Antibody-mediated Rejection Episodes Research Articles

Type and Extent of HLA Mismatch and Antibody-Mediated Rejection in Heart Transplantation

Purpose Advances in ex-vivo organ perfusion may soon allow for extension of the time between organ procurement and heart transplant. However, presently the necessity for short allograft ischemic time in heart transplantation makes human leukocyte antigen (HLA) matching between donors and recipients impractical. Our aim was to investigate whether HLA mismatch is correlated with antibody mediated rejection (AMR) in heart transplantation. Methods and Materials The records of patients transplanted at the UTAH Cardiac Transplant Program between 1992 and 2011 were reviewed. HLA-mismatch at major antigen class I loci HLA-A and HLA-B, and class II loci HLA-DR and HLA-DQ, were analyzed using the Cox proportional hazards regression model. AMR was defined with the occurrence of ≥ 3 AMR episodes. Results Four hundred and fifty one patients met our inclusion criteria, 77% were male and the age was 45±19 years. HLA-DR and DQ have significant association with the incidence of AMR within the first year and at any time ( table ). There was no significant difference in the incidence of antibody mediated rejection (AMR) in patients with HLA class I mismatch. Conclusions HLA-DR and HLA-DQ mismatch appear to be associated with increased incidence of AMR after heart transplant. Prospective HLA class II antigens matching may result in reduced incidence of AMR and better outcome in heart transplantation. [ Figure 1 ]

Neopterin Predicts Poor Short- and Long-Term Outcomes in Heart Transplant Recipients

Purpose Neopterin (NP), a product of activated macrophages, may be associated with adverse outcomes in patients after heart transplantation (HTx). The study was designed to analyze the association of NP plasma levels in early posttransplant period on short- and long-term outcomes in heart transplant recipients. Methods and Materials 98 heart recipients, 89 men and 9 women, aged 37.4±12.3 years, were followed prospectively for 1-11 years (5.7±3.9) after the operation performed for dilated (61 pts) or ischaemic (37 pts) cardiomyopathy. Immunosuppressive therapy included steroids, cyclosporine A or tacrolimus, and mycophenolate mofetil. The posttransplant variables analyzed included the evaluation of cardiac allograft vasculopathy (CAV), acute cellular (ACR) and antibody-mediated rejection (AMR). Plasma levels of NP were measured by ELISA. Results During follow-up, severe episodes of ACR (14 pts, 14.3%, at 6.5±5.2 months after HTx), AMR (17 pts, 17.34%, at 8.5±10.6 months after HTx), and CAV (16 pts, 16.32%, at 36.5±25.5 months after HTx) occurred in 37 patients (37.7%). NP plasma levels correlated with severity of ACR (11.3±4.3, 47.5±27.8, and 148.6±37.7 nmol/l in recipients with grade “0”, “1R”and “2R” resp., rs=0.86, t=16.5, p Conclusions Early post-transplant macrophage activation, as reflected by NP levels, is highly predictable for the development of ACR and AMR in short-term and is associated with CAV development in long-term period after HTx.

ATG Induction Improves Outcome for Sensitized Patients Who Have Undergone Heart Transplantation

Purpose Heart transplant recipients who are sensitized pre transplant are at increased risk for the development of antibody mediated and cellular rejection post transplantation. The use of induction therapy with anti-thymocyte globulin (ATG) may reduce the incidence of antibody mediated rejection (AMR), but this has not been formally studied in a randomized controlled trial. The purpose of this study was to determine the impact of ATG induction on the incidence of AMR in a large single-center experience. Methods and Materials We identified 170 heart transplant (HTx) patients transplanted between January 1994 and October 2011, with pre-transplant panel reactive antibodies (PRA) >10%. Induction therapy was given based on the treating physician’s preference. One-year outcomes were assessed, including the incidence of treated rejection and pathology-defined AMR. Results Of the 170 HTx, 91 received ATG induction and 79 did not. The mean pre-transplant PRA was significantly higher in the ATG group (59 ± 31% vs 43 ± 32%, p=0.0015). In the ATG induction group, there were fewer treated rejection episodes (14% vs 30%, p= 0.01) and fewer pathology-defined AMR episodes (12% vs 26%, p=0.016). There was no difference in the incidence of cellular rejection (12% in both groups). Conclusions ATG induction therapy for sensitized patients results in fewer treated rejection epiosdes and a decreased incidence of pathology-defined AMR. This suggests that ATG induction is beneficial in sensitized patients, and the results should be confirmed with a randomized trial. No ATG (n=79) ATG (n=91) p-value All Treated Rejections, n (%) 24 (30%) 13 (14%) 0.01 Cellular Rejections, n (%) 10 (12%) 11 (12%) 0.74 Any-Treated AMR, n (%) 21 (26%) 11 (12%) 0.02

Pre-Transplant Circulating Antibodies Predict Antibody-Mediated Rejection Using the New ISHLT Grading Scale

Purpose The presence of pre-transplant circulating anti-HLA antibodies (PRA) portend worse survival and increase the risk of antibody-mediated rejection (AMR) after transplantation. The diagnosis of AMR is now standardized with the new ISHLT grading scale. The purpose of the current study was to determine whether the presence of pre-transplant PRA is associated with an increased incidence of AMR according to the new ISHLT AMR grading scale. Methods and Materials 106 heart transplant recipients transplanted January 2010 to July 2011 were divided into groups based on the peak pre-transplant PRA: 0%, 1-25%, and 26-100%. 1152 biopsies from the 106 patients were examined. Endpoints were total number of pAMR episodes, highest grade of pAMR on biopsy, and incidence of treated AMR. Results Of the 106 patients, 66 had PRA 0%, 10 had PRA 1-25%, and 30 had PRA 26-100%. Patients with elevated PRA were younger, more often female, and more likely to have a ventricular assist device. Patients with elevated pre-transplant PRA had a higher incidence of pAMR on biopsy, a higher incidence of higher grade pAMR, were more likely to have AMR requiring treatment, and had a higher median number of pAMR episodes ( Table ). Conclusions Pre-transplant circulating anti-HLA antibodies are associated with more frequent pAMR on biopsy, higher grade of pAMR on biopsy, a higher incidence of treated AMR. This suggests that patients with elevated pre-transplant PRA should be considered for augmentation of immuonosuppression. Peak PRA 0% (66 pts; 701 biopsies) Peak PRA 1-25% (10 pts; 113 biopsies) Peak PRA 26-100% (30 pts; 338 biopsies) pAMR0 98% (701) 88% (100/113) 85% (286/338) pAMR1 2% (12/701) 10% (11/113) 11( (37/338) pAMR2 0 2% (2/113) 4% (15/338) pAMR3 0.1% (1/701) 0 0 Total pAMR 2% (13/701) 12% (13/113) 15% (52/338) Treated AMR 0 10% (1/10) 17% (5/30) Median AMR episodes per patient 1 1.5 3

Evolving Trends in the Costs Associated With Hospital Use of Immunosuppressive Drugs

Evolving Trends in the Costs Associated With Hospital Use of Immunosuppressive Drugs

Successful Experiences of ABO-Incompatible Adult Living Donor Liver Transplantation In a Single Institute: No Immunological Failure in 10 Consecutive Cases

ABO-incompatible (ABOi) adult living donor liver transplantation (ALDLT) is a feasible therapeutic option for countries with a scarcity of deceased donors. This report presents our initial experiences in ABOi ALDLT in 10 patients between December 2008 and September 2009. The mean age of recipients was 48.5 ± 5.7 years (range, 40–54 years). The mean Model for End-stage Liver-Disease score was 13.9 ± 4.0 (range, 9–22). All patients were administered preoperative rituximab once and plasma exchanges according to the hemagglutinin titer. The spleen was preserved in all cases. For local infusion therapy, hepatic arterial infusion was performed in 9 patients and portal vein infusion in 1 subject. The 10 patients experienced no in-hospital mortality. At a mean follow-up period of 31.8 ± 2.9 months (range, 4.1–34.9 months), 1 patient has died (postoperative month 4 due to sepsis following a biliary stricture. The 3-month patient and graft survivals were 100%, and 1- and 2-year survivals, 90.0%. There was no episode of antibody-mediated rejection. The promising results of our initial experience may have been due to the use of preoperative rituximab and the good preoperative conditions of the patients.

First Clinical Experience With Polysol Solution: Pilot Study in Living Kidney Transplantation

In this study, we assessed the safety of the new organ preservation solution polysol solution in the clinical setting of living kidney transplantation. We conducted a prospective pilot study in nine adult donor-recipient couples using polysol solution for washout and cold storage of kidney grafts. Adverse reactions possibly related to the use of polysol solution as well as renal function at 1, 6, and 12 months after transplantation were monitored. All living kidney transplantation performed in adults in our center within 2002 to 2008 using the University of Winconsin solution served as controls (n = 190). The use of polysol solution was associated with a higher acute rejection rate compared to University of Wisconsin solution at all time points. Also, antibody-mediated rejection occurred more frequently in the polysol group. Renal function at all time points was also comparable between the groups. This pilot study in living kidney transplantation is the first clinical study on the use of polysol solution. Although the study was not powered on the endpoint rejection, we observed a high number of acute rejection and antibody-mediated rejection episodes in recipients of polysol solution preserved grafts as compared to University of Wisconsin solution controls. As a consequence the study was terminated prematurely.

Late and Chronic Antibody-Mediated Rejection: Main Barrier to Long Term Graft Survival

Antibody-mediated rejection (AMR) is an important cause of graft loss after organ transplantation. It is caused by anti-donor-specific antibodies especially anti-HLA antibodies. C4d had been regarded as a diagnosis marker for AMR. Although most early AMR episodes can be successfully controlled or reversed, late and chronic AMR remains the leading cause of late graft loss. The strategies which work in early AMR have limited effect on late/chronic episodes. Here, we reviewed the lines of evidence that late/chronic AMR is the leading cause of late graft loss, characteristics of late AMR, and current strategies in managing late/chronic AMR. More effort should be put on the management of late/chronic AMR to make a better long term graft survival.

Serum Level of Soluble Fibrinogen-Like Protein 2 in Renal Allograft Recipients With Acute Rejection: A Preliminary Study

BackgroundSoluble fibrinogen-like protein 2 (sfgl2), which is mainly secreted by T cells, is a novel effector of regulatory T cells with immunosuppressive functions. The aim of this study was to investigate serum levels of sfgl2 among renal allograft recipients. MethodsFrom November 2010 to August 2011 we retrospectively divided 47 renal allograft recipients into an acute rejection (n = 19) versus a stable group (n = 28) according to allograft biopsy results, using the Banff 2007 classification. The acute rejection group was subdivided into grade I (n = 8) versus grade II T-cell–mediated (n = 6) or antibody-mediated rejection episodes (n = 5). Peripheral blood samples were collected at the time of biopsy. Fourteen healthy volunteers were included as normal group controls. Serum levels of sfgl2 were analyzed by enzyme-linked immunosorbent assay. ResultsSerum levels of sfgl2 were increased among renal allograft recipients suffering from biopsy-proven acute rejection episodes (61.91 ± 45.68 ng/mL), versus those with stable allografts (38.59 ± 19.92 ng/mL, P < .05) or healthy volunteers (29.10 ± 18.08 ng/mL, P < .05). The sfgl2 level was significantly higher among patients with antibody-mediated (118.48 ± 55.54 ng/mL) than T-cell–mediated acute rejection episodes (41.71 ± 16.44 ng/mL, P < .01). Serum sfgl2 levels were remarkably elevated in patients with grade II (51.87 ± 19.13 ng/mL) versus grade I T-cell–mediated rejection (34.10 ± 9.26 ng/mL, P < .05). ConclusionsSerum sfgl2 levels were increased among renal allograft recipients with acute rejection episodes to an extent dependent upon the pathological type and severity of the response.

Deceased Donor HLA Antibody Incompatible Renal Transplantation without Antibody Removal: High Incidence of Acute Rejection Reduced by T-Cell Depleting Induction Therapy

Introduction: Screening for HLA-specific antibodies (Ab) is routine for patients on kidney transplant waiting lists. In the UK screening is performed at least every 3 months, and HLA antigens to which a patient has detectable Ab are listed as ‘unacceptable mismatches’. Many units use a stringent definition of unacceptable, for example any HLA antigen to which Ab can be detected with an MFI >1000 (using the Luminex® platform). Whilst this approach is effective in preventing a positive crossmatch (XM) following allocation, it also precludes the offer of organs to sensitized patients. Here we describe our experience of deceased donor (DD) renal transplantation knowingly performed in the presence of donor-specific anti-HLA Ab (DSA). Methods: 21 patients received HLA Ab-incompatible (HLAi) DD transplants in one of two circumstances: (1) Patients in whom the threshold for ‘unacceptable’ for any HLA specificity was increased to a Luminex MFI >3000 (n=8), and (2) Patients with a positive flow cytometry B-cell crossmatch (FC-BXM) known to have anti-HLA-DP Ab (n=13). Since donors in the UK are not routinely DP genotyped, the presence of DP DSA was assumed, and confirmed retrospectively by donor DP genotyping. Complement-dependent cytotoxicity crossmatch (CDC-XM) using a recent pre-transplant serum sample was negative in all patients. FC-BXM was positive in 15 (71%). The mean DSA MFI was 5268 (range 1086-16356) and mean follow-up length was 20.8 months (range 1-64). All episodes of antibody-mediated rejection (AMR) and T cell-mediated rejection (TCMR) were analyzed. Results: All patients received tacrolimus, MMF and prednisolone. Induction agents used were Basiliximab (n=8), Alemtuzumab (n=9) and Thymoglobulin (n=4). No planned Ab removal was used. Death-censored 1 year graft survival was 92% (12/13 patients with >12 months follow up). Acute rejection (AR) was significantly more common in those receiving basiliximab at induction compared to a T-cell depleting agent (75% (6/8: 3 with TCMR and 3 with AMR) versus 15% (2/13: both AMR) respectively, p=0.018). Patients developing AMR were more likely to have a positive CDC-XM using historic serum (3/5 with AMR versus 1/16 without AMR, p=0.028). Of the 12 patients with isolated DP DSA, 2 experienced AMR and 2 TCMR. All episodes of AMR were reversed with plasma exchange. Mean creatinine for those patients with graft function at baseline (18/21) was 137μmol/L and at 1 year was 133μmol/L (n=12). There were 3 deaths (post-operative haemorrhage at 2 weeks, disseminated aspergillosis at 3 weeks and a cerebral lymphoma at 4 years) and 1 graft loss (graft rupture with Banff 2B AR at 1 week). Conclusions: HLAi DD renal transplantation is associated with a high incidence of AR, with AMR in 24% of patients despite negative CDC-XM. Our limited experience suggests that: (1) T-cell depleting induction is beneficial, (2) A current negative but historic positive CDC-XM could prompt prospective antibody removal and (3) donor HLA-DP genotyping should be routine practice. Despite high rates of AR, transplantation in these high-risk recipients is still achievable with satisfactory allograft function at up to 5 years post-transplant.

Impact of Pretransplant Rituximab on Kidney Graft in Highly-Sensitized Recipients; Compared with Non-Rituximab Group

Background: Highly sensitized patients with a high level of panel reactive antibody (PRA) can have more episodes of antibody-mediated rejection (AMR) and poorer graft survival than non-sensitized patients. Rituximab is a well known monoclonal anti-CD20 antibody for the depletion of B lymphocyte. The study aim was to compare a rituximab-administered group with a non-administered group in highly sensitized recipients. Methods: We enrolled 43 patients with over 50% PRA (class I or II), who underwent living donor kidney transplantation. Sixteen patients (group R) received one dose (375mg/m2) of rituximab at 2 days prior to transplantation and 27 patients (group NR) did not. ABO-incompatible kidney transplantations were excluded. Results: Mean follow-up duration was 14.9 and 38.1 months in groups R and NR, respectively. The patients' demographics such as age, sex, dialysis duration and kind of immunosuppressive agent were not different between the two groups. There were no side effects from rituximab administration in group R. Class I PRA of group R (75.6±37.7%) was higher than that of group NR (45.7±35.8%; p=0.013). There were more acute rejection episodes within 1 year in group NR but the difference with group R was not significant (Table 1). However, two AMR episodes occurred only in group NR. The renal function of the two groups was not different. In group R, CD19 and CD20 rapidly decreased 2 days after rituximab infusion.[Figure 1.]Conclusion: There were no differences in cell-mediated rejection from the administration of rituximab. However, AMR tended to decrease in the rituximab group. To confirm the long-term anti-rejection and beneficial effect of rituximab, further study should be performed in a larger cohort. Rituximab administration 2 days prior to transplantation can be effective and safe.

Immune Function Surveillance: Association With Rejection, Infection and Cardiac Allograft Vasculopathy

BackgroundRejection, cardiac allograft vasculopathy (CAV), and infection are significant causes of mortality in heart transplantation recipients. Assessing the immune status of a particular patient remains challenging. Although endomyocardial biopsy (EMB) and angiography are effective for the identification of rejection and CAV, respectively, these are expensive, invasive, and may have numerous complications. The aim of this study was to evaluate the immune function and assess its utility in predicting rejection, CAV, and infection in heart transplantation recipients. MethodsWe prospectively obtained samples at the time of routine EMB and when clinically indicated for measurement of the ImmuKnow assay (IM), 12 cytokines and soluble CD30 (sCD30). EMB specimens were evaluated for acute cellular rejection, and antibody-mediated rejection (AMR). CAV was diagnosed by the development of angiographic coronary artery disease. Infectious episodes occurring during the next 30 days after testing were identified by the presence of positive bacterial or fungal cultures and/or viremia that prompted treatment with antimicrobials. ResultsWe collected 162 samples from 56 cardiac transplant recipients. There were 31 infection episodes, 7 AMR, and 4 CAV cases. The average IM value was significantly lower during infection, (P = .04). Soluble CD30 concentrations showed significantly positive correlation with infection episodes, (P = .001). Significant positive correlation was observed between interleukin-5(IL-5) and AMR episodes (P = .008). Tumor necrosis factor–α and IL-8 showed significant positive correlation with CAV (P = .001). ConclusionsImmune function monitoring appears promising in predicting rejection, CAV, and infection in cardiac transplantation recipients. This approach may help in more individualized immunosuppression and it may also minimize unnecessary EMBs and cardiac angiographies.

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Aim Presence of anti-donor HLA antibodues is a contraindication to transplantation in most solid organs. In contrast, most patients with high titer donor specific antibodies (DSA) and positive flow cytometric crossmatch (FCXM) still undergo liver transplantation. Antibody mediated rejection (AMR) may or may not develop after liver transplantation in such patients. We speculated that despite positive crossmatch results, cytotoxic function of existing and/or de novo DSA is what will ultimately predict development of AMR. Methods In this study we report two conflicting cases of liver transplant patients with high titer pre-transplant DSA and positive FCXM. Pre-transplant sera of patient A and B were retrospectively tested with a C1q assay to determine the cytotoxic function of DSAs. Results One patient (patient A) developed hyperacute AMR shortly after transplantation while the second patient (patient B) did not develop any signs of AMR and her post-transplant period was uneventful. In patient A, shortly after transplantation, serum amino transaminase and bilirubin levels became elevated. Serum HLA antibody testing showed high levels of class I and class II DSAs that resulted in positive T and B cell FCXM. Positive C4d staining of liver allograft biopsy indicated an episode of AMR. Patient was treated with plasmapheresis (days 1-9), Rituximab and IVIG (days 9-13) and Thymoglobulin (days 2-8). Levels of DSA and positive FCXM decreased overtime and 4 years post-transplant DSA antibodies were no longer present. In contrast, patient B did not develop any signs of post-transplant complications related to presence of HLA antibodies. Consistent with our hypothesis at the time of transplant, DSA of patient A were positive for C1q factor. In contrast C1q was negative on DSA of patient B. Conclusions We conclude that pre-transplant antibody testing and C1q assay should be considered as pre-transplant tests to be performed to liver transplant patients. Larger studies should be performed to confirm our findings.

Role of plasmapheresis in ABO-incompatible renal transplantation

BackgroundThousands of patients with chronic renal failure die yearly and are unable to have a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to remove ABO antibodies and permit ABO-incompatible (ABO-I) kidney transplants, but there is only limited research within this area and a lack of standardized protocols for TPE. This article reviews the literature to provide a historical perspective of TPE for ABO-I kidney transplantation and also provides the Johns Hopkins Hospital protocol with a focus on both titers and TPE. Study design and methodsThe TPE treatment plan is based on ABO titers with the goal of a titer of 16 or less at the anti-human globulin (AHG) phase before surgery. Pretransplant therapy consists of every-other-day TPE followed immediately by cytomegalovirus hyperimmune globulin. ABO antibody titers are closely monitored before and after transplantation. After transplantation, TPE therapy is performed for all patients to prevent rebound of anti-A and anti-B titers until tolerance or accommodation occurs. The TPE is discontinued and reinstituted based on the clinical criteria of creatinine levels, biopsy results, and ABO titer. ResultsFifty-three ABO-I kidney transplants have been completed with no episodes of hyperacute antibody-mediated rejection (AMR), and only three episodes of AMR. One-year death-censored graft survival is 100% and patient survival is 97.6%. ConclusionWhile randomized clinical trials are needed to evaluate the optimal method and protocol to remove ABO antibodies, the current literature and our results indicate a critical role for TPE in ABO-I renal transplantation.

Longitudinal evaluation of microvessel density in survivors vs. nonsurvivors of cardiac pathologic antibody-mediated rejection

Antibody-mediated rejection (AMR) of cardiac allografts is associated with reduced long-term graft survival, but not every patient with AMR develops premature graft failure. The tissue level mechanisms leading to graft failure in some patients with antibody-mediated rejection are poorly characterized. We assessed changes in myocardial microvessel density (number of capillaries per unit area) in endomyocardial biopsies over time using whole-slide microscopic imaging of CD34-stained slides and computer-assisted image analysis. Changes were compared among eight heart transplant recipients with multiple episodes of pathologic AMR who died from cardiovascular causes, eight age- and gender-matched patients with pathologic AMR who were still alive at a similar follow-up interval, and six matched controls without AMR or cellular rejection. Microvessel density decreased in the last biopsies (mean 6.52 years post-transplant) from patients with pathologic AMR and cardiovascular mortality compared to their biopsies at 6 and 12 months post-transplant [respectively, -22% (P=.02) and -25% (P=.02)]. A similar decrease was not seen for the other groups. Significantly reduced myocardial microvessel density does occur in a subset of patients with pathologic AMR who have a worse outcome. These data provide insights into the interplay between AMR, microvascular injury, and clinical outcomes.

Impact of pretransplant rituximab induction on highly sensitized kidney recipients: comparison with non-rituximab group

PurposeHighly sensitized patients with a high level of panel reactive antibody (PRA) experience more episodes of antibody-mediated rejection (AMR) and poorer graft survival than non-sensitized patients. Rituximab is a well-known monoclonal anti-CD20 antibody that causes the depletion of B lymphocytes. The aim of this study was to compare a rituximab-administered and a non-administered group of highly sensitized recipients.MethodsForty-three kidney recipients with a PRA level of ≥50% were included. Sixteen (group R) received one dose of rituximab at 2 days prior to transplantation and 27 patients (group NR) did not.ResultsPatients' demographics, such as age, sex, dialysis duration, and type of immunosuppressive agent were not different in the two groups. No side effects due to rituximab administration were observed in group R. Class I PRA of group R (75.6 ± 37.7%) was higher than that of group NR (45.7 ± 35.8%, P = 0.013). More acute rejection episodes occurred within 1 year after transplantation in group NR but the difference between the groups was not significant (18.8% in group R vs. 29.6% in group NR, P = 0.631). However, two AMR episodes occurred only in group NR. Renal functions were not different in the two groups. In group R, CD19 and CD20 rapidly decreased 2 days after rituximab infusion. Furthermore, the administration of rituximab was not linked to acute rejection.ConclusionTo confirm the long-term anti-rejection and beneficial effects of rituximab, further studies should be performed with a larger cohort. In conclusion, rituximab administration 2 days prior to transplantation is both effective and safe.

Terminal Complement Inhibition Decreases Antibody-Mediated Rejection in Sensitized Renal Transplant Recipients

Sensitized renal transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).

Human leukocyte antigen epitope analysis to assess complement- and non-complement-binding donor-specific antibody repertoire in a pediatric heart transplant recipient

This case report summarizes the spectrum of anti-human leukocyte antigen (HLA) antibody reactivity determined by single-allele Luminex immunoglobulin G and C1q binding assays before transplant, during an episode of antibody-mediated rejection (AMR), and following treatment in a sensitized pediatric heart transplant (Tx) recipient. We were able to discriminate between complement- and non-complement-binding epitope-specific antibodies present against a single donor antigen (HLA-A2) during the progression of AMR and its resolution. Our findings illustrate the usefulness of determining antibody specificities against epitopes using various Luminex-based assays.

Early and Late Acute Antibody-Mediated Rejection Differ Immunologically and in Response to Proteasome Inhibition

The efficacy of plasma cell targeted therapies for antibody-mediated rejection (AMR) has not been defined in detail. The purpose of this study was to compare early and late acute AMR in terms of immunologic characteristics and responses with proteasome inhibitor (PI) therapy. Renal transplant recipients with acute AMR were treated with PI-based regimens. Early acute AMR was defined as occurring within 6 months posttransplant. Immunodominant donor-specific antibody (iDSA) was defined as the DSA with the highest level. Results are expressed as early or late acute AMR. Thirty AMR episodes (13 early, 17 late) were treated in 12 and 16 patients. Early but not late AMR was associated with presensitization. Late AMR iDSA levels were higher, and specificities were primarily class II (DQ being most frequent). Early AMR patients demonstrated greater reduction in iDSA at 7, 14, and 30 days and at the posttreatment nadir (81.5%+21.2% vs. 51.4%+27.6%; P<0.01). Early AMR patients were more likely to demonstrate histologic resolution/improvement (87.5% vs. 53.8%; P=0.13). Both groups demonstrated significant improvement in renal function. Early and late AMR exhibit distinct immunologic characteristics and respond differently to PI therapy.

31 Value of Immunoperoxidase Staining of C3d in the Diagnosis of Antibody Mediated Rejection in Heart Transplant Recipients

Purpose: According to a recent consensus conference on antibody-mediated rejection (AMR), AMR should be defined solely by pathologic criteria. The presence of donor specific antibody (DSA) was not mandated in the AMR definition as DSA were not always detected during AMR episodes. This may be due to DSA being adhered to the donor heart. It is believed that the detection of DSA during AMR episodes might lead to worse outcome. We reviewed our heart transplant patients with AMR to assess this hypothesis. Methods and Materials: We evaluated 53 patients status post heart transplant from 2003 to 2010 with treated AMR within the first year post transplant. Of these, 14 patients had concomitant circulating DSA and 39 patients did not. Outcomes were compared for subsequent 3-year survival, freedom from cardiac allograft vasculopathy (CAV, stenosis 30%), and freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, heart failure, coronary stenting, need for defibrillator, stroke, and new peripheral vascular disease). Results: Patients who developed treated AMR with and without circulating DSA were found to have similar subsequent 3-year survival (71% vs. 82%, p 0.37), subsequent 3-year freedom from CAV (80% vs. 86%, p 0.62), and freedom from NF-MACE (100% vs. 92%, p 0.29). There was no difference in the incidence of hemodynamic compromise rejection between groups (7% vs. 8%, p 0.96). Conclusions: The finding of DSA in conjunction with pathology confirmed AMR does not appear to impact 3-year outcome after heart transplantation. Further studies to assess strength and other characteristics of DSA during AMR episodes may shed light to define its role in clinical AMR.