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.     

Transplants from living donors in the United Kingdom and Ireland: a centre survey.

A survey was carried out to determine for the first time the extent of transplantation from living donors in the United Kingdom and Republic of Ireland and the views of transplant surgeons regarding future developments. Questionnaires were sent to 32 transplant centres representing 18 health regions and covered their extent of experience of transplantation, sources of donors, ages of donors and recipients, outcome of transplantation, and views on expansion of living donor transplantation services. Replies received from 27 transplant centres representing 17 health regions gave data on more than 1200 transplants from living donors. Transplants from living donors accounted for 0-25% of the total experience of health regions. Two centres had abandoned living donor transplantation. Sixty per cent of transplant surgeons favoured expansion of the living donor programme to meet a shortage of kidneys from cadavers, and the remainder thought that existing programmes were optimal. Living donor transplantation promises to be an important factor in the future planning of health care resources.     

Une évaluation des besoins en transplantation d'organes au Québec.

OBJECTIVES: To evaluate the demand for organs for transplantation and to recommend a reorganization of transplantation services in Quebec. DESIGN: Retrospective study. SETTING: Province of Quebec, 1988 to 1992. PATIENTS: All patients on waiting lists for organ transplantation and patients who received transplants registered in national data banks. MAIN OUTCOME MEASURES: The actual annual demand for organ transplantation and the rate of transplantations performed. RESULTS: The rates of heart transplantation were lower than the actual annual demand, which resulted in many patients dying while awaiting transplantation. The actual annual demand for heart transplantation decreased during the last 5 years from 10.9 per million people in 1987 to 6.7 in 1992. The rates of heart transplantation in Quebec were higher than the Canadian average. The actual demand for lung transplantation was only 2.9 per million people on average in 1992. Demand for liver transplantation increased annually, reaching 8.6 per million in 1992. The rate of transplantation increased likewise but remained insufficient. The demand for kidney transplantation reached 27.2 per million people in 1992, and the transplantation rate was 17.8. CONCLUSIONS: Taking into account the actual demand for and supply of organ transplantation, to insure high-quality service and to control costs associated with organ transplantation, we recommend that the present system in Quebec be reorganized so that transplantations are performed in 12 centres: 7 for kidney transplantation, 2 for hearts, 2 for livers and 1 for lungs.     

Primary vascularization of the graft determines the immunodominance of murine minor H antigens during organ transplantation

Grafts can be rejected even when matched for MHC because of differences in the minor histocompatibility Ags (mH-Ags). H4- and H60-derived epitopes are known as immunodominant mH-Ags in H2(b)-compatible BALB.B to C57BL/6 transplantation settings. Although multiple explanations have been provided to explain immunodominance of Ags, the role of vascularization of the graft is yet to be determined. In this study, we used heart (vascularized) and skin (nonvascularized) transplantations to determine the role of primary vascularization of the graft. A higher IFN-γ response toward H60 peptide occurs in heart recipients. In contrast, a higher IFN-γ response was generated against H4 peptide in skin transplant recipients. Peptide-loaded tetramer staining revealed a distinct antigenic hierarchy between heart and skin transplantation: H60-specific CD8(+) T cells were the most abundant after heart transplantation, whereas H4-specific CD8(+) T cells were more abundant after skin graft. Neither the tissue-specific distribution of mH-Ags nor the draining lymph node-derived dendritic cells correlated with the observed immunodominance. Interestingly, non-primarily vascularized cardiac allografts mimicked skin grafts in the observed immunodominance, and H60 immunodominance was observed in primarily vascularized skin grafts. However, T cell depletion from the BALB.B donor prior to cardiac allograft induces H4 immunodominance in vascularized cardiac allograft. Collectively, our data suggest that immediate transmigration of donor T cells via primary vascularization is responsible for the immunodominance of H60 mH-Ag in organ and tissue transplantation.     

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.     

Kidney transplantation in elderly patients

The Eurotransplant Senior Program (ESP) allocates kidneys from elderly donors to elderly recipients (> or = 65 years old). During the last 39 years, 922 kidney transplantations were performed in our transplant center. We retrospectively analysed patients included in the ESP from the our center. Eleven patients > or = 65 years old recieved kidney from donors 65 years old. Cold ischemia time was approximately 15 hours. Dual kidney transplantation was performed in one patient. Appropriate immunosuppressive protocol was given to all patients. Surgical complications were relatively common and included dissection of renal artery (1 patient), thrombosis of renal artery (1 patient), ureterovesical obstruction (1), lymphocele (1), bleeding (1), acute abdomen (2) and wound dehiscence (1). One rejection episode was registered. Delayed graft function was observed in the two patients with full recovery of kidney function. Seven patients until now have good functioning graft. Four kidneys were lost. One patient died because of pneumonia. Kidney transplantation in elderly is feasible procedure but with greater number of complications than usually.     

Treatment results of childhood Hodgkin's lymphoma in Hungary

Lymphomas are the third most frequent malignancies in childhood. The Hungarian Pediatric Oncology Group was founded in 1971, and since then the same chemotherapeutic protocols have been used in the whole country. In this study we analyzed the data of childhood Hodgkin's lymphoma in Hungary in the last 11 years (1988-1998). We also compared our results with the international (German) data. The incidence of Hodgkin's lymphoma (0-15 years) was 7.1/1,000,000 child/year (the same for non-Hodgkin's lymphoma was 7.5/1,000,000/year); 5.5% of all pediatric malignancies in Hungary). The patients were treated according to the German DAL-HD-82 and 90 protocols. The therapy consisted of 2-6 cytostatic blocks, depending on the stage, followed by involved field irradiation. The overall survival was 94.7+/-2.0% at 5 years and 91.9+/-2.7% at 10 years. These results are very similar to the German data: 94% at 5 years and 93% at 10 years. The good results are due to the well organised network and the uniformed treatment. The results may be ameliorated by using autologous bone marrow transplantation.     

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 Modified Method for Heterotopic Mouse Heart Transplantion

Mice are often used as heart transplant donors and recipients in studies of transplant immunology due to the wide range of transgenic mice and reagents available. A difficulty is presented due to the small size of the animal and the considerable technical challenges of the microsurgery involved in heart transplantation. In particular, a high rate of technical failure early after transplantation may result from recipient death and post-operative complications such as hind limb paralysis or a non-beating heart. Here, the complete technique for heterotopic mouse heart transplantation is demonstrated, involving harvesting the donor heart and its subsequent implantation into a recipient mouse. The donor heart is harvested immediately following in situ perfusion with cold heparinized saline and transection of the ascending aorta and pulmonary artery. The recipient operation involves preparation of the abdominal aorta and inferior vena cava (IVC), followed by end-to-side anastomosis of the donor aorta with the recipient aorta using a single running 10-0 microsuture and a similar anastomosis of the donor pulmonary artery with the recipient IVC. Following the operation the animal is injected with 0.6 ml normal saline subcutaneously and allowed to recover on a 37 °C heating pad. The results from 227 mouse heart transplants are summarized with a success rate at 48 hr of 86.8%. Of the 13.2% failures within 48 hr, 5 (2.2%) experienced hind limb paralysis, 10 (4.4%) had a non-beating heart due to graft ischemic injury and/or thrombosis, while 15 (6.6%) died within 48 hr.     

Quality of screening for diabetic retinopathy in the Rijeka region of Croatia

The aim of this study was to compare the quality of screening for diabetic retinopathy in cities of Rijeka and Zagreb, Croatia. Review of a random sample of 500 diabetic patient records and prospective ophthalmologic survey of 466 randomly selected diabetic patients in a secondary level diabetologic service in Rijeka (coastal region of Croatia). The main outcome measures were proportion of diabetic patient records with notes on ophthalmologic examination; rate of diabetic patients involved with screening for diabetic retinopathy; comparison with rates in Zagreb (Croatian capital). A total of 67% patients visited the ophthalmologist at least once after diagnosed with diabetes, and notes on ophthalmologic examination were found in only 28% patient records. Fifty percent of patients underwent an ophthalmologic examination within two years. Only one third of patients diagnosed with DM in last two years visited the ophthalmologist within this time, and 14% of patients older than 50 years never visited the ophthalmologist. Model of screening for diabetic retinopathy in Croatia works better in Zagreb than in Rijeka region, and needs certain improvements. The authors suggested modern methods of screening, the incorporation of the mechanisms of quality control, the obligatory reporting of newly diagnosed diabetic patients to the national registry, and the direct referral from diabetologist to ophthalmologist.     

Banking of the human heart valves and the arteries at the European homograft bank (EHB) – Overview of a 14-year activity in this International Association in Brussels<Superscript>*</Superscript>

Processing of the human heart valves and arteries has been carried out at the European Homograft Bank (EHB) in Brussels since 1989 and 1991, respectively. Heart valve donors of 0–65 years were classified in (1) Beating heart donors (BHD), of which recipients of heart transplantation (RHT) and multiorgan donors (MOD) after brain death, and (2) non-beating heart donors (NBHD) with warm ischaemic time (WIT) of less then 6 h. Past history of the donors has been checked for malignant and chronic diseases, as well as biology for transmissible and infectious diseases. Perfect collaboration has been established with the transplant coordinators and transplant teams of the implanting centres. Dissection, decontamination, cryopreservation and storing in fluid nitrogen has been carried out in accordance with the Belgian and European Standards of cardiovascular allografts. During this period, a total of 2.828 hearts, 28 predissected valves and 616 batches of arteries arrived in the EHB. 3.537 valves and 1.137 different arteries were accepted for implantation. The main reasons for tissue rejection were morphology, contamination and cuts during the tissue retrieval or dissection. A huge network of different hospitals in Belgium and elsewhere in Europe and Switzerland were included in this process. Pulmonary allografts were not sent for implantation in the left ventricular outflow tract after 1998, since the early and mid-term results after 76 implantations were disappointing. The number of implanted aortic and pulmonary allografts remains stable from year to year, however the number of the allografts used for Ross operation is still increasing. Since the results of the follow up were disappointing, we still only require the implantation and immediate postoperative results, whereas the follow-up information only for specific study purposes. This revised version was published online in July 2006 with corrections to the Cover Date.     

The secular trend in the incidence of hemorrhagic stroke in the region of Osijek,Eastern Croatia in the period 1988-2000--a hospital based study

The purpose of the study was to establish the possible environmental influences in the observed peculiar rising and falling oscillations in the numbers of hemorrhagic stroke (HS) in Eastern Croatia (region of Osijek) during the last thirteen-years' period (1988-2000). In this period 1,222 HS were registered and treated. A constant increase in the incidence of HS was observed, from 60 (in 1988) to 139 (in 1998), with an average annual proportion of 16.5% of all stroke cases. A sharp increase in proportion of HS in total stroke incidence was recorded during the war in Croatia (1991-1995), with a peak incidence of 27.4% in 1993. Typical hypertensive intracerebral hemorrhage (ICH) was the most common (57.1%), atypical ICH occurred in 26.4%, subarachnoid hemorrhage (SAH) in 16.5%. Analysis of the annual number of hypertensive-ICH and SAH disclosed peculiar rising and falling oscillations. These variations were in correlation with heavy living conditions. During the war-period the SAH incidence sharply rose. Immediately after the war it suddenly decreased. The authors named this phenomenon a "pool depletion", supposing the relatively stable proportion of the bearers of aneurysms in population. The observed variations seem to be the consequence of the war stress and other negative psychosocial and economic factors in post-war period, which increases the risk for SAH and typical hypertensive-ICH through complex pathophysiological mechanisms.     

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.     

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.     

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.     

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.     

Risk factors for rejection for morphological reasons of heart valves for transplantation

The study aim was to identify risk factors for morphological rejection of aortic and pulmonary valves for transplantation that could be used to optimize donor selection. The files of all Dutch heart valve donors, donating in a 2.5 years period, whose hearts were processed at Heart Valve Bank Rotterdam, were reviewed for all factors that could be relevant for valve rejection and related to outcome of morphological assessment of the valves. Valves were retrieved from 813 deceased Dutch donors, 24.1% also donating organs. For 797 aortic and 767 pulmonary valves, who met retrieval criteria, morphological assessment was done. 69.5% of aortic and 37.5% of pulmonary valves were considered unsuitable for transplantation at morphological assessment. Backward stepwise multivariate logistic regression analysis, showed age, cardiac cause of death, cerebrovascular accident as cause of death or in medical history, and number of cardiovascular risk factors in a donor to be independent risk factors for morphological rejection of aortic valves. Age, sex, weight >100 kg and ruptured aortic aneurysm as cause of death were independent risk factors for morphological rejection of pulmonary valves. Being an organ donor was an independent predictor of morphological approval of aortic and pulmonary valves, while hypertension was an independent predictor for morphological approval of aortic valves. Thus, independent factors were identified that are associated with morphological rejection of aortic and pulmonary valves for transplantation, and that could be used to optimize donor selection by preventing unnecessary retrievals, limiting costs, while improving yield per donor with minimal compromise for availability.     

Acute Ethanol Exposure Increases the Susceptibility of the Donor Hearts to Ischemia/Reperfusion Injury after Transplantation in Rats

Background

Many donor organs come from youths involved in alcohol-related accidental death. The use of cardiac allografts for transplantation from donors after acute poisoning is still under discussion while acute ethanol intoxication is associated with myocardial functional and morphological changes. The aims of this work were 1) to evaluate in rats the time-course cardiac effects of acute ethanol-exposure and 2) to explore how its abuse by donors might affect recipients in cardiac pump function after transplantation.

Methods

Rats received saline or ethanol (3.45 g/kg, ip). We evaluated both the mechanical and electrical aspects of cardiac function 1 h, 6 h or 24 h after injection. Plasma cardiac troponin-T and glucose-levels were measured and histological examination of the myocardium was performed. In addition, heart transplantation was performed, in which donors received ethanol 6 h or 24 h prior to explantation. Graft function was measured 1 h or 24 h after transplantation. Myocardial TBARS-concentration was measured; mRNA and protein expression was assessed by quantitative real-time PCR and Western blot, respectively.

Results

Ethanol administration resulted in decreased load-dependent (−34±9%) and load-independent (−33±12%) contractility parameters, LV end-diastolic pressure and elevated blood glucose levels at 1 h, which were reversed to the level of controls after 6 h and 24 h. In contrast to systolic dysfunction, active relaxation and passive stiffness are slowly recovered or sustained during 24 h. Moreover, troponin-T-levels were increased at 1 h, 6 h and 24 h after ethanol injection. ST-segment elevation (+47±10%), elongated QT-interval (+38±4%), enlarged cardiomyocyte, DNA-strand breaks, increased both mRNA and protein levels of superoxide dismutase-1, glutathione peroxydase-4, cytochrome-c-oxidase and metalloproteinase-9 were observed 24 h following ethanol-exposure. After heart transplantation, decreased myocardial contractility and relaxation, oxidative stress and altered protein expression were observed.

Conclusions

These results demonstrate acute alcohol abuse increases the susceptibility of donor hearts to ischemia/reperfusion in a rat heart transplant model even though the global contractile function recovers 6 h after ethanol-administration.     

Methods of synthesis of glycosyl fluorides

In recent years glycosyl fluorides have been utilized as versatile sugar donors in the synthesis of natural products and carbohydrates. This paper provides an update on the advances made in the preparation of glycosyl fluorides during the last decade (1988-1998).     

Recent experience with heart transplantation.

The major factors contributing to the recommencement of clinical heart transplantation in the United Kingdom last year were the steadily improving results from Stanford University, the clarification of the diagnosis of brain death, and advances in preserving donor hearts. Twelve men aged 16 to 52 years received heart transplants at Papworth Hospital from January 1979 to July 1980. Six had cardiomyopathies and six ischaemic heart disease. The donors were aged 16 to 35 (mean 21) years. A combination of road and air transport was used to transport the heart to Papworth in seven cases. The total donor heart ischaemic time ranged from 108 to 171 minutes (mean 151), and early graft function was satisfactory in all cases. Postoperative management was directed towards preventing rejection and infection. Equine antihuman thymocyte globulin, prednisolone, and azathioprine were used for immunosuppression. Endomyocardial biopsy was performed every 10 to 14 days during the early postoperative period. There were three deaths: one at 17 days from brain damage and two at 59 and 76 days from rejection. Of the remaining nine patients six left hospital and three returned to work. The number of patients who might benefit from heart transplantation is large, but the cost is high. The cost would fall if an effective non-toxic immunosuppressive agent were developed. Meanwhile, a careful evaluation of the benefits of heart transplantation should continue.