ABO-Incompatible Matching Significantly Enhances Transplant Rates in Kidney Paired Donation

BACKGROUND: Although preformed donor-specific anti-human leukocyte antigen antibodies (DSA) can be overcome by plasmapheresis-based strategies with some success in renal transplantation, kidney paired donation (KPD) is a more effective strategy to avoid DSA. In contrast, ABO incompatibility can be crossed with outcomes equivalent to ABO-compatible transplantation. Here, we report the ability of accepting human leukocyte antigen-compatible but ABO-incompatible donors to increase the number of exchanges in a KPD program.
METHODS: In the Australian KPD program, virtual crossmatch is used to allocate suitable donors to recipients. Acceptance of ABO-incompatible donors is allowed in cases where anti-blood group antibody titres are deemed amenable to removal by apheresis or immunoabsorption. The number of matched recipients, identified chains, and transplants performed with and without acceptance of ABO incompatibility was analyzed.
RESULTS: In 2 years, 115 pairs were included in nine quarterly match runs. Incompatibility due to DSA accounted for 86% of the listed pairs and 52% were also blood group incompatible to their coregistered donor. Median calculated panel-reactive antibody in registered recipients was 83% (mean, 67%±37%). ABO-incompatible donors were accepted for 36 patients. Two waitlist recipients and 48 KPD candidates were matched and transplanted. Ten recipients (20%) of an ABO-incompatible donor kidney were distributed across 8 chains that resulted in 21 recipients being transplanted. Thus, without ABO-incompatible matching, only 27 recipients in 12 chains would have been transplanted.
CONCLUSION: Acceptance of blood group-incompatible donors for patients with low to moderate anti-blood group antibody significantly increases transplant rates for highly sensitized recipients (read more)

Kidney Allograft Survival After Acute Rejection, the Value of Follow-Up Biopsies

Kidney allografts are frequently lost due to alloimmunity. Still, the impact of early acute rejection (AR) on long-term graft survival is debated. We examined this relationship focusing on graft histology post-AR and assessing specific causes of graft loss. Included are 797 recipients without anti-donor antibodies (DSA) at transplant who had 1 year protocol biopsies. 15.2% of recipients had AR diagnosed by protocol or clinical biopsies. Compared to no-AR, all histologic types of AR led to abnormal histology in 1 and 2 years protocol biopsies, including more fibrosis + inflammation (6.3% vs. 21.9%), moderate/severe fibrosis (7.7% vs. 13.5%) and transplant glomerulopathy (1.4% vs. 8.3%, all p < 0.0001). AR were associated with reduced graft survival (HR = 3.07 (1.92–4.94), p < 0.0001). However, only those AR episodes followed by abnormal histology led to reduced graft survival. Early AR related to more late alloimmune-mediated graft losses, particularly transplant glomerulopathy (31% of losses). Related to this outcome, recipients with AR were more likely to have new DSA class II 1 year posttransplant (no-AR, 11.1%; AR, 21.2%, p = 0.039). In DSA negative recipients, early AR often leads to persistent graft inflammation and increases the risk of new DSA II production. Both of these post-AR events are associated with increased risk of graft loss (read more)

Analysis of Anti-HLA Antibodies in Sensitized Kidney Transplant Candidates Subjected to Desensitization with Intravenous Immunoglobulin and Rituximab

Background: Preexisting donor-specific antibodies against human leukocyte antigens are major risk factors for acute antibody-mediated and chronic rejection of kidney transplant grafts. Immunomodulation (desensitization) protocols may reduce antibody concentration and improve the success of transplant. We investigated the effect of desensitization with intravenous immunoglobulin and rituximab on the antibody profile in highly sensitized kidney transplant candidates. Methods: In 31 transplant candidates (calculated panel-reactive antibody [cPRA], 34%–99%), desensitization included intravenous immunoglobulin on days 0 and 30 and a single dose of rituximab on day 15. Anti–human leukocyte antigen antibodies were analyzed before and after desensitization. Results: Reduction of cPRA from 25% to 50% was noted for anti–class I (5 patients, within 20–60 days) and anti–class II (3 patients, within 10–20 days) antibodies. After initial reduction of cPRA, the cPRA increased within 120 days. In 24 patients, decrease in mean fluorescence intensity of antibodies by more than 50% was noted at follow-up, but there was no reduction of cPRA. Rebound occurred in 65% patients for anti–class I antibodies at 350 days and anti–class II antibodies at 101 to 200 days. Probability of rebound effect was higher in patients with mean fluorescence intensity of more than 10,700 before desensitization, anti–class II antibodies, and history of previous transplant. Conclusions: The desensitization protocol had limited efficacy in highly sensitized kidney transplant candidate because of the short period with antibody reduction and high frequency of rebound effect (read more)

ASKP1240, a Fully Human Anti-CD40 Monoclonal Antibody, Prolongs Pancreatic Islet Allograft Survival in Nonhuman Primates

A strategy for inhibiting CD40 has been considered as an alternative approach for immunosuppression because of undesirable effects of anti-CD154 monoclonal antibodies (mAbs). Previously, we demonstrated that ASKP1240, which is a fully human anti-CD40 mAb, significantly prolonged kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic complications. Herein, we evaluated the effect of ASKP1240 on pancreatic islet transplantation (PITx) in cynomolgus monkeys. Diabetes was induced by total pancreatectomy, and islet allografts were transplanted into the liver. Following PITx (8201–12 438 IEQ/kg), blood glucose levels normalized promptly in all animals. Control islet allografts were rejected within 9 days (n = 3), whereas ASKP1240 (10 mg/kg) given on postoperative days 0, 4, 7, 11 and 14 (induction treatment, n = 5) significantly prolonged graft survival time (GST) to >15, >23, 210, 250 and >608 days, respectively. When ASKP1240 (5 mg/kg) was administered weekly thereafter up to post-PITx 6 months (maintenance treatment, n = 4), GST was markedly prolonged to >96, >115, 523 and >607 days. During the ASKP1240 treatment period, both anti-donor cellular responses and development of anti-donor antibodies were abolished, and no serious adverse events were noted. ASKP1240 appears to be a promising candidate for immunosuppression in clinical PIT (read more)

B cell regulation and its application to transplantation

There has been increasing interest in the role played by B cells and their associated antibody in the immune response to an allograft, driven by the need to undertake antibody-incompatible transplantation and evidence suggesting that B cells play a role in acute T cell-mediated rejection and in acute and chronic antibody-mediated rejection. This review focuses on the molecular events, both activating and inhibitory, which control B cell activation, and considers how this information might inform therapeutic strategies. Potential targets include the BAFF (B cell-activating factor belonging to the tumour necrosis factor family) and CD40-CD40L pathways and inhibitory molecules, such as CD22 and FcγRIIB. B cells can also play an immunomodulatory role via interleukin (IL)10 production and may contribute to transplant tolerance. The expansion of allograft-specific IL10-producing B cells may be an additional therapeutic goal. Thus, the treatment paradigm required in transplantation has shifted from that of simple B cell depletion, to that of a more subtle, differential manipulation of different B cell subsets (read more)

Elevated Pretransplantation Soluble BAFF Is Associated With an Increased Risk of Acute Antibody-Mediated Rejection

BACKGROUND: B cells play an important role in renal allograft pathology, particularly in acute and chronic antibody-mediated rejection (AMR). B-cell activating factor belonging to the tumor necrosis factor family (BAFF; also known as BLyS) is a cytokine that enhances B-cell survival and proliferation.
METHODS: We analyzed serum BAFF levels in 32 patients undergoing antibody-incompatible (Ai) renal transplantation and 319 antibody-compatible transplant recipients and sought to determine whether there was a correlation with acute rejection and with transplant function and survival.
RESULTS: We demonstrate that, in patients undergoing Ai transplantation, elevated serum BAFF levels at baseline (before both antibody removal/desensitization and transplantation) are associated with an increased risk of subsequent AMR. In antibody-compatible transplant recipients at lower risk of AMR, no statistically significant association was observed between pretransplantation serum BAFF and AMR.
CONCLUSIONS: These data raise the possibility that, in high immunologic risk patients undergoing Ai transplantation, the presence of elevated pretransplantation serum BAFF might identify those at increased risk of AMR. BAFF neutralization may be an interesting therapeutic strategy to explore in these patients, particularly because such agents are available and have already been used in the treatment of autoimmunity (read more)

A prospective study evaluating the role of donor-specific anti-endothelial crossmatch (XM-ONE assay) in predicting living donor kidney transplant outcome

Anti-endothelial cell antibodies (AECAs) may play a role in allograft rejection. We prospectively tested 150 consecutive living donor kidney transplant recipients, with transplants performed at Northwestern Memorial Hospital between January and December 2010, using the donor-specific endothelial (XM-ONE) crossmatch. 88/150 Patients received standard of care (SOC) immunosuppression and analyzed separately, in addition to the complete study cohort. Patients were followed for one year and XM-ONE results were analyzed in relation to occurrence of acute rejection, proteinuria, serum creatinine levels, and biopsy proven fibrosis. No correlation was found between XM-ONE results and protocol or "for-cause" biopsy proven acute rejection or vasculopathy at 12months. When IgG+ and IgM+ results of the XM-ONE assay were combined, a correlation with proteinuria at 12months was observed (p=0.047). Although IgG+XM-ONE results were associated with significantly higher creatinine at 6months (p=0.018), significance was lost at 12months. Conversely, patients with an IgM+XM-ONE crossmatch had significantly lower creatinine at 1month (p=0.019), 3months (p=0.0045), and 6months (p=0.038) post-transplant, but lost statistical significance at 12months (p=0.67) post-transplant. In summary, the presence of AECAs as determined by a positive XM-ONE result was not predictive of overall poorer graft outcome after one year in our center (read more)

Vimentin antibody production in transplant patients and immunomodulatory effects of vimentin in-vitro

We investigated the presence of antibodies to vimentin in 150 patients awaiting transplant, (50 kidney, 50 liver and 50 thoracic) and in 51 previously transplanted kidney patients whose grafts had failed. Patients with primary end stage thoracic or kidney disease did not have increased levels of vimentin antibodies, but those with primary liver failure and those with kidney graft failure did. Those with kidney graft failure were more likely to form vimentin antibodies if the patient was HLA-DQ2 positive (p=<0.001). Further to this, we observed antibody mediated rejection in five HLA-DQ2 positive re-transplant patients where no other antibodies were identified. We investigated the effects of vimentin protein on cytokine production in phytohaemagglutinin stimulated and unstimulated peripheral blood mononuclear cells. When exposed to vimentin at low levels there was increased production of IL-10. When cultures were stimulated, there was a decrease in IL-10, IL-2 and IFN-gamma production and a large increase in IL-4 production (p=0.028) compared to the controls. These results suggest that under normal conditions exposure to vimentin can lead to regulation of the immune response. However, if the immune system is active, exposure to vimentin can enhance Th-2 immunity (read more)

Structural aspects of HLA class I epitopes reacting with human monoclonal antibodies in Ig-binding, C1q-binding and lymphocytotoxicity assays

This study addresses the reactivity patterns of human cytotoxic HLA class I epitope-specific monoclonal antibodies in Ig-binding and complement component C1q-binding Luminex assays in comparison with complement-dependent lymphocytotoxicity data reported at the 13th International HLA Workshop. Some monoclonal antibodies reacted similarly with epitope-carrying alleles in all three assays but others showed different reactivity patterns. These reactivity differences were analyzed with HLAMatchmaker and we incorporated the concept that eplets are essential parts of structural epitopes which can contact the six Complementarity Determining Regions (CDRs) of antibody. The data show that technique-dependent reactivity patterns are associated with distinct differences between polymorphic amino acid configurations on eplet-defined structural epitopes. The findings have been viewed in context of antigen-antibody complex formation that results in the release of free energy necessary to stabilize binding and to induce conformational changes in the antibody molecule to expose the C1q binding site, the first step of complement activation. Moreover the amount of free energy should be sufficient to induce a conformational change of C1q thereby initiating the first stages of the classical complement cascade leading to lymphocytotoxicity. The complement-fixing properties of HLA antibodies require not only specific recognition eplets but also depend on interactions of other CDRs with critical amino acid configurations within the structural epitope. Eplet-carrying alleles that lack such configurations may only bind with antibody. This concept is important to our understanding whether or not complement-fixing donor-specific HLA antibodies can initiate antibody-mediated rejection (read more)

Role of anti-vimentin antibodies in allograft rejection

Production of anti-vimentin antibodies (AVA) after solid organ transplantation are common. Although classically thought to be expressed mainly within the cytosol, recent evidence demonstrates that extracellular or cell surface expression of vimentin is not unusual. This review examines the evidence to assess whether AVA contribute to allograft pathology. Clinical studies suggest that AVA are associated with cardiac allograft vasculopathy in heart transplant recipients. Studies in non-human primates confirm that production of AVA after renal and heart transplantation are not inhibited by Cyclosporine. Experimental studies have demonstrated that mice pre-immunised with vimentin undergo accelerated acute rejection and vascular intimal occlusion of cardiac allografts. Adoptive transfer of hyperimmune sera containing AVA into B-cell-knock-out mice caused accelerated rejection of allografted hearts, this is clear evidence that antibodies to vimentin accelerate rejection. AVA act in concert with the alloimmune response and AVA do not damage syngeneic or native heart allografts. Confocal microscopy of allografted organs in vimentin immunised mice shows extensive expression of vimentin on endothelial cells, apoptotic leukocytes and platelet/leukocyte conjugates, co-localising with C4d. One explanation for the ability of AVA to accelerate rejection would be fixation of complement within the graft and subsequent pro-inflammatory effects; there may also be interactions with platelets within the vasculature (read more)