Transplantation and regeneration in the heart of the Mediterranean

The second half of the 20th century witnessed the birth of organ transplantation, and failing organs can now be replaced with healthy ones procured from living or cadaveric donors, allowing their recipient to start, or return to, an active life. Major milestones in the field were set in the eighties and nineties at the University of Pittsburgh Medical Center (UPMC), an institution that made it a mission to spread its expertise internationally. A successful partnership between UPMC and the Region of Sicily gave rise to the Mediterranean Institute for Transplantation and Highly Specialized Therapies (ISMETT), the only Italian facility entirely dedicated to transplantation of all solid organs and therapies for the treatment of end-stage organ failure. In its first seven years of activity, ISMETT has become a major referral center for patients from the entire Mediterranean Basin and the Middle East. Despite the fact that organ transplantation is the current gold standard for end-stage organ failure, the field is facing a worldwide emergency represented by the chronic shortage of organ donors. Research aimed at understanding the molecular networks involved in organ-specific ageing and their relationship with maintenance networks and organ failure should be actively encouraged and supported as it could ultimately allow to control organ performance and lifespan, increasing the number of organs available for transplant.     

Invasive mycosis in solid organ transplantation]

Invasive mycosis in solid organ transplantation is mainly caused by Candida and Aspergillus, and its risk is higher in small bowel, liver, pancreas, and lung transplantation. Although limited analyses propose not a few risk factors for invasive mycosis in respective transplanted organs, the efficacy of prophylactic use of antifungal agents or preemptive treatments based on the information is not fully supported by prospective randomized controlled clinical data. The final guideline should be helpful for tailor-made evidence-based management based on the stratification of patients by pretransplant, surgical, immunosuppressive and organ specific characteristics. The process of repeated proposals and verification in a large number of patients is necessary.     

ABO-incompatible organ transplantation

Increases in the patients on the organ transplant wait list have far out paced the number of available organs. This has lead to longer time awaiting transplantation and thus increased morbidity and mortality associated with it. Making more organs available for transplantation remains critical, and hence, extended criteria donors and ABO-incompatible organs are being utilized. Recent reports on the use of conventional immunosuppressive regimens for ABO-incompatible grafts suggest outcomes can be obtained similar to those of ABO-compatible transplants. The delay in the development of natural antibodies to ABO antigens in infants provides an 'immunological window' that allows for successful ABO-incompatible transplants in this age group. This also allows for a unique mechanism long-term tolerance to the graft in infants. ABO incompatibility may no longer be a contraindication in case of kidney transplantation and paediatric heart transplantation. Increased utilization of ABO-incompatible grafts can alleviate the shortage for organs and decrease waitlist times and associated morbidity. In this review, we will discuss the current status of ABO-incompatible transplantation in adult and paediatric solid organ transplantation with attention on recent developments on understanding the mechanisms of graft acceptance in these ABO-incompatible organs.     

Complement-mediated inflammation and injury in brain dead organ donors

The importance of the complement system in renal ischemia-reperfusion injury and acute rejection is widely recognized, however its contribution to the pathogenesis of tissue damage in the donor remains underexposed. Brain-dead (BD) organ donors are still the primary source of organs for transplantation. Brain death is characterized by hemodynamic changes, hormonal dysregulation, and immunological activation. Recently, the complement system has been shown to be involved. In BD organ donors, complement is activated systemically and locally and is an important mediator of inflammation and graft injury. Furthermore, complement activation can be used as a clinical marker for the prediction of graft function after transplantation. Experimental models of BD have shown that inhibition of the complement cascade is a successful method to reduce inflammation and injury of donor grafts, thereby improving graft function and survival after transplantation. Consequently, complement-targeted therapeutics in BD organ donors form a new opportunity to improve organ quality for transplantation. Future studies should further elucidate the mechanism responsible for complement activation in BD organ donors.     

关于活体器官供者的伦理思考☆

背景：活体器官伦理问题逐渐成为人们视野中的焦点和难点。 目的：对活体器官供体伦理问题进一步研究。 方法：应用计算机检索CNKI和 VMIS数据库中2001-01/2011-05关于器官移植的文章,在标题和摘要中以“活体、供体”和“器官移植、伦理”为检索词进行检索。纳入与活体供体关联度高、本领域内的文献,主要选择权威杂志、核心期刊或者近期发表的文章。排除与此文目的无关的、内容和观点陈旧的及重复研究的文献。入选18篇文献和4本医学伦理学书籍进行综述。 结果与结论：为了生命的健康续存,必须完善器官移植和捐献的法律法规,规范供体来源渠道,避免由于科技利益和经济利益的驱使任由活体供体买卖现象的存在空间,研究器官移植活体供体伦理问题,可促使人们提高活体供体捐赠积极性和主动性,解决器官移植供体短缺状况。     

First two AB-incompatible living kidney transplantations in the Balkans--should it be a procedure of choice in a developing country?

Kidney transplantation is the best available medical intervention for the treatment of end-stage renal failure. However, as a consequence of the growing gap between organ supply and demand, many patients die waiting for an organ each year. In order to increase the number of organs, living donor (LD) transplantation from unrelated and ABO-incompatible (ABOi) donors have been introduced over the last few decades. While in the past ABOi transplantation resulted in hyperacute or acute antibody-mediated rejection, the tremendous progress in this area in recent years has shown that it can be overcome by careful patient management, including protocols to remove or lower antibodies, along with stronger immunosuppression and intensive monitoring. The organ shortage problem is even more prominent in regions such as the Balkans where cadaver transplantation has not been well developed. In addition to the introduction of expanded criteria for living donation (elderly and marginal donors), we performed the first two ABOi/LD transplantations in the Balkans in the last 2 years using an already established preconditioning regimen and maintenance therapy with cyclosporine, mofetil mycophenolate and prednisolon. We report our modest experience of a case in which the patient developed lymphadenopathy, sarcomatosis and died after one year; and a second case with accelerated acute rejection and hemorrhagic necrosis with explantation of the graft after a month. Taking into account the high cost of the desensitization procedure and induction therapy as well as the need for intensive monitoring throughout the standardized procedures and facilities, we might reconsider whether ABOi living kidney transplantation should be a procedure of choice in developing countries.     

在校医学生器官移植与捐献态度及认知的调查

背景：在校医学生对器官移植的认知与态度影响着整个社会对器官移植和捐献的认知,进而影响中国器官捐献移植工作的进程。 目的：调查在校医学生对人体器官移植与捐献的态度与认知。 方法：选择济宁医学院400名学生为被试进行问卷调查。内容主要包括：①对器官移植、器官(遗体)捐献知识的掌握程度。②器官移植、器官(遗体)捐献知识的来源。③对捐献器官(遗体) 所持态度。 结果与结论：69.8%在校医学生了解器官移植捐献概念,44.6%赞成捐献自己身后器官。说明在校医学生能较好认同器官移植作为治疗终末期器官功能衰竭的有效手段,但对器官捐献所持态度不很乐观,影响其捐献态度的主要因素为家属情感和捐献程序和传统观念。一年级赞同率最低,为26.6%,五年级最高,为61.4%,赞同率随着年级的升高而增加,55.6%的在校医学生认为应该给予器官捐献者一定的奖励或补偿。     

Xenografts are an achievable breakthrough

The objective of this communication is to show that pig-to-human organ transplantation could be feasible through genetic engineering. By introducing into donor pigs several different tolerance promoting genetic modifications there can be a synergistic effect to produce extended tolerance for xenografted organs in human recipients. Nuclear-transfer cloning allows production of pigs with knockout mutations in the galactose-alpha-1,3-galactosyl transferase gene, in principle eliminating hyperacute rejection. Once hyperacute rejection is circumvented, long-term tolerance of xenografted organs should be possible through a combination of transgenic immunomodulating molecule, bone marrow chimerism and short to intermediate term use of immunosuppressive drugs. If immunomodulating transgenes are deleterious during pig development, inducible cre-recombinase excision of stop codons provides a means to delay expression of such transgenes until after transplantation. Zoonotic diseases can be circumvented via pathogen-free colonies and additional knockout mutations to disable porcine endogenous retrovirus and prion disease. Thus, there is now a technical and theoretical framework for serious efforts at cross-species transplantation.     

Ethicolegal issues of organ donation as the main obstacle to the progress of clinical transplantation

Ethicolegal issues present the main factor hindering obtaining organs from corpses and living donors, the distribution of cadaveric organs, and the financial providence of donorship in Russia. The actual Russian legislation is contradictory in terms of obtaining relatives' consent for the transplantation of cadaveric organs. There are no precise definitions of the degree of genetic relationship between the donor and recipient sufficient for transplantation. Selling and purchasing human organs is strictly prohibited, while financial compensation of the living donor seems to be a fair measure. Providing the possibility to verify brain death is a necessary condition for expanding the cadaveric organ pool. The organ shortage leads to improper distribution of donor organs. All these problems have to be solved for the progress of organ transplantation in Russia.     

The deceased organ donor with an "open abdomen": proceed with caution

In solid organ transplantation, the disparity between donor supply and patients awaiting transplant continues to increase. The organ shortage has led to relaxation of historic contraindications to organ donation. A large percentage of deceased organ donors have been subjected to traumatic injuries, which can often result in intervention that leads to abdominal packing and intensive care unit resuscitation. The donor with this "open abdomen" (OA) presents a situation in which the risk of organ utilization is difficult to quantify. There exists a concern for the potential of a higher risk for both bacterial and fungal infections, including multidrug-resistant (MDR) pathogens because of the prevalence of antibiotic use and critical illness in this population. No recommendations have been established for utilization of organs from these OA donors, because data are limited. Herein, we report a case of a 21-year-old donor who had sustained a gunshot wound to his abdomen, resulting in a damage-control laparotomy and abdominal packing. The donor subsequently suffered brain death, and the family consented to organ donation. A multiorgan procurement was performed with respective transplantation of the procured organs (heart, liver, and both kidneys) into 4 separate recipients. Peritoneal swab cultures performed at the time of organ recovery grew out MDR Pseudomonas aeruginosa on the day after procurement, subsequently followed by positive blood and sputum cultures as well. All 4 transplant recipients subsequently developed infections with MDR P. aeruginosa, which appeared to be donor-derived with similar resistance patterns. Appropriate antibiotic coverage was initiated in all of the patients. Although 2 of the recipients died, mortality did not appear to be clearly associated with the donor-derived infections. This case illustrates the potential infectious risk associated with organs from donors with an OA, and suggests that aggressive surveillance for occult infections should be pursued.     

Artificial organs and transplantation

Nowadays artificial devices are not able to totally and undefinitely replace the loss of function of all vital organs and artificial organs can be used only to bridge the time to transplantation, which must be considered the first choice in the therapeutical approach for many chronic diseases. Since general population aging process is leading to an increase of organ demand, the gap between performed and requested transplantation is hard to fill. Xenotransplantation is nowadays only an experimental alternative solution and we have to do our best using available artificial organs to increase and improve the survival of patients waiting for transplantation. In this meeting we particularly dealt about organ function replacing therapy, especially regarding the kidney, heart, liver, pancreas and ear.     

Experience with anencephalic infants as prospective organ donors

Recent advances have made organ transplantation in newborns feasible, but the paucity of organs small enough for this age group remains a major limitation. Because anencephalic infants can survive for no more than a few weeks, they have been considered as possible organ donors for other infants. Under current law, however, they cannot be used as donors until their brain-stem activity ceases and the criteria for total brain death are thereby met. If anencephalic infants receive customary care, their solid organs usually undergo irreversible hypoxic injury during the process of dying and become unsuitable for donation by the time of death. We modified the medical care of 12 live-born anencephalic infants for one week to determine whether organ viability could be maintained and whether the criteria of total brain death could be met. Six received intensive care from birth, and six only when signs of imminent death developed. Only two infants met the criteria for total brain death within one week, and no solid organs were procured. Most organs were suitable for transplantation at birth. When intensive care was provided from birth, organ function was maintained; however, brain-stem activity ceased in only one infant within the first week. When intensive care was delayed until death was imminent, most organs were damaged to an extent that made them no longer suitable for transplantation. Our findings suggest that it is usually not feasible, with the restrictions of current law, to procure solid organs for transplantation from anencephalic infants.     

Optimal modes and targets of gene therapy in transplantation

Summary:  Genetic modification strategies have the potential to improve outcome following cell/organ transplantation. A unique opportunity in transplantation is that gene therapies need not be restricted to in vivo approaches and that ex vivo genetic modification of cell and/or organs can be of value. Improvements in vector design, production, and delivery should enhance transfection efficiency and optimize gene expression. Herein, we discuss potential modes of gene therapy, focusing on viral, liposome, or naked DNA-based systems for gene delivery. We suggest gene therapy targets taking into consideration the essential constituents of anti-allograft repertory. In addition to strategies that may have salutary effects in mitigating the threat of acute rejection, we suggest genetic strategies for minimizing ischemia/reperfusion injury as well as for the perennial problem of progressive functional loss of the transplanted organ. Data from pre-clinical transplant models support the idea that gene therapy may improve allograft function and survival. We are optimistic that gene therapy will be of clinical value in the near future in the management of recipients of allografts; we believe that genetic strategies would be essential for successful breaching of the formidable challenge of xenotransplantation.     

Recent advances in understanding xenotransplantation: implications for the clinic

The results of organ and cell allotransplantation continue to improve, but the field remains limited by a lack of deceased donor organs. Xenotransplantation, for example, between pig and human, offers unlimited organs and cells for clinical transplantation. The immune barriers include a strong innate immune response in addition to the adaptive T-cell response. The innate response has largely been overcome by the transplantation of organs from pigs with genetic modifications that protect their tissues from this response. T-cell-mediated rejection can be controlled by immunosuppressive agents that inhibit costimulation. Coagulation dysfunction between the pig and primate remains problematic but is being overcome by the transplantation of organs from pigs that express human coagulation-regulatory proteins. The remaining barriers will be resolved by the introduction of novel genetically-engineered pigs. Limited clinical trials of pig islet and corneal transplantation are already underway.     

Transplantation tolerance: from theory to clinic

Tolerance induction and alloreactivity can be applied to the clinic for the transplantation of solid organs and in the treatment of human cancers respectively. Hematopoietic chimerism, the stable coexistence of host and donor blood cells, guarantees that a solid organ from the same donor will be tolerated without a requirement for maintenance immunosuppression, and it also serves as a platform for the adoptive immunotherapy of hematologic malignancies using donor lymphocyte infusions. This review focuses on clinically relevant methods for inducing hematopoietic chimerism and transplantation tolerance, with a special emphasis on reduced intensity transplantation conditioning and high dose, post-transplantation cyclophosphamide to prevent graft rejection and graft-versus-host disease (GVHD). Reduced intensity transplantation regimens permit a transient cooperation between donor and host immune systems to eradicate malignancy without producing GVHD. Their favorable toxicity profile also enables the application of allogeneic stem cell transplantation to treat non-malignant disorders of hematopoiesis and to induce tolerance for solid organ transplantation.     

Transplantability tests for isolated preserved organs

The demand for suitable organs for transplantation, and especially for kidneys, requires the establishment of efficient organ procurement and preservation programmes. The success of such programmes depends, amongst other things, on the ability to preserve organs for long periods of time and the ability to assess organ viability before transplantation. The characteristics of an ideal criterion of viability, or transplantability, are discussed. A short survey of currently used, or suggested, criteria is presented. A new method is suggested that employs the dynamic response of the organ. The organ is considered as a ‘black box’ that is repetitively subjected to small perturbations in its input. System-identification techniques are used to identify the dynamic parameters of the organ with respect to the specified input. Using a priori statistical data, the parameter space is divided into several regions, each denoting a different state of viability. The transplantability of the organ is determined by the location of the parameter vector in the parameter space. Prognostic decisions can be made by calculating the gradients of this vector, and estimating its location in some near future time.     

调节性T细胞及其CD45亚群在肝移植免疫耐受中的相关研究

调节性T细胞(Tr)作为一种具有免疫抑制功能的细胞在器官移植免疫耐受中发挥了重要作用.它通过细胞接触抑制排斥反应发生、诱导移植免疫耐受,并且这种免疫抑制具有免疫过继作用.其中CD45亚群被认为是Tr中抑制功能较强的一群细胞,在移植免疫耐受中发挥着重要作用.而肝脏作为一种免疫特惠器官,与其他器官移植相比更易产生免疫耐受....     

Non heart-beating donors in England

When transplantation started all organs were retrieved from patients immediately after cardio-respiratory arrest, i.e. from non heart-beating donors. After the recognition that death resulted from irreversible damage to the brainstem, organ retrieval rapidly switched to patients certified dead after brainstem testing. These heart-beating-donors have become the principal source of organs for transplantation for the last 30 years. The number of heart-beating-donors are declining and this is likely to continue, therefore cadaveric organs from non-heart-beating donor offers a large potential of resources for organ transplantation. The aim of this study is to examine clinical outcomes of non-heart-beating donors in the past 10 years in the UK as an way of decreasing pressure in the huge waiting list for organs transplantation.     

Transmission of hepatitis C virus by organ transplantation.

BACKGROUND. Liver disease is a frequent and major complication after organ transplantation. We sought to determine whether hepatitis C virus (HCV) is transmitted by organ transplantation and whether it causes post-transplantation liver disease. METHODS. Serum samples from all cadaver organ donors to the New England Organ Bank between 1986 and 1990 were screened retrospectively for antibodies to HCV (anti-HCV) by enzyme-linked immunosorbent assay (ELISA). We reviewed the hospital records of all recipients of organs from anti-HCV-positive donors for evidence of liver disease. Serum samples from recipients obtained before transplantation and during follow-up were analyzed for anti-HCV. RESULTS. Of 716 organ donors, 13 (1.8 percent) were positive for anti-HCV. Their organs (19 kidneys, 6 hearts, and 4 livers) went to 29 recipients. Non-A, non-B hepatitis developed after transplantation in 14 of the 29 (48 percent), for a prevalence 7.4 times the 6.5 percent prevalence after transplantation from untested donors that was previously reported by two institutions in the organ bank (P less than 0.0001). The liver disease began a mean of 3.8 months after transplantation and became chronic in 12 patients; the other 2 had subfulminant hepatic failure. Liver disease was more frequent in the patients who had received antilymphocyte preparations (P = 0.04). HCV was the cause of the post-transplantation liver disease in 12 of the 13 recipients (92 percent) for whom serum samples were available. Anti-HCV was detected by ELISA in eight and enzyme immunoassay in one; in three others, HCV RNA was detected by polymerase chain reaction in serum samples obtained after transplantation. CONCLUSIONS. Organ transplantation can transmit hepatitis C. This raises serious questions about the continued acceptance of organs from donors positive for anti-HCV.