Desensitization Strategies Research Articles

P118 : HEART TRANSPLANT AFTER ANTIBODY REDUCTION WITH BORTEZOMIB AND PLASMAPHERESIS IN A HIGHLY SENSITIZED PATIENT

Aim To describe the case of a successful heart transplant in a highly sensitized individual by antibody reduction with bortezomib and plasmapheresis. Methods A 38 year old female patient with a pre-transplant cPRA of 81% (Class I & II) was desensitized with 5 sessions of plasmapheresis and two doses of bortezomib. The alloimmune status was determined by solid phase single antigen and phenotype bead based assays. Post transplant follow up included endocardial biopsies and DSA monitoring. Results The patient’s class I and class II PRAs decreased from 81% to 44% and 31% respectively by day 6 of desensitization. The overall strength of HLA antibodies was also reduced. A prospective crossmatch was performed with a local donor. The crossmatch was technically negative, but the Flow median Channel Shift (MCS) was closer to the positive cut off value. The patient underwent another PP and was tested and crossmatched again when the MCS was significantly below the positive cutoff value. The patient received the transplant and is doing well 18 months post transplant. Conclusions This case report demonstrates the potential efficacy of bortezomib therapy in addition to plasmapheresis to transplant highly sensitized patient awaiting heart transplant. Because of limitations with the prospective crossmatch for heart transplant candidates, desensitization of the potential recipient to increase the likelihood for an acceptable donor by depleting pre-existing antibodies against the unacceptable antigens is an attractive option. Plasmapheresis and IVIG in combination with rituximab has been utilized in kidney transplant recipients with a living donor; however, candidates awaiting a deceased donor represent a significant immunological and logistical challenge. Rituxan does not deplete circulating plasma cells that produce antibodies. Bortezomib has been shown to induce plasma cell apoptosis. However, its use prior to heart transplant has been limited. More studies are needed to evaluate the efficacy of bortezomib-based desensitization strategy in heart transplant set up. Patient is currently pursuing her degree as an echo technician.

Dry roasting enhances peanut-induced allergic sensitization across mucosal and cutaneous routes in mice

Dry roasting enhances peanut-induced allergic sensitization across mucosal and cutaneous routes in mice

Approach to the Sensitized Patient Awaiting Heart Transplantation

The management of the sensitized patient awaiting heart transplant remains a challenge and an active area of research. The development of solid-phase immunoassays (including the C1q assay) has allowed high-resolution determination of antibodies most likely to be associated with antibody-mediated rejection and adverse outcomes. The precision of these techniques has permitted the adoption of the virtual crossmatch, substantially expanding the donor pool for sensitized patients and reducing wait times to transplant. Desensitization strategies continue to evolve, and the most effective therapies appear to be a combined approach utilizing antibody depletion, targeted B cell or plasma cell therapy, or immunomodulation. Further therapy in addition to cytolytic induction may be required at transplant, with judicious monitoring post-transplant for antibody rebound and rejection.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

First Experiences With Kidney Transplantation in a Model of Sensitized Rhesus Macaques.

[Background] Sensitized patients comprise up to a third of the kidney waiting list. Preformed and de-novo alloantibody post transplantation (TX) significantly deteriorate graft survival. Currently used desensitization strategies are time-consuming, expensive and moderately effective. To better understand the mechanisms involved in allograft rejection in sensitized patients we aim to establish a rigorous model of solid organ TX in sensitized non-human primates (NHP). [Methods] Fully mismatched rhesus macaques were sensitized with kidney or skin TX. Immunologic responses were monitored by T-cell crossmatch by flow cytometry. After stabilization the animals underwent native nephrectomy and kidney TX from their prior kidney/skin donor. Immunosuppression (IS) included Basiliximab (0.3mg/kg IV day 0,4), Tacrolimus (0.05mg/kg IM BID, trough level 10-15ng/ml) and Mycophenolate mofetil (MMF; 30mg/kg PO BID) combined with tapered methylprednisolone. Assessment comprised laboratory testing, urine output and clinical monitoring. After sacrifice kidney grafts were submitted to pathology for H&E, PAS and C4d staining. Survival results were compared to a group of non-sensitized monkeys with comparable mismatch and IS for 140 days post kidney TX. [Results] 5 monkeys were transplanted. T-cell flow crossmatch showed mean fluorescence intensities between 1.7 and 6.5 fold over baseline on the day of the TX. Survival calculated by Kaplan-Meier method was median 6 days compared to 183 days in the non-sensitized group (p<0.001). All sensitized animals had to be sacrificed due to worsening clinical state and concomitant kidney failure. Histology revealed mixed cellular and humoral rejection in 2/5 grafts, BANFF ACRIIa, C4d1 and ACRIII, C4d2; these had the longest survival, 4 and 8 days respectively. Other grafts showed acute tubular injury/necrosis without signs of rejection. [Conclusion] These results show that kidney TX into sensitized recipients using conventional IS leads to aggressive and rapid mixed rejection. These results support the use of more potent induction therapies, such as T cell depletion, in order to overcome the immune barrier established in sensitized patients. Currently we are optimizing such therapies for the use in NHP. We believe that this preclinical model will be an invaluable tool in the development of novel desensitization therapies.

Tailored desensitization strategies in ABO blood group antibody incompatible renal transplantation

ABO blood group incompatible renal transplantation, using desensitization procedures, is an effective strategy. Efforts have been made to reduce desensitization: these are usually applied to all patients indiscriminately. The Guy's Hospital ABO blood group incompatible desensitization regimen uses a tiered approach, tailoring strategy according to initial antibody titres. Sixty-two ABO blood group incompatible living donor transplant recipients were compared with 167 recipients of blood group compatible living donor renal transplants. There were no statistically significant differences in allograft survival rates at 1 or 3 years post-transplant, rejection in the first year post-transplant or renal function in the first 3 years post-transplant. There was a higher rate of death in ABO blood group incompatible transplant recipients - this could be associated with differences in age and HLA mismatch between the two groups. Four ABO blood group incompatible patients experienced antibody-mediated rejection (no episode was associated with a rise in ABO blood group antibodies). Of the patients who received no desensitization, or rituximab alone, none has experienced antibody mediated rejection or experienced allograft loss. Tailoring the use of desensitization in ABO blood group incompatible renal transplantation according to initial ABO blood group antibody titres led to comparable results to blood group compatible transplantation.

There Is Hope: Autogenic Biofeedback Training for the Treatment of Psoriasis

Many college students experience stress-related illness, and in one study, 82% of students reported significant improvement in health when they participated in a semester-long stress management program. The factors that contribute to symptom reduction are illustrated by the case report of a 23-year-old male student who had been suffering from psoriasis for the past 5 years, which was not alleviated with medication and traditional medical treatment. He participated in an integrated self-regulation program consisting of daily self-healing home practice for 3 weeks, a desensitization strategy, autogenic training, and biofeedback training, coupled with pre- and posttreatment biofeedback assessments. Results showed a significant improvement in the clearing of the skin, more positive self-talk, and improved posture. The benefits have been maintained at the 4-month follow-up. Discussed are the training components and procedures along with factors that contributed to the clinical success and that can be applied to numerous other stress-related disorders.

Interleukin 5 immunotherapy depletes alloreactive plasma cells

BackgroundLong-lived plasma cells (PCs) that form after alloantigen sensitization produce donor-specific alloantibodies that generate a positive serum crossmatch and preclude transplantation. New approaches for desensitization, including PC depletion with proteasome inhibition, show promise but carry considerable toxicity. Recently, eosinophils have been shown to govern PC persistence. Interleukin 5 (IL-5) depletion is known to reduce eosinophils in human asthmatics. We hypothesized that treatment with an anti-IL-5 antibody can deplete alloreactive PCs, reduce donor-specific alloantibodies, and serve as a less toxic alternative to proteasome inhibition. MethodsBALB/c mice were sensitized with B6 skin allografts. Starting at 8 wk after sensitization, control mice received injections of phosphate-buffered saline, whereas experimental mice received weekly injections of an anti-IL-5 antibody. PCs were enumerated by enzyme-linked immunosorbent spot after 8 wk. ResultsAll control and experimental recipients of skin allografts developed positive crossmatches when screened at 8 wk after sensitization. All experimental mice treated with anti-IL-5 showed a reduction in their total PC numbers. Also, in contrast to the known adverse effects of proteasome inhibition, experimental mice treated with anti-IL-5 exhibited negligible weight loss or lymphopenia. ConclusionsTreatment with anti-IL-5 is sufficient to reduce, but not eliminate, alloreactive PCs in the bone marrow. This is because of the targeted reduction of eosinophils leading to a reduction in the PC survival factors a proliferation-inducing ligand and IL-6. Generalized toxicity was not observed in experimental mice. Overall, IL-5 directed immunotherapy can eliminate PC's but is unlikely to be a clinically significant desensitization strategy given the persistence of DSA

Kidney transplantation across HLA and ABO antibody barriers

A significant number of kidney transplantations in industrialized countries is currently performed over human leukocyte antigen (HLA) or ABO antibody barriers after living donation to encounter the increasing shortage of organs from deceased donors. Although patients with moderate titers of anti-A/B antibodies may easily be desensitized with no negative impact on allograft survival, recipients with high titers and HLA sensitized patients demonstrate a substantial risk for antibody-mediated rejection, limiting long-term outcomes. The use of powerful desensitization strategies including plasmapheresis and immunoadsorption, extended therapeutic options such as the application of the recently introduced complement inhibitors, and refined antibody detection techniques may further facilitate transplantations, especially in the HLA-sensitized kidney transplant recipient. On the contrary, special strategies such as the Eurotransplant Acceptable Mismatch Program or kidney paired exchange help improving long-term outcomes in these difficult to transplant patients by circumventing the HLA (or ABO) antibody barrier. As compared with waiting for a compatible deceased donor organ, HLA and ABO incompatible transplantations performed in experienced centers have become a reasonable alternative for end-stage kidney disease patients with an incompatible live donor. Whenever possible, however, the transplantation should be performed between ABO compatible donor-recipient pairs in the absence of positive crossmatch results.

Heart Transplant with Donor-Specific Antibody after Immunoadsorption plus Rituximab: A Case Report

Different desensitization strategies are available for treating patients with preformed human leukocyte antigen (HLA) antibodies. A highly presensitized heart recipient received immunoadsorption and rituximab therapy. The patient, with end-stage heart failure, was positive only for antibodies of HLA class I (anti-A2, A10, B17), and Luminex platform (One Lambda kit) showed a panel-reactive antibody score of 64%. The patient's serum was tested repeatedly in both complement-dependent cytotoxicity and flow-cytometry crossmatches against cells from different potential organ donors. The results of these crossmatches were positive on flow cytometry when tested with HLA-A2, A10, and B17 but were still negative on cytotoxicity. The patient was treated with a desensitization regimen; this treatment immediately decreased antibody levels of 70% and the patient subsequently received a transplant with donor-specific HLA antibody (HLA-A2). After more than 2 years, graft function remains normal and the clinical status of the patient is stable.

Outcome of Desensitization in Human Leukocyte Antigen– and ABO-Incompatible Living Donor Kidney Transplantation: A Single-Center Experience in More Than 100 Patients

BackgroundAntibody-mediated rejection (AMR) and inferior graft outcome remain the 2 most important obstacles to successful kidney transplantation in human leukocyte antigen (HLA)- and ABO-incompatible recipients. We report a single-center experience in the outcome of desensitized living donor HLA- and ABO-incompatible kidney transplantation. MethodsSince 2007 we included 2 groups in our desensitization program. HLA-incompatible living donor kidney transplant candidates displaying donor-specific antibodies (DSA) with or without a positive T-cell and/or B-cell flow crossmatch (FCXM). Second, those displaying DSA with positive T-cell immunoglobulin (Ig)G AHG CDC CXM with a titer of ≤1:8, as well as all ABO-incompatible living donor kidney transplant candidates with an IgM isoagglutinin titer ≤ 256. They were risk stratified for AMR and underwent individualized desensitization protocol: ABO-incompatible and HLA-incompatible candidates with either positive AHG CDC CXM or positive T and/or B IgG flow CXM with repeat HLA mismatch from a previous transplantation were deemed to be high risk and received a single dose of Rituximab, therapeutic plasma exchange and high-dose intravenous immunoglobulin (IVIG) (2 g/kg). HLA-incompatible candidates with negative CDC but positive T and/or B IgG FCXM were deemed intermediate risk, receiving rituximab and high-dose IVIG. Those with positive DSA but negative flow and CDC CXM were deemed low risk, receiving low-dose IVIG (1 g/kg). All patients received induction with thymoglobulin and were maintained on a tacrolimus-based immunosuppressive regimen. ResultsAmong 124 incompatible recipients, 85 received HLA-incompatible and 39 ABO-incompatible living donor kidney transplantations after desensitization. Risk stratification for HLA-incompatible transplants revealed 61 high-risk, 42 intermediate-risk, and 21 low-risk cases. Ninety-nine (80%) were primary transplants. At a median follow-up of 23 (range 1–53) months, patient survival was 98% and death censored graft survival 96%. Mean serum creatinine was 84 μmol/L (range 41–169). Acute cellular rejection was observed in 15 (12%) and AMR in 5 (4%) patients. All rejection episodes responded to treatment except 1 AMR in an ABO-incompatible transplant that led to graft failure. ConclusionOur risk stratification for desensitization strategy achieved a low incidence of AMR among HLA- and ABO-incompatible kidney transplant recipients. Their 2-year data appear to be comparable to HLA- and ABO-compatible transplantations.

Mesenchymal stem cell transfusion for desensitization of positive lymphocyte cross‐match before kidney transplantation: outcome of 3 cases

Donor specific antibodies (DSA) and a positive cross-match are contraindications for kidney transplantation. Trials of allograft transplantation across the HLA barrier have employed desensitization strategies, including the use of plasmapheresis, intravenous immunoglobulins, anti-B-cell monoclonal antibodies and splenectomy, associated with high-intensity immunosuppressive regimens. Our case 1 report suffered from repeatedly positive lymphocyte cross match after 1st renal transplantation. Graft nephrectomy could not correct the state of sensitization. Splenectomy was done in a trial to get rid of the antibody producing clone. Furthermore plasmapheresis with low dose IVIG could not as well revert the state of sensitization for the patient. About 50 millions donor specific MSCs were injected to the patient. MSCs transfusion proved to be the only procedure which could achieve successful desensitization before performing the second transplantation owing to their immunosuppressive properties. This case indicates that DS-MSCs is a potential option for anti-HLA desensitization. In cases 2 and 3 IV DS-MSCs transfusion was selected from the start as a successful line of treatment for pre renal transplantation desensitization to save other unnecessary lines of treatment that were tried in case 1.

Alloimmunosensitization in Left Ventricular Assist Device Recipients and Impact on Posttransplantation Outcome

Left ventricular assist devices (LVADs) have become an established surgical therapy for patients with end-stage heart failure who require hemodynamic support as a bridge-to-transplant or destination therapy. However, the anatomic and physiologic consequences of long-term LVAD support have yet to be fully clarified. Despite the clinical success of these devices, it has been reported that many patients bridged to transplantation with mechanical support develop circulating antibodies with potential donor reactivity. Transplanting against existing or historic donor-specific antibodies is associated with increased risk of antibody-mediated rejection, graft dysfunction, and decreased survival. Safe transplantation of allosensitized patients is dependent on using prospective crossmatching and antibody titer reduction techniques (desensitization). Strict protocols requiring a negative prospective crossmatch before transplantation result in a decreased donor pool and a longer duration of support in sensitized LVAD recipients with increased inherent morbidity such as infections and thromboembolic complications. The aim of this review is to present the current state of knowledge of possible immunologic mechanisms involved in alloimmunization of LVAD recipients, outline new methods of antibody detection, compare various desensitization strategies, and present an overview of clinical data assessing the impact of sensitization on posttransplantation outcome.

Outcome of Desensitization in HLA and ABO Incompatible Living Donor Kidney Transplantation: A Single Center Experience of More than 100 Patients

Introduction: Antibody mediated rejection (AMR) and inferior graft outcome remain the two most important obstacles to successful kidney transplantation in HLA and ABO incompatible recipients. We report a single center experience in the outcome of desensitized living donor HLA and ABO incompatible kidney transplantation. Methods: Since 2007, we included all HLA incompatible living donor kidney transplant candidates with T cell IgG AHG CDC crossmatch (CXM) titer of £1:8 and all ABO incompatible living donor kidney transplant candidates with IgM isoagglutinins titer of £ 256 in our desensitization program. All candidates were risk stratified for AMR and were subjected to an individualized desensitization protocols as follows: ABO incompatible and HLA incompatible candidates with positive AHG CDC CXM and positive donor specific antibody (DSA) by solid phase immunoassay (SPI) were deemed as high risk and received single dose Rituximab®, therapeutic plasma exchange (TPE) and high dose IVIG (2 gm/kg of body weight). HLA incompatible candidates with negative CDC and positive T and/or B IgG flow CXM and positive DSA by SPI were deemed as intermediate risk and received Rituximab® and high dose IVIG. HLA incompatible candidates with negative CDC and flow CXM and positive DSA by SPI were deemed as low risk and received small dose IVIG (1 gm/kg body weight). At transplant, all patients received induction with Thymoglobulin® and were maintained on Tacrolimus based immunosuppressive regimen. Results: There were 108 incompatible recipients; 33 received ABO incompatible and 75 received HLA incompatible living donor kidney transplantation after desensitization. Risk stratification for HLA incompatible transplant revealed 24 patients as high risk, 34 as intermediate risk, and 17 as low risk. 57 (53%) of the study population were females; average age was 43 (range: 15-83) years; 15 (14%) received pre-emptive kidney transplantation and 85 (79%) were primary transplants. Over a median follow up of 652 (range: 8-1444) days, patient survival was 98% and death censored graft survival was 96%. Average serum creatinine was 85 (32-160) mmol/L. Clinical and subclinical ACR was observed in 14 (13%) patients and clinical and subclinical AMR in 4 (3.7%) patients. All rejection episodes responded to treatment except one AMR in ABO incompatible transplant which led to graft failure. Conclusion: Within our inclusion criteria, risk stratification scheme and desensitization strategy, the short and intermediate outcome of HLA and ABO incompatible living donor kidney transplantation appears not to be different from those reported in HLA and ABO compatible transplantation. These excellent results are likely to positively impact the long term outcome.

Distribution of ABO Blood Group Antibody Titers in Pediatric Patients Awaiting Renal Transplantation

Blood group-incompatible transplantation is one strategy used when a potential recipient does not have a compatible living donor. Current practice includes desensitization strategies to reduce antibody titers. However, when antibodies are low, in cardiac transplantation in neonates for example, no desensitization is required. This study is the first to examine the distribution of ABO blood group antibody titers in a population of pediatric patients on the deceased-donor renal transplantation waiting list. All patients from two pediatric nephrology centers active on the national deceased-donor waiting list had antibody titers (total immunoglobulin load) measured. A simulation modeling the effect of allocating blood group-incompatible deceased-donor kidneys to those patients with titers of 16 or lower was developed. Twenty-four children were screened; eight (33.3%) had titers of either anti-A or anti-B antibodies of 8 or lower. A further three (12.5%) had either an anti-A or anti-B antibody titer of 16. Blood group A or B patients had lower antibody levels than blood group O patients. In blood group O patients, levels of anti-A antibodies were higher than anti-B antibodies (Wilcoxon signed rank test, P=0.028). The simulation model showed that a change in organ allocation policy would increase pediatric transplant activity by 2.2% and reduce the median waiting time for a transplant. This allocation strategy may be of particular benefit to those pediatric patients who have been on the deceased-donor waiting list for a long time or those with a high calculated reaction frequency.

Incompatible kidney transplantation: a brief overview of the past, present and future

Live kidney donor transplantation across immunological barriers, either blood group or positive crossmatch [ABO- and human leucocyte antigens (HLA)-incompatible kidney transplantation, respectively], is now practised widely across many transplant centres. This provides transplantation opportunities to patients that hitherto would have been deemed contra-indicated and would subsequently have waited indefinitely for a suitably matched kidney. Protocols have evolved with time as experience has grown and now a variety of desensitization strategies are currently practised to overcome such immunological barriers. In addition, desensitization protocols are complemented by kidney paired donation exchange schemes and therefore incompatible patients now have strategies to either confront or bypass immunological barriers, respectively. As the field expands it is clear that non-transplant clinicians will be exposed to incompatible kidney transplant recipients outside of experienced centres. It is therefore timely to review the evolution of practice that have led to current desensitization modalities, contrast protocols and outcomes of current regimens and speculate on future direction of incompatible kidney transplantation.

Improving Survival During Heart Transplantation: Diagnosis of antibody-mediated Rejection and Techniques for the Prevention of Graft Injury

The diagnosis of antibody-mediated rejection (AMR) has presented a challenge due to the pleiomorphic immunologic responses that represent the condition. A consensus with regard to its pathological diagnosis continues to evolve. Due to an increasing number of sensitized patients undergoing heart transplantation, its incidence appears to be on the rise and the condition is associated with worse outcomes than acute cellular rejection. Treatment of AMR is also more difficult and response to increases in conventional immunosuppression is often limited. Risk factors for AMR include the use of ventricular assist devices, prior exposure to blood products, allografts and multiparity. Detection of alloantibodies with a high specificity and sensitivity allows risk stratification of recipients at potential risk of AMR. Desensitization and AMR treatment strategies are focused on several therapeutic targets, including suppression of T and B cells and elimination or inhibition of circulating antibodies.

Current perspectives to overcome a positive crossmatch in living donor renal transplantation*

Transplantation of a living donor kidney is in general the best treatment option for patients with end-stage renal disease. Two major advantages as compared to transplantation with a deceased donor kidney are the avoidance of waiting time and the superior results in terms of renal function and graft survival. In some patients who are lucky enough to have a person in their neighborhood who are willing to donate a kidney, the transplantation cannot be performed directly because there is ABO blood type incompatibility between donor and recipient, or because of a positive lymphocyte crossmatch, based on the presence of donor-specific antibodies. During recent years, several strategies have been developed to enable transplantation in these cases. A first approach is to use a living donor kidney exchange program, which can result in successful matches in more than half of the crossmatch-positive couples [1]. With the incorporation of kidneys from nondirected, anonymous donors in such an exchange program, domino-paired chains of transplantations can be set up, which end with the transplantation of a living donor kidney to a recipient from the waiting list [2]. However, for a substantial number of recipients, these exchange programs do not result in a successful donor–recipient match. In these cases, desensitization strategies to reduce the titer of ABO blood group antibodies or anti-HLA antibodies can be employed. Desensitization techniques are based on the extracorporeal removal of antibodies, treatment with intravenous immunoglobulins, and on immunosuppressive therapy. Since these procedures carry additional risks for the transplant recipient, desensitization treatment should ideally be reserved for recipients who cannot be served with a donor kidney after several rounds of matching in a (multicenter) exchange program. Unfortunately, kidney exchange programs are not allowed by legislation in every country. In this issue of Transplant International, Morath et al. present the results of living donor kidney transplantation in nine crossmatch-positive patients with peritransplant immunoadsorption (IA) and induction therapy with the anti-CD20 antibody rituximab [3]. Three patients also underwent pretransplant plasmapheresis. In one additional patient with a negative crossmatch but high titers Correspondence L. B. Hilbrands, Department of Nephrology, Radboud University Nijmegen, PO Box 9101, 6500, HB Nijmegen, The Netherlands. E-mail: l.hilbrands@nier.umcn.nl

Proteasome inhibition by bortezomib: Effect on HLA-antibody levels and specificity in sensitized patients awaiting renal allograft transplantation

BackgroundSensitization to human leukocyte antigen (HLA) prolongs waiting list time and reduces allograft survival in solid organ transplantation. Current strategies for pretransplant desensitization are based on B-cell depletion and extracorporeal treatment. The proteasome inhibitor bortezomib allows direct targeting of the antibody-producing plasma cell and has been used in antibody-mediated rejection (AMR) and recipient desensitization with varying results. Here, we report the effect of bortezomib preconditioning on HLA antibody titers and specificity in highly sensitized patients awaiting renal allograft transplantation. Patients and methodsTwo highly sensitized patients awaiting third kidney transplantation were given one cycle of bortezomib (1.3mg/m², days 1, 4, 8, 11), as part of recipient desensitization. Time-course and levels of anti-HLA antibodies, as well as specificity to previous transplant antigens were monitored by luminex technology. In addition, measles and tetanus toxoid immunoglobulin G (IgG) was measured. ResultsFollowing bortezomib, overall changes in IgG levels were small and no sustained reduction in anti-HLA class I or II antibody levels was observed over more than 100days of follow-up to both, donor specific and non-donor specific antigens. Moreover, anti-measles and -tetanus toxoid IgG levels remained unchanged. ConclusionsBortezomib preconditioning alone does not result in sustained reduction of HLA antibody levels or alter protective immunity in sensitized patients. This supports the notion, that bortezomib requires activation of plasma cells, as in AMR, to effectively reduce HLA antibody production. Hence, in a pretransplant setting, combination strategies may be required to derive benefit from proteasome inhibition.

Renal transplant allocation criteria, desensitization strategies and immunosuppressive therapy in retransplant renal patients

This review covers the issue of kidney retransplantation. Patients waiting for a second transplant are increasing in number, and it is more and more difficult to find a suitable kidney. The main reasons are both clinical and immunological. Immunological problems are the most difficult to overcome. New techniques allow the identification of anti-HLA antibodies previously not easy to find. As a consequence, patients waiting for a new transplant are often hyperimmunized, and the cross-match is often positive. The authors discuss several immunosuppressive approaches for such patients and new allocation criteria to allow an easier retransplant. New allocation programs such as acceptable mismatch programs and paired kidney exchange programs are being implemented, and new drugs are now emerging allowing new desensitization criteria. Some of them are not yet on the market, but preliminary clinical studies show such drugs to be promising in a short time.