Pretransplant Antibodies Research Articles

Pre-transplant Screening for Non-HLA Antibodies: Who should be Tested?

Retrospective studies of angiotensin II type 1 receptor antibodies (AT1R-Ab) and anti-endothelial cell antibodies (AECA) have linked these antibodies to allograft injury. Because rising healthcare costs dictate judicious use of laboratory testing, we sought to define characteristics of kidney transplant recipients who may benefit from screening for non-HLA antibodies. Kidney recipients transplanted between 2011 and 2016 at Johns Hopkins, were evaluated for AT1R-Ab and AECA. Pre-transplant antibody levels were compared to clinical and biopsy indications of graft dysfunction. Biopsies were graded using the Banff' 2009–2013 criteria. AT1R-Ab and AECA were detected using ELISA and endothelial cell crossmatches, respectively. AT1R-Ab levels were higher in patients who were positive for AECAs. Re-transplanted patients (p < 0.0001), males (p = 0.008) and those with FSGS (p = 0.04) and younger (p = 0.04) at time of transplantation were more likely to be positive for AT1R-Ab prior to transplantation. Recipients who were positive for AT1R-Ab prior to transplantation had increases in serum creatinine within 3 months post-transplantation (p < 0.0001) and developed abnormal biopsies earlier than did AT1R-Ab negative patients (126 days versus 368 days respectively; p = 0.02). Defining a clinical protocol to identify and preemptively treat patients at risk for acute rejection with detectable non-HLA antibodies is an important objective for the transplant community.

Detection and clinical impact of human leukocyte antigen antibodies in lung transplantation: A systematic review and meta‐analysis

There is significant variability in lung transplant centers' approach to HLA antibodies, creating heterogeneity regarding their clinical significance. Some institutions use beads coated with multiple HLA to screen candidate sera and then use single antigen bead (SAB) to determine antibody identity if the pre-screen is positive. Other centers do not pre-screen, using SAB alone, which may detect low-level antibodies of unknown significance. The primary objective of this study was to review the current literature to identify sources of heterogeneity in the identification of pre- and post-lung transplant HLA antibodies, particularly regarding antibody-detection methods. A random effects model meta-analysis was used to evaluate the relationship between pre-transplant HLA antibodies and the development of de novo donor-specific antibodies (dnDSA) and dnDSA and chronic lung allograft dysfunction (CLAD). Each outcome was stratified by the method of antibody detection (pre-screen followed by SAB vs SAB alone). We identified 13 cohort studies with a total of 3039 patients. The use of pre-screening followed by SAB testing and the use of induction immunosuppression were associated with lower prevalence of dnDSA. Patients with pre-transplant HLA antibodies were more likely to develop dnDSA (hazard ratio [HR] = 1.49, 95% confidence interval [CI]: 1.19-1.86, P < .001). dnDSA was associated with CLAD (HR = 2.02, 95% CI = 1.37-2.97, P < .001). When considering studies using SAB alone, however, pre-transplant antibody status was no longer associated with dnDSA and dnDSA was no longer associated with CLAD. Based on the current literature, SAB-alone testing may detect less clinically relevant antibodies than pre-screening followed by SAB.

P161 Kidney allograft outcomes associated with locus specific IgG antibodies to donor class I

Aim Early and late post transplant complications have been associated with antibodies (Abs) directed against donor HLA; however, the impact of pre-transplant Abs directed against donor HLA-C remains unresolved. In view of diminished display of HLA-C antigens on the cell surface compared to HLA-A or-B antigens, we hypothesized that the impact of pre-transplant Abs to donor HLA-C will be lesser compared to Abs directed at donor HLA-A and B. In the current investigation we studied the impact of circulating pre-transplant IgG antibodies to donor HLA-C locus antigens alone as compared to Abs to HLA- or B locus antigens. Methods We conducted a retrospective review of records of 1252 kidney allograft recipients transplanted at our center between January 2010 and January 2016 to identify patients with circulating pre-transplant IgG Abs directed at kidney donor HLA-A, B or C locus antigens. Abs were detected and reported using the Luminex Single Antigen Bead assay for HLA Class I. Pre and post-transplant data were collected and graft outcomes of 16 kidney graft recipients with Abs to HLA-C locus antigens alone were compared to the outcomes of 56 recipients with Abs to HLA-A or B locus antigens. Results The mean pre-transplant MFI value of DSA in those with Abs to HLA- A or B antigens was 3880 ± 3023 and 4331 ± 5540 in those with Abs to HLA- C antigens (P = 0.4). The one-year acute rejection rate was 6% in those with DSA to HLA-C antigens and 20% in those with DSA to HLA-A or B antigens (Fig. 1A). Incidence of AMR was increased in those with DSA-MFI value greater than 6000 (Fig. 1B). Kidney allograft survival rate was 100% in those with DSA to HLA-C antigens and 95% in those with DSA to HLA-A or B locus antigens (P > 0.05). Conclusions Our observations support the concept that circulating pre-transplant IgG antibodies directed at kidney donor HLA-C locus alone do not negatively impact kidney allograft outcomes and suggests that listing unacceptable HLA C locus antigens based on MFI of Single Antigen Bead Assay requires additional scrutiny and due caution. Download high-res image (125KB) Download full-size image

P045 Complement binding to single antigen beads is not directly related to antibody strength as determined in pairwise comparative studies

Aim Optical bead microarrays using Luminex have largely replaced anti-HLA antibody screening tests using cell based complement dependent cytotoxicity assays. One unintended consequence of this technologic development was the loss of the ability to distinguish between antibodies that fix complement from those that do not. This situation may have been addressed by the introduction of several assays that use the bead microarrays in conjunction with a reagent that detects whether components of the complement cascade are bound to the anti-HLA antibody – HLA complex on a reactive bead. One controversy centering on this technology has been the suggestion that the binding of complement in bead assays is dependent to a greater extend on the strength of the anti-HLA antibody rather than its complement binding activity. To address this issue we examined complement binding in single antigen bead (SAB) assays in sera that had multiple epitope specificities of different strengths. Methods Patient sera and sera from proficiency surveys were used. SAB assays of these sera were compared to C1q/C3d – SAB assays. The bead with the highest net MFI for each identified epitope in the microarray was recorded and compared to the same bead in C1q/C3d – SAB assays. Results We detected both strong and weak anti-HLA antibodies in SAB assay that were detected in C1q/C3d – SAB assays. In some sera complement bound to one set of epitope reactive SABs but not to another epitope set of SABs. Importantly, this was not dependent on the strength of the antibody. For example, in one patient’s sera, an epitope defined antigen bead, B∗42:01 (epitope 65GK), had an MFI of 12,989 (normalized score) in the SAB assay but only 99 MFI in the C1q – SAB assay. In the same serum another epitope defined bead (80 N), A∗23:01 with an MFI of 10,445 in the SAB assay exhibited an MFI of 9,162 in the C1q – SAB assay. We also observed the latter finding for HLA class 2 SABs and with the C3d assay. Conclusions Complement binding to SABs is not directly related to strength of the antibody as determined in pairwise comparative studies using sera that contained antibodies with different epitope specificities. C1q/C3d - SAB assays are therefore useful in evaluating the complement binding properties of pretransplant and post transplant anti-HLA antibodies.

P025 HLA antibody targets: Pre-transplant, post-transplant, post-graft loss

Aim It has often been noticed that the most frequent target of donor-specific HLA antibodies (DSA) in post-transplant monitoring are DQ antigens, at a rate significantly higher than that observed in patients awaiting transplant. This study is an attempt to quantify that observation. Methods From 2012 to 2017 sera from patients who had received or were waiting to receive a 1st or 2nd second kidney transplant were tested using the LABScreen Single Antigen kit. To avoid counting patients twice within a stage (pre-1st transplant, post-transplant, relisted for 2nd transplant) patients were evaluated for this study only on their most recent serum within each stage. 5896 patients pre-1st transplant (3458 males, 2438 females), 2626 patients who received post-transplant testing for DSA, and 754 patients who were relisted for a 2nd transplant were evaluated. As reliable transfusion and pregnancy information was unavailable for most pre-transplant patients, the difference between male and female sensitization rates was used as a surrogate for the different sensitizing effects of transfusion versus pregnancy in this stage. Results Sensitization to any HLA was 14% in pre-transplant males, 38% in pre-transplant females, 15% in post-transplant monitoring (but only evaluated for DSA), and 71% in patients relisted for a second transplant. Males and females pre-first transplant show significant differences in antibodies against class II, and also against HLA-B and to a lesser extent HLA-C. Post-transplant DSA shows a very high rate of antibodies against HLA-DQ, and relatively little against class I. Patients relisted for a second transplant show extensive antibody production against antigens of all loci, especially HLA-A, B, DRB1 and DQ. Conclusions The three major sources of sensitization to HLA, transfusion, pregnancy and transplantation, show different rates of sensitization to different HLA loci. Among HLA antibody producers, antibodies to DQ are 2–3 times more frequent as DSA than they are as pre-transplant antibody targets. Download : Download high-res image (215KB) Download : Download full-size image

Pre-transplant Sensitization for Patient Awaiting Lung Transplant: Are We Concerned?

The goal of this paper is to highlight the changes in detection, management, and prognosis of pre-transplant sensitized candidates and recipients. With improvements in technology, human leukocyte antigen (HLA) antibody testing has identified a significant proportion of lung transplant candidates with pre-transplant HLA antibody detection. Pre-transplant antibodies are associated with worse early outcomes after lung transplant if not addressed with targeted antibody therapy. There are promising new therapy plans to address pre-transplant HLA antibodies and potentially ameliorate the early risk of antibody-mediated graft injury. Pre-transplant sensitization continues to be a difficult problem in lung transplant. Detailed HLA antibody reports allow for precise identification of antibodies. The future challenge is how to manage these antibodies pre- and peri-transplant.

A 3-Center Study Reveals New Insights Into the Impact of Non-HLA Antibodies on Lung Transplantation Outcome.

The presence of antibodies to angiotensin type 1 receptor (AT1R) and endothelin type A receptor (ETAR) is associated with allograft rejection in kidney and heart transplantation. The aim of our study was to determine the impact of AT1R and ETAR antibodies on graft outcome in lung transplantation. Pretransplant and posttransplant sera from 162 lung recipients transplanted at 3 centers between 2011 and 2013 were tested for antibodies to AT1R and ETAR by the enzyme-linked immunosorbent assay (ELISA) assay. Clinical parameters analyzed were: HLA antibodies at transplant, de novo donor-specific antibodies (DSA), antibody-mediated rejection (AMR), acute cellular rejection, and graft status. Late AMR (median posttransplant day 323) was diagnosed in 5 of 36 recipients with de novo DSA. Freedom from AMR significantly decreased for those recipients with strong/intermediate binding antibodies to AT1R (P = 0.014) and ETAR (P = 0.005). Trends for lower freedom from acute cellular rejection were observed for recipients with pretransplant antibodies to AT1R (P = 0.19) and ETAR (P = 0.32), but did not reach statistical significance. Lower freedom from the development of de novo DSA was observed for recipients with antibodies detected pretransplant to AT1R (P = 0.054), ETAR (P = 0.012), and HLA-specific antibodies (P = 0.063). When the pretransplant antibody status of HLA-specific antibody (hazard ratio [HR], 1.69) was considered together with either strong binding to AT1R or ETAR, an increased negative impact on the freedom from the development of de novo DSA was observed (HR, 2.26 for HLA antibodies and ETAR; HR, 2.38 for HLA antibodies and ETAR). These results illustrate the increased negative impact when antibodies to both HLA and non-HLA antigens are present pretransplant.

Reactivation of Hepatitis B After Kidney Transplant in a Patient with Resolved Hepatitis B Infection and Review of Literature

Introduction: Hepatitis B infection is associated with significant morbidity and mortality in kidney transplant recipients (KTRs). Immunosuppression after kidney transplant (KT) affect T- and B- cell functions which plays an important role in maintaining immunological memory against hepatitis B infection. The reported incidence of reactivation varies from 0%-6.5% in KTRs. We present a case of resolved hepatitis B infection confirmed with negative hepatitis B surface antigen (HBsAg) and positive hepatitis B surface antibody (HBsAb) with a titer of < 100 IU/L who had reactivation of hepatitis B 5 months after kidney transplant. Case presentation: A 54-year-old male from Nigeria migrated 30 years ago with end-stage renal disease underwent cadaveric renal transplant. The patient had history of resolved hepatitis B infection confirmed biochemically and serologically. His lab work during KT showed negative HBsAg, positive HBsAb with a titer of 16.4 IU/L, positive hepatitis B core total antibody (HBcAb), negative Hepatitis B e-antigen (HBeAg) and positive Hepatitis B e-antibody (HBeAb). Hepatitis B virus (HBV) DNA was not detected by polymerase chain reaction (PCR) technique. Liver function test (LFT) was completely normal. The donor organ was free of hepatitis B infection. 5 months after KT, he presented with AST-844 IU/L, ALT- 1787 IU/L, ALP- 206 IU/L, TB- 12.2 mg/dl and INR- 3. HBV serology showed positive HBsAg, negative HBsAb, negative hepatitis B core IgM antibody (HBcIgMAb), positive HBcAb, negative HBeAg, positive HBeAb. HBV DNA was detected by qualitative PCR and viral load was found to be 1,550,000 IU/mL. Discussion: Kanaan et al. observed that patients who lost their HbsAb after KT had a pre-transplant antibody titer below 100 IU/L (like our patient) and there was no reactivation in patients with antibody titer >100 IU/L. Savas et al reported two cases of reactivation whose titer level of HbsAb were 12 IU/ml in one case and 33IU/ml in another. Based on these observations, we encourage physicians to consider raising the HBsAb titer to >100 IU/L prior to KT and maintaining at that level in post-transplant period.

P151 Acute antibody-mediated kidney rejection associated with anti-Bw6 originated from allosensitization to HLA-C14 during pregnancy: A case report

We report a case of a 36 year old Caucasian G4P4 female with chronic kidney disease stage 4 and no prior transfusions who received a living-related kidney transplant from her brother, which was a 0A-1B-1DR mismatch. She was discharged post-operative day 4 with good allograft function and a serum creatinine (SCr) of 0.76 mg/dL. Seven days later she presented with pain at the allograft site and a SCr of 3.6 mg/dL. Allograft biopsy showed evidence of thrombotic microangiopathy, hemorrhagic cortical necrosis, and peritubular capillary positivity for C4d. This strongly suggested an acute antibody mediated rejection (AMR), which was later corroborated by histology of the post-nephrectomy allograft specimen. HLA antibody screen at the time of AMR by single-antigen beads demonstrated a broad pattern of reactivity against all beads expressing Bw6-associated antigens and multiple HLA-C antigens. The MFI values of all Bw6-associated beads were above 15000 when tested at 1:25 dilution; MFI of the donor specific antibody against B62 (Bw6) was 19366. Only low-level reactivity against a small number of HLA-B antigens was detected prior to transplantation either with neat serum or at 1:25 dilution. These findings are consistent with an anamnestic alloantibody response against a common epitope present in HLA-B and HLA-C antigens, initially primed by exposure to her husband’s antigens during pregnancy and rechallenged by renal transplantation. HLA typing of the patient’s husband demonstrated no antigen mismatch at the A or B loci and one antigen mismatch at the C locus (patient is C16 and her husband is C14). Notably, C14 and all Bw6-associated antigens share a confirmed epitope, 80N (HLA epitope registry). This case demonstrates an unusual incidence of sensitization to Bw6-associated antigens via exposure to a Bw6-crossreactive C antigen. It also highlights the risk of occult alloimmunization that is undetectable in pre-transplant HLA antibody testing but may cause rapidly progressive allograft rejection.

Tracing clinically relevant HLA antibodies prior to kidney transplantation: Commentary on "Pre-transplant HLA antibodies detected by single antigen bead assay are a risk factor for long-term kidney graft loss even in the absence of donor specific antibodies".

Tracing clinically relevant HLA antibodies prior to kidney transplantation: Commentary on "Pre-transplant HLA antibodies detected by single antigen bead assay are a risk factor for long-term kidney graft loss even in the absence of donor specific antibodies".

Pre-transplant Panel Reactive Antibody and Survival in Adult Cystic Fibrosis Patients After Lung Transplantation.

Survival implications of pre-transplant antibodies to human leukocyte antigens prior to lung transplantation (LTx) in adult cystic fibrosis (CF) patients are unknown. Data from the United Network for Organ Sharing Registry (1987-2013) were used to compare survival differences in adult CF patients with pre-transplant class I and II panel reactive antibody (PRA) levels ≤10 versus >10%. Of 3149 CF LTx recipients, 1526 and 1399 were included in univariate survival analyses of class I and II PRA, respectively, while 1106 and 1001 were included in multivariate Cox analyses for class I and class II, respectively. Kaplan-Meier survival functions failed to demonstrate significant differences in survival with PRA >10% for class I (Log-rank test: χ (2) (df=1): 1.11, p=0.293) or class II (Log-rank test: χ (2) (df=1): 0.99, p=0.320). Adjusting for covariates, multivariate Cox models demonstrated that class II PRA >10% was associated with a significant increase in mortality hazard (HR 1.918; 95% CI 1.128, 3.261; p=0.016), whereas class I PRA >10% was uncorrelated with this outcome. Pre-transplant PRA class II >10% in adult CF patients is associated with elevated mortality hazard after LTx.

Desensitization Strategies Pre- and Post-Cardiac Transplantation.

Panel reactive antibody (PRA) testing has become standard in the evaluation of patients prior to cardiac transplant. Sensitizing events such as blood transfusions, which result in the accumulation of pre-transplant antibodies, should be avoided as clinically feasible. Desensitization therapy might be considered in sensitized patients with cPRA > 50% although distinct cutoff PRA values for initiating therapy pre-transplant are patient and transplant program dependent. Post-cardiac transplant, quantitative antibodies should also be periodically analyzed, at intervals individualized to the patient. Donor-specific antibodies (DSA) after cardiac transplantation have been shown to be associated with worsened survival. It appears that complement fixing DSA confer the greatest risk for antibody-mediated rejection post-transplant. Desensitization strategies aim to reduce the number of clinically important antibodies prior to and after transplant, both by removal of antibodies and cessation of further production. Current desensitization regimens include pharmacologic, procedural, and surgical modalities, and must be individualized to the patient. Currently, most cardiac transplant programs tailor the post-transplant immunosuppressive regimen based on clinical factors and immunologic assays and may include the use of cytolytic induction and/or intravenous immune gammaglobulin in higher risk patients.

Transfusion Reaction and Red Cell Antibody Formation in Allogeneic Hematopoietic Progenitor Cell Transplantation Recipients

Background: Little data exists on the incidence rate of transfusion reactions and red cell antibody formation following allogeneic (allo) hematopoietic progenitor cell transplant (HPCT) recipients.Study Design and Methods: Consecutive related and unrelated Allogeneic HPCTs from 2006 to 2013 were retrospectively reviewed regardless of graft source. Allo HPCT recipients were analyzed as a whole as well as divided into ABO compatibility groups of identical, minor mismatch, and major/bidirectional mismatch. Transfusions, transfusion reactions and antibodies were analyzed for the first year post-transplant while survival was recorded throughout the available follow-up period.Results: During the study period, 573 patients ranging in age from 0.6 to 72 years underwent first allo HPCT for various malignant and non-malignant etiologies: 278 acute leukemias, 89 lymphomas, 40 multiple myelomas, 134 other hematologic malignancies, 32 non-neoplastic etiologies. Of these, 52% underwent myeloablative conditioning and 48% reduced intensity conditioning.Transfusion reactions were reported in 93 of the 573 allo HPCT recipients. The incidence rate of transfusion reactions per 10,000 transfusion episodes was 45.54 in the ABO identical, 61.28 in the minor mismatch, and 29.95 in the major mismatch groups (p=0.04). The most common reaction type reported in all groups was allergic followed by febrile non-hemolytic, transfusion associated circulatory overload, and delayed hemolytic or serologic reactions. No acute hemolytic, transfusion related acute lung injury (TRALI), post transfusion purpura, transfusion associated graft-versus-host disease, or transfusion associated sepsis reactions were reported.A total of 43 unique patients(7.5%) developed new antibodies post-transplant: 16 allo HPCT recipients developed clinically significant antibodies, 17 developed clinically insignificant antibodies, and 17 developed auto antibodies post-transplant. Including those patients with pre-transplant antibodies the overall prevalence of red blood cell antibodies was 14.5%. See Table 1 for incidence rate for forming new rbc antibodies post-transplant.Table 1New RBC Antibody Formation Incidence Rate Post-TransplantABO Compatibility GroupClinically Significant Antibody Incidence /10,000 RBC TransfusionsClinically Insignificant Antibody Incidence/ 10,000 RBC Transfusions,Auto Antibody Incidence/10,000 RBC TransfusionsTotal Antibody Incidence/10,000 RBC TransfusionsIdentical39.3316.8539.3395.51Minor Mismatch35.8757.3943.04136.30Major Mismatch8.3416.678.3433.35A statistically significant difference (p=0.001) was seen in total antibody incidence when comparing the ABO compatibility groups. The most common, clinically significant allo antibodies formed were Anti-E, Anti-Jka, Anti-A1, Anti-K, Anti-D, and Anti-C.Survival of allo HPCT recipients as a whole was not statistically different for those who formed new rbc antibodies post-transplant following adjustment for ABO compatibility, age at transplant, diagnosis, graft source, and pre-transplant rbc infusions (p=0.068).Allo HPCT recipients that formed new rbc antibodies were not shown to have prolonged engraftment. Engraftment, neutrophils (ANC) and platelets (PLT), were not statistically different (p=0.34 ANC; p=0.20 PLT) when comparing all allo HPCT recipients to those who formed a new rbc antibody.Conclusion: Transfusion reaction and rbc antibody incidence rates were higher in the ABO minor mismatch when compared to the ABO identical and ABO major mismatch groups. The reaction etiology (predominantly antibody mediated) and the formation of new antibodies indicates a surprisingly active humoral immune system. The overall prevalence of antibody formation is likely affected by high exposure to transfusions. Development of a new rbc antibody did not affect engraftment or survival outcomes. DisclosuresNo relevant conflicts of interest to declare.

Cascade plasmapheresis as preconditioning regimen for ABO-incompatible renal transplantation: a single-center experience.

Removal of anti-ABO is an important component of the preconditioning regimen for ABO-incompatible (ABOi) renal transplant. Cascade plasmapheresis (CP) is one of the extracorporeal methods of antibody removal, others being conventional plasma exchange (PE) and immunoadsorption. There is no previous published experience with CP in this context. The purpose of this study was to present an early experience with this approach. Consecutive ABOi renal transplant recipients in whom CP was used for pre- and posttransplant anti-ABO removal were included. All the patients received intravenous rituximab 2 weeks before transplant. After 1 week, CP was started along with oral tacrolimus and mycophenolate sodium. Alternate-day CP was done to attain immediate pretransplant antibody titer of not more than 8. Fifteen ABOi renal transplant recipients had baseline (pretreatment) antibody titers ranging from 16 to 512. Desensitization rate was 100%. The mean number of procedures before transplant to achieve titer of not more than 8 was 3.27 ± 1.39. Patient survival was 93% and death-censored graft survival was 87%. Biopsy-proven acute rejection was seen in three patients (20%), one (6.67%) being acute antibody mediated rejection. The complication rate during CP was 4% and two patients had bleeding complication after surgery. Posttransplant infection rate was 13%. Based on limited number of patients, we conclude that CP is a safe and effective extracorporeal method for pretransplant ABO antibody removal in patients undergoing ABOi transplant. Patients undergoing CP met target preoperative antibody titers and the clinical outcomes were acceptable.

Current progress in ABO-incompatible kidney transplantation

ABO-incompatible kidney transplantation (ABOi KT) was introduced to expand the donor pool and minimize shortage of kidneys for transplantation. Because improved outcomes of ABOi KT were reported in Japan in the early 2000s, the number of ABOi KTs has been increasing worldwide. In addition, a better understanding of immune pathogenesis and subsequent aggressive immunosuppression has helped to make effective desensitization protocols. Current strategies of ABOi KT consist of pretransplant antibody removal using plasmapheresis or immunoadsorption to prevent hyperacute rejection and potent maintenance immunosuppression, such as tacrolimus and mycophenolate mofetil, to inhibit antibody-mediated rejection. Recent outcomes of ABOi KT are comparable with ABO-compatible KT. However, there are still many problems to be resolved. Very high anti-ABO antibody producers are difficult to desensitize. In addition, ABOi KT is associated with an increased risk of infection and possibly malignancy due to aggressive immunosuppression. Optimization of desensitization and patient-tailored immunosuppression protocols are needed to achieve better outcomes of ABOi KT. This review provides an overview of the history, immune mechanism, immunosuppressive protocol, outcomes, current obstacles, and future perspectives in ABOi KT.

Xenotransplantation literature update, May-June 2015.

Xenotransplantation literature update, May-June 2015.

Characteristics of Circulating Donor Human Leukocyte Antigen-specific Immunoglobulin G Antibodies Predictive of Acute Antibody-mediated Rejection and Kidney Allograft Failure.

Characteristics of pretransplant antibodies directed at donor human leukocyte antigen (HLA) donor-specific antibodies (DSA) associated with adverse outcomes in kidney transplant recipients are being elucidated but uncertainties exist. We prospectively screened pretransplant sera from 543 kidney recipients using single antigen bead assays and identified 154 patients with and 389 without DSA. We investigated the association of DSA features to acute rejection and graft failure. One-year acute rejection incidence was higher in DSA-positive group (P < 0.001), primarily due to antibody-mediated rejection (AMR, 13% vs. 1.8%, P < 0.001) and not T cell-mediated rejection (ACR, 5% vs.6%, P = 0.65). The sum of mean fluorescence intensity of DSA (DSA MFI-Sum) of 6,000 or higher (OR, 18; 95% CI, 7.0-47; P < 0.001) and the presence of DSA against both HLA class I and II (OR, 39; 95% CI, 14-106; P < 0.0001) predicted 1-year AMR, independent of other covariates. Calculated panel reactive antibody and a positive flow cytometry cross-match result were associated with AMR by bivariate analysis but neither was an independent predictor in a multivariable regression analysis that included DSA-MFI-Sum or HLA DSA class. In multivariable Cox proportional hazards models, the covariate-adjusted hazard ratio for graft failure was 2.03 (95%CI, 1.05-3.92; P = 0.04) for DSA MFI-Sum of 6,000 or higher and 2.23 (95% CI, 1.04-4.80; P = 0.04) for class I and II DSA. Prediction of graft failure was not independent of AMR. Our study suggests that DSA MFI-Sum and HLA class of DSA are characteristics predictive of AMR and graft failure. The elevated risk of graft failure in those with the identified features of DSA is attributable to increased risk of AMR.

Antibodies to BK virus in children prior to allogeneic hematopoietic cell transplant.

BK virus (BKV) is associated with kidney and bladder disease after hematopoietic cell transplantation (HCT) but less is known about the seroprevalence of pre-transplant antibodies to BKV in children. We measured BKV IgG antibody titers in 36 children before HCT. BKV IgG antibodies were detected in all 36 patients, with 28/36 (77.8%) developing BK viremia in the first 100 days. Pre-HCT BKV IgG antibody titers >1:40,960 were protective against later BK viremia ≥10,000 copies/ml. The seroprevalence of antibodies to BKV is high in children undergoing HCT and post-transplant BK viremia, which is associated with bladder and kidney injury, is common.

De-functioning polymorphism in the inhibitory receptor FcγRIIB does not impact upon kidney allograft survival.

De-functioning polymorphism in the inhibitory receptor FcγRIIB does not impact upon kidney allograft survival.

Role of de novo HLA-DQ antibodies in renal transplantation: analysis of a single center data

To explore the generation pattern and clinical relevance of de novo HLA-DQ antibodies in renal transplantation. A total of 175 primary renal transplant recipients without pre-transplant HLA antibodies were recruited from January 2012 to December 2013. The average follow-up period was 10 (6-18) years. They were divided into control group (n = 94) with normal renal graft function (serum creatinine <120 µmol/L); dysfunction group (n = 54) with continued serum creatinine >150 µmol/L over 6 months; and graft loss group (n = 27) with resumed hemodialysis. The sera were collected and screened for de novo HLA antibodies by flow PRA or Luminex mixed beads. And HLA-A, -B, -DR and -DQ specific antibodies were identified by HLA single antigen beads. Positive de novo HLA antibodies were detected in 48% (26/54) of patients from dysfunction group and in 52% (14/27) from graft loss group, but only in 17% (16/94) from control group (P < 0.01). The frequency of de novo DQ antibodies among patients with any positive HLA antibody was the highest in all three groups (14/16, 24/26 and 14/14). Additionally, the average mean peak fluorescence intensity of DQ antibodies was almost the highest when compared to other antibodies. Moreover, when those with positive HLA antibodies in each group were analyzed, 10/16 in control group were detected to have DQ antibodies alone. However, 17/26 of patients in dysfunction group and 14/14 in graft loss group were detected to have DQ antibodies plus HLA-DR and/or -A, -B antibodies. It indicated that the combined presence of DQ-and non-DQ- antibodies was associated with chronic renal graft failure. The presence of de novo HLA-DQ antibodies is frequent after renal transplantation. And it is associated with chronic graft failure when co-displaying with other HLA antibodies. The screening and detection of HLA-DQ antibodies after kidney transplantation may aid early warning of donor antigen-specific activation of immune system and subsequent graft dysfunction. Thus it serves as an indication for early treatment.