Incidence Of Antibody-mediated Rejection Research Articles

Risk Stratification Before Living Donor Kidney Transplantation in Patients With Preformed Donor-specific Antibodies by Different Crossmatch Methods.

Preformed donor-specific HLA antibodies (DSA) are a well-known risk factor in kidney transplantation. There is still considerable debate, however, about the optimal risk stratification among patients with preformed DSA. Additionally, data on the prognostic value of different crossmatch assays in DSA-positive patients are scarce. DSA-positive living kidney transplant recipients were selected from a multicenter study examining 4233 consecutive renal transplants. An additional 7 patients from 2 further centers were included. Flow cytometric crossmatches (FXM), Luminex-based crossmatches, and virtual crossmatches based on C1q- and C3d-binding antibodies (C1qXM and C3dXM) were performed retrospectively using pretransplant sera and lymphocytes isolated from fresh samples. These samples were obtained from 44 donor and recipient pairs from 12 centers. Clinical outcome data and the control group without DSA were compiled from the previous study and were supplemented by data on 10-y death-censored graft survival (10yGS). Between 19% (C3dXM) and 46% (FXM) of crossmatches were positive. Crossmatch-positive patients showed high incidences of antibody-mediated rejection (AMR) within 6 mo (up to 60% in B-cell FXM+ patients). The incidence of AMR in crossmatch-negative patients ranged between 5% (FXM-) and 13% (C1qXM-). 10yGS was significantly impaired in patients with positive T-cell FXM and total FXM compared with both patients without DSA and those with DSA with negative FXM. Especially FXM are useful for risk stratification, as the outcome of DSA-positive, FXM-negative patients is similar to that of DSA-negative patients, whereas FXM-positive patients have both more AMR and decreased 10yGS. Because of their lower sensitivity, the significance of Luminex-based crossmatches, C1qXM, and C3dXM would have to be examined in patients with stronger DSA.

#1016 Kidney transplantation in highly sensitized patients with preformed donor-specific antibodies through personalized delisting strategies

Abstract Background and Aims This study explores a personalized delisting strategy enabling kidney transplantation in highly sensitized patients with preformed donor-specific anti-HLA antibodies (DSA) trying to minimize the risk of antibody-mediated rejection (ABMR). Method Retrospective single-centre analysis of 50 kidney transplant recipients with preformed DSA (preDSA) after employing a delisting strategy to enhance their access to transplantation, and without received a pre-transplant or immediate post-transplant desensitization protocol. The delisting approach focused on allowing less deleterious antibodies according to their mean fluorescence intensity (MFI), anti-HLA class and C1q study results. The strategy consisted on eliminating as prohibited HLA antigens those recognized by antibodies with the lowest MFI in the following order: 1st- MFI < 5000; 2nd- MFI < 10000; 3rd-Any MFI. Additionally, delisting prioritized a single locus in the following order: 1st- one of the HLA class I loci (A, B, or Cw); 2nd- the rest of the class I loci; 3rd- HLA-DP, followed by DR. C1q studies were performed before delisting and transplantation was contraindicated in the presence of DSA detected in the C1q assay. Two comparative cohorts included 50 sensitized recipients without pre-transplant DSA (SwoDSA) and 50 non-sensitized recipients (NS). Results The delisting strategy allowed transplantation with preformed DSA and demonstrated comparable rejection rates to SwoDSA and NS groups (16%, 14% and 8%, respectively; log-rank = 0.28). However, the occurrence of acute ABMR was 12% in the preDSA group, significantly higher than in SwoDSA (1%) and NS (0%) (log-rank = 0.0093). The immunological risk assumed in delisting correlated with ABMR incidence (patients with ABMR had significantly higher sum MFI [mean ± SD: 9301 ± 6340 vs 4492 ± 5641; p = 0.049]), emphasizing the importance of tailored strategies. DSA persistence after transplantation correlated with higher MFI and increased ABMR risk. Of note, 16% of preDSA patients developed de novo DSA versus only the 4% of SwoDSA and 0% of NS patients (p = 0.004). After a mean follow-up of 3.1 ± 2.1 years, the 1-, 3- and 5-year death-censored allograft survival rates were 100%, 90% and 78%, respectively, in the preDSA group; 98%, 84% and 84% in the SwoDSA group and 100% in NS group (log-rank = 0.02). Conclusion The present study demonstrates the feasibility and acceptable outcomes of kidney transplantation in highly sensitized patients with preformed DSA through a personalized delisting strategy without using desensitization protocols.

The Incidence of Antibody-Mediated Rejection Is Age-Related, Plateaus Late After Kidney Transplantation, and Contributes Little to Graft Loss in the Older Recipients.

It is not known whether antibody-mediated rejection (ABMR) is age-related, whether it plateaus late after transplantation, and to what extent it contributes to graft loss in older recipients. Patients transplanted between 2010 and 2015 (n = 1,054) in a single center had regular follow-up until January 2023. Recipients were divided into age groups at transplantation: 18-39years ("young"), 40-55years ("middle age"), and >55years ("elderly"). Ten years after transplantation the cumulative % of recipients with ABMR was 17% in young, 15% in middle age, and 12% in elderly recipients (p < 0.001). The cumulative incidence of ABMR increased over time and plateaued 8-10years after transplantation. In the elderly, with a median follow-up of 7.5years, on average 30% of the recipients with ABMR died with a functional graft and ABMR contributed only 4% to overall graft loss in this group. These results were cross-validated in a cohort of recipients with >15years follow-up. Multivariate cox-regression analysis showed that increasing recipient age was independently associated with decreasing risk for ABMR. In conclusion, the cumulative risk for ABMR is age-dependent, plateaus late after transplantation, and contributes little to overall graft loss in older recipients.

Clinical Outcome of Kidney Transplant Recipients with C1q-Binding De Novo Donor Specific Antibodies: A Single-Center Experience.

Complement activation by HLA antibodies is a key component of immune-mediated graft injury. We examined the clinical outcomes of kidney transplant recipients with complement-fixing de novo donor-specific antibodies (dnDSA) who were followed in our center. The C1q-binding ability was retrospectively assessed in 69 patients with dnDSA and mean fluorescence intensity (MFI) values > 2000 out of the 1325 kidney transplant recipients who were screened for DSA between 2015 and 2019. Luminex IgG single antigen beads (SAB)and C1q-SAB assays (One Lambda) were used. C1q-binding dnDSA was identified in 32/69 (46.4%) of the patients. Significantly higher MFI values were observed in C1q-positive DSA (18,978 versus 5840, p < 0.001). Renal graft biopsies were performed in 43 of the kidney transplant recipients (62.3%) with allograft dysfunction. Antibody-mediated rejection (ABMR) was detected in 29/43 (67.4%) of the patients. The incidence of ABMR was similar among patients with C1q-binding and non-C1q-binding DSA (51.7% vs. 48.3%, p = 0.523). Graft loss occurred in 30/69 (43.5%) of the patients at a median time of 82.5 months (IQR 45-135) from DSA detection. C1q-binding DSA was present in more patients who experienced graft loss (53.1% vs. 35.1%, p = 0.152). Higher MFI values and inferior clinical outcomes occurred in most of the kidney transplant recipients with C1q-binding dnDSA.

Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?

Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46%vs. 7%) than in allotransplantation (3%vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti-donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti-inflammatory therapy. Depletion or neutralization of anti-pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG-degrading enzymes do not deplete IgM. Despite the expression of human complement-regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti-C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell-targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti-inflammatory agents, anti-IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti-inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ-source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD-L1, HLA E, and/or HLA-G.

Preventative effect of TSPO ligands on mixed antibody-mediated rejection through a Mitochondria-mediated metabolic disorder

BackgroundImmune-mediated rejection was the major cause of graft dysfunction. Although the advances in immunosuppressive agents have markedly reduced the incidence of T-cell-mediated rejection after transplantation. However, the incidence of antibody-mediated rejection (AMR) remains high. Donor-specific antibodies (DSAs) were considered the major mediators of allograft loss. Previously, we showed that treatment with 18-kDa translocator protein (TSPO) ligands inhibited the differentiation and effector functions of T cells and reduced the rejection observed after allogeneic skin transplantation in mice. This study we further investigate the effect of TSPO ligands on B cells and DSAs production in the recipients of mixed-AMR model.MethodsIn vitro, we explored the effect of treatment with TSPO ligands on the activation, proliferation, and antibody production of B cells. Further, we established a heart-transplantation mixed-AMR model in rats. This model was treated with the TSPO ligands, FGIN1-27 or Ro5-4864, to investigate the role of ligands in preventing transplant rejection and DSAs production in vivo. As TSPO was the mitochondrial membrane transporters, we then investigated the TSPO ligands effect on mitochondrial-related metabolic ability of B cells as well as expression of downstream proteins.ResultsIn vitro studies, treatment with TSPO ligands inhibited the differentiation of B cells into CD138+CD27+ plasma cells; reduced antibodies, IgG and IgM, secretion of B cells; and suppressed the B cell activation and proliferation. In the mixed-AMR rat model, treatment with FGIN1-27 or Ro5-4864 attenuated DSA-mediated cardiac-allograft injury, prolonged graft survival, and reduced the numbers of B cells, including IgG+ secreting B cells, T cells and macrophages infiltrating in grafts. For the further mechanism exploration, treatment with TSPO ligands inhibited the metabolic ability of B cells by downregulating expression of pyruvate dehydrogenase kinase 1 and proteins in complexes I, II, and IV of the electron transport chain.ConclusionsWe clarified the mechanism of action of TSPO ligands on B-cell functions and provided new ideas and drug targets for the clinical treatment of postoperative AMR.

Basiliximab induction versus no induction in adult heart transplantation.

Induction immunosuppression in heart transplant recipients varies greatly by center. Basiliximab (BAS) is the most commonly used induction immunosuppressant but has not been shown to reduce rejection or improve survival. The objective of this retrospective study was to compare rejection, infection, and mortality within the first 12months following heart transplant in patients who received BAS or no induction. This was a retrospective cohort study of adult heart transplant recipients given BAS or no induction from January 1, 2017 to May 31, 2021. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 12-months post-transplant. Secondary endpoints included ACR at 90days post-transplant, incidence of antibody-mediated rejection (AMR) at 90days and 1year, incidence of infection, and all-cause mortality at 1year. A total of 108 patients received BAS, and 26 patients received no induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the no induction group (27.7 vs. 68.2%, p<.002). BAS was independently associated with a lower probability of having a rejection event during the first 12-months post-transplant (hazard ratio (HR) .285, 95% confidence interval [CI] .142-.571, p<.001). There was no difference in the rate of infection and in mortality after hospital discharge at 1-year post-transplant (6% vs. 0%, p=.20). BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred to a no induction strategy in patients undergoing heart transplantation.

Basiliximab versus Methylprednisolone for Induction in Adult Heart Transplantation

<h3>Purpose</h3> Induction immunosuppression in heart transplant (OHTX) recipients varies greatly by center. Roughly 50% receive induction immunosuppression and no regimen has been shown to improve survival. Basiliximab (BAS) is an IL-2 receptor antagonist used as induction in OHTX. The objective of this retrospective study was to compare rejection, infection, and mortality within the first-year following heart transplant in patients who received BAS or steroid induction. <h3>Methods</h3> This was a retrospective cohort study of adult OHTX recipients given BAS or steroid induction from 1/1/2017 to 5/31/2021. Previous organ transplant or multi-organ transplant patients were excluded. Induction strategy was determined by chart review. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 1 year post-transplant. Secondary endpoints included ACR at 90 days post-transplant, incidence of antibody-mediated rejection (AMR) at 90 days and one year, incidence of infections (CMV, bacterial, fungal), and mortality after discharge at 1 year. <h3>Results</h3> 108 patients received BAS and 26 patients received steroid induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the steroid induction group (27.7 vs 68.2%, p < 0.002). Additionally, BAS was associated with a lower probability of having a rejection event during the first-year post-transplant (figure 1; p < 0.001). There was a statistically significant difference in CMV infections between BAS and steroid induction at 30- and 90-days post-transplant (0 vs 4%, p = 0.04; 0 vs. 8%, p = 0.004) but no difference in bacterial or fungal infections within the first 30 or 90 days. There was no difference in mortality after hospital discharge at one-year post-transplant (6 vs 0%, p = 0.20). <h3>Conclusion</h3> BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred induction strategy for patients undergoing heart transplantation.

Clinical Outcomes of 32 Heart Transplant Recipients Following Treatment of Antibody-Mediated Rejection Treatment: A Single-Center, Descriptive Study

<h3>Purpose</h3> Antibody-mediated rejection (AMR) is a complication following heart transplantation (HT). Improvements in immunosuppression have reduced the incidence of AMR, but management remains challenging. Due to the risks post-transplant, identifying definitive treatment options for the management of AMR is essential to improving patient outcomes. <h3>Methods</h3> We conducted a single-center retrospective review of all HT recipients undergoing AMR treatment from May 2016 to December 2019. The primary outcome was to describe our large institutional experience treating AMR utilizing a variety of treatment approaches. Additional outcomes included the presence of non-HLA antibodies at AMR diagnosis and infection within 90 days following AMR treatment. <h3>Results</h3> A total of 32 patients, with 47 unique AMR episodes, were included in the study. Patients were treated with one of the following treatment strategies: rituximab (RTX) + IVIG + therapeutic plasma exchange (TPE) (n=25), IVIG + TPE (n=14), or a combination of several treatment approaches (n=8). Patient characteristics at the time of initial AMR episode are described in Table 1. Graft function improved across all treatment groups and C4d declined following treatment. Overall infection rates (38%) were low and similar across groups. Patient and graft outcomes are reported in Table 2. <h3>Conclusion</h3> Our findings show an overall improvement in graft function following treatment of AMR. Further studies are warranted to confirm these results and to help identify the optimal treatment approach for this patient population.

Increased Levels of sCD30 Have No Impact on the Incidence of Early ABMR and Long-Term Outcome in Intermediate-Risk Renal Transplant Patients With Preformed DSA.

Background: It is still incompletely understood why some patients with preformed donor-specific anti-HLA antibodies (DSA) have reduced kidney allograft survival secondary to antibody-mediated rejection (ABMR), whereas many DSA-positive patients have favorable long-term outcomes. Elevated levels of soluble CD30 (sCD30) have emerged as a promising biomarker indicating deleterious T-cell help in conjunction with DSA in immunologically high-risk patients. We hypothesized that this would also be true in intermediate-risk patients.Methods: We retrospectively analyzed pre-transplant sera from 287 CDC-crossmatch negative patients treated with basiliximab induction and tacrolimus-based maintenance therapy for the presence of DSA and sCD30. The incidence of ABMR according to the Banff 2019 classification and death-censored allograft survival were determined.Results: During a median follow-up of 7.4 years, allograft survival was significantly lower in DSA-positive as compared to DSA-negative patients (p < 0.001). In DSA-positive patients, most pronounced in those with strong DSA (MFI > 5,000), increased levels of sCD30 were associated with accelerated graft loss compared to patients with low sCD30 (3-year allograft survival 75 vs. 95%). Long-term survival, however, was comparable in DSA-positive patients irrespective of sCD30 status. Likewise, the incidence of early ABMR and lesion score characteristics were comparable between sCD30-positive and sCD30-negative patients with DSA. Finally, increased sCD30 levels were not predictive for early persistence of DSA.Conclusion: Preformed DSA are associated with an increased risk for ABMR and long-term graft loss independent of sCD30 levels in intermediate-risk kidney transplant patients.

Bortezomib alleviates antibody-mediated rejection in kidney transplantation by facilitating Atg5 expression.

Antibody‐mediated rejection (AMR) is one of the most dominant mechanisms responsible for the loss of kidney grafts. Previous researches have shown that donor‐specific antibodies (DSAs) are the major mediators of AMR. In order to prolong the survival time of grafts, it is vital to reduce the incidence of AMR and inhibit the generation of DSAs. We established an animal model of AMR by performing kidney transplantation in pre‐sensitized rats. Then, we investigated the effect of bortezomib (BTZ) on AMR. We found that BTZ could reduce the serum level of DSAs and alleviate post‐transplantation inflammation in peritubular capillaries (PTCs) and glomeruli, which was demonstrated by the reduction of C4d and IgG deposition in PTCs, and the reduced number of B cell and plasma cell in peripheral blood and the transplanted kidney (p < 0.05). Our results also suggested that BTZ increased the number of regulatory T cell (Treg) and significantly reduced the proportion of T helper (Th17) cell (p < 0.05). Besides, BTZ induced the significant upregulation of anti‐inflammatory cytokines but downregulated pro‐inflammatory cytokines (p < 0.05). After dealing with Atg5 siRNA‐lentivirus, the effect of BTZ alleviating AMR was reversed and Th17/Treg proportions were also significantly modulated. Collectively, these findings show that BTZ slows down the process of AMR and Atg5 may be the key mechanism. Furthermore, Atg5 silencing results may be demonstrated that Atg5 alleviated AMR by modulating the ratio of Th17/Treg.

Rituximab Desensitization in Liver Transplant Recipients With Preformed Donor-specific HLA Antibodies: A Japanese Nationwide Survey.

Background.The significance of preformed donor-specific anti-HLA antibodies (DSAs) in liver transplant recipients is controversial. Moreover, there has been no established desensitization protocol for DSA-positive recipients.Methods.A Japanese nationwide survey was performed to investigate the clinical practice among preformed DSA-positive patients with special reference to rituximab desensitization.Results.There was a total of 47 cases, including 2 pediatric cases, in which rituximab (287 ± 159 mg [319 (50–916)/m2]) was administered to desensitize preformed DSA. The decision for the indication of rituximab desensitization was based on a single-antigen assay in the majority of cases (83%, 39/47), and the most frequent protocol was rituximab monotherapy (n = 12) followed by quadruple treatment with rituximab tacrolimus, mycophenolate mofetil, and plasmapheresis (n = 11). The overall 1-, 3-, and 5-y graft and patient survival rates among adult patients were 85%, 83%, 83%, and 81%, 77%, 74%, respectively, while neither graft loss nor death was observed in the 2 pediatric cases. The 1-, 3-, and 12-mo cumulative incidence of antibody-mediated rejection (AMR) was 11%, 13%, and 13%, respectively. The incidence of AMR was significantly higher in the lower rituximab dose group than in the higher rituximab dose group (cutoff 300 mg/m2, 4% versus 24%, P = 0.041). The rate of infusion-related adverse drug reactions (ADRs) was 4.4%, and all ADRs were mild and self-limiting. A total of 99 ADRs among 27 patients were reported, none of which were severe adverse events associated with rituximab.Conclusions.The rituximab induction was well tolerated among DSA-positive liver transplant recipients with a satisfactory outcome. A rituximab dose >300 mg/m2 was observed to achieve less incidence of the development of AMR.

The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes.

Allograft survival of deceased donor kidneys with suboptimal histology (DRTx/suboptimal histology: >10% glomerulosclerosis, >10% tubulointerstitial scarring, or >mild vascular sclerosis) is inferior to both DRTx with optimal histology (DRTx/optimal histology) and living donor kidneys irrespective of histologic changes (LRTx). In this report, we explored the reasons behind this guarded outcome with a special focus on the role of alloimmunity. We initially assessed gene expression in 39 time-zero allograft biopsies using the Nanostring 770 genes PanCancer Immune Profiling Panel. Subsequently, we studied 696 consecutive adult kidney allograft recipients that were grouped according to allograft type and histology at time-zero biopsy [DRTx/suboptimal histology (n = 194), DRTx/optimal histology (n = 166), and LRTx (n = 336)]. Part-1: Several immune pathways were upregulated in time-zero biopsies from DRTx/suboptimal histology (n = 11) compared to LRTx (n = 17) but not to DRTx/optimal histology (n = 11). Part-2: Amongst the three groups of recipients, DRTx/suboptimal histology had the highest incidence of acute rejection episodes, most of which occurred during the first year after transplantation (early rejection). This increase was mainly attributed to T cell mediated rejection, while the incidence of antibody-mediated rejection was similar amongst the three groups. Importantly, early acute T cell mediated rejection was a strong independent predictor for allograft failure in DRTx/suboptimal histology (adjusted HR: 2.13, P = 0.005) but not in DRTx/optimal histology nor in LRTx. Our data highlight an increased baseline immunogenicity in DRTx/suboptimal histology compared to LRTx but not to DRTx/optimal histology. However, our results suggest that donor chronic histologic changes in DRTx may help transfer such increased baseline immunogenicity into clinically relevant acute rejection episodes that have detrimental effects on allograft survival. These findings may provide a rationale for enhanced immunosuppression in recipients of DRTx with baseline chronic histologic changes to minimize subsequent acute rejection and to prolong allograft survival.

Incidence, risk factors, treatment, and consequences of antibody-mediated kidney transplant rejection: A systematic review.

Antibody-mediated rejection (AMR) is a leading cause of kidney allograft failure, but its incidence, risk factors, and outcomes are not well understood. We searched Ovid MEDLINE, Cochrane, EMBASE, and Scopus from January 2000 to January 2020 to identify published cohorts of ≥500 incident adult or 75 pediatric kidney transplant recipients followed for ≥1year post-transplant. At least two reviewers screened 5061 articles and abstracts; 28 met inclusion criteria. Incidence of acute AMR was 1.1%-21.5%; most studies reported 3%-12% incidence, usually within the first year post-transplant. Few studies reported chronic AMR incidence, from 7.5%-20.1% up to 10 years. Almost all patients with acute or chronic AMR received corticosteroids and intravenous immunoglobulin; most received plasmapheresis, and approximately half with rituximab. Most studies examining death-censored graft failure identified AMR as an independent risk factor. Few reported refractory AMR rates or outcomes, and none examined costs. Most studies were single-center and varied greatly in design. Cohort studies of kidney transplant recipients demonstrate that AMR is common and associated with increased risk of death-censored graft failure, but studies vary widely regarding populations, definitions, and reported incidence. Gaps remain in our understanding of refractory AMR, its costs, and resulting quality of life.

Discordance between immunofluorescence and immunohistochemistry C4d staining and outcomes following heart transplantation.

Capillary deposition of C4d is an important marker of antibody-mediated rejection (AMR) following heart transplantation (HT). There are two immunopathologic assay methods for detecting C4d: frozen-tissue immunofluorescence (IF) and paraffin immunohistochemistry (IHC). The clinical significance of discrepancy between the results of IF and IHC has not been understood. We reviewed 2187 biopsies from 142 HT recipients who had biopsies with assessment of both IF and IHC staining. Among them, 103 (73%) patients had negative IF and IHC C4d staining (Negative Group) and 32 (23%) patients had positive IF but negative IHC staining (Discordant Group). At the time of positive biopsy, 6 (19%) Discordant patients had graft dysfunction, compared to 5 (5%) Negative patients (p=.022). Cumulative incidence of cellular rejection at 1year was comparable (31% vs. 29%, p=.46); however, cumulative incidence of AMR was significantly higher in the Discordant group (21% vs. 4%, p=.004). Overall 1-year survival was comparable (90% vs. 96%, p=.24); however, freedom from heart failure (HF) was significantly lower in the Discordant group (70% vs. 96%, p<.001). The Discordant group showed higher rates of graft dysfunction, AMR and HF admission than the Negative group.

ABO-Incompatible Living-Donor Kidney Transplantation in a Developing Country: A Multicenter Experience in Malaysia

Malaysia has a low deceased-donor donation rate and has not embarked on a paired kidney exchange program; therefore, ABO-incompatible and HLA-incompatible transplantation remain the main contributor to the sustainability of the national kidney transplantation (KT) program. There were 26 cases of ABO-incompatible KTs performed from 2011 to 2018 in 3 major transplant centers, namely, Hospital Kuala Lumpur, University Malaya Medical Centre, and Prince Court Medical Centre. We collected perioperative and follow-up data through June 2019. The desensitization protocol varies and is center specific: the localized Japanese protocol and Swedish protocol with a target anti-A/B isoagglutinin titer of 16 or 32 on the day of transplant. The induction and tacrolimus-based maintenance protocol was nearly identical. The median follow-up time was 62.3 months (interquartile range, 37.0-79.7). Fifteen subjects had the highest predesensitization anti-A/B titer of ≥32 (57.7%). The acute cellular rejection and antibody-mediated rejection incidence were 12.5% (3 cases) and 8.3% (2 cases), respectively. Patient, graft, and death-censored graft survival rates were 96.2%, 92.3%, and 96.0%, respectively, 1 year post-living-donor KT (LDKT) and 96.2%, 87.2%, and 90.7%, respectively, 5 years post-LDKT. Our experience shows that ABO-incompatible LDKT using a suitable desensitization technique could be a safe and feasible choice for LDKT even with varied desensitization regimens for recipients with relatively high baseline isoagglutinin titers.

Abstract 15646: Pathological Assessment of Primary Graft Dysfunction Does Not Suggest a Prominent Role for an Adaptive Immune Response

Introduction: Primary graft dysfunction (PGD) is a major cause of mortality following heart transplant (HT). Pathological characteristics of PGD have not been well characterized. We sought to describe the clinical and pathological characteristics of patients who died or were re-transplanted due to PGD. Methods: We identified a cohort of 161 HT recipients between 3/7/2012 to 12/31/17 who developed PGD. Of these, 40 patients had severe PGD, and 16 died in the first month post-transplant. Autopsy or explant pathology was available in 6 patients, which was compared to pathology from the first endomyocardial biopsy in 24 patients with severe PGD that survived. Results: Of the 6 patients for whom pathology was available, mean age was 54, four were male and five were white. Half had non-ischemic dilated cardiomyopathy. Two were sensitized. Five patients had severe PGD and one patient had moderate PGD. There were five deaths and one re-transplant. On pathologic examination, most patients (4/6) had broad areas of myocardial necrosis with diffuse vascular thrombosis. Two patients had focal areas of myocardial necrosis. In no cases was there evidence of cellular rejection (ACR) or antibody-mediated rejection (AMR). In the 24 survivors of severe PGD, median age was 54 , twenty were male and half were white. Five were sensitized. On pathologic examination, ischemic changes were found in 10 patients (42%). While there was no significant ACR, 7/24 (30%) of cases showed evidence of either AMR 1 or AMR 2. Conclusions: In patients succumbing to moderate or severe PGD, PGD was associated with diffuse myocardial necrosis and vascular thrombi. In survivors of severe PGD, the most prominent finding was diffuse ischemic changes on routine heart biopsy. In both, there was no evidence of cellular rejection, however there was significant incidence of AMR, possibly induced by ischemic changes. These findings suggest that severe PGD may have an ischemic component characterized by vascular thrombosis.

HLA Matching in Cardiac Transplantation - Impact on Cardiac Allograft Vasculopathy, Rejection and Donor Specific Antibodies

Introduction HLA matching is not current practice in heart transplant (HT) donor allocation due to scarcity of donor organs and ischemic time. However HLA mismatch might adversely affect transplant outcomes. Even if HLA matching is not possible the degree of HLA mismatch might help inform clinicians on a patients risk for long term transplant complications. Hypothesis We hypothesize that the degree of HLA mismatch affects long-term complications in a stable HT cohort. Methods 65 clinically stable HT recipients (no cellular (ACR) or antibody mediated rejection (AMR) in the preceding 6 months) ≥ 2 years post transplant were enrolled. Serologic HLA typing was obtained for donor and recipients (D/R) pairs and the number of matches was analyzed combined for HLA class I and HLA II. Study endpoints were donor specific antibody (DSA) formation and significant cardiac allograft vasculopathy (CAV). Results HLA-A,-B,-C, -DR and-DQ (ABCDRQ) typing were available for 37 D/R pairs and were analyzed for matches. Additionally, 53 D/R pairs had HLA-A,-B, -DR (ABDR) typing. Meantime post HT was 8.5±5.4 years. A total of 28 patients had CAV and 9 patients had DSA. Among the ABCDRDQ cohort the number of matches was 1.54 ± 1.17 and 1.00 (0.00-1.00) in the ABDR cohort. There were no differences in the number of HLA matches for both cohorts among those with and without DSA and those with and without CAV (Table).However among the ABCDRDQ cohort there was a trend towards higher number of HLA matches in those without DSA 1.63 ± 1.19 versus 1.14 ± 1.07 in the DSA group (p 0.32), this was likely limited by the small sample size.There was no significant relationship between total HLA matches and number of ACR episodes (p 0.89). The incidence of AMR was too low for analysis. Conclusion In this highly selected cohort of clinically stable long time transplant survivors the degree of serological HLA matching was not associated with the development of CAV or ACR. However, there was a trend towards less DSA formation in those with more D/R HLA matches. Future longitudinal studies should evaluate the development of long-term complications as a function of HLA matching and potentially incorporate HLA mismatch as an indicator for the need of enhanced clinical surveillance.

P1639DEVELOPMENT OF SELF-LIMITED LOW-LEVEL BK VIREMIA/VIRURIA SUGGESTS IDEAL IMMUNOSUPPRESSION TO SUPPRESS T-CELL AND ANTIBODY-MEDIATED REJECTION AND PRESERVE KIDNEY ALLOGRAFT FUNCTION

Abstract Background and Aims Polyomavirus BK (BKV) viremia has been suggested as a surrogate marker of overimmunosuppression. Due to recent advances in monitoring strategies and pre-emptive therapy, progression to BKV-associated nephropathy (BKVN) has been reduced. Reduction of maintenance immunosuppression during BKVN, however, has been associated with both T-cell mediated rejection (TCMR), antibody-mediated rejection (ABMR), and inferior kidney allograft outcomes. Although the administration of intravenous immunoglobulins (IVIG) failed to treat BKVN, IVIG may have properties to reduce allosensitization. Method We studied 860 kidney transplant recipients (KTRs) predominantly under tacrolimus-based triple-drug maintenance immunosuppression from 2009 to 2018. We identified 130 KTRs (15.1%) with high-level BK viremia &amp;gt;10,000 copies/mL (presumptive BKVN), 180 KTRs (20.9%) with low-level BK viremia &amp;lt;10,000 copies/mL, 85 KTRs (9.9%) with isolated BK viruria, and 465 KTRs (54.1%) with no BK viruria/viremia. Kidney allograft outcomes with respect to TCMR, ABMR, development of de novo donor-specific antibodies (DSA), kidney allograft survival, and estimated glomerular filtration rate (eGFR) slope were analysed. Due to the increased incidence of TCMR and ABMR among KTRs with presumptive BKVN, 48 of 130 KTRs (36.9%) with high-level BK viremia starting from 2015 received IVIG (0.5 g/kg of body weight) on a biweekly basis during BKV replication. Results Very interestingly, KTRs with low-level BK viremia/viruria showed a significantly lower incidence of TCMR compared to KTRs with no BK viremia/viruria and KTRs with high-level BK viremia (p&amp;lt;0.05). In addition, KTRs with low-level BK viremia/viruria showed a significantly lower incidence of ABMR compared to KTRs with high-level BK viremia (p&amp;lt;0.05). No differences were observed with respect to the development of de novo DSA (MFI&amp;gt;5000) between KTRs with low-level BK viremia/viruria, KTRs with no BK viremia/viruria, and KTRs with high-level BK viremia (p&amp;gt;0.05). KTRs with low-level BK viremia/viruria showed superior kidney allograft survival and lower eGFR slope compared to KTRs with no BK viremia/viruria and KTRs with high-level BK viremia (p&amp;lt;0.05). The administration of IVIG during high-level BK viremia didn’t impact the development of TCMR, ABMR, development of de novo DSA, eGFR slope, and kidney allograft survival (p&amp;lt;0.05). Conclusion Our results show that low-level BK viremia/viruria is associated with suppression of TCMR and ABMR in the early period posttransplantation, and preservation of kidney allograft function in the long-term. The administration of IVIG didn’t prove beneficial to reduce allosensitization among KTRs with high-level BK viremia.

Outcomes of Heart Transplant in a Sensitized Latin American Population

The presence of preformed antibodies (Ab) in heart transplant (HTx) candidates increase mortality while in the waiting list, and also graft rejection risk and post transplant mortality during short and long term follow-up. The purpose was to analyze the prevalence of sensitized patients (Sp) with positive panel-reactive antibody-PRA (+)-in a HTx p population at a single center, and its association with antibody-mediated rejection (AMR), development of coronary artery vasculopathy (CAV) and mortality. All p with PRA (+) ≥10% were considered as Sp and their typification was evaluated. Up to 2012, the method of analysis used was cytotoxicity and afterwards the solid phase method (Luminex®). The organ allocation for all Sp was performed by prospective cross match after September 2015. Continuous variables were expressed by mean and standard or median deviation, and interquartile range and categorical variables, by absolute values and percentages. Survival was analyzed with Kaplan Meier method and compared with Long Rank test. A value of p< 0.05 was considered statistically significant. Retrospective analysis of 538 p assesed for HTx between January 2008 to December 2018.; 292 p (54%) underwent HTx. Patients ≤18 years old, combined HTx and retransplant were excluded. The population was 250 p; 182 (73%) were men; age 49± 13 years, 120 p (48%) were in A and B emergency status (UNOS Stage 1 and 2). The prevalence of Sp was 6% (14p): Ab anti-HLA Class I 64 % (9p) and Class II 43% (6p). PRA (+) ≥80% was detected in 1p and PRA (+) ≥50 in 4 p. Induction treatment: corticosteroids, 14 p (100%); thymoglobulin, 6 p (43%) and plasmapheresis, 7 p (50%). Table 1 shows the incidence of AMR, ACR, CAV and inhospital mortality during follow up. Survival was not statistically significant at 1 and 5 years (p=08). In the population analyzed, the presence of sensitization was associated with higher AMR and CAV, but not with a statistically significant increase in mortality.