Persistent Donor-specific Antibodies Research Articles

Clinical predictors for restrictive allograft syndrome: a nested case-control study.

Risk factors for restrictive allograft syndrome (RAS), a severe phenotype of chronic lung allograft dysfunction after lung transplantation, are currently not well known. In this retrospective nested case-control-study, we analyzed 69 RAS patients and 69 matched non-CLAD controls to identify clinical risk factors for RAS. RAS patients demonstrated overall higher blood eosinophils (p=0.02), increased bronchoalveolar eosinophils (p<0.001) and lymphocytes (p=0.03), and a higher incidence of infections, particularly Pseudomonas (p=0.003), invasive fungal disease (p<0.001, mainly Aspergillus species), SARS-CoV-2 (p<0.001) and CMV (p=0.04), compared to non-CLAD controls. Anti-HLA antibodies, especially persistent donor-specific antibodies (p<0.001), especially targeting HLA-DQ and HLA-DR loci, and antibody-mediated rejection (p<0.001), were strongly associated with later RAS. Histopathological lung injury patterns on transbronchial biopsy (p<0.001), and persistent chest CT opacities in absence of pulmonary dysfunction (p<0.001) were identified as early indicators of later RAS. Proactive detection and management of these risk factors could help mitigate future decline in allograft function, and reduce progression to clinical RAS. Future studies should explore early treatment strategies targeting these modifiable factors to preserve allograft function and improve long-term outcomes for lung transplant recipients.

Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation.

Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host's humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.

Clinical significance of low pre-transplant donor specific antibodies (DSA) in living donor kidney recipients with negative complement-dependent cytotoxicity crossmatches (CDCXM), and negative flow cytometry crossmatches (FLXM) – A single-center experience

BackgroundIt is controversial whether all donor-specific antibodies (DSA) detected by the solid-phase single antigen bead (SAB) assay negatively affect kidney transplantation outcomes. The study aimed to evaluate the possible clinical significance of low pre-transplant DSA in living donor kidney recipients. We analyzed a group of patients with HLA-A, B, and -DR DSA reactivities below a virtual crossmatch (VXM) value of 5000 MFI but with all VXM DSA reactivities at HLA-DQ, -DP, and -Cw, which were not typed routinely for donors prior to transplantation. We also investigated the incidence of persistent and de novo DSAs in available posttransplant SAB assays. MethodsFrom the historical cohort of living donor recipients transplanted between 2014 and 2018 at our center (n = 82), 55 patients met the inclusion criteria, namely: these patients were > 18 years old with non-HLA identical sibling donors, who were not desensitized, who had available pre-transplant SAB results, and who had negative both complement-dependent cytotoxicity crossmatch (CDCXM) and flow cytometry crossmatch (FLXM) results. An additional donor HLA typing, performed for all 55 recipients, identified donor additional HLA-DQ, -DP, and -Cw DSA reactivities. These patients were then divided by SAB reactivity into three groups: 1) those with DSA-positive reactivities; 2) those with non-donor-specific anti-HLA reactivities (NDSA); and, 3) those who were anti-HLA-negative. All these recipients were followed for three years and checked for their de novo or persistent DSA. ResultsIn the studied cohort, DSA-positive, NDSA reactive, and anti-HLA negative recipients constituted 33%, 36%, and 31% of 55 patients, respectively. Non-routinely considered pre-transplant HLA-DQ, -DP, and -Cw DSA-positive reactivities were shown in as many as 78% of DSA-positive cases (group 1) with the lowest MFI value of 319 to DP4 and the highest MFI of 5767 to DQ2. Of the pre-transplant HLA-A, B, and -DR DSA reactivities, only -DR52 DSA reactivity reached the highest MFI value of 2191. These detected DSAs did not reduce the mean estimated glomerular filtration rate (eGFR) values and did not increase the incidence of proteinuria in recipients. While the 3-year graft survival was lower in the DSA-positive group (94.4%) with one recipient who lost kidney transplant, the difference was not significantly different (p = 0.7) from the NDSA (100%) and negative (100%) groups. In terms of the incidence of de novo acute antibody-mediated rejection (AMR) at three years after transplantation, no case has been reported in the cohort. This may suggest that low DSA-positive recipients do not experience higher rejection rate. However, DSA-positive recipients had a tendency for a higher frequency of C4d deposits in peritubular capillaries (PTC) and de novo DSA. ConclusionOur 3-year follow-up of patients with low pre-transplant DSA found no association with a deterioration in graft function and worse graft survival. Furthermore, we did not observe an increase in AMR in our patients with low DSA. A larger cohort and a longer follow-up period may be needed to evaluate the tendency of low DSA-positive recipients towards the higher incidence of C4d deposits in PTC and/or de novo DSA.

Challenges of Treating Late Onset Severe Antibody Mediated Rejection Post Orthotopic Heart Transplant

<h3>Introduction</h3> Outcomes of severe antibody mediated rejection (AMR) post orthotopic heart transplant (OHT) are often poor & management a challenge. <h3>Case Report</h3> A 50-year-old multiparous female with stable donor specific antibodies (DSAs) presented with cardiogenic shock (CS) & severe left ventricular (LV) dysfunction 4 years post OHT. Maintenance immunosuppressants (IS) included tacrolimus, mycophenolate & prednisolone with good adherence. Urgent endomyocardial biopsy (EMB), coronary angiogram & right heart catheterisation were performed. Progression to SCAI Stage D shock necessitated venoarterial extracorporeal membrane oxygenation (VA ECMO) within 24 hrs. Based on clinical presentation, the patient was treated with methylprednisolone, intravenous immunoglobulin (IVIG) & IV thymoglobulin alongside hemodynamic & other organ support (dialysis, ventilation). EMB confirmed pAMR3 fulfilling criteria for severe AMR together with CS & raised DSAs. Within days the patient's cardiac output improved allowing removal of VA ECMO. Following MDT consensus given persistent graft dysfunction & DSAs an AMR specific regimen of plasmapheresis, IVIG & rituximab were administered resulting in significant improvement in LV function & DSAs. A serious consequence of high dose IS was severe CMV reactivation (CMV peak 18,000 copies/ml). Successful treatment with IV ganciclovir caused leukopenia requiring mycophenolate cessation. Fortunately our patient survived to discharge day 152 post admission with graft recovery & excellent functional capacity. Ongoing management remains a challenge due to severe CAV & balancing risks associated with high dose IS with AMR recurrence. <h3>Summary</h3> This case highlights the importance of urgent evaluation including EMB, hemodynamic support & targeted anti-rejection therapy in patients post OHT with severe allograft dysfunction. It exemplifies challenges when treating severe AMR illustrating the importance of a collaborative team approach for successful outcomes.

A virtual crossmatch-based strategy for perioperative desensitisation in lung transplant recipients with pre-formed donor-specific antibodies: 3-year outcome.

Pre-formed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch Hospital (Suresnes, France). We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity and those with low or no pre-formed DSAs, not desensitised. For all consecutive LTx recipients (January 2012 to March 2018), freedom from chronic lung allograft dysfunction (CLAD) and graft survival were assessed using Kaplan-Meier analysis and Cox multivariate analysis. We compared outcomes for desensitised patients with high pre-formed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3 and 6 months post-LTx (p<0.001, p<0.01 and p<0.001, respectively). Freedom from CLAD and graft survival at 3 years was similar in the desensitised group as a whole and other groups. Nevertheless, incidence of CLAD was higher with persistent high-level DSAs than cleared high-level (p=0.044) or no DSAs (p=0.014). Conversely, graft survival was better with cleared high DSAs than persistent high-level, low-level and no pre-formed DSAs (p=0.019, p=0.025 and p=0.044, respectively). On multivariate analysis, graft survival was associated with cleared high DSAs (hazard ratio 0.12, 95% CI 0.02-0.85 versus no DSAs; p=0.035) and CLAD with persistent DSAs (3.04, 1.02-9.17 versus no pre-formed DSAs; p=0.048). The desensitisation protocol in LTx recipients with high pre-formed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.

Imlifidase as a Potential Treatment for Antibody-Mediated Rejection

Antibody-mediated rejection (ABMR) is implicated as the leading cause of late kidney allograft failure. Current therapies inadequately control the antibody response and persistent donor-specific antibodies lead to chronic ABMR and allograft failure. Imlifidase is an IgG endopeptidase derived from Streptococcus pyogenes that cleaves human IgG into F(ab’)2 and Fc fragments, thereby protecting against complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Favorable outcomes with its use for desensitization in HLA-incompatible kidney transplantation have engendered interest in its use for ABMR. The experiences with imlifidase for a variety of antibody-mediated diseases, including anti-glomerular basement membrane disease, thrombotic thrombocytopenic purpura, and desensitization in HLA-incompatible kidney transplantation, are reviewed to provide a rationale for using imlifidase to treat ABMR in kidney transplantation. Imlifidase is currently being evaluated in comparison to plasmapheresis in a clinical trial and is a potential therapy for ABMR in kidney transplantation.

The Effects of Donor-Specific Antibody Characteristics on Cardiac Allograft Vasculopathy

Purpose Cardiac allograft vasculopathy (CAV) is a major cause of late graft dysfunction and mortality after heart transplantation. The pathophysiology of CAV consists of a complex interplay between donor risk factors, recipient comorbidities, and immune-mediated processes. Despite many studies showing a correlation between donor-specific antibodies (DSA) and CAV, the effects of different DSA types on the severity of CAV remains elusive. This study investigates the characteristics of DSA amongst different CAV severity groups. Methods We evaluated 526 adult heart transplant recipients at a single tertiary medical center between January 2010 and August 2015. Subjects were screened for DSA at the time of transplant, 1 month, 3 months, 6 months, 1 year, and then annually thereafter. CAV screening was performed with annual angiography. Subjects were divided into those with DSA (n= 143) and those without DSA (control group, n =383). Subjects with DSA were further categorized into those with persistent DSA (n=34), transient DSA (n=106), 1:8 dilution positive DSA (n=45), complement-binding (C1q) DSA (n=36), Class I DSA (n=36), and Class II DSA (n=106). The mean duration of follow up was 3.6 years. The outcomes are the incidence of CAV based on the ISHLT grading scale. Results Subjects with persistent DSA were found to have higher incidence of moderate-to-severe CAV (CAV2/3) compared the control group (p= Subjects with 1:8 dilution positive DSA and C1q positive DSA also had a higher incidence of CAV2/3 when compared those without DSA (p=0.001, p= Conclusion DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. Given CAV2/3 is linked with higher mortality post-transplantation, these DSA characteristics may serve as prognostic markers of disease and may warrant consideration for treatment.

Role of Memory B Cells in Antibody Mediated Rejection: A Proof of Concept

<h3>Introduction</h3> Antibody mediated rejection (AMR) diagnosis, monitoring and treatment is exclusively based on circulating donor specific antibodies (DSA). However, DSA often fails to predict and diagnose AMR, since it does not represent the whole HLA-specific memory B cell (mBc) repertoire. Central and peripheral donor (HLA)-sp B-cell responses may offer a new diagnostic and therapeutic target. <h3>Case Report</h3> 44 years old female affected from an advanced Chagasic cardiomyopathy refractory to therapy was listed for heart transplant with a PRA of 67% in 03/2019. She was transplanted in 11/2019, with a negative CDC-XM. Induction was based on basiliximab and tacrolimus-based triple therapy with Mycophenolate mofetil and steroids. Despite a negative CDC-XM, 5 C3q-fixing DSA were detected (A3, DR1, DR7, DPB1, DQ2 and DQ5). Post-op was uneventful and biventricular function was preserved at day 7. The 14-day endomyocardial biopsy showed acute cellular rejection G2R and p(AMR)1 i+ with persistent DSAs. High doses of esteroids, IVIG and plasmapheresis were started. The SAB assay on day 25 showed persistent detection of all DSA, although with lower MFI levels. To characterize B-cell immune response, we used a novel HLA-specific B-cell FluorSpot assay. Bone marrow aspirate and peripheral blood demonstrated high frequencies of donor(HLA)-sp IgG-producing plasma cells and circulating donor-specific mBc, respectively, against different donor(HLA)-Ag specificities <b>(figure 1)</b>. Given patient's favorable evolution, with two main immune compartments showing anti-donor B-cell activation requiring a combined immunosuppressive therapy, no additional treatment was started. At 12 months of follow-up the patient remains clinically stable with negative ACR/pAMR EMB. <h3>Summary</h3> Our data highlights the need of a more accurate evaluation of the anti-donor humoral immune response leading to DSA production in order to refine current immune-risk stratification and ultimately help decision-making regarding the type of rescue immunosuppressive therapy.

Management of Antibody Mediated Rejection (AMR) in Heart Transplant Patients: The Real World in a French Single Center Treating All Pathological AMR

<h3>Purpose</h3> There is no consensus for the treatment of antibody mediated rejection (AMR) in heart transplant patients (HTP), only expert recommendation with a grey zone in patients without graft dysfunction. The purpose of the study was to report our AMR management since we perform routine screening of donor-specific antibodies (DSA) with EMB in case of positive DSA and treat AMR irrespective of graft dysfunction, severity of AMR or presence of DSA. <h3>Methods</h3> We retrospectively reviewed HTP between 2011 and 2019 and studied patients with AMR defined only on endomyocardial biopsy (EMB) according to the latest ISHLT criteria. <h3>Results</h3> A total of 15 patients developed AMR (5 patients with pAMR 1 and 10 with pAMR2) (Figure1), followed for a mean of 4.6 years; 3 patients (20%) had a graft dysfunction (EF<40%) and 3 (20%) did not have circulating DSA. All patients received intravenous steroids, plasmapheresis (5 to7 sessions only for DSA+ patients) IVig for 2 days and rituximab. The 7 more recent patients had additional IVig therapy (high-dose regimen) for 6 weeks and 5 patients received bortezomib. At the end of the treatment, 12 patients (60%) had normal EMB, 6 patients (50%) had persistent DSA with MFI>5000, 1 patient had persistent graft dysfunction and 80% were alive (Figure1). <h3>Conclusion</h3> despite a short follow up, our experience is encouraging to treat aggressively all pathological AMR irrespective of graft dysfunction or presence of DSA to prevent graft dysfunction and poor outcomes.

Lung Transplantation Outcomes after Crossing Low Level Donor Specific Antibodies without Augmented Immunosuppression

<h3>Purpose</h3> Lung transplant recipients with pre-transplant donor specific antibodies (DSA) are often treated with augmented immunosuppression. It is unknown whether some DSA can be safely crossed without additional therapies. We implemented a protocol allowing transplant when crossing select low level DSA (defined as mean fluorescence intensity (MFI) 1000-5000) without planned augmented immunosuppression. <h3>Methods</h3> This was a single center retrospective cohort study between 4/1/2015-8/31/2020. All recipients received solumedrol and basiliximab induction without desensitization. Presence of low level pre-transplant DSA was recorded. All post-transplant DSA was monitored within 14 days of transplant and then at routine intervals. The primary study outcomes were overall survival, definite CLAD≥1-free survival, and definite antibody mediated rejection (AMR), all defined according to ISHLT consensus guidelines. <h3>Results</h3> Of the 453 recipients, 36 (7.9%) had a low-level pre-transplant DSA crossed at transplant (Table 1). 13 had Class I antibodies and 26 had Class II. The median historical DSA MFI was 1800 (IQR 1300-2400) and the median most recent MFI was 1200 (IQR 950-2000). Among recipients where pre-transplant DSA was crossed, 17 (47.2%) had persistent post-transplant DSA with a median peak MFI of 7400. Class II antibodies were more likely to be detected post-transplant than Class I (57.7% vs 15.4%, p=0.02). There was no statistical difference in definite AMR in recipients where pre-transplant DSA was and was not crossed (8.3% vs 3.1%, p=0.11). With a median follow-up time of 2.4 years, there were no differences in adjusted overall survival (HR=1.14, 95% CI=0.57-2.32, p=0.71) or CLAD≥1-free survival (HR=0.82, 95% CI=0.44-1.54, p=0.54). <h3>Conclusion</h3> Lung transplantation in the presence of low level DSA without planned augmented immunosuppression was not associated with worse overall or CLAD-free intermediate-term survival but may be associated with increased AMR.

Chronic Active Antibody-Mediated Rejection Following COVID-19 Infection in a Kidney Transplant Recipient: A Case Report

Kidney transplant recipients who develop coronavirus disease 2019 (COVID-19) are at increased risk of life-threatening illness, which often requires reducing immunosuppression despite the potential risk of causing an allograft rejection. Herein, we describe the clinical presentation and course of a kidney transplant recipient who acquired COVID-19 and was hospitalized with severe symptoms and hypoxemia. Upon admission, the patient was found to have elevated de novo donor-specific antibodies (DSA) yielding a positive cytotoxicity crossmatch and concurrent elevated plasma donor-derived cell-free DNA (dd-cfDNA) level, indicating a possible ongoing rejection despite improvement in his serum creatinine. Because of persistent positive COVID-19 tests and stable serum creatinine, a kidney allograft biopsy was initially deferred and his dd-cfDNA and DSA were monitored closely postdischarge. Three months later, because of persistent elevated dd-cfDNA and positive DSA, a kidney allograft biopsy was performed, which showed chronic active antibody-mediated rejection. Accordingly, the patient was treated with intravenous immunoglobulin and his maintenance immunosuppressive regimen was increased.

Long-term survival of the transplanted kidney and the clinical relevance of donor-specific antibodies

The aim of our study was to evaluate the relevance of donor-specific antibodies (DSA) as defined by solid-phase single-antigen (SA) assays for predicting long-term graft survival after kidney transplantation. Sera from 132 kidney transplant recipients were retrospectively tested before, 3, 6 and 12 months after transplantation. The incidence of rejection and graft survival was followed up for 7 years. We found 29 episodes of acute cellular rejection (CR), 21 cases of antibody-mediated rejection (AMR) and 18 graft failures due to immunological reasons. Pre-transplant DSA and DSA three months after transplantation correlated with an increased rate of AMR and impaired graft function. After the fourth year, recipients with persistent DSA were at a higher risk of graft failure (p = 0.0317). Antibody specificity was prevailingly to HLA class I antigens (66.6% DSA, 75% non-DSA). During the first year after transplantation, the number of patients with non-DSA decreased (30.3% to 10.7%), while, due to de novo production of antibodies, the number of DSA positive patients remained constant. Conclusion: Detection of antibodies to HLA antigens using solid-phase assays, especially single-antigen bead technology before and three months after transplantation is predictive for increased incidence of antibody-mediated rejection and impaired long-term kidney graft survival.

Long-term outcomes and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation: a prospective study in a pilot cohort.

the presence of donor-specific antibodies (DSA) is thought to affect survival of the allograft and patient after liver transplantation (LT). However, their significance is not well understood. a prospective study was performed of 32 adult patients who underwent LT in 2011 to analyze the existence of DSA, associated risk factors and medium-term impact. Immunological determinations were performed immediately before LT and at three, six, 12 months and five years after LT. eight patients (24.2 %) presented pre-formed DSA. However, titers were negative in all patients five years after LT and there were no associated events. Eight out of 24 patients (33.3 %) developed de novo DSA. After five years, only two remained positive; both were class II with high mean fluorescence intensity (MFI) values at diagnosis (over 15,000). No association was found between the development of DSA and the risk of rejection, graft loss or death. However, an increase in liver stiffness values was observed in patients with persistent DSA, and focal sinusoidal deposition of C4d and moderate liver fibrosis were reported. the incidence of DSA is high after LT. In addition, the persistence of de novo DSA could be associated with silent liver fibrosis with a potential impact on graft outcomes.

The clinical impact of donor-specific antibodies on antibody-mediated rejection and long-term prognosis after heart transplantation.

Outcomes after cardiac transplantation have improved over past decades, but long-term graft survival remains limited in part because of uncertainty regarding clinical implications of donor-specific antibodies (DSAs). The purpose of this review is to consolidate recent advances in knowledge on the topic of DSA and their potential to impact long-term prognosis after heart transplantation. The presence of persistent DSA increases the risk of poor outcome after heart transplantation, including development of antibody-mediated rejection (AMR), graft failure, cardiac allograft vasculopathy, and mortality. Importantly, different DSA vary in clinical significance. DSA capable of activating the complement cascade portend a higher risk of developing AMR. human leukocyte antigen class I and class II antigens are expressed differently within the heart, and so, clinical manifestations of class I and class II DSA vary accordingly. Further, compared with class I, class II DSA carry an increased risk of graft loss and mortality. When comparing preexisting DSA with formation of de-novo DSA, de-novo DSA are associated with worse outcome. DSAs are generally associated worse long-term prognosis after heart transplantation but vary in their clinical significance. Recognition of specific risk profiles is essential for guiding posttransplant antibody management.

Increased Hazard of Chronic Lung Allograft Dysfunction in the Presence of Persistent and Complement Fixing Donor-Specific Antibodies

Purpose Long-term survival in lung transplant recipients (LTR) is limited in large part due to chronic lung allograft dysfunction (CLAD). Donor-specific antibodies (DSA) have been previously associated with more rapid high-grade rejection and mortality. Characteristics of these DSA may predict which antibodies are more harmful than others. The purpose of this investigation was to determine if C1q+ DSA is associated with increased CLAD in LTRs versus no DSA and C1q- DSA. Methods This was a single-center, retrospective cohort study of adult LTRs. Clinical data was extracted from the electronic medical record and laboratory systems. Patients were tested by Luminex Single Antigen Bead (SAB) IgG and C1q. IgG-SAB MFI > 1000 and C1q-SAB MFI > 500 were considered positive. DSA that were positive at more than one time point were classified as persistent, while those that were not were considered transient. Patients were grouped as no DSA, C1q- DSA, or C1q+ DSA. The primary outcome was CLAD. Secondary outcomes included CLAD subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Outcomes were assessed using Kaplan-Meier methods and multivariable Cox regression with a time-dependent covariate. Results 582 LTRs were analyzed. 335 (57.6%) had no DSA, 194 (33.3%) were DSA+ C1q-, and 53 (9.1%) were DSA+ C1q+. Of 247 LTRs who developed any DSA, Class II DSA (206 LTRs, 84%) were more common than Class I DSA (106, 43%), including those with both classes. 177 LTRs (72%) had persistent DSA, including all 53 with C1q+ DSA . There was no difference in time to CLAD for any DSA vs no DSA (p=0.26). Patients with persistent DSA had shorter time to CLAD vs no DSA and transient DSA (p=0.04) and trended towards significance on multivariable assessment (HR: 1.70 95%CI: 1.00-2.92, p=0.05). DSA+ Cq1+ had shorter time to CLAD vs no DSA and DSA+ C1q- (p Conclusion Persistent DSA were associated with shorter time to CLAD. C1q+ DSA were associated with increased hazard of CLAD, BOS, and RAS. Larger cohorts are needed to evaluate other clinical outcomes.

Effect of recipient gender and donor-specific antibodies on antibody-mediated rejection after heart transplantation.

Gender-difference regarding antibody-mediated rejection (AMR) after heart transplantation has been described. However, no study accounted for the presence of preformed donor-specific antibodies (pfDSA), a known risk factor of AMR, more common among women than men. In a single-institution 6-year cohort (2010-2015), time to AMR was assessed, comparing men with women by survival analysis with a 1-year death-censored follow-up. All AMRs were biopsy proven. Confounding variables that were accounted for included mean intensity fluorescence (MFI) of pfDSA, recipient age, HLA-, size- and sex-mismatch. 463 patients were included. Overall incidence of AMR was 10.3% at 1year. After adjusting for confounding variables, independent risk factors of AMR were female recipient gender (adjusted hazard-ratio [adj. HR]=1.78 [1.06-2.99]), P=.03) and the presence of pfDSA (adj. HR=3.20 [1.80-5.70], P<.001). This association remained significant when considering pfDSA by their MFI; female recipient gender had an adj. HR=2.2 (P=.026) and MFI of pfDSA (per 1 MFI-increase) adj. HR=1.0002 (P<.0001). In this cohort, women were at higher risk of AMR than men and this risk increase was additive to that of pfDSA. These findings may suggest a gender-related difference in the severity of pfDSA.

Impact of persistent and cleared preformed HLA DSA on kidney transplant outcomes

Preformed HLA donor-specific antibodies (DSA) only detected with Luminex have been associated with increased risk of antibody-mediated rejection (ABMR) and graft failure after kidney transplantation (KT). Their evolution after KT may modify this risk. We analyzed postransplant evolution of preformed DSA identified retrospectively and their impact on outcomes of 370 KT performed 2006–2014. Antibodies were monitored prospectively at 1-3-5 years after KT and if any dysfunction. Early acute ABMR was more frequent among patients with preformed DSA class-I or I + II than isolated class-II (29.4% vs 4.5%, p = 0.02). One year post-KT, 20 of 34 patients with functioning KT had persistent DSA. Preformed DSA class-II persisted more frequently than class-I/I + II (66.7% vs 33.3%; p = 0.031). The only risk factor independently associated with persistence was pretransplant MFI. Patients with de novo DSA had the highest risk of ABMR (HR 22.2 [CI 6.1–81.2]). Although recipients with persisting preformed DSA had significantly increased ABMR risk (HR 14.7 [CI 6.5–33.0]), those with cleared preformed DSA also had a higher risk than those without DSA (HR 7.01 [CI 2.2–21.8]).Preformed DSA are a very important risk factor for ABMR and graft loss. Patients who clear preformed DSA still show an increased risk of ABMR and graft loss after KT.

Donor-specific and -nonspecific HLA antibodies and outcome post lung transplantation.

Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) are associated with chronic lung allograft dysfunction (CLAD) and mortality post lung transplantation, but data concerning prevalence, time of onset, persistence and effects on long-term outcome remain scarce.We assessed the association between HLA antibodies and CLAD-free and graft survival in a cohort of 362 patients. We stratified our analysis according to DSA status, persistence of antibodies and timing of antibodies (pre-transplant, early or late post-transplant).Within our cohort, 61 (17%) patients developed DSAs (mostly against HLA-DQ), which was associated with worse CLAD-free and graft survival (p<0.0001 and p=0.059, respectively). Persistent (hazard ratio (HR) 3.386, 95% CI 1.928-5.948; p<0.0001) as well as transient (HR 2.998, 95% CI 1.406-6.393; p=0.0045) DSAs were associated with shorter CLAD-free survival compared with patients without DSAs. Persistent DSAs (HR 3.071, 95% CI 1.632-5.778; p=0.0005) but not transient DSAs were negatively associated with graft survival compared with patients without DSAs, likely due to the higher incidence of restrictive CLAD. HLA non-DSAs and pre-transplant HLA antibodies had no effect on post-transplant outcome.We demonstrated an important difference in prognosis between persistent and transient DSAs. Moreover, the observed association between DSAs and restrictive CLAD suggests an overlap between antibody-mediated rejection and restrictive CLAD that needs further investigation.

(906) - Only Persistent Donor Specific Antibodies are Associated with Subsequent Cardiac Allograft Vasculopathy After Heart Transplantation

(906) - Only Persistent Donor Specific Antibodies are Associated with Subsequent Cardiac Allograft Vasculopathy After Heart Transplantation

OR38: CARFIZOMIB FOR REFRACTORY ANTIBODY MEDIATED REJECTION IN LUNG TRANSPLANTATION THE IMPACT ON DSA

Aim Antibody mediated rejection (AMR) after lung transplantation (LTx) is associated with early and severe chronic rejection and death. Conventional therapies consisting of plasma exchange and IVIG with and without Rituximab are partially effective. Newer therapies with proteasome inhibitors (Carfizomib (CFZ) and Bortezomib (BTZ)) that target both B and plasma cells may be more effective in removing the donor specific antibodies (DSA). CFZ, unlike BTZ, irreversibly inhibits the activity of 20S proteasome and results in less neuropathic side effects. Method We evaluated the impact of CFZ therapy in 7 LTx on DSA level and function and correlated with clinical outcome as measured by pulmonary function test. All 7 patients had DSA IgG specificity and titer measured by single antigen bead Luminex assay and DSA function of complement binding by C1q-screen at baseline and at 1 month and 3 months post-treatment. Results The specificity, strengths and C1q reactivity pre- and post-therapy is summarized in Table below. All 7 patients had class II DSA and 6/7 were DQ specific with C1q reactivity. 5/7 LTx responded to initial treatment with a drop in IgG DSA level, with negative C1q DSA reactivity ( 15,000 MFI the IgG DSA was inhibited (“prozone effect”), however IgG DSA significantly increased in the presence of EDTA (LTx 3, 5, 6, 7). Conclusion In this small cohort of LTx who mostly failed conventional therapies and have persistent DSA, CFZ based approach appears to be useful, initially. However, 5/7 LTx recovered their C1q DSA reactivity upon longer follow-up suggesting that one cycle of CFZ it may not be effective to impact the rebound of circulating DSA.