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The immediate and fulminant rejection of human renal allografts in sensitized recipients was first described more than 30 years ago [1]. The process of hyperacute rejection, occurring within minutes or hours after revascularization, is thought to be primarily mediated by pre-existing anti-donor antibodies (Abs) [2]. That it has become rare in recent years is primarily ascribed to improved crossmatching techniques [3]. However, at present, over 20% of patients with end-stage renal disease on waiting transplant lists are considered highly sensitized. Apart from prior failed allografts, this may result from blood transfusions or pregnancies. These highly sensitized patients experience an increased rate of graft rejection, compared to unsensitized individuals, which is often irreversible and unresponsive to currently used immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

The risk of viral recurrence after liver transplantation for viral related liver disease is high. Viral reinfection is characterized by a viral reactivation, high amount of virus, difficulty to control viral replication in these immunosuppressed patients, occurrence of graft disease, and sometimes graft failure. For these reasons, retransplantation for viral recurrence is controversial due to the high risk of recurrence on the second graft and to the overall poor results in a context of organ shortage. [ABSTRACT FROM AUTHOR]

In order to look at heart retransplantation in its right perspective, a number of preliminary pieces of information must be kept in mind. First, the actual scope of the problem is limited. From the largest two international heart transplant registries [1,2] and the organ procurement registries [3], we know that retransplantations currently account for 1.5-2.5% of the 4600-4800 heart transplantations performed annually worldwide, i.e. the total retransplant volume is 70-120 procedures per year. There has been no increase in the proportion of heart retransplantation over the past 10 years (Table 1). Second, the available experience is scattered. A majority of heart transplant centers have at some time performed heart retransplantation, although in any given year only 20-25% of centers report such activity. The number of retransplantations per center is mostly very limited so that worldwide there are probably fewer than 10 centers with a total heart retransplantation experience of τ20 patients (Table 2). Third, the global survival rate after retransplantation continues to be inferior to that after a first transplant, even if a slight improvement has been noted over the last years (Table 3). Finally, death rate on the waiting list decreased from 14.5% in 1988 to 12.8% in 1992 and 10.2% in 1996 [1]. [ABSTRACT FROM AUTHOR]

While the results of renal transplantation in adults and children have improved over the past decade, there still remains a cohort of patients in whom primary graft failure is inevitable. Early failure results not only from technical and surgical complications but immunological reasons still account for the persistent failure of grafts and an inevitable reduction in graft survival. While in adults the return to haemodialysis or peritoneal dialysis seems to offer a temporary solution, in the paediatric group, the continuation of these modalities of treatment does not offer a viable solution to children who require to grow and develop into near normal adolescent and adult life. The problem of failure has been compounded by the serious problem of non-compliance and even meticulous supervision does not resolve the dangers related in this select group of patients. Most transplant centres have a 15% retransplantation rate. [ABSTRACT FROM AUTHOR]

In spite of continuous improvement in transplant techniques and patient management there are still a significant number of graft failures affecting every kind of solid organ transplantation. Graft failure after kidney transplantation makes more demanding to find another compatible organ for that patient. More dramatic, primary failure of heart or liver graft is a medical emergency that jeopardizes the patient's life. Retransplantation has been associated with a decreased patient and graft survival for each type of transplant considered [1-4], and significantly increases the cost of the overall process [5,6]. The inclusion on waiting list (WL) of patients considered for retransplantation might carry a decreased chance of getting an organ for those awaiting a primary graft. Given the shortage of transplantable organs, some authors have advocated that previous transplant history should be taken in account when setting the criteria for organ allocation as it is done with ABO blood group matching [5,7]. Other have been willing to limit the number of organs available for retransplantation [8] and even completely to ban retransplantation procedures [9] as the way to preserve fairness and justice in the transplantation process. [ABSTRACT FROM AUTHOR]

Long-term follow-up studies of renal transplant patients have shown that chronic rejection is the single most prevalent cause of graft failure after the first post-transplant year [1]. It is not known how many of these patients will undergo retransplantation but data from our own institution suggest that 60-70% of retransplants lost a previous graft due to chronic rejection. There are no large registry data available to directly confirm this impression but of the more than 14000 second cadaver kidney transplants reported to the Collaborative Transplant Study Registry, 57% had a previous graft that had lasted for more than 6 months and 49% had a previous graft that had lasted for more than 1 year. As chronic rejection is the single most important cause of graft failure in this time frame, it would seem that avoidance of chronic rejection will reduce the need for retransplantation. The aim of the current review is to evaluate the risk factors of chronic rejection and to suggest strategies to decrease its prevalence. [ABSTRACT FROM AUTHOR]

The merits of retransplantation have often been debated [1-15]. Opponents are of the opinion that patients who have not had a previous transplant should be given a fair opportunity to receive one. Proponents of retransplantation argue that organs should be allocated based on medical urgency. They believe that patients awaiting their first graft stand a reasonable chance of receiving a donor organ at a later date. A retransplant candidate often has a diminished probability of survival. [ABSTRACT FROM AUTHOR]

Living donors have been used for a large number of kidney retransplants, but so rarely for extra-renal organs that an analysis is not possible. Hence, the data and discussion presented here on living donors is restricted to the kidney. [ABSTRACT FROM AUTHOR]

During the last 10 years results of kidney, liver and heart transplantation in childhood have steadily improved and are at least equal to those in adults. After renal transplantation five year patient and graft survivals of over 90 and 80%, respectively, can be achieved with FK 506, induction or triple therapy, and in all age groups [1,2]. The most common causes of graft loss are chronic rejection, acute rejection, recurrence of the basic disease, and technical problems [3]. [ABSTRACT FROM AUTHOR]

The success rate and the frequency of pancreas transplants have increased in recent years. Pancreas transplantation establishes a neuglycemic, insulin-inde-pendant state, and the potential to favorably influence the evolution of secondary complications of diabetes involving the eyes, nerves, and kidneys has been shown. Failure of a pancreas transplant is not an immediate life threatening problem, nevertheless the original course of diabetes is resumed. Thus justifications of pancreas retransplantation will be herein discussed in examining three steps: efficacy justification, economical justification, ethical justification. [ABSTRACT FROM AUTHOR]

This is a difficult question which involves medical, ethical, economic and social considerations. The pool of available liver grafts is limited so liver grafts have to be used with the best efficiency. Unfortunately results for liver retransplantation are not as good as for first liver transplantation [1]. The number of first transplantations in Europe and in the United States is from 3000 to 5000 and the frequency of retransplantation is from 11% to 20%[2]. The rate of retransplantation decreases with the teams experience and it can be noted the results of transplantation are improved. Retransplantation is more frequent in emergency[3]. The main causes of retransplantation in emergency [4] are, first: primary non function of the graft, second: hepatic artery thrombosis of the graft, third: refractory acute rejection episodes and chronic rejection diseases leading to graft loss. [ABSTRACT FROM AUTHOR]

The subject of organ retransplantation has generated a great deal of debate and discussion as physicians, ethicists and health care payers as well as patients address such intrinsically conflicting principles as distributive justice and the drive to maximize individual patient survival. As is the case with other organ allografts, it is inevitable that a certain number of cardiac allograft recipients will redevelop some form of end-stage heart disease and become potential candidates for retransplantation. While there may be no strictly right or wrong answer to the question of whether heart retransplantation should ever be performed, we felt that examining the experience at a single relatively high-volume institution which has performed retransplantation over a several decade period could be instructive both in terms of assessing what the best result to be obtained might be as well as identifying subsets of retransplant candidates with predictable better outcome than others. Thus, we present a retrospective analysis of our institutions 2.9 year experience with cardiac retransplantation. [ABSTRACT FROM AUTHOR]

Over the past few years, our understanding of the mechanisms involved in the rejection of discordant xenografts has greatly increased. Several molecules potentially involved in the rejection process have been identified, and the way in which they mediate their pathologic effect largely elucidated. At the same time, improvements in the technology of transgenesis in the pig have made it possible to produce donor animals expressing some of these molecules, particularly on endothelial cells, so that their actual role in the process of pig-to-primate xenograft rejection can be evaluated. One factor limiting genetic manipulation in pigs, however, is that the embryonic stem cells necessary for homologous recombination are currently unavailable, which makes it impossible to knock out a gene in that species. Emerging techniques such as intrabody-mediated phenotypic knockout, overexpression of dominant negative mutants, anti-sense RNA or ribozymes may represent alternatives and result in the production of donor animals with reduced expression of factors that initiate rejection. It is our assumption that combined expression of several protective transgenes associated with reduced expression of some of the endogenous proteins that promote rejection will make it possible to maintain a pig organ in the human body. [ABSTRACT FROM AUTHOR]

Indication for a repeat cardiac transplantation is not an infrequent situation [1]. The risks of the retransplantation are significantly higher than the risk of the first operation [2]. The increasing difficulty for a patient listed for a first transplantation to receive a good donor graft within a reasonable period of time, the attempt in most of the cardiac transplant centers to optimize as much as possible the use of the scarce donor grafts explain the difficulties for a patient selected for a retransplantation to actually receive a graft. This situation justifies an analysis of the real possibilities of mechanical circulation support as an alternative to a retransplantation. [ABSTRACT FROM AUTHOR]

Retransplant patients are an immunologically unique group since they have already experienced graft loss and have been exposed to a bolus of alloantigen. Having previously lost a transplant, these patients are often sensitized and have poorer early graft function resulting in patient management problems [1, 2]. Survival rates for cadaveric retransplantations have been consistently lower than those for primary grafts [3-6]. Some of the risk factors associated. with poor retransplantation outcome include patient high PRA, recipient-donor HLA mismatches, positive flow cytometry crossmatches and, perhaps the most important, previous graft survival time less than 3-6 months [3, 4, [7-9]. Since the introduction of cyclosporine based immunosuppressive protocols in 1983, the one year regraft survival rate of second cadaver donor renal allografts has remained relatively constant, whereas that of first transplants has significantly improved [9]. However, since 1988 survival rates for retransplant cadaver-donor grafts have improved each year with the difference between first and second transplant one year survival rates decreasing from 8% in 1988 to 2% in 1991 [10]. These recent improvements may reflect the impact of more efficacious immunosuppression and more sensitive and informative crossmatching [6, 11]. However, data from the UNOS Registry suggests that a decreasing number of high-risk patients, especially reTx patients with short previous graft survival times, have been retransplanted in recent years and that selection of more low-risk reTx candidates may be an important contributing factor in explaining improved regraft survivals [8]. [ABSTRACT FROM AUTHOR]

Classical immunological dogma stipulates that reexposure to antigen results in an immediate and forceful response by the adaptive immune system. In the context of organ retransplantation this response is influenced by several factors, including antibody specificity of the primary response [1], affinity and isotype of preformed antibody, dose and immunogenicity of the antigen, immune responsiveness and health of the recipient. The pioneering work of Kissmeyer-Nielsen in Europe and Terasaki in the USA in the mid 1960s established that kidney transplants could be rejected hyperacutely by thrombosis of the transplant due to binding of preformed recipient antibody to donor antigen. It is now accepted that the most frequent target antigens in such instances are HLA antigens, coded for by the class I (HLA-A, -B, -Cw) or class II (HLA-DR,-DQ) genes of the major histocompatibility complex. Primary sensitization in transplant recipients usually occurs by one of three routes: blood transfusions, pregnancy and organ transplantation [2]. [ABSTRACT FROM AUTHOR]

It is well recognized that pre-existing antibodies to HLA antigens expressed by the allograft is detrimental to survival of kidney allografts and results in hyperacute and accelerated rejection [1]. Furthermore, it has been shown that heart and liver transplant recipients with pre-existing anti-donor HLA antibodies experience lower graft survival than patients without anti-donor anti-HLA antibodies [2, 3]. In hyperacute rejection, the injury occurs immediately, and the classical pathological features are infiltrating neutrophils, fibrinoid necrosis, and platelet thrombi. Fortunately, the occurrence of this type of rejection has been largely reduced by performing a pretransplant cross-match with the donor. The role of anti-HLA antibodies in chronic rejection is less well understood. Chronic rejection is the major limiting factor to long-term survival of organ allografts [4-6]. It is responsible for the loss of 50% of kidney allografts and 45% of cardiac allografts by 5 years after transplantation. The graft survival rates for other organ transplants generally show comparable results, with the exception of liver, which seems somewhat better tolerated. Chronic rejection, is defined as progressive functional deterioration of transplanted tissue occurring months or years after engraftment. The hallmark of chronic rejection is accelerated graft atherosclerosis which is characterized by diffuse, concentric, intimai occlusive lesions leading to gradual fibrosis of the transplanted organ [4-6]. [ABSTRACT FROM AUTHOR]

The presence of broadly reactive antibodies directed at allogeneic lymphocytes is a major and increasing cause of delay in transplantation of patients with end-stage renal disease. In addition, hyperimmunized status is associated with a lower graft success rate that non-immunized status, unless patients were transplanted with excellent matched graft. Hyperimmunized patients represent an increasing proportion of graft waiting list, caused by previous graft failure, pregnancies and blood transfusions. [ABSTRACT FROM AUTHOR]

The phenomenon of' second set' or ‘accelerated' rejection which characterizes the rapid destruction of a second tissue or organ transplant from the same donor into the same recipient was first described by Medawar and coworkers. Those observations made in untreated recipients were considered as a major evidence for the immunological mechanisms of allograft rejection since such capacity to reject transplants of donor strain origin in an accelerated mode could be transferred to naive recipients by T cells from the presensitized hosts. Cross-reactive grafts from donors sharing MHC class I and/or class II alleles with the sensitizing donor were also rejected in an accelerated fashion, suggesting that accelerated rejection was mediated by sensitized CD4 + and/or CD8 + donor specific alloreactive T cells. The capacity to mount an anamnestic rejection could persist several weeks or months after completion of the first graft rejection, suggesting that memory T cells had been produced following the first transplant. However the mechanisms of memory induction and the phenotypic and functional differences between memory and effector T cells remain controversial. The allograft response entails the clonal expansion of donor MHC class II and MHC class I specific CD4 + and CD8 + T cells, associated with several phenotypic changes, including increased surface expression of CD2 and CD58 (LFA-3), increased affinity of the integrin CD11a/CD18 (LFA-1), de novo expression of the integrin α4β1 (CD29/49d, VLA-4), changes in expression of CD62L and CD44 and decrease of the CD45RA isoform with a compensatory increase of the shorter CD45RO isoform. [ABSTRACT FROM AUTHOR]

This study was performed to investigate whether recipients of second or subsequent renal cadaveric allografts require more intensive immunosuppression than recipients of first grafts. Oxford data demonstrates that the outcome of patients with regrafts is overall identical to those with first cadaveric grafts [1] although Registry data has shown that regrafts do not do so well [2, 3], with regraft survival up to 10% lower than first grafts [4]. In most transplant centres this difference in survival between first and second grafts has decreased in the last 15 years and this has no doubt been influenced by the use of cyclosporine [5, 6]. Hirata et al. [7] describe a difference of as little as 1% between first and second graft survival in their patients, compatible with our own data. Kidney regraft candidates now comprise about 27% of all patients awaiting renal transplantation, but only receive 13-14% of the annual cadaveric transplants [8]. The reasons for this are multifactorial, but include high sensitization and associated positive crossmatches, and a presumption of worse outcome for regrafts [9]. Patients awaiting regrafting share the common experience of having lost a previous transplant and having been exposed to foreign HLA antigens. Only some of these graft losses will be the result of rejection, others having been lost to technical problems such as renal vein or artery thrombosis or to primary non-function. It is the sub-group who have mounted an immunological response sufficient to reject the primary graft that are likely to be the more difficult group in which to achieve success with a regraft, and in whom more aggressive immunosuppression might be indicated. [ABSTRACT FROM AUTHOR]

In allotransplantation the common causes of sensitization are blood transfusion, pregnancy and rejection of an allograft. An additional route of sensitization that should not be overlooked is the potential crossreactivity of T cells responding to enviromental antigens or pathogens that may be able to cross react with alloantigens expressed by the antigen presenting cells (APC) within an organ graft. In this situation the T cells of the host would be sensitized to the alloantigens of the organ donor even though the donor alloantigens themselves had not been encountered previously. The frequency of crossreactive T cells present in a recipient and their contribution to the rejection of allografts is extremely difficult to assess with the tools currently available. [ABSTRACT FROM AUTHOR]

From the clinical point of view, the conditions associated with recurrence in the transplanted kidney can be classified into 3 groups: (i) inherited inborn errors of metabolism (IEM), (ii) systemic diseases with multiple organ involvement and (iii) glomerulonephritis [1]. Organ transplantation has been introduced during the last 15 years as a possible therapy of IEM. Such a management requires an accurate diagnosis, an early intervention in most cases and a precise knowledge of the biochemical defect. Because of the possible consequences and risks of transplantation, the place of organ replacement is the following issue of conventional therapy of IEM, i.e. treatment at the clinical phenotype level, at the metabolic level and at the dysfunctional protein level [2]. In most cases, transplantation provides the normal protein in its physiological cellular and subcellular locations with respect to its substrates and cosubstrates. Four main conditions can be considered (Tables 1 and 2): (1) transplantation as a replacement of an isolated damaged target organ, such as kidney in nephropathic cystinosis or heart in familial hypercholesterolemia; (2) transplantation as a source for a deficient protein such as displacement marrow transplantation in lysosomal storage diseases or orthotopic liver transplantation in primary hyperoxaluria type 1 (PH1); (3) transplantation as a concommittent protein source and replacement of damaged organ, such as liver transplantation in α-antitrypsin deficiency or tyrosinemia type 1; (4) in cases of combined transplantation, another organ has to be grafted as a replacement of the damaged native one, such as liver + heart in familial hypercholesterolemia or liver + kidney in PH1 [2]. [ABSTRACT FROM AUTHOR]

Patients who receive second cadaver transplants continued to pose unique challenges as they are considered to be immunized by their previous grafts. However, the success rates for renal retransplantation have significantly improved in recent years as a result of improved pretransplant screening and posttransplant management, including sensitive crossmatching, better HLA matching, and more potent immunosuppressive agents [1-3]. The present study is an updated report on second cadaver donor transplants in the United States. [ABSTRACT FROM AUTHOR]

Noncompliant behavior — considered for a long time as an important risk factor in cardiovascular and cancer treatments — is now being recognized as an important element in organ transplantation outcome. Its existence is most vexing to the members of the transplant team and to the patient's family since it is universally recognized that a large amount of effort and sacrifice goes into organ donation and transplantation. Careful analysis of this problem is necessary in order to identify its exact prevalence, the magnitude of the problem, the importance of noncompliance in patient death and graft loss, as well as in other post transplant complications. [ABSTRACT FROM AUTHOR]

Lymphomas and lymphoproliferations comprise 24% of posttransplant malignancies and Kaposi's sarcoma (KS) 6%, if non-melanoma skin cancers and in situ carcinomas of the uterine cervix are excluded, as they are from most studies of patterns of malignancy [1]. A gratifying feature is that following treatment 41% of lymphomas and 36% of KS undergo complete remission. In some patients a complication of such therapy is loss of the allograft, which may necessitate retransplantation. A question that arises is whether retransplan-tation, with reinstitution of full dose immunosuppressive therapy will precipitate recurrence of the neoplasm. The current study examined the data accumulated by the Cincinnati Transplant Tumor Registry (CTTR) from the fall of 1968 till May 1997 to address this question. [ABSTRACT FROM AUTHOR]

Though recurrent primary glomerulonephritis (PG) currently accounts for only less than 2% of all graft failures in the adult [1-4], this rate is expected to increase with both the improvement of patient and graft survivals and the ineffectiveness of most attempts at recurrence treatment. The patient who has lost a first graft to PG recurrence expectedly wishes proper information on the risk of recurrence in a further graft. Except for focal glomerulosclerosis (FGS) [5-7], there is very scarce data on this issue in the literature. We thus decided to review our experience with the fate of a second transplant in patients who had recurrence of PG in their first transplant. [ABSTRACT FROM AUTHOR]

Although organ transplant success rates have improved in recent years due to improved patient management and the availability of more effective immuno-suppressive drugs, immunological rejection remains an important problem. Patients who reject a transplant become candidates for retransplantation. The situation is fundamentally different for kidney transplant recipients, who usually return to dialysis after rejection and can be retransplanted electively, and heart and liver recipients for whom life saving machine support is not routinely available. Therefore, kidney retransplants are performed at a much higher rate than heart or liver retransplants. [ABSTRACT FROM AUTHOR]

Transplantation of marrow or hematopoietic stem cells (HSC) from a normal donor requires high-dose marrow ablative conditioning in order to achieve full and sustained engraftment [1]. Graft failure is an uncommon problem following transplantation of marrow from an HLA identical sibling, but occurs more frequently in recipients of marrow from an HLA incompatible donor [2]. Graft failure can have catastrophic consequences, and prolonged pancytopenia may place the patient at high risk of infection or hemorrhage. Although severe graft failure is often fatal, autologous recovery of hematopoiesis can occur in some patients. The absence of donor cells and presence of host lymphoid cells suggests rejection as the cause of graft failure. Severe graft failure refractory to treatment with hematopoietic growth factors is a primary indication for retransplantation. Retransplantation may also be necessitated by recurrence of hematological malignancy. Additional immune suppression is usually necessary before retransplantation, and patients are usually very sensitive to the toxicity of additional conditioning therapy, especially if the time interval after initial transplantation is short. The feasibility of retransplantation and the optimal method depend on the primary disease and the condition of the patient. [ABSTRACT FROM AUTHOR]

Treatment of end stage renal failure (ESRF) is achieved either by chronic dialysis (haemodialysis or peritoneal dialysis) or by renal transplantation (RTx). The advantages of RTx over dialysis include lower mortality (annual death rate about 1% for transplanted patients, compared with 14% for dialysed patients in year 1995 for France) [1], better long-term rehabilitation of patients, regular improved graft survival (we can expect about 60% at 10 years under triple therapy) and lower cost (on a 10 year basis, the cost of transplantation is 5.5 times less than the cost of hospital dialysis). All these previous demonstrations were made with global data including 85-90% of first grafts. [ABSTRACT FROM AUTHOR]