J Pratschke

Brain death and its influence on donor organ quality and outcome after transplantation.

Transplantation has evolved as the treatment of choice for many patients with end-stage organ disease. However, despite the .80% one-year functional survival rate of most transplanted organs at the present time, the ultimate goal—to provide long-term treatment for an irreversible process—has not been achieved; the rate of attrition over time has not changed appreciably throughout the entire experience (1). Although recurrent disease, de novo infections, malignancies, and other factors may contribute to late graft deterioration, chronic rejection remains the most important etiologic factor (2). Despite well-characterized functional and morphological changes, the mechanisms leading to this progressive state remain poorly understood. Its pathophysiology has been conceptualized as stemming from both antigendependent and -independent risk factors (3). Although immune-mediated events are considered to be primarily responsible for the late graft changes, it seems increasingly that the influence of nonimmunological events has been underestimated. This concept has been emphasized by recent pooled United Network of Organ Sharing data that show that the survival rates of kidneys from living-unrelated and one haplotype-matched living-related donors are identical despite potentially important differences in genetic relationship with the given recipient (4). In addition, organs from all living donors demonstrate consistently superior results to those from cadaver sources over both the shortand long-term. Various nonimmunological factors that might explain these discrepancies include the effects of initial ischemia/reperfusion injury, inadequate functioning nephron mass, viral infections, and drug toxicity. Brain death is a rarely considered risk factor uniquely relevant to the cadaver donor. Multivariate analysis has emphasized that both initial and long-term results of engrafted cadaver organs may be dependent upon donor demographics and the etiology of the central injury (5). In virtually all experimental studies of organ transplantation, young, healthy living animals are used as donors; in clinical practice, in contrast, a relatively low percentage of organs comes from living donors, as cadavers remain the primary source of supply. Amongst other variables, the difference between the two donor populations implies the effect of profound physiological and structural derangements that may occur during and subsequent to brain death and before the actual engraftment procedure.

A model of gradual onset brain death for transplant-associated studies in rats

BACKGROUNDnThe relatively few studies that have examined the systemic events after brain death have primarily involved large animals. For more precise definition of the physiology of this central catastrophe and its influence on peripheral organs, we have established a reproduceable model of gradual onset brain death in rats.nnnMETHODSnThe central injury is induced by graded inflation of a Fogarty catheter placed intracranially under EEG and blood pressure monitoring. The rats were mechanically ventilated for 6 hr before removal of their kidneys. Complications and mortality are discussed.nnnRESULTSnThe majority (83%) of the 100 experimental animals could be used as organ donors. After a transient period of autonomic storm, the mean arterial blood pressure remained consistently between 80-100 mmHg, not appreciably different from controls. Despite normotension, the transplanted kidneys from brain dead donors showed a significantly longer interval to regain uniform cortical color and turgor than kidneys from control animals.nnnCONCLUSIONSnWe describe a controlled model of gradual onset brain death in the rat in which normotension can be sustained for several hours before the kidneys are removed for transplantation. Despite stable donor blood pressure, ischemia of peripheral organs may explain in part the increased incidence of delayed graft function of cadaver kidneys compared with those from living donors. This model is suitable for transplant-related studies involving organs from donors with irreversible central injury.

What can be learned from brain‐death models?

Brain death of the donor is an important risk factor influencing graft outcome. In addition to its nonspecific effects, it potentiates graft immunogenicity and increases host alloresponsiveness. Thus brain death in addition to other unspecific injuries such as organ procurement, preservation and consequences of ischemia/reperfusion injury, contributes towards the change of an inert organ to an immunological altered graft. Prior to engraftment, brain death initiates a cascade of molecular and cellular events including the release of proinflammatory mediators leading to cellular infiltrates. Those events may affect the incidence of both acute and chronic changes, developing and contributing to reduced graft survival. Consequently, strategies to reduce the immunogenicity or the pro‐inflammatory status of the graft are becoming more attractive and might even help to improve organ quality and graft function.

Ischemia and reperfusion injury

Abstract Organ allografts, particularly from less than optimal donors, may not be biologically inert at the time of transplantation but may trigger or amplify subsequent host responses against the foreign tissues. These potentially activated organs may provoke a continuum between the inflammatory changes evoked in the recipient by initial nonspecific, antigen-independent insults and the later onset of antigen-dependent, immunologic alloresponsiveness. Older donors, hypertension and other donor factors, the peripheral events surrounding brain death, the use of non-heart-beating donors, and ischemia-reperfusion injury may all contribute to initial graft injuries. These in turn may provoke the eventual onset of progressive chronic graft dysfunction. The effects of these insults, with special reference to cardiac transplants, are reviewed.

Chronic rejection: increasing evidence for the importance of allogen-independent factors

Chronic rejection is a process caused by an interplay of different risk factors. Early injury regardless of type, seems to be an important prognostic event. Later insults appear to contribute. As the individual components of the process are increasingly dissected and understood, means to modulate or normalize them will be forthcoming.

Nonresponse to pre-operative chemotherapy does not preclude long-term survival after liver resection in patients with colorectal liver metastases

BACKGROUNDnLiver resection is the only curative treatment offering a chance of long-term survival in patients with colorectal liver metastases (CRM). Recent data indicated that liver resection in patients with tumor progression while receiving chemotherapy was associated with poor outcome. The aim of the study was to identify risk factors for poor outcome in patients with pre-operative chemotherapy of CRM.nnnMETHODSnWe analyzed 160 patients after liver resection for CRM with preoperative systemic. chemotherapy. Three groups of patients were identified: 44 patients (27.5%) had a tumor response, 20 (12.5%) showed stable disease, and 96 (60%) patients had tumor progression while on chemotherapy. Median follow-up was 2.4 years (range, 6 days-11.1 years). All available clinicopathologic variables possibly associated with outcome were evaluated.nnnRESULTSnSurvival was 88%, 53%, and 37% at 1, 3, and 5 years. Noncurative resection, carcinoembryonic antigen levels >200 ng/ml, tumor grading, size of the largest tumor >5 cm, and number of metastases were associated with poor patient outcome. In the multivariate analysis, tumor free margin and tumor grading correlated with the outcome. Tumor progression while on chemotherapy had no influence on the long-term survival.nnnCONCLUSIONnLiver resection offers a long-term survival benefit for patients with CRM, even when tumor growth proceeds during pre-operative chemotherapy.

Chronically rejected rat kidney allografts induce donor-specific tolerance.

Previous studies on pathophysiological mechanisms of chronic graft rejection demonstrated the impact of both alloresponsiveness and nonspecific immunological events on the process. To study the role of alloantigen-specific factors further, we hypothesized an acceleration of chronic graft rejection after presensitization. Chronically rejected renal allografts in the established Fischer 344 --> Lewis rat model were replaced sequentially by native allografts of donor origin. Grafting of second allografts was performed 2, 4, 8, and 12 weeks after the original transplantation and followed long term. Second allografts demonstrated significantly ameliorated functional and structural alterations with few cellular infiltrates. These changes were independent from the time interval between first and second engraftment (2-12 weeks); immunosuppressive treatment after the second engraftment was not influential. The nonresponsiveness was not restricted to the second kidney allografts, as heart allografts of donor origin in these recipients also functioned indefinitely, whereas third-party grafts (Lewis x Brown Norway F1) and Fischer 344 heart grafts in untreated Lewis control rats were acutely rejected. Thus, donor-specific and tissue-nonspecific graft acceptance is achieved by second engraftment of donor-specific allografts in a model of chronic graft rejection. Those observations demonstrate the synergistic effects of alloresponsiveness and of the injured graft itself for the development of chronic graft failure.

Quadruple tacrolimus-based induction therapy including azathioprine and ALG does not significantly improve outcome after liver transplantation when compared with standard induction with tacrolimus and steroids : Results of a prospective, randomized trial

BACKGROUNDnTacrolimus in combination with prednisolone has been proven to be a safe and effective immunosuppressive induction therapy in solid organ transplantation. However, it remains unclear whether a tacrolimus-based quadruple induction regimen with azathioprine and an antilymphocytic preparation could further improve the results after orthotopic liver transplantation. Therefore, we designed a prospective, randomized study to compare the immunosuppressive efficacy of dual (tacrolimus and prednisolone) and quadruple (tacrolimus, azathioprine, ALG Merieux and prednisolone) induction after liver transplantation.nnnMETHODSnAfter randomization, 120 consecutive patients of primary liver transplants were divided into the dual group (n=59) and the quadruple group (n=61) and followed for a minimum of 3 years.nnnRESULTSnPatient survival at 3 years was 88.2% in the dual versus 94.9% in the quadruple group. Overall 25 patients in each group (41 and 42%, respectively) developed acute rejection. There was no difference in the number and severity of rejections. In each group only four patients required OKT3-therapy, however, although three of four patients in the quadruple group responded to OKT3 and cleared rejection, none of the four patients in the dual group were treated successfully with OKT3 (P<0.02). Rejection in these patients resolved only after additional treatment with mycophenolate mofetil. Adverse events and infections were equally distributed in both groups. Asymptomatic Cytomegalovirus infections were more common in the quadruple group (P<0.02). As of today, only one patient developed posttransplant lymphoproliferative disease (dual group).nnnCONCLUSIONSnThe data from our single-center study indicate that both tacrolimus-based dual and quadruple immunosuppressive induction regimens yield similar safety and effectiveness after liver transplantation.

Non-heartbeating kidney donors

The kidneys used in the early years of transplantation were primarily from non-heartbeating donors (NHBD). Death was pronounced when cardiac function ceased, and organ retrieval procedures were largely based on autopsy practice. As a result, the period of warm ischemia was prolonged, and many of the early grafts failed to function. In time, criteria for donor brain death were established, emanating predominantly from the deliberations of the Ad Hoc Committee of the Harvard Medical School in 1968. With improvements in donor stabilization and more effective techniques to protect organs, the engraftment of kidneys has become a well-established treatment for end-stage renal disease, a fatal condition with profound medical and social ramifications. In addition to pre-transplant measures, the success rate of renal allografts from cadaver donors, the primary source of such organs, has also significantly improved, due to better patient care, fuller understanding of end-stage disease processes, human leukocyte antigen (HLA) tissue matching, and advances in immunosuppressive therapy. As a result, ever-increasing numbers of patients are accepted into transplant programs to await an appropriate organ. In 1988, UNOS reported approximately 14000 registrations for a kidney transplant. By 1998, there were 42000 potential recipients on the waiting list (1). Besides the progressive influx of new patients, those who return to dialysis after losing their previous graft from chronic rejection, non-compliance, or other reasons, and desire a new transplant, swell the rolls (2). Despite intensive efforts in promoting organ donation through education of the public and professionals alike, the number of donors has remained relatively static over the past decade, increasing only from 3876 in 1988 to 5078 in 1997 (1). Because of this progressing discrepancy between supply and demand, other potential donor sources have been investigated. As organs from living-related and unrelated sources comprise approximately 10% of the total donor pool, not only has there been renewed interest in the use of ‘marginal’ or ‘extended’ cadaver donors, but in organs from NHBD as well.

Promising recent data on ABO incompatible liver transplantation: restrictions may apply

The success of organ transplantation has improved progressively over the past decades based on refined surgical techniques, improvements in organ procurement and intensive care treatment, and in particular on more effective immunosuppressants. With this development, donor and recipients selection criteria have expanded drastically and organ shortage has developed as one of the foremost current issues. Organ scarcity is particularly dramatic in live threatening situations as fulminate hepatic failure (FHF). Renal transplants have been performed with great success rates in patients with a positive T-cell cross matches and also across ABO blood group incompatibilities. Recent clinical reports avoided splenectomies and were based on plasmapheresis, IVIG and Retuximab, an antibody selectively targeting and depleting CD20+ B-cells. However, the long-term success of those approaches remains to be determined [1]. Interesting are preliminary and ongoing clinical desensitization trials for patients awaiting deceased renal transplants. This approach attempts to facilitate renal transplantation for sensitized patients who have been on the waiting list for extensive time periods [2]. Successful liver transplants across ABO barriers have been reported already in the 1980s [3,4]. While ABO compatibility was associated with a significantly improved outcome, transplantation across ABO blood groups had been ‘surprisingly’ successful. Under an immunosuppressive treatment with Cyclosporine, Prednisone and OKT 3, applied in some cases for acute rejections, five out of 13 grafts continued to function after 3 years [3]. A more recent study in the 1990s analyzed risk factors retrospectively and compared the outcome of ABO compatible and incompatible liver transplants in emergency situations. Of note, 1-year graft survival in recipients of blood groups A, B or AB was only 13% [5]. Two articles in the current issues of Transplant International address the topic of ABO incompatibility and liver transplantation: Koukoutsis et al. [6] from Birmingham, UK, analyzed recipients with FHF retrospectively over a 20-year period receiving either identical, compatible or incompatible liver transplants. While the small number of incompatible livers transplanted in this report does not allow a conclusive analysis, a minor improvement of patient and graft survival was observed when recipients of blood group identical liver transplants were Transplant International ISSN 0934-0874