Development Of Donor-specific HLA Antibodies Research Articles

Optimization of Hypercholesterolemia Treatment after Heart Transplant: The Role of PCSK9 Inhibitors.

Previous studies have reported the benefit of statins after heart transplant (HT). However, the use of high-dose statins might be limited in some HT patients due to intolerance and interactions with immunosuppression or might not be enough to achieve low-density lipoprotein (LDL) cholesterol goals. Hyperlipidemia has been associated with coronary allograft vasculopathy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors might be a safe and effective option in HT patients with suboptimal lipid control. In a retrospective study, we identified HT patients in our center with LDL cholesterol >100 mg/dL, after diet modifications and up-titration of statins to maximum tolerated dose, treated with PCSK9i. The primary endpoint was LDL reduction one month after, and secondary endpoints were the development of donorspecific HLA antibodies (DSA) and the presence of coronary allograft vasculopathy or rejection. From January, 2018, to January, 2024, we identified five HT patients treated with PCSK9 inhibitors. In all cases, evolocumab was used. A significant reduction in LDL cholesterol was observed (151.6 ± 13.5 mg/dl to 72.4 ± 14.6 mg/dl; p = 0.04, mean reduction 75.7 ± 14.1 mg/dl), as well as in total cholesterol (231 ± 34.6 mg/dl to 152.2 ± 38.9 mg/dl; p < 0.01, mean reduction 78.8 ± 22.2 mg/dl). A significant increase in HDL cholesterol was not observed (45.4 ± 10.9 mg/dl to 46.2 ± 11.1 mg/dl; p = 0.60). One patient developed DSA five years after treatment onset. Rejection and coronary allograft vasculopathy were not observed. PCSK9 inhibitors are safe and effective in reducing LDL in HT patients. However, larger studies are needed to clarify if they can reduce the development of coronary allograft vasculopathy.

#3654 ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION LOWERS INCIDENCES OF DE NOVO DONOR-SPECIFIC ANTIBODIES AND CHRONIC ANTIBODY-MEDIATED REJECTION

Abstract Background and Aims ABO-incompatible kidney transplantation has been associated with an increased risk for antibody-mediated rejection (ABMR) and early graft loss attributable to isoagglutinins. Its impact on the development of de novo donor-specific HLA antibodies (DSA) and DSA-induced chronic ABMR, however, remains less well studied. Method We analyzed 297 kidney transplant recipients (KTRs) who underwent living donor transplantation at the University Hospital Zurich from 2009 to 2021. 58 ABO-incompatible (iABO) KTRs were compared to 239 ABO-compatible (cABO) KTRs concerning the development of de novo donor-specific antibodies (DSA) and antibody-mediated rejection (ABMR). ABO desensitization was performed using rituximab and antigen-specific immunoadsorption. The HLA-derived epitope-mismatches were calculated per HLA-locus and in total using the Predicted Indirectly Recognizable HLA-Epitopes (PIRCHE-II) algorithm. High-resolution re-typing was performed from protocol kidney allograft biopsies if necessary. Results The incidence of TCMR/ABMR in the first post-transplant year was comparable between iABO KTRs (19%) and cABO KTRs (13%; p = 0.207). De novo DSA were detected in only 1 of 58 iABO KTRs but 12 of 239 cABO KTRs in the first post-transplant year and 2 of 58 iABO KTRs but 50 of 239 cABO KTRs in the long-term follow-up (p = 0.001). ABMR was diagnosed in only 1 of 58 iABO KTRs but 28 of 239 cABO KTRs after the first post-transplant year (p = 0.021). iABO kidney transplantation decreased the risk of de novo DSA development (HR 7.222, CI 1.755-29.722, p = 0.006) and ABMR (HR 7.362, CI 1.000-54.239; p = 0.050) after the first-post-transplant year independent from the presence of preformed DSA. Total PIRCHE-II scores and PIRCHE-II scores per locus were not associated with the development of de novo DSA in all 297 living-donor KTRs (p&amp;gt;0.05). Conclusion Our findings suggest that iABO kidney transplantation is associated with a lower incidence of de novo DSA and ABMR in the long term, independent from the HLA-derived epitope mismatch load. Whether this protective effect offers new therapeutic options against kidney allograft injury needs to be investigated in future studies.

Predictive value of molecular matching tools for the development of donor specific HLA-antibodies in patients undergoing lung transplantation.

Molecular matching is a new approach for virtual histocompatibility testing in organ transplantation. The aim of our study was to analyze whether the risk for de novo donor-specific HLA antibodies (dnDSA) after lung transplantation (LTX) can be predicted by molecular matching algorithms (MMA) and their combination. In this retrospective study we included 183 patients undergoing LTX at our center from 2012-2020. We monitored dnDSA development for 1 year. Eplet mismatches (epMM) using HLAMatchmaker were calculated and highly immunogenic eplets based on their ElliPro scores were identified. PIRCHE-II scores were calculated using PIRCHE-II algorithm (5- and 11-loci). We compared epMM and PIRCHE-II scores between patients with and without dnDSA using t-test and used ROC-curves to determine optimal cut-off values to categorize patients into four groups. We used logistic regression with AIC to compare the predictive value of PIRCHE-II, epMM, and their combination. In total 28.4% of patients developed dnDSA (n = 52), 12.5% class I dnDSA (n = 23), 24.6% class II dnDSA (n = 45), and 8.7% both class II and II dnDSA (n = 16). Mean epMMs (p-value = 0.005), mean highly immunogenic epMMs (p-value = 0.003), and PIRCHE-II (11-loci) (p = 0.01) were higher in patients with compared to without class II dnDSA. Patients with highly immunogenic epMMs above 30.5 and PIRCHE-II 11-loci above 560.0 were more likely to develop dnDSA (31.1% vs. 14.8%, p-value = 0.03). The logistic regression model including the grouping variable showed the best predictive value. MMA can support clinicians to identify patients at higher or lower risk for developing class II dnDSA and might be helpful tools for immunological risk assessment in LTX patients.

Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation.

Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity ≤1000 nM; netMHC: binding affinity ≤500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development. Donor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft function deterioration in paediatric kidney transplantation.

Autoantibodies and Donor-specific Antibodies are Associated With Graft Dysfunction in Pediatric Liver Transplantation.

Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. AAb were detected in 27 (43.3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (P = 0,032) and deceased donor LT (P = 0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (P < 0,001), and an association was found with the presence of nonspecific histologic alterations (P = 0,032) in the absence of de novo autoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (P < 0,001), ALT (P < 0,001), AST (P < 0,001), γ-GT (P = 0,001), IgG (P = 0,011) and lower albumin (P = 0,029). Fourteen out of 50 (28%) patients were DSA-positive, mostly anti-HLA class II. DSA positivity was associated with T-cell-mediated rejection (P = 0,019), higher total (P = 0,033), and direct (P = 0,012) bilirubin and γ-GT (P < 0,001). The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the causal relationships between AAb and DSA development and outcome parameters post pediatric LT.

P045 Kidney transplant with historic but no current DSA – A case study

Presence of donor-specific HLA antibodies (DSA) at the time of transplant is associated with poor outcome. DSA may be present in historic serum samples but not at the time of a kidney offer. Going forward with the transplant holds the risk of a memory B-cell response upon re-exposure to a specific HLA antigen or epitope. A patient with X-linked Alport syndrome was investigated for a kidney transplant. Anti-HLA class II antibodies were observed following pregnancy, which were specific to her husband’s mismatched DR and DQ antigens. A year later, she received a blood transfusion and had an episode of aseptic peritonitis while on dialysis. Class I HLA antibodies appeared but were observed over a period of 7 months. Thereafter, anti-HLA antibody screening using FlowPRA beads and identification using Luminex single antigen beads showed disappearance of class I antibodies but persistence of a single anti-HLA-DR antibody developed after prior pregnancy. Three years later, a kidney from a DCD donor was offered and transplanted despite presence of historic DSA against 2 HLA-B antigens. A CDC crossmatch proved negative using a current serum whereas a flow cytometric crossmatch using 3 DSA-containing historic sera gave positive but inconsistent results (T + B+, T-B+, T-B-). One week after transplant, historic DSA reappeared (3000 MFIs). Despite absence of biopsy-proven rejection, short-term treatment comprising plasmapheresis, rituximab and low-dose IVIg was initiated. DSA quickly disappeared from circulation with only an HLA-DR-specific reactivity from the previous pregnancy. Without any further desensitization treatment, the patient has not demonstrated re-appearance of DSA nor experienced antibody-mediated rejection (AMR) as demonstrated upon for-cause and protocol biopsies, up to 8 months posttransplant at the time of abstract submission. This case demonstrates that, although DSA may reappear following re-exposure to a sensitizing HLA antigen/epitope, acceptable transplant outcome can be achieved without AMR. Time between DSA development and transplant could be a factor in identifying acceptable HLA mismatches.

Impact of the Trough Level of Calcineurin Inhibitor on the Prevalence of Donor-Specific Human Leukocyte Antigen Antibodies During Long-Term Follow-Up After Pediatric Liver Transplantation: Antibody Strength and Complement-Binding Ability.

BackgroundIn pediatric patients, long-term immunosuppression after liver transplantation (LT) is typically minimal. However, posttransplant donor-specific HLA antibodies (DSAs) may be prevalent under these conditions. Here, we evaluated the effects of minimized calcineurin inhibitor (CNI) on DSA development to assess the validity of minimized/withdrawn immunosuppression.MethodsWe retrospectively examined 66 patients who underwent pediatric LT at our institution between July 1991 and October 2013. Patients were divided into 2 groups based on the CNI trough level. The cutoff trough levels were 3 and 30 ng/mL for tacrolimus and cyclosporine, respectively. Luminex single-antigen bead assays were performed, and the cutoff for a positive reaction was set at a mean fluorescence intensity (MFI) of at least 1000.ResultsThe mean recipient ages at the time of LT were 29.1 and 77.2 months for the low and regular CNI groups, respectively (P = 0.0007). Univariate logistic regression analysis revealed that recipient age at LT younger than 3 years (P = 0.0099) and low CNI (P < 0.0001) were significantly associated with DSA development. In multivariate analysis, low CNI was an independent risk factor of DSA development (P = 0.0011). Of 15 high-MFI DSAs, 3 were anti-DR, and 12 were anti-DQ. Two of 3 anti-DR DSAs and 11 of 12 anti-DQ DSAs had complement-binding ability and high MFIs.ConclusionsCNI minimization was an independent risk factor for posttransplant DSA during long-term follow-up after pediatric LT. Adjusting CNI to appropriate levels is a safe first step to prevent the immunological effects of DSA.

Non-HLA-matched 3rd party vascular allograft in renal transplant may lead to sensitization against donor HLA.

3rd party donor vessels are often used for vascular reconstruction in organ transplantation. While current practice ensures that 3rd party vessels are blood group matched, HLA matching to the non-intended recipient is not performed. This practice potentially sensitizes the recipient and may reduce their future chance of renal transplant from a larger pool of donors. We examined our cohort of renal transplant recipients who received non-HLA-matched 3rd party vessels for the de-novo development of donor-specific HLA antibodies. Our institution's Human Tissue Authority (HTA) blood vessel registers were examined to identify stored donor vessels and their non-intended recipients. Donor vessel HLA status was cross-referenced with the recipient HLA status. Between 2004 and 2014, five patients were identified that received 3rd party non-HLA-matched vessels for vascular reconstruction during renal transplantation. Three patients (60%) subsequently developed donor-specific HLA antibodies. These data provide evidence that use of non-HLA-matched stored 3rd party vascular grafts may lead to sensitization in the recipient. Where time permits, HLA matching should be performed to avoid this allogeneic response. Laboratories monitoring DSA should be aware of any patient receiving a non-HLA-matched 3rd party vascular graft, and recipients may benefit from increased post-transplant immunological vigilance.

P072 De novo anti-HLA-class II donor specific antibodies are associated with patient mortality after lung transplant failure

Aim The development of donor-specific HLA antibodies (DSA) after lung transplantation has been implicated in acute and chronic rejection. The diagnosis of lung antibody mediated rejection (AMR) is based upon histology, DSA testing and clinical assessment of graft function. Post-transplant DSA monitoring has become more and more common as a guide toward diagnosis and sometimes institution of AMR treatment. In this study, we aimed to assess DSA with biopsy surveillance and associate with patient mortality after lung transplant failure (MLTF). Methods We retrospectively selected 127 patients, transplanted between Jan, 2004 and July, 2015 whose DSA were tested for clinical indications post-transplantation. Protocol biopsies were performed for these patients at 1, 3, 6, 9, and 12-months after transplant for clinical suspicions. DSA were monitored using LabScreen single antigen bead assays. Biopsy HE however, no association was found for Class I DSA. No significant relationship between DSA and histological changes of AMR in lung transplant biopsies was found in this cohort. Conclusion HLA Class II DSA is associated with graft dysfunction and mortality in pulmonary transplant patients although we did not find the correlation with biopsy findings. Our study suggests that post-transplant protocol DSA surveillance may add value to assess allograft function and to treat graft rejection at the early stage.

The importance of non-HLA antibodies in transplantation.

The development of post-transplantation antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, compelling experimental and clinical findings demonstrate that antibodies directed against autoantigens such as angiotensin type 1 receptor, perlecan and collagen, contribute to the process of antibody-mediated acute and chronic rejection. The mechanisms that underlie the production of autoantibodies in the setting of organ transplantation is an important area of ongoing investigation. Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens (such as soluble antigens, extracellular vesicles or apoptotic bodies) that are presented to B cells in the context of the transplant recipient's antigen presenting cells and stimulate autoantibody production. Type 17 T helper cells orchestrate autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promote allograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection, and the development of targeted therapies to treat such rejection, are sorely needed to improve both graft and patient survival.

The Clinical Spectrum of De Novo Donor-Specific Antibodies in Pediatric Renal Transplant Recipients

The development of donor-specific HLA antibodies (DSA) is associated with worse renal allograft survival in adult patients. This study assessed the natural history of de novo DSA, and its impact on renal function in pediatric renal transplant recipients (RTR). HLA antibodies were measured prospectively using single-antigen-bead assays at 1, 3, 6 and 12 months posttransplant followed by 12-monthly intervals and during episodes of allograft dysfunction. Of 215 patients with HLA antibody monitoring, 75 (35%) developed DSA at median of 0.25 years posttransplant with a high prevalence of Class II (70%) and HLA-DQ (45%) DSA. DSA resolved in 35 (47%) patients and was associated with earlier detection (median, inter-quartile range 0.14, 0.09-0.33 vs. 0.84, 0.15-2.37 years) and lower mean fluorescence intensity (MFI) (2658, 1573-3819 vs. 7820, 5166-11 990). Overall, DSA positive patients had more rapid GFR decline with a 50% reduction in GFR at mean 5.3 (CI: 4.7-5.8) years versus 6.1 (5.7-6.4) years in DSA negative patients (p = 0.02). GFR decreased by a magnitude of 1 mL/min/1.73 m(2) per log10 increase in Class II DSA MFI (p < 0.01). Using Cox regression, independent factors predicting poorer renal allograft outcome were older age at transplant (hazard ratio 1.1, CI: 1.0-1.2 per year), tubulitis (1.5, 1.3-1.8) and microvasculature injury (2.9, 1.4-5.7). In conclusion, pediatric RTR with de novo DSA and microvasculature injury were at risk of allograft failure.

Impact ofde novodonor-specific HLA antibodies detected by Luminex solid-phase assay after transplantation in a group of 88 consecutive living-donor renal transplantations

De novo donor-specific HLA antibodies (DSA) after renal transplantation are known to be correlated with poor graft outcome and the development of acute and chronic rejection. Currently, data for the influence of de novo DSA in patient cohorts including only living-donor renal transplantations (LDRT) are limited. A consecutive cohort of 88 LDRT was tested for the occurrence of de novo DSA by utilizing the highly sensitive Luminex solid-phase assay for antibody detection. Data were analyzed for risk factors for de novo DSA development and correlated with acute rejection (AR) and graft function. Patients with de novo DSA [31 (35%)] showed a trend for inferior graft function [mean creatinine change (mg/dL/year) after the first year: 0.15 DSA (+) vs. 0.02 DSA (-) (P = 0.10)] and a higher rate of AR episodes, especially in case of de novo DSA of both class I and II [6 (55%), (P = 0.05)]. Antibody-mediated rejection (AMR) appeared in five patients and was significantly correlated with de novo DSA (P = 0.05). Monitoring for de novo DSA after LDRT may help to identify patients at risk of declining renal function. Especially patients with simultaneous presence of de novo DSA class I and class II are at a high risk to suffer AR episodes.

De Novo Donor-Specific HLA Antibodies Decrease Patient and Graft Survival in Liver Transplant Recipients

The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre- and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.

HLA Antibodies after Lung Transplantation: Early Results of the HALT Study

<h3>Purpose</h3> The development of donor-specific HLA antibodies (DSA) after lung transplantation (LT) is a significant risk factor for bronchiolitis obliterans syndrome (BOS). The HALT study aimed to determine the incidence of DSA development & characterize DSA profiles early after LT. <h3>Methods and Materials</h3> We conducted a prospective observational study at 6 US LT centers that used similar induction & maintenance immunosuppression. Recipients were screened for DSA using the LABScreen® Single Antigen assay at 10, 30, 60, 90, & 120 days after LT, & if clinically indicated. DSA was defined as bead reactivity with an absolute MFI>1000, & an increase in MFI>30% & an increase in absolute MFI≥500 when compared to pre-LT reactivity. <h3>Results</h3> 115 patients were enrolled at the 6 sites between 12/2011 and 6/2012.[table1]Study follow-up will be complete in 11/2012. An interim analysis through 8/2012 showed that 40 of the 115 (35%) recipients developed DSA after LT; 6 (5%) had class I DSA only, 22 (19%) had class II DSA only, & 12 (10%) had class I & class II DSA. DSA were identified a mean 29.6±24.4 days after LT.[figure 1]The median DSA MFI was 4534 (range: 1068-18150). <h3>Conclusions</h3> DSA development is common early after LT & most DSA are directed at class II HLA. Future studies should evaluate long-term outcomes after early DSA development & the potential benefit of preemptive DSA depletion. The HALT Study is funded by the NHLBI (R34 HL105412). Recipient Demographics (n = 115)VariableAge, mean (SD)56.8 (12.4)Female, n (%)47 (41%)Diagnosis, n (%)COPD37 (32%)ILD51 (44%)CF17 (15%)PAH2 (2%)Other8 (7%)Bilateral, n (%)86 (75%)Allosensitized pre-LT, n (%)16 (14%)Number of HLA mismatches for A, B, C, DRB1, DQ, median (IQR)8 (3)

Time from Development of De Novo Donor-Specific HLA Antibodies to Rejection or Graft Loss in Pediatric Cardiac Transplantation

Purpose There is increasing evidence that de novo donor-specific HLA antibodies (DSA) are associated with poor outcome following cardiac transplantation. Management of these remains problematic and there is little data on lag time from DSA development to an adverse event. We aimed to determine average time from first detection of DSA to rejection, cardiac allograft vasculopathy(CAV) or graft loss in a pediatric cohort. Methods and Materials Luminex screens and single antigen tests were performed on stored samples taken at 3, 6, 12 months and then annually in patients transplanted age Results 108 patients, mean age at transplant 7.4 (0.1-15.9) years were studied, mean follow-up 8.2 (1.9-15.7) years. All had a CDC-negative crossmatch and retrospective serum analysis confirmed they had no DSA prior to transplant. 43/108 (40%) patients had DSA with median time from transplant to DSA development of 2 (0.25-11) years. Freedom from DSA was 91% at 3 months, 86% at 6 months, 84% at 1 year, 69% at 5 years, 58% at 10 years and 48% at 15 years post-transplant. 9 patients with DSA (21%) developed CAV, and in 6 (67%), DSA were detected prior to CAV diagnosis with median lag time of 2.2 (1-4.9) years. 14 patients (33%) had a rejection episode, 9 (64%) had DSA prior to rejection with median lag time time of 2.8 (0.2-7.2) years. 10 patients (23%) died or were re-transplanted, with median time from development of DSA to graft loss of 1.7 (0.1-4.8) years. 28/33 (85%) patients with an adverse outcome had Class II DSA with anti-DQ the most prevalent. Conclusions In patients with DSA in whom an adverse event occurred (CAV, Rejection or Graft loss) DSA were detected in 25/33 (76%) prior to the adverse outcome. The majority of patients with an adverse outcome in this study had Class II DSA detected prior to that event. These findings suggest that once DSAs have developed increased surveillance for adverse events should be implemented.

Mycophenolate Acid Reduce Donor Specific HLA Antibody Strength in Kidney Transplant Recipients

Introduction: The development of donor-specific HLA antibodies (DSA) post-transplant has been associated with chronic rejection and graft failure. We hypothesized that mycophenolic acid (MPA) dose escalation will reduce DSA. Methods: Thirty stable DSA positive recipients consented to participate in this 2 year study. MPA was increased in increments of 180/250mg at baseline and at 3 month intervals as tolerated or until maximum manufacturer's recommended dose was achieved. DSA and laboratory data were collected monthly during escalation. HLA single antigen beads analyzed in the Luminex instrument were used to establish donor specificity and strength of the antibodies measured as mean fluorescence intensity (MFI). All recipients received anti-lymphocyte induction therapy. Maintenance immunosuppression consisted of a calcineurin inhibitor, prednisone and MPA. Results: Twenty of 29 (69%) recipients had a reduction or stabilization in DSA MFI within the first 6 months of the study.Figure: [Pre and Post Escalation DSA MFI]One recipient was lost to follow-up at time of submission. Twenty-one of 29 (72%) recipient's renal function improved or remained stable. Notably, DSA development occurred from 2-96 months post-transplant with a mean range of 32 months. Conclusion: MPA dose escalation appears to benefit recipients with DSA in this preliminary 6 month data. Maximum tolerated MPA should be attempted to minimize DSA formation and therefore improve graft function and long term graft survival. Longer follow- up is needed to determine significance.

Development of Donor-Specific HLA-Antibodies after Kidney Transplantation Is Associated with Inferior Renal Function

Introduction: The clinical relevance of donor-specific HLA antibodies (DSA) detected in highly sensitive solid phase assays such as Luminex prior to kidney transplantation has been discussed controversially. Furthermore, the impact of de novo HLA antibodies occuring posttransplant detected with the same method on graft outcome is unclear. The aim of our study was to investigate to which extent preexisting as well as de novo donor-specific and non-donor-specific HLA antibodies (non-DSA) influence renal allograft function after kidney transplantation. Patients and methods: We retrospectively analyzed 1278 patients with negative complement-dependent cytotoxicity crossmatches who received a kidney transplantation within the last 15 years. Patient sera obtained prior of transplantation as well as at 2 time points thereafter (approximately 2 and 4 years) were investigated for the presence of HLA antibodies. HLA class I and II antibodies were specified by means of a solid phase assay (Luminex, Genprobe). The results were correlated with renal allograft function at the two given time points. To estimate renal function serum creatinine levels were measured within the same samples. Results: The mean age in our study population was 48 ±12 years, 62% were male recipients. The majority (90.5%) of recipients had received an organ from a cadaveric donor. One hundred sixty of 1278 patients (12.5%) were retransplanted. Only 9.4% (120/1278) of our patients were already immunized before transplantation as indicated by the presence of DSA in the sera obtained pretransplantat. Notabley, renal function did not differ in patients with DSA as compared to patients without DSA at 2 and 4 years after transplantation (serum creatinine 1.5mg/dl vs 1.6mg/dl and 1.7mg/dl vs 1.6 mg/dl, respectively). However, 3.3% of recipients (42/1278) developed de novo DSA at 2 years after transplantation and 7.3% (93/1278) at 4 years after transplantation. Furthermore, de novo non-DSA could be detected in the sera of 5.0% (64/1278) and 4.5% (58/1278) recipients at the 2 time points. The presence of de novo DSA correlated with higher serum creatinine levels at any investigated time point suggesting that the development of DSA negatively influences renal function, while the presence of non-DSA did not impact renal function. Renal function was significantly impaired in patients with de novo DSA (serum creatinine 2.4 ± 0.8 mg/dl) as compared to those with de novo non-DSA (1.9 ± 0.7 mg/dl) and patients without HLA antibodies (1.6 ± 1.0 mg/dl) 4 years after transplantation (p< 0.05). Conclusion: Our data suggest, that the development of de novo donor-specific antibodies is detrimental for the outcome after kidney transplantation, while the existence of DSA prior to transplantation as well as the development of non-DSA after transplantation seem to be less harmfull. A periodically defined post TX monitoring for de novo HLA antibodies should therefore be taken into account to guide further therapeutic considerations.

Development of Donor-Specific HLA-Antibodies after Kidney Transplantation Is Associated with Inferior Renal Function

Development of Donor-Specific HLA-Antibodies after Kidney Transplantation Is Associated with Inferior Renal Function

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Aim Antibodies against AT1R have been observed in patients with acute rejection of kidney and chronic rejection of heart transplants. Our study sought to determine if AT1R antibodies are associated with graft failure after rejection. Methods We enrolled a total of 133 kidney recipients who had biopsy-proven rejection episodes. Serial post-transplant sera (n = 873) were tested for the presence of both anti-AT1R and donor specific HLA antibodies (DSA). Results High levels of anti-AT1R were more prevalent in the failed patients than functioning patients (87% vs. 13%, P Download full-size image Conclusions This longitudinal analysis of serial post-transplant sera showed the significant association of high levels of anti-AT1R with graft failure after rejection episodes. While high-level anti-AT1R is independently associated with the highest risk of graft loss, the development of both DSA and high-level anti-AT1R may augment the detrimental effect that leads to lower graft survival. The importance of monitoring and therapeutic targeting of non-HLA as well as HLA is emphasized. Taniguchi: One Lambda, Inc.: Employee. Hopfield: One Lambda, Inc.: Employee. Terasaki: One Lambda, Inc.: Stockholder.

Donor-Specific HLA Antibodies in a Cohort Comparing Everolimus With Cyclosporine After Kidney Transplantation

Donor-specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody-mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3-4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow-up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log-rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log-rank: p = 0.036). Four of 10 patients with AMR-all in the everolimus group-lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus-based immunosuppression is associated with an increased risk for the development of DSA and AMR.