Successful Renal Transplantation across Simultaneous ABO Incompatible and Positive Crossmatch Barriers

ABO incompatibility and human leukocyte antigen (HLA) sensitization remain the two largest barriers to optimal utilization of kidneys from live donors. Here we describe the first successful transplantation of patients who were both ABO incompatible and crossmatch positive with their only available donor. A preconditioning regimen of plasmapheresis (PP) and low-dose CMV hyperimmune globulin (CMVIg) was delivered every other day until donor-specific antibody (DSA) titers were reduced to a safe level and isoagglutinin titers were < or =16. Each patient received quadruple sequential immunosuppression, splenectomy and three protocol post-transplant PP/CMVIg treatments. There was no hyperacute rejection. Two of the three patients had a persistent positive cytotoxic crossmatch on the day of transplant and eliminated their DSA subsequently. Antibody-mediated rejection (AMR) in one patient was reversed by reinitiating PP/CMVIg and anti-CD20. The patients are more than 9 months post-transplant with excellent graft function. Preconditioning with PP/CMVIg results in a durable suppression of DSA and permits accommodation of the allograft to a discordant blood type. The ability to cross these two barriers simultaneously is clinically important as sensitized patients have often exhausted their blood type compatible living donors during previous transplants.     

Overcoming a Positive Crossmatch in Living-Donor Kidney Transplantation

Many patients who have an otherwise acceptable living-kidney donor do not undergo transplantation because of the presence of antibodies against the donor cells resulting in a positive crossmatch. In the current study, 14 patients with a positive cytotoxic crossmatch (titer 相似文献   

ABO Antibody Titer and Risk of Antibody‐Mediated Rejection in ABO‐Incompatible Renal Transplantation

Therapeutic plasma exchange (TPE) preconditioning with immunosuppressive therapy reduces ABO antibody titers, permitting engraftment of ABO‐incompatible (ABO‐I) kidney transplants. The posttransplant predictive role of ABO antibody titers for antibody‐mediated rejection (AMR) is unknown. This retrospective study evaluated 46 individuals who received TPE to permit ABO‐I kidney transplantation. ABO antibody titers were performed using donor‐type indicator red cells. Seven individuals (15.2%) experienced clinical or subclinical AMR. There was no significant difference between recipient blood group, number of pretransplant TPE and baseline titer between those with and without AMR. At 1–2 weeks posttransplant the median titer was 64 (range 4 – 512) among individuals with AMR and 16 (range 2 – 256) among individuals without AMR. Total agglutination reactivity score was significantly higher among individuals with AMR (p = 0.046). The risk of AMR was significantly higher among individuals with an elevated posttransplant titer of ≥64 (p = 0.006). The sensitivity of an elevated posttransplant titer was 57.1% with a specificity of 79.5%. The positive predictive value was 33.3% and the negative predictive value was 91.2%. Most individuals with AMR have an elevated titer, however, the positive predictive value of a high titer for AMR is poor.     

Baseline Donor‐Specific Antibody Levels and Outcomes in Positive Crossmatch Kidney Transplantation

Renal transplant candidates with donor‐specific alloantibody (DSA) have increased risk of antibody‐mediated allograft injury. The goal of this study was to correlate the risk of antibody‐mediated rejection (AMR), transplant glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of pretransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (?XM) transplants performed between April 2000 and July 2007. Using a combination of cell‐based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and ?XM groups. In +XM transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of ?XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody‐mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long‐term allograft survival highlighting the need for improved therapy for these candidates.     

Targeting B Cells and Antibody in Transplantation

There has been increasing interest in the role played by B cells, plasma 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 cellular rejection and in acute and chronic antibody‐mediated rejection. A number of immunosuppressive agents have emerged which target B cells, plasma cells and/or antibody, for example, the B cell‐depleting CD20 antibody rituximab. This review describes recent developments in the use of such agents, our understanding of the role of B cells in alloimmunity and the application of this knowledge toward novel therapies in transplantation. It also considers the evidence to date suggesting that B cells may act as regulators of an alloimmune response. Thus, future attempts to target B cells will need to address the problem of how to inhibit effector B cells, while enhancing those with regulatory capacity.     

Desensitization in kidney transplantation: review and future perspectives

More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti‐HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high‐dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high‐dose IVIg+rituximab in non‐randomized trials. Overall experience in multiple centers, however, has shown high antibody‐mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low‐dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low‐dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell‐targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non‐deletional strategies with IVIg.     

Management of the sensitized cardiac recipient: the use of plasmapheresis and intravenous immunoglobulin

Previously, we reported that the combination of plasmapheresis (PP) and intravenous immunoglobulin (IVIg) allow sensitized patients to undergo orthotopic heart transplantation (OHT), even across a positive crossmatch. In the current study, the effect of that combination, PP+IVIg, on survival of a larger group of such recipients is investigated. The latter group (I) consisted of 35 sensitized patients who received PP+IVIG together with standard immunosuppressive drugs. Rejection was seen in 11 patients, findings strongly suggestive of a vascular (humoral) being identified in five of those cases. Four deaths occurred, two of them in the immediate post-operative period, one after almost six months, and one after almost two yr post-OHT. Follow-up range 4.5 months to 7.8 yr post-OHT (average=1.1 yr). Patient survival was analyzed after generation of a Kaplan-Meier plot. Comparison with a control OHT group (II) given standard immunosuppressive drugs only (N=276) showed enhanced survival of group I (p=0.0414 by log-rank test). We conclude that the combination of PP and IVIG (i) is associated with declines in T- and B-percent-reactive antibody and in crossmatch positivity, and (ii) is very useful in the management of the sensitized cardiac patient undergoing OHT, often allowing a successful outcome to transplantation in the face of a positive crossmatch.     

ABO incompatible living donor kidney transplantation in Korea: highly uniform protocols and good medium‐term outcome

The organ shortage is as serious in Korea as in other parts of the world. As about one‐third of the potential living donors are ABO incompatible (ABOi), transplantation across the blood group barrier can help overcome this shortage. One hundred and twenty‐five ABOi kidney transplantations (KTs) were performed between 2007 and 2010 in Korea. We collected the perioperative and follow‐up data for 118 of these patients until September 2011. The preconditioning and immunosuppressive protocols were almost identical across the different transplant centers, with rituximab but no splenectomy; pre‐transplant plasmapheresis (PP) with target anti‐A/B titer 8 or 16 on transplant day, on‐demand, rather than routine, post‐transplant PP, and tacrolimus‐based immunosuppressants. The number of patients and participating centers showed a rapid increase over time, and in 2010, ABOi KT (n = 79) comprised 10% of all the living donor KTs in Korea. The mean follow‐up period was 21 months (range, 1–56 months). Sixteen (14%) patients developed acute rejection, and three of these had antibody‐mediated rejection (AMR). Two‐yr patient and graft survival were 99.2% and 97.5%, respectively. No graft was lost due to AMR. ABOi KT is rapidly expanding in Korea with excellent medium‐term outcome and will help mitigate the organ shortage.     

Splenic Irradiation for the Treatment of Severe Antibody‐Mediated Rejection

Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody‐mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long‐term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor‐specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short‐ or medium‐term adverse effects of the radiation therapy. One‐year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy.     

Prognostic tools to assess candidacy for and efficacy of antibody‐removal therapy

Currently, the ability to predict or monitor the efficacy of HLA antibody–removal therapies is deficient. We previously reported that titration studies are a consistent and accurate means of assessing antibody strength. To test whether titration studies can also predict which patients are better candidates for desensitization, we studied 38 patients from 3 centers (29 receiving plasmapheresis/low‐dose intravenous immunoglobulin [IVIg]; 9 patients receiving high‐dose IVIg). For patients undergoing plasmapheresis/low‐dose IVIg, antibody titer reduction correlated with number of treatment cycles for both class I and II antibodies but only up to approximately 4 cycles. Reduction in titer slowed with additional cycles, suggesting a limit to the efficacy of this approach. Furthermore, initial titer (predesensitization) can guide the selection of candidates for successful antibody‐removal treatment. In our experience, patients with antibodies at an initial titer >1:512 could not be reduced to the goal of a negative lymphocyte crossmatch, corresponding to a 1:16 titer, despite a significant increase in the number of treatment cycles. Change in mean fluorescence intensity (MFI) value did not correlate with success of treatment if initial MFI values were >10 000, likely due to single antigen bead saturation. Overall, we present a potential prognostic tool to predict candidacy and a monitoring tool to assess efficacy of desensitization treatment.     

A2/A2B to B Renal Transplantation: Past,Present, and Future Directions

One component of the new national kidney allocation system (KAS) in the United States that was implemented on December 4, 2014, was the allocation of kidneys from A₂ and A₂B (A, non‐A₁ and AB, non‐A₁B) deceased donors into blood group B candidates (A₂/A₂B → B). In so far as this is an important component of the new KAS that has the potential to further increase the access to transplantation for blood group B candidates on the waiting list, most of whom are minority candidates, we will review the body of evidence and historical perspectives that led to its inclusion in the new KAS. This review will also describe prospects for more widespread use of A₂/A₂B → B transplantation and a novel mechanism of humoral immunosuppression in B patients before and after transplantation with an A₂ or A₂B kidney.