Prevention of hemolytic transfusion reactions with intravenous immunoglobulin prophylaxis in U- patients with anti-U.

BACKGROUND: The U- phenotype is extremely rare and is found predominantly in black African populations at a frequency of between 0.2 and 1.7%. In European populations, U- units are therefore rare, with limited availability in the United Kingdom. Anti-U is clinically significant and is known to cause hemolytic transfusion reactions (HTRs) and hemolytic disease of the fetus and newborn. It has been suggested that intravenous immunoglobulin (IVIG) may be considered as an option among supportive therapy for urgent transfusion when clinically significant antigen-matched units are not available. We report three cases with anti-U transfused with least-incompatible RBC units, their outcomes, and their clinical management. STUDY DESIGN AND METHODS: Intravenous immunoglobulin was prescribed when least-incompatible units must be issued in patients with anti-U to ameliorate acute HTR and prevent the development of delayed HTR. We report the outcome of these cases. RESULTS: Of the case reports described, one patient with weak anti-U developed a delayed HTR after transfusion with incompatible units due to an anamnestic response. Two additional patients are described, with the use of IVIG as a precautionary measure to prevent the development of HTRs when transfused with antigen-positive incompatible units. No acute HTRs or delayed HTRs were noted upon follow-up. CONCLUSION: U- units are not always readily available and transfusion support requires close collaborative working among a multidisciplinary team. Transfusion with antigen-positive incompatible units with IVIG cover both ameliorates acute HTRs and prevents the development of delayed HTRs.

Efficacy of single, extended and goal directed immunoadsorption in ABO incompatible living related donor liver transplantation.

BACKGROUND: Liver transplantation is one of the solid organs most commonly being transplanted across the world. The indications, affordability and accessibility have grown manifold. To increase the donor pool, inclusion of ABO incompatible liver donors is being considered. To enhance the graft functioning and survival, immunoadsorption apheresis to reduce the ABO hemagglutination titres are on the rise. CASE REPORT: We report three cases ABO incompatible liver transplantation with immunoadsorption protocol. The patients were in poor general condition with Child-Turcotte-Pugh (CTP) class 'C' and there were no suitable ABO compatible grafts at the time. For all three cases, immunosuppressive protocol consisted of induction with Rituximab, followed by tacrolimus, mycophenolate mofetil and corticosteroids. The third patient received basiliximab for induction, in addition to the above protocol. First 2 patients received 1 immunoadsorption (IA) session with Glycosorb ABO® system (Glycorex AB, Sweden), pre-operatively. The third patient received 2 IA sessions pre-operatively. Baseline IgM plus IgG titres were 1024; 64 and 1024 for anti-B, anti-A and anti-B for patient 1, 2 and 3 respectively. Target pre-operative antibody titre was ≤16. Average post-operative length of stay was 17.3 days. There were no acute rejection. None of them, required any post-operative plasma exchange. CONCLUSION: Immunoadsorption is effective in reducing hemagglutination titres in recipients of ABO incompatible donor liver.

ABO-incompatible living donor kidney transplantation without post-transplant therapeutic plasma exchange.

Blood group incompatibility remains a significant barrier to kidney transplantation. Approximately, one-third of donors are blood group incompatible with their intended recipient. Options for these donor-recipient pairs include blood group incompatible transplantation or kidney paired donation. However, the optimal protocol for blood group incompatible transplantation is unknown. Protocols differ in techniques to remove ABO antibodies, titer targets, and immunosuppression regimens. In addition, the mechanisms of graft accommodation to blood group antigens remain poorly understood. We describe a blood group incompatible protocol using pretransplant therapeutic plasma exchange (TPE), high-dose intravenous immunoglobulin, and rituximab in addition to prednisone, mycophenolate mofetil, and tacrolimus. In this protocol, we do not exclude patients based on a high initial titer and do not implement post-transplant TPE. All 16 patients who underwent this protocol received a living donor transplant with 100% patient and graft survival, and no reported episodes of antibody-mediated rejection to date with a median follow-up of 2.6 years (range 0.75-4.7 years). We conclude that blood group incompatible transplantation can be achieved without post-transplant TPE.

Evaluation of blood group antibodies in ABO-incompatible living-donor kidney transplantation.

OBJECTIVE: To assess changes in anti-blood type antibody titers and postoperative outcomes (graft survival and rejection rates) at our center with the use of the immunosuppressant, rituximab, in ABO-incompatible kidney transplants from living donors. Confirming anti-donor blood group antibodies is important for avoiding humoral rejection in ABO-incompatible kidney transplants. Splenectomy has been carried out in our hospital according to Alexandre's policy in order to suppress the production of anti-donor blood group antibodies. However, splenectomy has recently been avoided due to the administration of the immunosuppressant rituximab, which gives satisfactory outcomes. Thus, pre- and postoperative anti-donor blood group antibodies were measured, and the outcomes achieved with rituximab were examined. METHODS: A total of 134 cases of ABO-incompatible kidney transplants were carried out at Toho University Omori Medical Center between March 1989 and February 2013. These cases were classified as follows: azathioprine group (n = 62 patients); mycophenolate mofetil group (n = 33 patients); rituximab group (n = 39 patients). The anti-donor blood group antibodies levels (immunoglobulin G and immunoglobulin M) were measured in all groups before antibody removal, immediately before surgery, and 1, 2, 4 weeks and 3 months after surgery, and then compared. RESULTS: Rates of antibody-mediated rejection, including hyperacute rejection, in the azathioprine, mycophenolate mofetil, and rituximab groups were 32.2%, 18.1% and 7.6%, respectively. Graft survival rates were higher in the mycophenolate mofetil and rituximab groups than in the azathioprine group, but were lower in patients with higher preoperative antibody titers (≥128-fold higher immunoglobulin G) than in those with lower titers (<128-fold higher immunoglobulin G). In addition, postoperative anti-blood type antibody titers were significantly suppressed in the rituximab group. CONCLUSIONS: Administration of rituximab results in better antibody control than previous protocols including splenectomy, even in the postoperative period during which humoral rejection often occurs. This protocol eliminates the physical invasiveness of pre-transplant splenectomy, and is expected to provide better outcomes in chronic renal failure patients who undergo kidney transplants.

Samaritan donor interchange in living donor liver transplantation.

BACKGROUND: In order to overcome ABO blood group incompatibility, paired donor interchange has been practised in living donor liver transplantation. Liver transplantations using grafts donated by Samaritan living donors have been performed in Europe, North America, South Korea, and Hong Kong. Such practice is clearly on strong biological grounds although social and psychological implications could be far-reaching. Local experience has been satisfactory but is still limited. As few centers have this arrangement, its safety and viability are still being assessed under a clinical trial setting. METHODS: Here we report a donor interchange involving an ABO-compatible pair with a universal donor and an ABO-incompatible pair with a universal recipient. This matching was not only a variation but also an extension of the donor interchange scheme. RESULTS: The four operations (two donor hepatectomies and two recipient operations) were successful. All the two donors and the two recipients recovered well. Such donor interchange further supports the altruistic principle of organ donation in contrast to exchange for a gain. CONCLUSIONS: Samaritan donor interchange certainly taxes further the ethical challenge of donor interchange. Although this practice has obvious biological advantages, such advantages have to be weighed against the potential increase in potential psychological risks to the subjects in the interchange. Further ethical and clinical evaluations of local and overseas experiences of donor interchange should guide future clinical practice in utilizing this potential organ source for transplantation.

Blood transfusion; additional historical aspects. Part 1. The birth of transfusion immunology.

The decades around the turn of the 19th into the 20th centuries covered a seminal period in the history of transfusion medicine as there was an increasing appreciation of a potential role in the management of surgical and obstetric bleeding, and also in severe non-surgical anaemias. The main obstacles to transfusing human blood were first the occasional devastating adverse reactions due, we now know, to ABO blood group incompatibility; and second the awkward propensity of shed blood to clot. This article describes in more detail how the pioneers in human transfusion immunology in the late 19th century and early 20th century learnt to recognise and avoid ABO incompatibility, and includes some hitherto obscure and rarely cited material. A companion article (Boulton, 2013, Submitted for publication) describes early attempts to find suitable anticoagulants.

[Renal transplantation - new developments]. / Neue Entwicklungen in der Nierentransplantation.

Renal transplantation has become an established option for renal replacement therapy in many patients with end stage renal disease. Living donation is a possibility for timely transplantation, hampered in 20 % of all possible donors and recipients byincompatible blood groups. AB0-incompatible renal transplantation overcomes this hurdle with acceptable allograft survival compared to conventional living-donor renal transplantation. During the last 10 years, the number of patients awaiting renal transplantation older than 65 years has nearly doubled. The decision to transplant those patients and their medical treatment is a growing challenge in transplantation. On the other hand donor age is increasing with potential negative consequences for long-term outcome of organ function. Antibody-mediated humoral rejection have been identified lately as an important cause for allograft failure during long-term follow up of renal transplant patients. New immunological methods to detect donor-specific antibodies, like solid-phase assays (Luminex®), have increased the knowledge and understanding of humoral rejection processes. This will lead hopefully to modified immunosuppressive strategies to minimize organ failure due to chronic rejection.

Exchange living donor liver transplantation to overcome ABO incompatibility in adult patients.

ABO incompatibility is the most common cause of donor rejection during the initial screening of adult patients with end-stage liver disease for living donor liver transplantation (LDLT). A paired donor exchange program was initiated to cope with this problem without ABO-incompatible LDLT. We present our results from the first 6 years of this exchange adult LDLT program. Between July 2003 and June 2009, 1351 adult LDLT procedures, including 16 donor exchanges and 7 ABO-incompatible LDLT procedures, were performed at our institution. Initial donor-recipient ABO incompatibilities included 6 A to B incompatibilities, 6 B to A incompatibilities, 1 A to O incompatibility, 1 A+O (dual graft) to B incompatibility, 1 O to AB incompatibility, and 1 O to A incompatibility. Fourteen matches (87.5%) were ABO-incompatible, but 2 (12.5%) were initially ABO-compatible. All ABO-incompatible donors were directly related to their recipients, but 2 compatible donors were each undirected and unrelated directed. After donor reassignment through paired exchange (n = 7) or domino pairing (n = 1), the donor-recipient ABO status changed to A to A in 6, B to B in 6, O to O in 1, A to AB in 1, A+O to A in 1, and O to B in 1, and this made all matches ABO-identical (n = 13) or ABO-compatible (n = 3). Two pairs of LDLT operations were performed simultaneously on an elective basis in 12 and on an emergency basis in 4. All donors recovered uneventfully. Fifteen of the 16 recipients survived, but 1 died after 54 days. In conclusion, an exchange donor program for adult LDLT appears to be a feasible modality for overcoming donor-recipient ABO incompatibility.

Current progress in ABO-incompatible liver transplantation.

BACKGROUND: ABO-incompatible (ABOi) living donor liver transplantation (LDLT) in adult patients has been controversial because of the high risk of antibody-mediated rejection (AMR) mediated by preformed anti-ABO antibodies. However, outcomes have recently improved owing to various treatment advances. MATERIALS AND METHODS: This review article describes the history and current progress in ABOi liver transplantation, mainly from the viewpoint of the Japanese experience. RESULTS: The typical clinical manifestations of AMR are hepatic necrosis and intrahepatic biliary complication. The outcomes of early ABOi LDLT were poor, especially in older children and adult cases. Since we first introduced portal vein infusion therapy into adult ABOi LDLT in 1998, local graft infusion therapy has emerged in Japan as a crucial breakthrough to overcome the ABO blood group barrier. From 2003, rituximab prophylaxis has been widely used with local graft infusion, and has resulted in markedly improved patient survival. The novel approach of intravenous immunoglobulin induction may become another option to suppress AMR. Continued patient enrollment and controlled trials will allow further validation of these treatments. CONCLUSIONS: The outcome of ABOi LDLT is now similar to that of blood-type-matched transplantation in Japan. However, infection is the major cause of morbidity and mortality after ABOi LDLT. Thus, evaluation of the patients' immune status and adjustment of immunosuppression will be the way forward in the future.

Effect of Rituximab Used as Induction in Patients with ABO Mismatch Kidney Transplant: A Systematic Review and Meta-analysis.

INTRODUCTION: ABO-incompatible living kidney transplantation (ABOILKT) has steadily become more widespread. However, the optimal immunosuppressive regimen for ABOILKT remains uncertain. We aimed to determine the outcomes according to dose of rituximab induction. METHODS: We conducted a systematic review and meta-analysis using random-effects modeling. We searched the following databases for all studies published through May 15, 2019: Cochrane Central Register, OVID MEDLINE, EMBASE, and PubMed. We reviewed all relevant reviews, registered trials, and relevant conference proceedings to compare clinical outcomes and survival according to dose of rituximab as induction in kidney transplantation. RESULTS: Five trials with a total of 390 patients were included. Glomerular filtration rates, graft loss, antibody mediated rejection, T cell mediated rejection, fungal infection (Candida), and patient survival rates did not differ between the 200 mg single dose and 375 mg/m2 in rituximab groups. However, incidence rate of infection 0.470 (95% confidence interval [CI], 0.264 to 0.838) had a lower result than the 200 mg rituximab group. CONCLUSIONS: The using of a 200 mg single dose of rituximab induction in ABOILKT has not only the same results for rejection, graft survival, and patient survival but also low incidence of infection after transplantation.

Successful ABO-incompatible heart transplantation in a child despite blood-group sensitization after ventricular assist device support.

In the first two yr of life blood-group incompatible (ABO-incompatible) heart transplantation can be performed leading to immune tolerance to donor blood group. Antibody titers should be below 1:4. VAD use is correlated with sensitization toward blood-group antigens. A boy was diagnosed with dilated cardiomyopathy at nine months of age and listed for 0-compatible transplantation. Progressive heart failure required implantation of a left VAD. His listing was extended for ABO-incompatible transplantation despite antibody titers of 1:32 anti-A and 1:8 anti-B. After 26 days on VAD, he was transplanted with a B donor heart. No hyperacute or acute rejection occurred in 12 months post-transplant. Anti-B antibodies rose to a maximum of 1:2. No use of rituximab or plasmapheresis was required. There are no signs of graft vasculopathy. This indicates that inclusion criteria for ABO-incompatible transplantation may be extended to immediate cases. This is the first case with a healthy immune system to show signs of tolerance development after ABO-incompatible heart transplantation with increased prior antibody titers and without specific treatment.

Vital transfusion in patients with multiple antibodies against common erythrocyte antigens.

The transfusion of blood components could be needed in certain types of surgical procedures. Blood type components and the requested number of units will depend on the estimated loss of blood, type of surgery, surgical technique to be employed and risk factors for bleeding. Problems can appear when multiple antibodies against common erythrocyte antigens are detected in blood samples and this situation worsens if blood units are requested as quickly as possible. We report a case of a patient with a non frequent erythrocytic phenotype where multiple antibodies acting against high-frequency antigens were detected and who required urgent surgery.

Intentional ABO-incompatible lung transplantation.

We report on a case of intentional blood group incompatible lung transplantation. A blood group O cystic fibrosis patient was mechanically ventilated and put on interventional lung assist for severe respiratory decompensation. Since timely allocation of a blood group O donor lung was impossible, an AB deceased donor lung rescue allocation was accepted and the transplant performed using a pre-, peri- and postoperative antibody depletion protocol including plasmapheresis, ivIg administration, rituximab and immunoadsorption. Nine months after the transplant the patient is at home and well.

Eculizumab for Prevention of Antibody-Mediated Rejection in Blood Group-Incompatible Renal Transplantation.

Antibody-mediated rejection (AMR) is one of the leading causes of allograft failure especially in patients undergoing ABO-incompatible (ABOi) renal transplantation. We hypothesized that complement inhibition with eculizumab, a C5 inhibitor, would protect against AMR and maintain graft function in ABOi renal transplant recipients. Four patients undergoing living donor kidney transplant from ABOi donors were treated with a 9-week eculizumab course without therapeutic plasma exchange, intravenous immunoglobulin, or splenectomy. All patients had successful transplants and have normal graft function at the time of last follow-up. There were no cases of AMR or acute cellular rejection. Of note, 2 patients were transplanted despite persistent ABO antibody titers of 1:32, conventionally considered a contraindication to proceed in standard protocols. Eculizumab is a promising option to prevent AMR with ABOi renal transplantation without the need for splenectomy, post-transplant therapeutic plasma exchange, and intravenous immunoglobulin. Future multicenter studies are needed to determine long-term efficacy and safety.

Acute Cellular Rejection in ABO-Incompatible Renal Transplant Recipients Receiving Rituximab Is Associated with Delayed-Onset Neutropenia.

BACKGROUND Rituximab induces long-lasting B cell depletion in the peripheral blood and increases the levels of proinflammatory cytokines associated with regulatory B cell depletion. Previous reports showed that B cell-related cytokine release after administration of rituximab may induce acute cellular rejection (ACR) and delayed-onset neutropenia. The present study was conducted to investigate the correlation between acute rejection and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation. MATERIAL AND METHODS From June 2006 to July 2015, 47 patients with chronic renal failure received ABO-incompatible renal transplant with rituximab induction at Osaka City University Hospital. All 47 patients underwent plasmapheresis due to removal of anti-A/B antibodies and administration of rituximab, and their transplants were carried out successfully. We investigated the correlation between ACR and delayed-onset neutropenia in ABO-incompatible renal transplant recipients who underwent administration of rituximab for 1 year after transplantation. RESULTS Fourteen patients (29.8%) experienced ACR (group A), and 33 recipients did not develop ACR (group B). The frequency of delayed-onset neutropenia was higher in group A than in group B (p=0.0503). Multivariate logistic regression analysis revealed that the frequency of ACR correlated significantly with the prevalence of delayed-onset neutropenia. CONCLUSIONS Our results indicated that ACR in ABO-incompatible renal transplant recipients receiving rituximab was associated with delayed-onset neutropenia.

Effects on the anti-ABO titers of military blood donors from a predeployment vaccination program.

BACKGROUND: The use of blood group O as "universal blood" for emergency whole blood transfusions carries the risk for a hemolytic transfusion reaction mediated by incompatible A/B antibodies. This risk can be minimized by assuring that the donor has a low titer of anti-A and anti-B. The level of these naturally occurring antibodies has been shown to be increased by vaccination with most biologically derived vaccines. This boostering effect has been investigated for the new generation of vaccines. METHODS: The 120 crew members of a Swedish naval ship deployed for 7 months to the Indian Ocean were tested for anti-A and anti-B before their predeployment vaccination program and after returning to Sweden. The vaccination program contained vaccines against cholera, diphtheria, hepatitis A and B, influenza, measles, meningitis, mumps, pertussis, polio, rubella, TBE virus, tetanus, typhus and yellow fever. Paired antibody titrations were performed for both IgM and IgG using microtube gelcards (Diamed GMBH). RESULTS: No crew member, including the six belonging to the "high titer" group, showed a sign of a booster effect by any of the used vaccines. CONCLUSION: The earlier reported boostering effects mediated by different vaccines cannot be replicated with the new vaccines of today. This is probably a result of the new manufacturing techniques resulting in much purer vaccines. LEVEL OF EVIDENCE: Therapeutic/care management study, level II.

Autoimmunity, alloimmunization and immunotherapy of AIDS.

The nature of clinical and physiological manifestations associated with HIV infection suggests that AIDS is an autoimmune disease. The conventional immunotherapeutic approaches aimed at enhancing the immune response against HIV have repeatedly failed when applied in the clinical practice. The results of several dozen therapeutic AIDS vaccine trials have consistently shown that while in vitro measured HIV-specific immune responses were evident as a result of vaccination the clinical improvement has been seldom observed. The clinical benefit, however, was invariably associated with the usage of vaccines that acted in accord with the principles of alloimmunization. The majority of these vaccines were derived from the blood of HIV carriers or a cell culture and thus they inherently contained alloantigens unrelated to HIV. The clinical experience with alloimmunization in a range of autoimmune diseases indicates that immune tolerization is an active immune process with benefits the vaccinees. The alloimmunization, which primarily induces tolerance rather than immune activation, might be a better strategy for the immunotherapy of AIDS.