The highly sensitized patient. Therapeutic alternatives for kidney transplantation

Patients become sensitized after exposure to non-self human leukocyte antigen (HLA) during pregnancy, blood transfusion, and organ transplantation. Performing transplantation in highly sensitized receptors represents a challenge for transplant programs, organ allocation organizations and usually patients are forced to stay on transplant waiting lists for many years and ultimately may never find a donor. There are various approaches that can be adopted in order to transplant these patients such as plasmapheresis, immunoadsorption, intravenous immune globulin, anti-thymocyte agents, monoclonal antibodies (anti CD-20) and splenectomy with similar results as obtained in non highly sensitized patients with the increased risk of severe and recurrent rejection which may carry implications for long-term graft outcomes. Thus a positive crossmatch test is not necessarily an absolute contraindication and allows access for transplantation.     

Immunologic markers of the risk of cytomegalovirus infection among immunosuppressed patients

ELISA and complement fixation test (CF) were compared for the determination of the Cytomegalovirus (CMV) humoral immune status of donors and recipients before and after graft. ELISA-IgG was more sensitive than the CF test and permitted a better identification of the high risk donors and recipients. The presence of IgM antibodies in the recipient at the day of transplantation is an index of greater susceptibility to chronic or recurrent infection at a later date. In primary renal allograft recipient the detection of specific IgM antibodies by ELISA provides more rapid diagnosis than that by CF. In bone marrow transplants, ELISA-IgM showed a better correlation with the virus isolation than the CF test. In the reinfected renal allograft patients the presence of IgM was related to clinical manifestations. Using ELISA, specific decreases of CMV antibody titers were detected before virus isolation.     

A game-theoretic approach to donor kidney sharing

Graft survival in renal transplantation is a function, amongst other things, of the degree of histocompatibility lymphocyte-A (HLA) tissue matching achieved between donor and recipient. Yet a donor procured at centre A might match a transplant candidate at centre B and vice versa. This raises the question of whether, and under what circumstances, surgeons will offer and exchange donor kidneys and gain from such trade in terms of graft survival. We analyse the problem in a game-theoretic framework where the choice of strategy 'to offer or not?' is evaluated in the context of the uncertainty of reciprocation by the other player(s) in the game. The equilibrium solution to a number of variations of the game is predicted to be non-cooperation resulting in collectively sub-optimal graft survival rates. Some policy options for improving cooperation are considered including exchange incentives and coercive measures.     

A therapeutic DNA vaccination strategy for autoimmunity and transplantation

De novo autoimmunity induced by an allograft may play a significant role in chronic organ rejection, which remains a major barrier to successful transplantation. Accordingly, immunization with non-polymorphic antigens found in both donor allograft and recipient would be an attractive means to prevent long-term graft rejection, because it would rely on recipient mechanisms of immune homeostasis and could minimize the need to identify appropriate donor polymorphic antigens for induction of graft tolerance. Here we show that intradermal injection of plasmid DNA encoding glutamic acid decarboxylase (GAD) polypeptide, which is synthesized in both pancreatic islet and skin tissue, ameliorated new-onset type 1 diabetes in NOD mice and increased skin allograft survival in a BALB/c-C57BL/6 model system in a donor-specific manner. Successful therapy of autoimmune diabetes required CpG-methylation of plasmid DNA and co-delivery of a cDNA coding for the pro-apoptotic BAX protein, which was shown previously to induce Foxp3⁺ regulatory T cells in NOD mice. In contrast, significantly increased skin allograft survival after immunization of recipient only required CpG-methylation of plasmid DNA coding for GAD alone. Injection of unmethylated plasmid DNA coding for BAX alone near the allograft also promoted graft survival, but induced a pro-inflammatory response to self-antigens. Our results reveal a promising potential for autoimmunity-targeting DNA vaccination to be applied to transplantation.     

Tissue-typing laboratories for organ transplantation

The tissue typing laboratory performs genetic analysis: the safety and the reproducibility of results are mandatory, because HLA typing can be crucial both in donor-recipient compatibility assessment for organ transplantation and for the diagnosis of immune related disease. The HLA laboratory should perform analysis, as quickly as possible, in order to define donor-recipient matching and to assess the presence of anti-donor specific antibodies in recipient's serum to prevent iperacute rejection. The aim of this report is to define the guidelines that should be followed in all laboratories for each specific transplantation in order to acquire national and international accreditation, and to obtain the best clinical results.     

The importance of HLA-matching before kidney transplantation: a recommendation of the Health Council of the Netherlands

In a recent report, the Health Council of the Netherlands concluded, on the basis of the literature, that HLA-matching is still relevant for graft survival in renal transplant patients. Since the HLA DR antigen system is less heterogeneous than the class I HLA antigen system, it would seem wise to match primarily for these antigens, since this may lead to a reduced exchange of organs between countries and shorten the cold ischaemia period. This may in turn improve the results of transplantation. In the Netherlands, the number of living donor kidney transplants has recently shown a remarkable increase, due partly to the introduction of the paired, living donor, kidney exchange protocol. The introduction of a living donor list exchange programme may further increase this number. Finally, citizens need to be motivated to list themselves as possible organ donors.     

The role of immunologic response in chronic allograft rejection

Chronic allograft rejection is an active immunologic and inflammatory process leading to graft failure. It is associated with many disorders evidencing increased reactivity of the host against graft alloantigens. Among the most important ones are: de novo synthesis of antibodies against HLA class I and II, immunoglobin deposits on vascular endothelial and tubular basement membrane, C4d complement deposits in peritubular capillaries, increased proliferation of lymphocytes in response to mismatched HLA-DR, and elevated expression of cytokines on infiltrating mononuclears and tubular cells. Prevention of chronic rejection comprises of transplanting undamaged organs, avoidance of acute rejection, incorporation of medicines inhibiting remodelling of vascular wall into therapy, and elimination of factors accelerating graft damage. In case of humoral chronic rejection suppression of humoral arm immune response is required. Early diagnosis and effective suppression of antibody production may allow to avoid progression of allograft failure.     

Immunology in medical practice. XXX. Organ transplantation: indications and results

During the past 30 years, solid organ transplantation has developed into a routine medical procedure. Currently, one-year transplant survival rates for kidney, heart, liver and pancreas are between 80 and 90%; for most organs, the long-term results are fair with 5-year survival rates of 60%. Inclusion criteria for potential recipients have become less stringent. These days, potential recipients are rarely excluded on the basis of their calendar age alone. The development of more and stronger immunosuppressive drugs has facilitated transplantation across wider immunological differences between donor and recipient with good results. While the number of patients on the waiting lists for organ transplantation increased, the number of organs offered for donation decreased. This has resulted in waiting times of several years for most organ transplantations. While the short-term outcome has improved significantly over the past decades, the long-term outcome has not. Most renal transplants, for example, are lost due to chronic rejection. The challenge for the future will be to improve the long-term outcome of organ transplantation and to decrease the morbidity associated with chronic immunosuppressive therapy.     

Current and future prospects for xenotransplantation

The transplantation of organs and tissues between animal species, or xenotransplantation, is the focus of a growing field of research, owing primarily to the increasing shortage of allogeneic donor organs. The pig stands out as the most suitable donor animal for humans; however, xenografts (e.g. pig organs) used for human transplantation are normally destroyed by the host within minutes by hyperacute xenograft rejection. An improved understanding of the immune recognition and rejection of xenografts has resulted in new therapies that can partially overcome hyperacute rejection (HAR), delayed xenograft rejection (DXR) or acute vascular xenograft rejection. Strategies to diminish immunogenicity following xenotransplantation can be divided into two approaches: those directed at the recipient (e.g. antibodies or complement depletion or inhibition and tolerance induction) and those directed at the donor (e.g. transgenic modifications to express human complement-regulatory proteins or removal or displacement of alphaGal epitopes). DXR is likely to be controlled by transgenic inhibition of endothelial cell activation (e.g. inhibition of NF-kappaB). Transgenic pigs required for xenotransplantation will soon be generated at a greater efficiency and precision using nuclear transfer and cloning when compared to pronuclear injection. Of greater significance is that nuclear transfer offers the ability to target gene insertion selectively to specific gene loci and to delete specific genes in the pig. Experimental pig-to-primate organ xenotransplantation is currently under way, and results show increased transplant function from minutes to days and weeks. The final therapeutic regimen that allows survival of a discordant xenograft is likely to involve a combination of 'modified' functional genes in the donor organ, the development of immunological tolerance to pig antigens and administration of novel therapeutic agents, including immunosuppressants, that can control natural killer (NK) cell and monocyte mediated responses.     

大鼠颈部异位心脏移植模型的改进

目的 探讨大鼠颈部心脏移植模型的改进和研究心脏移植排斥反应。方法 将Chen术式加以改进，采用供心主动脉与受体颈总动脉行端侧吻合，进行40次大鼠颈部心脏移植。结果 新方法使供心总缺血时间缩短至30min，7d存活率提高到93％。结论 改进的术式简单实用，存活率高，值得推广。     

Transplantation-transmitted tuberculosis--Oklahoma and Texas, 2007

Approximately 28,000 organ transplants were performed in the United States in 2007. When infections are transmitted from donors, the implications can be serious for multiple recipients. Tuberculosis (TB), a known infectious disease complication associated with organ transplantation, occurs in an estimated 0.35%-6.5% of organ recipients in the United States and Europe posttransplantation. In 2007, the Oklahoma State Department of Health identified Mycobacterium tuberculosis in an organ donor 3 weeks after the donor's death. This report summarizes results of the subsequent investigation, which determined that disseminated TB occurred in two of three transplant recipients from this donor, and one recipient died. Genotypes of the donor and recipient TB isolates were identical, consistent with transmission of TB by organ transplantation. To reduce the risk for TB transmission associated with organ transplantation, organ recovery personnel should consider risk factors for TB when assessing all potential donors. In addition, clinicians should recognize that transplant recipients with TB might have unusual signs or symptoms. When transmission is suspected, investigation of potential donor-transmitted TB requires rapid communication among physicians, transplant centers, organ procurement organizations (OPOs), and public health authorities.     

Joint testing of donor and recipient genetic matching scores and recipient genotype has robust power for finding genes associated with transplant outcomes

Genetic matching between transplant donor and recipient pairs has traditionally focused on the human leukocyte antigen (HLA) regions of the genome, but recent studies suggest that matching for non-HLA regions may be important as well. We assess four genetic matching scores for use in association analyses of transplant outcomes. These scores describe genetic ancestry distance using identity-by-state, or genetic incompatibility or mismatch of the two genomes and therefore may reflect different underlying biological mechanisms for donor and recipient genes to influence transplant outcomes. Our simulation studies show that jointly testing these scores with the recipient genotype is a powerful method for preliminary screening and discovery of transplant outcome related single nucleotide polymorphisms (SNPs) and gene regions. Following these joint tests with marginal testing of the recipient genotype and matching score separately can lead to further understanding of the biological mechanisms behind transplant outcomes. In addition, we present results of a liver transplant data analysis that shows joint testing can detect SNPs significantly associated with acute rejection in liver transplant.     

Update on immunosuppressive drugs used in solid-organ transplantation and their nutrition implications.

The success of solid organ transplantation rests heavily on the major advances in immunosuppressive therapy. The early years of organ transplantation were plagued with high failure rates and frequent episodes of acute rejection. With the introduction of improved immunosuppressive agents, successful organ transplantation has become the norm. The emphasis of immunosuppressive therapy has shifted from preventing rejection to balancing acceptable rates of rejection with moderation in adverse effects of the immunosuppressive agents. Among the many possible adverse effects of immunosuppressive therapy is the potential for these agents to affect the nutrition status of the transplant recipient. Given the fact that many patients undergoing transplantation are catabolic and nutritionally vulnerable, it is particularly important for those involved in the care of these patients to be familiar with the nutrition implications of immunosuppressive drugs. In this article, we review the different classes of immunosuppressive medications used in transplantation and emphasize their interactions with the nutrition status of the transplant recipient.     

Chimerism and tolerance

The goal of transplant immunology since its beginnings has been, and continues to be, the induction of long lasting unresponsiveness to a foreign graft. Although the transplantation of solid organs and cellular grafts is already a clinical routine, life-long nonspecific immunosuppression is still required to maintain the graft. Malignancies, opportunistic infections and organ toxicity are the main limitations of the antirejection therapy. One approach that finally could make the dream of tolerance induction come true, is hematopoietic chimerism. Hematopoietic chimerism is defined as the coexistence of donor and host hematopoietic cells in the recipient's system. This coexistence might induce the mechanisms of central or peripheral tolerance to foreign, donor's antigens. The aim of this paper is to present current knowledge about relationship between the state of macro- or microchimerism and transplantation tolerance in bone marrow and organ transplantations.     

Transmission of hepatitis C virus through transplanted organs and tissue--Kentucky and Massachusetts, 2011

On September 29, 2011, the United Network for Organ Sharing notified CDC of two patients who tested positive for hepatitis C virus (HCV) infection approximately 6 months after receiving kidney transplants from a deceased donor. Before transplantation, the donor had tested negative for HCV antibody by the organ procurement organization. Tissue also was procured from the donor for possible transplantation. The tissue bank performed an HCV antibody test on the donor's serum specimen that was negative and nucleic acid testing (NAT) that was positive, but misread as negative. Retesting of the donor specimen during the investigation confirmed the NAT results as positive. Donated tissue included 43 musculoskeletal grafts and one cardiopulmonary patch, which were distributed to health-care facilities in several states. An investigation was initiated to 1) identify potential sources of the donor's infection, 2) document the mode of transmission to the organ recipients, and 3) ensure timely notification of the implanting surgeons and testing of tissue recipients. Implantation of infected HCV tissue occurred after recognition of new HCV infection in the organ transplant recipients, highlighting the need for rapid communication between transplant centers, organ procurement organizations, tissue banks, and public health authorities regarding suspected transplantation transmission events.     

Antilymphocytic Serum: Its Properties and Potential

Antilymphocytic serum is unique in abolishing cell-mediated immune responses, such as graft reactions, while largely sparing humoral antibody responses. This quality suggests such clinical uses as facilitation of interspecies organ transplants and induction of specific tolerance. A L s may also shed light on oncogenetic processes and pave the way for synthesis of new, specific immunosuppressant drugs.     

Impact of stage differentiation on diagnosis of toxoplasmosis

Within its intermediate host, such as man, the protozoan parasite Toxoplasma gondii interconverts between tachyzoites and bradyzoites. The replicative tachyzoite stage is thought to be responsible for acute/active infection and expresses immunodominant antigens thereby inducing a strong cellular immune response, which vice versa triggers the differentiation process into dormant and immunologically weak cyst stages. The immunodominance of tachyzoites is also responsible for the induction of a strong humoral immune response leading to the formation of antibodies specifically directed against tachyzoite antigens. In contrast, the bradyzoite stage which is associated with inactive/chronic infection, seems not to be a strong inducer of specific antibodies. However, since the humoral antibody response is also directed against antigens that are expressed in both stages, serodiagnosis cannot always adequately discriminate between active and inactive/chronic infection. This short review focuses on the impact of stage differentiation and discusses the potential of stage-specifically expressed antigens that might be useful in a recombinant form in order to improve future serodiagnostical approaches.     

The Current Status of Liver Transplantation

More than thirty patients have now undergone liver transplantation in Denver, some more than once, and survivals of up to two and a half years have been achieved. Through this and other experience it has been learned that graft viability is more critical than histocompatibility matching but that the most important factor in the ultimate outcome is prevention of rejection through vigorous immunosuppressive therapy.     

HLA class I antibody screening and typing in the sera of dialyzed patients with CDC and ELISA techniques: association with graft survival

AIM: As generally accepted, HLA antibody screening and typing in dialyzed kidney patients are important for the successful outcome of transplantation. METHOD: Authors investigated the serum samples of 133 patients from the north-eastern region of Hungary for HLA class I antibodies with complement dependent cytotoxicity(CDC) and solid phase enzyme linked immunosorbent (ELISA) techniques (Biotest Abscreen and Abident class I), respectively. RESULTS: The comparison of the results revealed a strong correlation (c2=7,23, p < 0,01) for antibody screening. However, the two methods detect two slightly different antibody populations. The deviation is mainly to be attributed to the higher sensitivity of ELISA, which resulted in antibody positivity of some CDC negative sera (25/106-23,6%), despite the fact that ELISA detects IgG alone. The authors investigated 56 patients, who had already undergone transplantation but got back on the waiting list later and found that average graft survival was shorter in the group of patients with antibody, regardless to the method applied. However, the difference in graft survival proved to be more significant if the patients were assorted to groups by ELISA rather than CDC positivity (ELISA: 58,4 vs 111,2 months - p < 0,001, CDC:50,5 vs 75,6 months - p > 0,05, n.s.). CONCLUSION: This observation suggests that the clinical relevance of antibodies detected by ELISA alone -- due to its higher sensitivity -- are not to be ignored. In this context authors emphasize the HLA class I antibody screening and typing in the post-transplantation period.     

The first successful combined heart-kidney transplantation in Hungary

Combined heart-kidney transplantation has become a new therapeutic solution for patients with coexisting, irreversible heart and kidney failure. Though this combined approach has several theoretical advantages over sequential transplantation, it remains to be established whether it has a jeopardizing impact on patient and graft outcome. The authors report their experience of the first successful combined heart-kidney transplantation in Hungary from a single donor and review the literature in order to clarify this issue. Young male patient candidate for heart transplantation was suffering from concurrent end stage kidney disease. Donor was selected on the basis of weight and size matching, AB0 compatibility and negative T-cell cross-match. The heart was grafted first, and after the hemodynamic stabilization kidney from the same donor was transplanted. The surgical procedure was uneventful. Heart and kidney function recovered quickly, and the patient is doing very well with good cardiac and renal function even a year following the double organ transplantation. The first Hungarian experience showed that combined heart-kidney transplantation is a therapeutic solution for patients with end stage heart and kidney failure. The lower rate of rejection compared to single heart or kidney transplantation, known from the literature as well, supports their current approach to immunosuppression.