Hematopoietic stem cell transplantation for thalassemia

Hematopoietic stem cell transplantation (HSCT) represents the only cure for patients with thalassemia. At present HSCT in younger patients from an HLA- matched sibling donor offers 80% to 87% probability of cure according to risk classes. However, results HSCT in adult patients continue to be inferior due to advanced of disease. High-resolution tissue typing techniques have enabled transplant centres to offer allogeneic HSCT from unrelated donors to patients with thalassemia who could not benefit from matched sibling donor transplantation with results comparable to those obtained using sibling donors. Advances in transplantation biology have made it possible to perform haploidentical HSCT in patients with thalassemia who lack a related or unrelated matched donor. Although limited number of patients, results of unrelated cord blood transplantation for thalassemia are encouraging. Patients with graft failure could now benefit from second transplantation using the same donor with a high disease-free survival rate. Most ex-thalassemics continue to have disease and treatment-related complications acquired before transplantation which require adequate treatment following BMT.     

On the acceptability of xenografts

Transplantation represents a major advance in modern medicine with a major impact on the interactions between individuals and society. The numbers of patients undergoing organ transplantation increased steadily over the years and around 250,000 individuals are living nowadays in Europe with a transplanted organ. On the other hand, the numbers of cadaveric (brain-dead) donors used for organ transplantation remains stable, at around 5,000 each year, and the numbers of transplantation from living donors only slowly increase in Europe. Therefore, a gap is growing between the numbers of patients in need of a transplant and the numbers of organs available for transplantation. About 45,000 patients are currently on renal transplant waiting lists in Europe and, depending on the countries considered, 15 to 30 % of candidates for liver or heart transplantation die before a life-saving transplant becomes available to them. There is therefore an urgent need to implement innovative research and to take full advantage of recent biotechnological advances to explore new avenues in xenotransplantation, and to simultaneously address the ethical, societal and public health issues related to organ replacement. Much progresses have been accomplished in the understanding of xenograft rejection processes that include hyperacute, acute vascular and cellular rejection mechanisms. Strategies to promote xenograft survival that are currently under evaluation include genetic engineering of donor pigs, adapted immunosuppressive treatments and tolerance induction. Also, the psychological acceptance has been evaluated.     

Organ transplantation in Bulgaria

The transplantation program in Bulgaria started in 1968 with renal transplantations to a child and adult woman. In 1986 the first heart transplantation was performed. To date a total of 10 heart transplants have been performed, including one combined heart/lung. A liver transplantation program was launched in 2005 with a total number of 16 transplantations—7 from living donors and 9 from deceased donors. The highest transplantation activity is registered in the field of renal transplantation. During the period 1980–2006, 462 Bulgarian recipients of kidney were transplanted in Bulgaria. The ratio between transplantations from deceased and living related donors is approximately 1:0.9. Annual transplantation activity varies among the years from 1 to 12 renal transplantations p.m.p./per year. The 1- (80.7% vs. 63.1%), 5- (57.86% vs. 39.0%) and 10-year (42.65% vs. 23.62%) graft survival rates are higher for recipients of living donor kidneys compared to those of deceased donor. In 1983 a National kidney waiting list was established. Currently the number of the registered patients eligible for renal transplantation is 885. The proportion of sensitized patients in the waiting list is 20.45% and 4.34% of them are hyperimmunized. Recently HLAMatchmaker program has been implemented not only for sensitized patients but also for those with rare alleles and haplotypes. Post-transplant immunological monitoring showed a strong association between alloantibody presence and delayed graft function (Chi-square = 10.73, P < 0.001), acute rejection (Chi-square = 14.504, P < 0.001), chronic rejection (Chi-square = 12.84, P < 0.001) and graft loss (Chi-square = 20.283, P < 0.001). Based on the experience in our transplant center a strategy for improvement of long-term renal graft survival was developed and implemented.     

Capacity of neural crest cells from various axial levels to participate in thymic development

Summary In order to assess the capacity of neural crest from different sources to participate in thymic development, neural crest from selected axial levels was transplanted unilaterally from quail donors to the region in chick hosts from which neural crest cells normaly migrate to interact with the primordial thymus. The greatest representation of donor cells was observed after isotopic transplantation and when donor tissue was taken from the hyoid and mesencephalic regions of the neural crest. The capacity for transplants to contribute cells decreased both anteriorly and posteriorly, so that neural crest close to the usual origin of mesenchyme-producing cells contributed a larger number of donor cells around the developing thymus than neural crest from anterior and posterior regions. Cells from the transplant were inserted as an addition to the host chick cells. Thus, a special relationship and capacity for interaction in thymic development is expressed by neural crest at usual levels over a limited span of axial regions, but to some extent by all regions. This study has established that the capacity for neural crest cells from different axial levels to interact with developing organs is not uniform, but may vary, depending upon the nature of the interaction with a particular organ.This study was supported by Grant No. 2332, The Council for Tobacco Research, USA, Inc.     

The enigmatic nature of altruism in organ transplantation: a cross-cultural study of transplant physicians' views on altruism

Background

Although altruism is a key principle in our current organ donation and transplantation system, the meanings and implications of the term have been widely debated. Recently, a new type of living organ donation--anonymous and non-directed, also called living altruistic donation (LAD)--has brought the issue into sharper focus. Transplant physicians' views on altruism might influence their attitudes and actions toward living altruistic donors. This study aimed to explore such views among transplant physicians in France and Quebec.

Findings

A total of 27 French and 19 Quebec transplant physicians participated in individual, semi-structured interviews between October 2004 and December 2005. The majority of these participants associated altruism with gratuitousness and saw altruistic acts as multiple and varied, ranging from showing consideration to saving a person's life.

Conclusions

The transplant physicians' discourses on altruism were quite diverse, leading us to question the relevance of the concept in organ transplantation and the appropriateness of the term "living altruistic donation."

     

Organ transplantation in Nepal: Ethical,legal, and practical issues

In Nepal, live donor organ transplantation is only 14 years old with the first successful kidney transplant made in 2008 and a successful liver and bone marrow transplant made in 2016. However, transplantation of cadaveric cornea dates back to 1998. There are still no cases of animal-to-human organ transplantation in Nepal. There are stringent laws to regulate human body organ transplantation in Nepal which are amended from time to time. However, there is a racket of human traffickers who lure rural people from this low-income country into the illegal organ trade. Furthermore, there is a substantial lack of awareness of organ donation among the general public. This article focuses on the stipulations of ethical, legal, and practical issues of obtaining organs procured from living and brain-dead donors that support the process of transplantation in Nepal. In addition, the article also explores the legal and practical issues of organ trafficking and organ donation awareness in Nepal on the basis of factual data and findings from other studies.     

Selection and procurement of hearts for transplantation.

The success of orthotopic heart transplantation depends wholly on satisfactory function of the new heart on completion of the operation. This in turn depends on the quality of the donor heart before its removal, the effectiveness of the methods used to preserve it during transport from the donor to the recipient hospital, and the accuracy of the operative procedure. From January 1979 to December 1983, 62 donor hearts were transplanted into 61 recipients at Papworth Hospital. These hearts were selected from 250 offered for consideration. The most common reasons for not proceeding with an initial inquiry were failure of the donor to meet the medical criteria for selection (77 cases) and lack of intensive care facilities or staff shortages such that a transplant could not be accommodated at the time of inquiry (80). Eight early deaths occurred, of which three were due to primary failure of the donor heart. Actual one and three year survivals for the whole programme were 58% and 50% respectively, the current actual one year survival being 70%. Forty per cent of patients selected for transplantation died while waiting for a heart to become available. Their average survival time was 46 days. The number of donor hearts referred for transplantation depends on public attitudes towards organ transplantation, the willingness of doctors looking after brain dead patients to seek permission from relatives for the heart to be donated, and the cooperation of local kidney transplant surgeons. A larger number of suitable donor hearts to choose from would enable more patients to be treated, as transplant operations could be arranged so that existing facilities were used to their maximum capacity.     

Should Deceased Donation be Morally Preferred in Uterine Transplantation Trials?

In recent years much research has been undertaken regarding the feasibility of the human uterine transplant (UTx) as a treatment for absolute uterine factor infertility (AUFI). Should it reach clinical application this procedure would allow such individuals what is often a much‐desired opportunity to become not only social mothers (via adoption or traditional surrogacy arrangements), or genetic and social mothers (through gestational surrogacy) but mothers in a social, genetic and gestational sense. Like many experimental transplantation procedures such as face, hand, corneal and larynx transplants, UTx as a therapeutic option falls firmly into the camp of the quality of life (QOL) transplant, undertaken with the aim, not to save a life, but to enrich one. However, unlike most of these novel procedures – where one would be unlikely to find a willing living donor or an ethics committee that would sanction such a donation – the organs to be transplanted in UTx are potentially available from both living and deceased donors. In this article, in the light of the recent nine‐case research trial in Sweden which used uteri obtained from living donors, and the assertions on the part of a number of other research teams currently preparing trials that they will only be using deceased donors, I explore the question of whether, in the case of UTx, there exist compelling moral reasons to prefer the use of deceased donors despite the benefits that may be associated with the use of organs obtained from the living.     

Donor derived malignancy following transplantation: a review

Organ and tissue transplant is now the treatment of choice for many end stage diseases. In the recent years, there has been an increasing demand for organs but not a similar increase in the supply leading to a severe shortage of organs for transplant resulted in increasing wait times for recipients. This has resulted in expanded donor criteria to include older donors and donors with mild disease. In spite of implementation of more stringent criteria for donor selection, there continues to be some risk of donor derived malignancy. Malignancy after transplantation can occur in three different ways: (a) de-novo occurrence, (b) recurrence of malignancy, and (c) donor-related malignancy. Donor related malignancy can be either due to direct transmission of tumor or due to tumor arising in cells of donor origin. We will review donor related malignancies following solid organ transplantation and hematopoeitic progenitor cell transplantation. Further, we will briefly review the methods for detection and management of these donor related malignancies.     

Regulatory aspects of tissue donation,banking and transplantation in India

Amendments to India’s Transplantation of Human Organs Act, 1994, have established the legality of tissue donation and transplantation from deceased donors and the conditions under which they are permitted. The amended Act, now known as The Transplantation of Human Organs and Tissues Act, 1994, seeks to prevent the commercialization of tissue donation and to guarantee the safety of indigenous allografts. Registration of tissue banks, compliance with national standards and the appointment of transplant co-ordinators in hospitals registered under the Act are now mandatory. A national registry and Regional and State networks for donation and transplantation of tissues have been introduced. Despite the amendments a few anomalies of the principal Act persist as some of the differences between tissue and organ donation and transplantation have been overlooked. These include the possibility of skin donation in locations other than hospitals; the donation of medical and surgical tissue residues which does not pose any risk to the living donor; the non-requirement for compatibility between donor and recipient; the delayed time factor between tissue donation and transplantation which makes identification of a recipient at the time of donation impossible; and the easy availability of alternatives to tissues which make waiting lists redundant for many tissues. Rules for the implementation of the amended Act were framed in 2014 but like the Act must be adopted by the State health assemblies to become universally applicable in the country.     

Selected contribution: mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung.

Pulmonary edema is common in organ donors and lung transplant recipients. Therefore, we assessed the responsiveness of human donor lungs to pharmacological agents that stimulate clearance of alveolar edema. Organ donors whose lungs were rejected for transplantation were studied. After resection, transport (4 degrees C), and rewarming (37 degrees C) of lungs, alveolar fluid clearance was measured with (n = 8 donors) or without (n = 23 donors) beta-adrenergic stimulation. Terbutaline-stimulated clearance (10(-4) M) was higher than unstimulated clearance (7.1 +/- 1.3 vs. 4.8 +/- 2.4%/h, P < 0.01). Second, we determined whether medications given to the organ donor were associated with the extent of pulmonary edema or the rate of alveolar fluid clearance in the harvested lung. Preharvest administration of dopamine in low to moderate doses was associated with faster alveolar fluid clearance (r = 0.62, P < 0.01). Preharvest administration of diuretics was associated with lower extravascular lung water-to-dry weight ratios. This study provides the first evidence that a beta(2)-adrenergic agonist stimulates alveolar fluid clearance in the human donor lung. Aerosolized beta(2)-adrenergic agonists may have therapeutic value for hastening the resolution of alveolar edema during the management of donors before resection of lungs for transplantation or in the posttransplant setting.     

A sequential stratification method for estimating the effect of a time-dependent experimental treatment in observational studies

Survival analysis is often used to compare experimental and conventional treatments. In observational studies, the therapy may change during follow-up and such crossovers can be summarized by time-dependent covariates. Given the ever-increasing donor organ shortage, higher-risk kidneys from expanded criterion donors (ECD) are being transplanted. Transplant candidates can choose whether to accept an ECD organ (experimental therapy), or to remain on dialysis and wait for a possible non-ECD transplant later (conventional therapy). A three-group time-dependent analysis of such data involves estimating parameters corresponding to two time-dependent indicator covariates representing ECD transplant and non-ECD transplant, each compared to remaining on dialysis on the waitlist. However, the ECD hazard ratio estimated by this time-dependent analysis fails to account for the fact that patients who forego an ECD transplant are not destined to remain on dialysis forever, but could subsequently receive a non-ECD transplant. We propose a novel method of estimating the survival benefit of ECD transplantation relative to conventional therapy (waitlist with possible subsequent non-ECD transplant). Compared to the time-dependent analysis, the proposed method more accurately characterizes the data structure and yields a more direct estimate of the relative outcome with an ECD transplant.     

Tissue Matching and Early Rejection of Cadaveric-Donor Renal Allografts: The Importance of Unidentified Donor Antigens

Tissue typing has been reviewed in a series of 100 technically successful cadaveric-donor kidney grafts. The criterion of transplant failure was immunological rejection causing total loss of function within three months of operation.No significant correlation was observed between matching grade and graft failure due to early acute rejection. This is attributed to the failure to detect at least one “LA” or “4” antigen (as defined in our laboratory), representing a potential incompatibility, in 89% of the grafts, and in the remaining 11% to the lack of an available recipient with identical “LA” and “4” typing. Undetected antigens on the donor are usually incompatible, and probably these incompatibilities unfavourably influence early graft survival.If the results of cadaveric-donor renal transplantation are to equal those of transplantation from well-matched living related donors it will be necessary to type with sera which can recognize individually all HL-A antigens, including those not yet identified, and to create an international pool of over 1,000 potential recipients.     

Isolation of primary human hepatocytes from normal and diseased liver tissue: a one hundred liver experience

Successful and consistent isolation of primary human hepatocytes remains a challenge for both cell-based therapeutics/transplantation and laboratory research. Several centres around the world have extensive experience in the isolation of human hepatocytes from non-diseased livers obtained from donor liver surplus to surgical requirement or at hepatic resection for tumours. These livers are an important but limited source of cells for therapy or research. The capacity to isolate cells from diseased liver tissue removed at transplantation would substantially increase availability of cells for research. However no studies comparing the outcome of human hepatocytes isolation from diseased and non-diseased livers presently exist. Here we report our experience isolating human hepatocytes from organ donors, non-diseased resected liver and cirrhotic tissue. We report the cell yields and functional qualities of cells isolated from the different types of liver and demonstrate that a single rigorous protocol allows the routine harvest of good quality primary hepatocytes from the most commonly accessible human liver tissue samples.     

ARGUMENTS AGAINST PROMOTING ORGAN TRANSPLANTS FROM BRAIN‐DEAD DONORS,AND VIEWS OF CONTEMPORARY JAPANESE ON LIFE AND DEATH

As of 2009, the number of donors in Japan is the lowest among developed countries. On July 13, 2009, Japan's Organ Transplant Law was revised for the first time in 12 years. The revised and old laws differ greatly on four primary points: the definition of death, age requirements for donors, requirements for brain‐death determination and organ extraction, and the appropriateness of priority transplants for relatives. In the four months of deliberations in the National Diet before the new law was established, various arguments regarding brain death and organ transplantation were offered. An amazing variety of opinions continue to be offered, even after more than 40 years have elapsed since the first heart organ transplant in Japan. Some are of the opinion that with the passage of the revised law, Japan will finally become capable of performing transplants according to global standards. Contrarily, there are assertions that organ transplants from brain‐dead donors are unacceptable because they result in organs being taken from living human beings. Considering the current conditions, we will organize and introduce the arguments for and against organ transplants from brain‐dead donors in contemporary Japan. Subsequently, we will discuss the primary arguments against organ transplants from brain‐dead donors from the perspective of contemporary Japanese views on life and death. After introducing the recent view that brain death should not be regarded as equivalent to the death of a human being, we would like to probe the deeply‐rooted views on life and death upon which it is based.     

Is it ethical for patients with renal disease to purchase kidneys from the world's poor?

BACKGROUND TO THE DEBATE: In many countries, the number of patients waiting for a kidney transplant is increasing. But there is a widespread and serious shortage of kidneys for transplantation, a shortage that can lead to suffering and death. One approach to tackling the shortage is for a patient with renal disease to buy a kidney from a living donor, who is often in a developing country, a sale that could--in theory at least--help to lift the donor out of poverty. Such kidney sales are almost universally illegal. Proponents of kidney sales argue that since the practice is widespread, it would be safer to formally regulate it, and that society should respect people's autonomous control over their bodies. Critics express concern about the potential for exploitation and coercion of the poor, and about the psychological and physical after-effects on the donors of this illegal kidney trade.     

Requirements for the adoptive transfer of antibody responses to a priming antigen in man

Antibody responses to recall vaccines can be adoptively transferred after marrow transplantation in man. Transfer of responses to priming Ag has not been successful, although this would broaden the range of organisms to which recipients could be protected. To investigate the importance of T cells and Ag in such transfer we primed marrow donors with keyhole limpet hemocyanin (KLH) 1 or 3 wk before marrow harvesting. B cells secreting IgM and IgG anti-KLH antibody were present in donor marrow at both 1 and 3 wk after immunization. After T cell depletion, donor marrow was infused into chemo-irradiated recipients, half of whom were immunized pretransplant with KLH. We found no evidence for the transfer of the IgM component of the response. Clonal expansion of the transferred IgG antibody-secreting cells with a corresponding rise in recipient serum IgG antibody levels was seen only when donors were primed 3 wk before marrow harvest and when the recipients were also immunized. IEF and immunoblotting demonstrated that successful transfer coincided with maturation of the IgG primary response from a polyclonal to an oligoclonal pattern and confirmed that donor oligoclonal bands appeared in the recipient serum. We conclude that the immunization protocols required for the transfer of antibody responses to priming Ag reflect the initial dependence of unprimed B cells on T cell help and on prolonged Ag stimulation. Ag-stimulated primary B cells in T cell-depleted marrow respond only to the noncognate growth and differentiation signals available in the chemo-irradiated recipient after an initial period of clonal selection and expansion in the donor which is both T cell and Ag dependent. Even after this initial selection, continued expansion of antibody-secreting clones in recipients retains an absolute dependence on Ag stimulation. Immunization techniques to protect transplant recipients against organisms such as Pseudomonas and CMV may need to be modified accordingly.     

Support of unrelated stem cell donor searches by donor center-initiated HLA typing of potentially matching donors

Large registries of potential unrelated stem cell donors have been established in order to enable stem cell transplantation for patients without HLA-identical related donors. Donor search is complicated by the fact that the stored HLA information of many registered donors is incomplete. We carried out a project that was aimed to improve chances of patients with ongoing donor searches to find an HLA-matched unrelated donor. For that purpose, we carried out additional donor center-initiated HLA-DRB1 typing of donors who were only typed for the HLA loci A and B so far and were potential matches for patients in need of a stem cell transplant. In total, 8,861 donors were contacted for donor center-initiated HLA-DRB1 typing within 1,089 donor searches. 12 of these donors have donated stem cells so far, 8 thereof for their respective target patients. We conclude that chances of patients with ongoing donor searches to find an HLA-matched unrelated donor can indeed be improved by donor-center initiated typing that is carried out in addition to the standard donor search process. Our results also raise questions regarding the appropriate use of incompletely typed donors within unrelated donor searches.     

"They Don''t Have to Suffer for Me": Why Dialysis Patients Refuse Offers of Living Donor Kidneys

In the present climate of organ shortage, high demand for kidney transplants, and better clinical outcomes from living donors, health care professionals expect and encourage patients to accept offers of living related donor (LRD) kidneys. When patients decide not to adhere to this course of treatment, scholars and policy makers may question why, given that it delays their chances of receiving a transplant. This article reports on patients' decisions to refuse LRD kidney offers. An 18-month study was conducted of treatment decisions by hemodialysis patients (N = 79). Fewer than half of those offered an LRD kidney (N = 64) were willing to accept it, suggesting that sociocultural factors inform decisions. Patients expressed concerns about the potential donors' well-being over their own and about compromising their relationships with the donors. This article concludes that social relations, emotions, and ethnomedical beliefs play an important role in patients' treatment decisions and thus contributes to the anthropology of decision making.     

Eighteen years of heart transplantation--a single center experience

The best option for the treatment of a failing heart is heart transplantation. The transplantation program at the University Hospital Center Rebro Zagreb started in 1988. To the best of our knowledge this is the first retrospective study on cardiac transplantation in Croatia looking into survival following heart transplantation. Between 1988 and 2006, we performed 81 heart transplantations at the University Hospital Center Rebro Zagreb. Our study focused on the last ten years after establishment of the Department of cardiac surgery as a separate institution. There were thirteen different hospitals throughout Croatia, which contributed to the donor network. Average age of the heart recipient was 48+/-11.8 years (range 14-72), and average age of the heart donor was 34+/-10.7 years (range 14-56). There were more women among the heart donors (34%) then among the heart recipients (18%). During the first ten years, from 1988-1998, the average number of cardiac transplantations was 3 per year In the period from 1998-2006, average number of cardiac transplantations increased to 6 per year. The average thirty-day mortality for the last nine years was 27%. It declined from 30% and 40% in 1998 and 1999, respectively down to 0% in the last two years. Average age of the patients who died was 50+/-6.5years (range 44-62) and did not significantly differ from those who survived. The donor network has grown up to fourteen different hospitals throughout Croatia. The limiting factor in cardiac transplant surgery is the number of available donors. Therefore in attempt to form a good transplant program it is crucial to form an efficient donor network. The number of performed cardiac transplantations is expected to rise until it reaches the number of available donors. With advances in operative technique and postoperative management--immunosuppressive therapy we have observed a remarkable drop in the early operative mortality in the studied period.