of developing de novo donor-specific antibodies (dnDSA) in kidney transplantation. This strategy may offer more precise risk stratification than conventional approaches. This study aimed to find the association between HLA eplet mismatches and dnDSA formation in Thai kidney transplant recipients. A retrospective cohort study of kidney transplant recipients transplanted between 2000 and 2021 at Ramathibodi Hospital was performed. Recipients with pretransplant panel reactive antibody >0% or without DSA testing post-transplant were excluded. One hundred fifty recipients were included in the final study. High-resolution HLA typing was imputed by the HaploStat application. HLA eplet mismatch analysis was conducted using HLAMatchmaker. The association between the number of eplet mismatches and the risk of dnDSA formation was assessed by Cox regression analysis. Of 150 recipients, 43 were dnDSA-positive, and 107 were dnDSA-negative patients. Compared with the dnDSA-negative group, patients with class II dnDSA had significantly more HLA-DR/DQ antibody (Ab)-verified eplet mismatches (6 [IQR 4-8] vs 4 [IQR 1-7], P = .045). The receiver operating characteristics analysis showed that the HLA-DQ Ab-verified eplet mismatches ≥2 were the best predictive of HLA class II dnDSA development. The number of HLA-DQ Ab-verified eplet mismatches ≥2 had the highest hazard rate of HLA class II dnDSA occurrence (adjusted HR, 3.74; 95%CI, 1.24-11.24, P = .019). HLA-DQ Ab-verified eplet mismatches are significantly associated with class II dnDSA development. Our data supports the utility of HLA eplet mismatching for donor-recipient risk assessment.

Impacts of Pre-transplant Panel-Reactive Antibody on Post-transplantation Outcomes: A Study of Nationwide Heart Transplant Registry Data.

The number of sensitized heart failure patients on waiting lists for heart transplantation (HTx) is increasing. Using the Korean Organ Transplantation Registry (KOTRY), a nationwide multicenter database, we investigated the prevalence and clinical impact of calculated panel-reactive antibody (cPRA) in patients undergoing HTx. We retrospectively reviewed 813 patients who underwent HTx between 2014 and 2021. Patients were grouped according to peak PRA level as group A: patients with cPRA ≤10% (n= 492); group B: patients with cPRA >10%, <50% (n=160); group C patients with cPRA ≥50% (n=161). Post-HTx outcomes were freedom from antibody-mediated rejection (AMR), acute cellular rejection, coronary allograft vasculopathy, and all-cause mortality. The median follow-up duration was 44 (19-72) months. Female sex, re-transplantation, and pre-HTx renal replacement therapy were independently associated with an increased risk of sensitization (cPRA ≥50%). Group C patients were more likely to have longer hospital stays and to use anti-thymocyte globulin as an induction agent compared to groups A and B. Significantly more patients in group C had positive flow cytometric crossmatch and had a higher incidence of preformed donor-specific antibody (DSA) compared to groups A and B. During follow-up, group C had a significantly higher rate of AMR, but the overall survival rate was comparable to that of groups A and B. In a subgroup analysis of group C, post-transplant survival was comparable despite higher preformed DSA in a desensitized group compared to the non-desensitized group. Patients with cPRA ≥50% had significantly higher incidence of preformed DSA and lower freedom from AMR, but post-HTx survival rates were similar to those with cPRA <50%. Our findings suggest that sensitized patients can attain comparable post-transplant survival to non-sensitized patients when treated with optimal desensitization treatment and therapeutic intervention.

Impacts of pretransplant panel-reactive antibody on posttransplantation outcomes: a study of nationwide heart transplant registry data

Impacts of pretransplant panel-reactive antibody on posttransplantation outcomes: a study of nationwide heart transplant registry data

Differences between Very Highly Sensitized Kidney Transplant Recipients as Identified by Machine Learning Consensus Clustering.

Background and Objectives: The aim of our study was to categorize very highly sensitized kidney transplant recipients with pre-transplant panel reactive antibody (PRA) ≥ 98% using an unsupervised machine learning approach as clinical outcomes for this population are inferior, despite receiving increased allocation priority. Identifying subgroups with higher risks for inferior outcomes is essential to guide individualized management strategies for these vulnerable recipients. Materials and Methods: To achieve this, we analyzed the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database from 2010 to 2019 and performed consensus cluster analysis based on the recipient-, donor-, and transplant-related characteristics in 7458 kidney transplant patients with pre-transplant PRA ≥ 98%. The key characteristics of each cluster were identified by calculating the standardized mean difference. The post-transplant outcomes were compared between the assigned clusters. Results: We identified two distinct clusters and compared the post-transplant outcomes among the assigned clusters of very highly sensitized kidney transplant patients. Cluster 1 patients were younger (median age 45 years), male predominant, and more likely to have previously undergone a kidney transplant, but had less diabetic kidney disease. Cluster 2 recipients were older (median 54 years), female predominant, and more likely to be undergoing a first-time transplant. While patient survival was comparable between the two clusters, cluster 1 had lower death-censored graft survival and higher acute rejection compared to cluster 2. Conclusions: The unsupervised machine learning approach categorized very highly sensitized kidney transplant patients into two clinically distinct clusters with differing post-transplant outcomes. A better understanding of these clinically distinct subgroups may assist the transplant community in developing individualized care strategies and improving the outcomes for very highly sensitized kidney transplant patients.

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT. In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared. The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup. High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

Misidentification of preformed anti-HLA-DP antibodies leads to antibody-mediated kidney transplant rejection: a case report

BackgroundPatients who are HLA-sensitized are at high risk for early antibody-mediated rejection (AMR) and worse outcomes. Therefore, it is crucial to detect the presence of donor-specific antibodies (DSAs) using pretransplant antibody identification and crossmatch assays. An error in antibody identification can lead to disastrous clinical outcomes. We present a case of acute AMR associated with preformed HLA-DPα and HLA-DPβ DSAs that were not identified before transplantation.Case presentationA 27-year-old woman received a second kidney transplant from a deceased donor. Her pretransplant panel-reactive antibody level was 94%. The complement-dependent cytotoxicity crossmatch was negative for T and B cells at the time of transplantation. She experienced early acute AMR proven by a kidney biopsy. Single antigen bead testing of the patient’s serum at the time of rejection as well as the pre-second transplant serum revealed strong antibodies against the DPA1*01:03 and DPB1*02:01 alleles in the second donor. These antibodies were not identified by phenotypic bead assay during the patient’s time on the waiting list. The patient was treated with plasmapheresis and anti-thymocyte globulin. However, she experienced abdominal pain on day 37 post-transplantation. Surgical exploration revealed a laceration on the transplanted kidney, which was then repaired. Subsequently, infected hematoma was suspected and the transplanted kidney was removed.ConclusionThe present case highlights the clinical significance of preformed HLA-DPα and HLA-DPβ DSAs. Accuracy in determination of HLA antibodies before transplantattion is critical for transplant outcome. HLA-DP typing and single antigen bead testing are recommended for a precise antibody interpretation, especially in highly sensitized patients. Careful interpretation of antibody testing results is essential for the success of organ transplantation.

The role of sensitization in post-transplant outcomes in adults with congenital heart disease sensitization in adults with congenital heart disease

IntroductionThe number of heart transplants in adults with congenital heart disease (CHD) is increasing, though outcomes remain unfavorable compared to those without CHD. The etiology of this mortality difference remains uncertain. Panel reactive antibody (PRA) is a predictor of survival post-transplantation, and adult CHD patients have been observed to have higher PRA levels. Here we assessed the relationship between PRA and outcomes in adult patients with CHD who underwent heart transplantation. MethodsThis is a retrospective cohort study using the 2004–2015 ISHLT Thoracic Organ Transplant Registry to investigate the role of sensitization in the observed excess mortality. The composite outcome of mortality or graft failure within 1-year of transplantation was compared among CHD vs. non-CHD recipients, according to sensitization as measured by pre-transplant panel reactive antibodies (PRA). ResultsAdults with CHD (n = 1188) had higher PRA level compared to non-CHD (n = 38,201) recipients (27% vs. 18% PRA>10%, respectively, p < 0.001). CHD diagnosis remained independently associated with a higher incidence of the composite outcome in multivariable analysis after adjusting for PRA and other variables. Further, even after age-matching, patients with CHD and PRA ≤10% were at higher risk of the primary outcome compared to non-CHD (OR 2.1 [1.4–3.4], p = 0.001), though both groups had comparable outcomes when PRA was >10% (OR 1.1 [0.6–2.0], p = 0.852). ConclusionsAdults with CHD are more likely to have higher sensitization and worse outcomes than non-CHD recipients. Higher sensitization rates alone do not fully explain their excess risk of adverse outcomes after heart transplantation.

Prevalence of Clinical Events Following High Donor Derived Cell Free DNA in the Absence of Rejection in Heart Transplant Recipients

Purpose Donor-derived cell free DNA (dd-cfDNA) is a noninvasive biomarker used to assess graft injury following heart transplant (HTx). While the relationship between increased levels of dd-cfDNA and acute cellular rejection (ACR) and antibody mediated rejection (AMR) has been well studied, less is known about the frequency of other processes that damage the allograft following an elevated dd-cfDNA measurement. The goal of this analysis was to assess the prevalence of clinical events following a high dd-cfDNA measurement in the absence of rejection. Methods This retrospective study included 223 HTx recipients from the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry (D-OAR) with elevated dd-cfDNA (AlloSure®), defined as a level ≥0.20% that did not occur within 14 days of biopsy proven ACR (grade ≥2R) or AMR (pAMR≥1). Clinical events included the presence of donor specific antibodies (DSA), cardiac allograft vasculopathy (CAV; ISHLT grade ≥1), graft dysfunction [left ventricular ejection fraction (LVEF) ≤45% or a proportional decrease in LVEF ≥25% from the first D-OAR study visit], ACR, AMR and death. Clinical data were collected for 180 days following the first elevated dd-cfDNA. Allosensitization was defined as a pre-transplant panel reactive antibody ≥10%. Results The study consisted of 68% men and 71% Caucasians (mean ± SD age at HTx 52 ± 14 years), with non-ischemic cardiomyopathy (46%) representing the primary reason for HTx. The median time post-HTx to the first non-rejection elevated dd-cfDNA was 241 days (IQR 154-362). Fifty-seven of the 223 patients (26%), of whom 6 were allosensitized, experienced 70 clinical events in the 180 days post-elevated dd-cfDNA. The presence of at least one DSA (n=36) was the most common clinical event, of which 28/36 (78%) were de novo DSA. Graft dysfunction (n=14), CAV (n=9), AMR (n=5), death (n=4), and ACR (n=2) were the next most common. Median time (IQR) from elevated dd-cfDNA to these events was as follows: DSA, 37 days (15-104); graft dysfunction, 22 days (0-77); AMR, 70 days (42-91); and death, 100 days (75-124). Conclusion Elevated dd-cfDNA levels in the absence of allograft rejection appeared to precede the development of clinically relevant events within the next 6 months. Further studies are needed to determine whether elevated dd-cfDNA should trigger a change in clinical management. Donor-derived cell free DNA (dd-cfDNA) is a noninvasive biomarker used to assess graft injury following heart transplant (HTx). While the relationship between increased levels of dd-cfDNA and acute cellular rejection (ACR) and antibody mediated rejection (AMR) has been well studied, less is known about the frequency of other processes that damage the allograft following an elevated dd-cfDNA measurement. The goal of this analysis was to assess the prevalence of clinical events following a high dd-cfDNA measurement in the absence of rejection. This retrospective study included 223 HTx recipients from the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry (D-OAR) with elevated dd-cfDNA (AlloSure®), defined as a level ≥0.20% that did not occur within 14 days of biopsy proven ACR (grade ≥2R) or AMR (pAMR≥1). Clinical events included the presence of donor specific antibodies (DSA), cardiac allograft vasculopathy (CAV; ISHLT grade ≥1), graft dysfunction [left ventricular ejection fraction (LVEF) ≤45% or a proportional decrease in LVEF ≥25% from the first D-OAR study visit], ACR, AMR and death. Clinical data were collected for 180 days following the first elevated dd-cfDNA. Allosensitization was defined as a pre-transplant panel reactive antibody ≥10%. The study consisted of 68% men and 71% Caucasians (mean ± SD age at HTx 52 ± 14 years), with non-ischemic cardiomyopathy (46%) representing the primary reason for HTx. The median time post-HTx to the first non-rejection elevated dd-cfDNA was 241 days (IQR 154-362). Fifty-seven of the 223 patients (26%), of whom 6 were allosensitized, experienced 70 clinical events in the 180 days post-elevated dd-cfDNA. The presence of at least one DSA (n=36) was the most common clinical event, of which 28/36 (78%) were de novo DSA. Graft dysfunction (n=14), CAV (n=9), AMR (n=5), death (n=4), and ACR (n=2) were the next most common. Median time (IQR) from elevated dd-cfDNA to these events was as follows: DSA, 37 days (15-104); graft dysfunction, 22 days (0-77); AMR, 70 days (42-91); and death, 100 days (75-124). Elevated dd-cfDNA levels in the absence of allograft rejection appeared to precede the development of clinically relevant events within the next 6 months. Further studies are needed to determine whether elevated dd-cfDNA should trigger a change in clinical management.

Rejection-associated Phenotype of De Novo Thrombotic Microangiopathy Represents a Risk for Premature Graft Loss.

Thrombotic microangiopathy (TMA) significantly affects kidney graft survival, but its pathophysiology remains poorly understood. In this multicenter, retrospective, case-control paired study designed to control for donor-associated risks, we assessed the recipients' risk factors for de novo TMA development and its effects on graft survival. The study group consists of patients with TMA found in case biopsies from 2000 to 2019 (n = 93), and the control group consists of recipients of paired kidney grafts (n = 93). Graft follow-up was initiated at the time of TMA diagnosis and at the same time in the corresponding paired kidney graft. The TMA group displayed higher peak panel-reactive antibodies, more frequent retransplantation status, and longer cold ischemia time in univariable analysis. In the multivariable regression model, longer cold ischemia times (odds ratio, 1.18; 95% confidence interval [CI], 1.01-1.39; P = 0.043) and higher peak pretransplant panel-reactive antibodies (odds ratio, 1.03; 95% CI, 1.01-1.06; P = 0.005) were found to be associated with increased risk of de novo TMA. The risk of graft failure was higher in the TMA group at 5 y (hazard ratio [HR], 3.99; 95% CI, 2.04-7.84; P < 0.0001). Concomitant rejection significantly affected graft prognosis at 5 y (HR, 6.36; 95% CI, 2.92-13.87; P < 0.001). De novo TMA associated with the active antibody-mediated rejection was associated with higher risk of graft failure at 5 y (HR, 3.43; 95% CI, 1.69-6.98; P < 0.001) compared with other TMA. Longer cold ischemia and allosensitization play a role in de novo TMA development, whereas TMA as a part of active antibody-mediated rejection was associated with the highest risk for premature graft loss.

Clinical significance of tacrolimus intra-patient variability on kidney transplant outcomes according to pre-transplant immunological risk

High intra-patient variability (IPV) of tacrolimus trough concentrations is increasingly recognized as a predictor of poor long-term outcomes in kidney transplant. However, there is a lack of information regarding the association between tacrolimus IPV and graft outcomes according to immunological risk. We analyzed tacrolimus IPV using the coefficient of variability from months 6–12 after transplantation in 1080 kidney transplant recipients. Patients were divided into two immunological risk groups based on pre-transplant panel reactive antibodies and donor-specific antibodies. High immunological risk was defined as panel reactive antibodies ≥ 20% or the presence of donor-specific antibodies. The effects of tacrolimus IPV on graft outcomes were significantly different between low and high immunological risk patients. A multivariable Cox regression model confirmed that high tacrolimus IPV was an independent risk factor for graft failure in the high risk group (HR, 2.90; 95% CI, 1.42–5.95, P = 0.004). In the high risk group, high tacrolimus IPV was also significantly associated with increased risk of antibody-mediated rejection (P = 0.006). In contrast, death-censored graft survival and antibody-mediated rejection in the low immunological risk group was not significantly different by tacrolimus IPV. High tacrolimus IPV significantly increases the risk of graft failure and antibody-mediated rejection in patients with high immunological risk.

Panel Reactive Antibody and Donor-Recipient Sex Differences Do Not Affect Long-Term Lung Transplant Outcomes

PurposePatients with elevated panel reactive antibody (PRA) experience delayed transplant and higher waitlist mortality than minimally sensitized patients. If transplanted, the importance of elevated PRA observed with donor-recipient sex differences on long-term outcomes remain unknown.MethodsThe United Network for Organ Sharing database was reviewed for all adult patients who underwent isolated lung transplantation between 2005 and 2015. All patients without known BOS status on follow up were excluded. The date of first BOS diagnosis, if present, was used for analysis. All remaining patients were censored at time of last follow up in absence of BOS, graft dysfunction, or death. Baseline and post-transplant outcomes were reviewed using descriptive and Kaplan-Meier analyses.ResultsBetween 2005 and 2015, 15596 lung transplant recipients with known BOS status were included in analysis and divided into donor-recipient subgroups: male to male (M-M; n=6846, 44%), male to female (M-F: n=2581, 16%), female to male (F-M: n=2347, 15%), and female to female (F-F: n=3822, 25%) - Table 1. The time between listing and transplant was highest among M-F, 263 (95% CI [246-280]), and F-F, 275 days (95% CI [261-289]), subgroups. Female recipients also had higher pre-transplant PRA%, 13.7 (F-F) and 15.0 (M-F), compared to males (p < 0.001 between groups). Overall, there were no differences in freedom from BOS (p=0.282) or graft dysfunction (p=0.602) when adjusted for single or double transplant and donor-recipient subgroup. Composite survival differed between groups (p < 0.001 by log rank test); however, this was unaffected by subgroup PRA% when analyzed continuously or stratified by quartiles.ConclusionDonor-recipient sex differences are associated with elevated pre-transplant PRA levels in female recipients; however, pre-transplant PRA had no observed impact on graft and survival outcomes in all disease groups. The clinical significance of PRA after transplant selection, if any, remains unclear. Patients with elevated panel reactive antibody (PRA) experience delayed transplant and higher waitlist mortality than minimally sensitized patients. If transplanted, the importance of elevated PRA observed with donor-recipient sex differences on long-term outcomes remain unknown. The United Network for Organ Sharing database was reviewed for all adult patients who underwent isolated lung transplantation between 2005 and 2015. All patients without known BOS status on follow up were excluded. The date of first BOS diagnosis, if present, was used for analysis. All remaining patients were censored at time of last follow up in absence of BOS, graft dysfunction, or death. Baseline and post-transplant outcomes were reviewed using descriptive and Kaplan-Meier analyses. Between 2005 and 2015, 15596 lung transplant recipients with known BOS status were included in analysis and divided into donor-recipient subgroups: male to male (M-M; n=6846, 44%), male to female (M-F: n=2581, 16%), female to male (F-M: n=2347, 15%), and female to female (F-F: n=3822, 25%) - Table 1. The time between listing and transplant was highest among M-F, 263 (95% CI [246-280]), and F-F, 275 days (95% CI [261-289]), subgroups. Female recipients also had higher pre-transplant PRA%, 13.7 (F-F) and 15.0 (M-F), compared to males (p < 0.001 between groups). Overall, there were no differences in freedom from BOS (p=0.282) or graft dysfunction (p=0.602) when adjusted for single or double transplant and donor-recipient subgroup. Composite survival differed between groups (p < 0.001 by log rank test); however, this was unaffected by subgroup PRA% when analyzed continuously or stratified by quartiles. Donor-recipient sex differences are associated with elevated pre-transplant PRA levels in female recipients; however, pre-transplant PRA had no observed impact on graft and survival outcomes in all disease groups. The clinical significance of PRA after transplant selection, if any, remains unclear.

Use of Panel-Reactive Antibody Testing in the Planning and Management of Ocular Surface Stem Cell Transplantation.

Panel-reactive antibody (PRA) testing has been widely adopted in solid organ transplantation for risk assessment in potential allograft recipients but has not been studied in the context of ophthalmic transplantation. The purpose of this study is to evaluate outcomes in patients undergoing ocular surface stem cell transplantation (OSST) for limbal stem cell deficiency (LSCD) relative to preoperative PRA level. This is retrospective chart review of all eyes with documented PRA level that underwent OSST for LSCD between May 2000 and March 2019 at a single institution. Eyes with stable ocular surface but <1 year of follow-up and eyes without updated PRA before repeat OSST were excluded. Eyes were grouped by PRA <80% and ≥80%. The primary outcome was ocular surface failure, whereas the secondary outcome was clinical allograft rejection. Sixty-nine surgeries met inclusion criteria, consisting of 54 living-related conjunctival limbal allografts, 5 keratolimbal allografts, and 10 combined living-related conjunctival limbal allografts/keratolimbal allografts (Cincinnati procedure). The most common etiologies for LSCD were aniridia (33%), chemical/thermal injury (28%), and contact lens associated (14%). Surface failure occurred in 5 of 12 eyes (58%) with PRA ≥80% versus 12 of 57 eyes (21%) with PRA <80% (P = 0.01). The relative risk for surface failure with PRA ≥80% was 2.8 [confidence interval (CI), 1.38-5.55]. There was no significant difference in acute rejection (P = 1). Pretransplant PRA level is an important prognostic factor for ocular surface stability in eyes undergoing OSST for LSCD, with implications for donor selection, perioperative management, and systemic immunosuppression.

Increasing Pretransplant Panel Reactive Antibodies Worsens Survival in A Contemporary Heart Transplantation Cohort

Background Allosensitization as measured by presence of panel reactive antibodies (PRA) negatively impacts survival in adult heart transplant (HT) recipients. Questions remain whether these trends remain in more contemporary cohorts. We examined the interaction between long-term survival and pre-transplant PRA level in HT recipients from 2000-2018. Methods We identified adult HT recipients between 2000 and 2018 who had a pretransplant PRA in the Scientific Registry of Transplant Recipients. Study cohort was divided into groups with PRA levels; group with 0%, 1-10%, 11-24% and ≥25% PRA levels. We compared 3- and 5-year survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk adjusted influence of PRA category and PRA as a continuous value on survival. Results We included 24,655 HT recipients. PRA was 0% in 17,391 (70.5%) recipients, 1-10% in 3,331 (13.5%) recipients, 11-24% in 1,330 (5.4%) recipients, and ≥25% in 2,603 (10.6%) recipients. Patients with a PRA ≥25% were younger, had fewer comorbidities, and were more likely to be on ECMO or LVAD prior to HT. Unadjusted 3- and 5-year estimated survival was lower with increasing PRA category (Figure). After risk-adjustment, 5-year survival was higher for the 0% cohort compared to the 1-10% (HR 1.10, 95% CI 1.02-1.18), 11-24% (HR 1.20, 95%CI 1.08-1.34), and ≥25% (HR 1.16, 95% CI 1.07-1.26). When analyzed continuously, increasing PRA was associated with a lower survival (HR 1.003, 95% CI 1.002-1.005). Sensitivity analysis of those transplanted from 2013-2018 showed similar results. Conclusions In this contemporary cohort of HT recipients, increasing pretransplant PRA was associated with lower survival. Given the appreciable portion of HT recipients with elevated PRA, improvements in recipient selection and HT management may help improve outcomes.

CT-371: Impact of Donor-Specific Anti-HLA Antibody on Platelet Transfusion Refractoriness in Haplo-Identical Hematopoietic Stem Cell Transplant Patients: A Single-Center Experience

Context Outcomes of haplo-identical hematopoietic stem cell transplantation (haploSCT) have recently improved due to better control of allo-reactive reactions related to the major HLA mismatch between the recipient and the donor. Presence of pretransplant donor-specific anti-HLA antibodies (DSA) is associated with higher risk of graft failure. However, little is known regarding the association between the presence of these antibodies and platelet transfusion refractoriness (PTR) post-haploSCT that could predict poor transplant outcomes. Objective The aim of this study is to evaluate the association between DSA status of the recipient and the corrected platelet count increment (CCI) from day 0-100 post-haploSCT as an objective measure of PTR. Design This is a retrospective study that comprises chart review of patients who underwent haplo-SCT between June 2015 and January 2020 at the American University of Beirut medical center in Lebanon. Main outcome measures Pretransplant panel reactive antibodies (PRA) and DSA status at the time of transplant were collected, and the 24-hour CCI was calculated for every platelet donor transfusion. Results We identified 69 patients with a median age of 36 years (range: 16-77). 44 patients (64%) were males and 52 patients (75%) had myelodysplastic syndrome or acute leukemia. Median time from diagnosis to transplant was 13.8 months (range: 2.5-91.7), and 43 patients (62%) were in complete remission at transplant. Of all patients, only 6 patients (8.7%) were DSA+ at time of transplant, 14 (20.3%) were PRA+/DSA-, and the remaining 49 (71%) were PRA-. All 6 patients with DSAs underwent desensitization with a median MFI decrease of 375 (range: -541-1603). One of these 6 did not reach platelet nor leukocyte engraftment. Patients with persistent DSAs had lower mean CCI (9.27, range: 4.58-12.37) compared to those without DSAs (mean CCI: 11.93, range: 1.34-29.71; p=0.017). Statistical significance was maintained upon comparing PRA+DSA+ patients to PRA+DSA- and to PRA- patients with mean CCI of 14.04 (range: 1.39-29.71; p=0.005) and 11.38 (range: 1.34-28.00, p=0.024), respectively. Conclusions Presence of anti-HLA DSAs in haploSCT recipients, even at MFI lower than 1500, was associated with increased PTR. Larger number of patients is needed to evaluate its impact on survival outcomes.

Antibody-Mediated Rejection Due to Donor-Specific HLA-DQB1 and DQA1 Antibodies After Kidney Transplantation: A Case Report

BackgroundDonor-specific HLA antibody (DSA) is associated with the risk of allograft loss due to antibody-mediated rejection (ABMR). The majority of de novo DSA after kidney transplantation is directed toward donor HLA-DQ antigens. A HLA-DQ antigen is a heterodimer consisting of an alpha and beta chain. Traditionally, HLA-DQA1 typing has not been part of the pretransplant evaluation. Therefore, DQ alpha proteins are not usually taken into account in the interpretation of HLA-DQ antibody reactions. MethodsWe hereby present a case of a kidney transplant recipient with 0% pretransplant panel reactive antibody. She received kidney allograft from her husband. Two years after transplantation, she experienced abdominal swelling, and enlargement of transplanted kidney was identified. A biopsy of the allograft kidney demonstrated chronic active ABMR. DSAs were investigated using immunoglobulin G (IgG) and C1q single antigen bead (SAB) assay. HLAMatchmaker analysis was performed to identify eplets that explain the antibody reactivity patterns. ResultsThe IgG SAB analysis of a patient’s serum at the time of rejection showed positive reactions with all DQ2-carrying beads with mean fluorescence intensity (MFI) > 10000. However, the C1q assay demonstrated strong reaction to only HLA-DQA1∗05:01-DQB1∗02:01-carrying bead with MFI = 22462, whereas weak or no reactions against other HLA-DQ2-carrying beads were found. High-resolution HLA typing revealed that HLA-DQA1∗05:01 and DQB1∗02:01 were mismatched donor antigens. HLAMatchmaker analysis showed that the antibodies were reactive toward 40GR3 eplet on DQA1 and 45GE3 eplet on DQB1. ConclusionsThis case highlights the clinical significance of antibodies specific to both DQ alpha and DQ beta chains after kidney transplantation.

Factors Affecting eGFR Slope of Renal Transplant Patients During the First 2 Years

PurposeIn healthy individuals, glomerular filtration rate decreases by 1 mL/min/y after a peak level of 125.0 mL/min has been reached in adulthood. Any reduction greater than this is a progressive slope (slope more negative than −1 mL/min/y, stable [−1 to +1]), or an improvable slope if it shows more of an increase, that is, greater than +1.0 mL/min/y). The aim of the study was to determine the factors affecting estimated glomerular filtration rate (eGFR) slope during the first 2 years of renal transplant in patients with negative pretransplant panel-reactive antibody. Materials and MethodsThe characteristics of 59 renal transplant patients, such as age, sex, etiology, and 2 years of laboratory data, were collected retrospectively. For each patient, the eGFR decline rate (slope) (mL/min−1/1.73 m2−1/y−1) was determined by linear regression analysis using all calculated eGFR values over the study period. FindingsOf 59 patients, 7 (11.8%) had a progressive slope, 22 (37.2%) had a stable slope, and 30 (50.8%) had an improvable slope. The first-year mean tacrolimus level was lower in patients with progressive slope than in the patients with stable slope and improvable slope (P < .022). The determinants of eGFR slope in multiple regression analysis were post-transplant hypertension (β = −0.393; P = .002) and the first-year mean tacrolimus level (β = 0.320; P = .01), whereas age, serum albumin, and 2-year mean tacrolimus level did not reach the level of significance. ConclusionKeeping tacrolimus levels high in the first year to prevent eGFR declining is important.

Graft vasculopathy of vascularized composite allografts in humans: a literature review and retrospective study.

Mechanisms of chronic rejection of vascularized composite allografts (VCA) remain poorly understood and likely present along a spectrum of highly varied clinicopathological findings. Across both animal and human VCA however, graft vasculopathy (GV) has been the most consistent pathological finding resulting clinically in irreversible allograft dysfunction and eventual loss. A literature review of all reported clinical VCA cases with documented GV up to December 2018 was thus performed to elucidate the possible mechanisms involved. Relevant data extracted include C4d deposition, donor-specific antibody (DSA) formation, extent of human leukocyte antigen (HLA) mismatch, pretransplant panel reactive antibody levels, induction and maintenance immunosuppression used, the number of preceding acute rejection episodes, and time to histological confirmation of GV. Approximately 6% (13 of 205) of all VCA patients reported to date developed GV at a mean of 6 years post-transplantation. 46% of these patients have either lost or had their VCAs removed. Neither C4d nor DSA alone was predictive of GV development; however, when both are present, VCA loss appears inevitable due to progressive GV. Of utmost concern, GV in VCA does not appear to be abrogated by currently available immunosuppressive treatment and is essentially irreversible by the time of diagnosis with allograft loss a likely eventuality.

Induction with Rabbit-Thymoglobulin (r-ATG) is Associated with Lower Cardiac Allograft Vasculopathy (CAV)

Purpose CAV has an immunological component and continues to limit long term outcomes in heart transplantation (HT). Smaller single center studies have suggested that induction with r-ATG may reduce development of CAV. We evaluated the association of induction with r-ATG, Basiliximab (BxB), or ‘no induction’ and CAV in HT recipients, traditionally considered not highly sensitized [pre-transplant panel reactive antibody (PRA) class 1 and class 2 ≤ 10%]. Methods Between 6/2004 and 03/2015, we identified 4,654 adult HT recipients in UNOS who either had induction with r-ATG, BxB or ‘no induction’ at the time of HT, and had information on pre-HT PRA levels and CAV. Donor age above 55 years or structural abnormalities, multi-organ or repeat transplants were excluded. The 3 groups: r-ATG (n=644), BxB (n=991), no induction (n=3019) were compared for baseline donor/recipient characteristics and CAV. Results Overall, pre-transplant PRA 1 and 2 levels were 0.5±1.7% and 0.3±1.3% respectively. Compared to no induction or BxB, HT recipients in r-ATG group were slightly younger (53 vs 55 vs 56 yrs), more black race (23% vs 16% vs 22%), less Status 1A (49% vs 59 vs 62%). BxB group had more recipients with creatinine >1.5 (24% vs 23% in r-ARG vs 17% no-induction) (all p Conclusion Although rates of CAV were higher in our specific cohort than previously reported for the overall HT population, r-ATG was associated with lower CAV in HT recipients who are traditionally considered to be not highly sensitized.

Cardiac Transplantation across Preformed HLA-Antibody Barriers: Results of a Peritransplant Desensitization Protocol

Purpose A growing number of patients awaiting heart transplantation presents with preformed anti-HLA antibodies. This allosensitization prolongs waiting times and increases morbidity and mortality. In 2017, we designed aprotocol for peritransplant desensitization of heart-transplanted patients showing preformed anti-HLA donor specific antibodies (pfDSA), i.e. a positive virtual crossmatch. The protocol included: an intraoperative single dose of the IL-6 receptor antibody Tocilizumab (10mg/kg) just before releasing the aortic clamp; 5 sessions of plasmapheresis (PE, 1 before transplantation, 1 during transplantation and 3 thereafter); an infusion (2g/kg) of IgA and IgM-enriched human immunoglobulins G (IgGAM) after the last PE; and a single Rituximab dose (375mg/m2) after IgGAM. IgGAM are repeated every 4 weeks (0.5g/kg) for a maximum of 6 months, if DSA are still positive. Aim of this study was to present the preliminary results of this peritransplant desensitization protocol. Methods Records of heart-transplanted patients at our institution between 01/2017 and 10/2018 were reviewed. Patients with pfDSA (positive virtual crossmatch) formed the case group, remaining patients the control group. Median (IQR) follow-up amounted to 9 (5, 16) months. Results During the study period, among the 42 transplanted patients, 9 (21%) patients formed the case group and the remaining 33 (79%) the control group. All 9 case patients showed pfDSA with >50% pre-transplant panel reactive antibodies (PRA). Pretransplant recipient and donor characteristics did not differ between groups. Post-transplant, no case patients showed severe primary graft dysfunction, but 6 (19%) control patients did (p=0.19). At treatment end, pfDSA were cleared in 4 (44%) patients. At 1-year follow-up, survival was 100% vs. 75% in case and control patients (p=0.18); freedom from biopsy-confirmed rejection (Grade >1R) was 89% vs. 92% in case (n=1) and control (n=2) patients (p=0.78); and from steroid-pulsed therapy 89% vs. 82% in case (n=1) and control (n=5) patients (p=0.76), respectively. One case patient showed minimal AMR (pAMR 1+). Conclusion The present study showed that heart transplantation across positive crossmatch barriers can be feasible and safe. The present peritransplant desensitization protocol yielded good survival and rejection-free survival.

Identical Twin Small-bowel Transplantation Without Maintenance Immunosuppression: A 5-year Follow-up and Literature Review.

BackgroundThe availability of an identical twin donor that allows avoidance of complications related to graft rejection and immunosuppression represents an ideal treatment option for irreversible intestinal failure.Methods and ResultsWe described a 45-year-old woman who lost most of her small bowel due to acute superior mesenteric thrombosis received a living-related small bowel transplant from her identical-twin sister. Monozygosity was established by buccal smear DNA amplification using short tandem repeat. A pretransplant panel-reactive antibody was 47.5% with several HLA antibodies in higher titers. The patient received a brief course of steroids without any additional immunosuppressive agents after transplantation. Her postoperative course was uneventful without an episode of rejection or infection. The preformed HLA antibodies steadily declined over time after transplantation. At a 5-year follow-up, the patient achieved full enteral autonomy from parenteral nutrition with a regular lifestyle.ConclusionsIdentical-twin intestinal transplantation appears to provide the best outcomes by avoiding complications related to rejection and immunosuppression. We provide evidence that it may confer greater long-term immunological advantages even in a high-immunologic risk recipient.