Apoptosis in cardiac transplant rejection.

Apoptosis occurs in human cardiac allograft rejection and may occur with all degrees of rejection and even in its absence. The prevalence and severity of apoptosis is determined predominantly by the intensity of macrophage infiltration and may be mediated by NO-related mechanisms. Apoptosis of interstitial, endothelial, and inflammatory cells is also present in heart allografts and may influence the degree and extent of vascular injury contributing to allograft rejection. Ongoing apoptosis of inflammatory cells suggests an immunoregulatory role. Studies of the involvement of NO in myocyte damage and Fas-FasL interactions in peripheral tolerance have raised the exciting possibility that these pathways can be exploited in a beneficial way. Further understanding of the role of apoptosis and the cellular and biochemical mechanisms that are involved in cardiac myocyte death and in inflammatory, endothelial, and interstitial cell death may provide insights into therapeutic modalities to suppress allograft rejection and vasculopathy.     

Noninvasive detection of cardiac transplant rejection using electronic monitoring

Cardiac transplantation has become the therapy of choice for the treatment of end-stage congestive heart failure. One of the major problems after cardiac transplantation is acute cellular rejection. The diagnosis of rejection is crucial to the management of transplant patients because rejection must be successfully diagnosed and reversed. Endomyocardial biopsy is the major method for detecting cardiac transplant rejection; however, this approach is invasive and is associated with morbidity and mortality. One noninvasive approach for detecting rejection is to monitor changes in the intramyocardial electrograms using pacemakers. Changes in the ventricular evoked response amplitude (VERA) obtained during ventricular pacing have been correlated with the presence of acute cellular rejection in both single center studies in Europe and a multicenter trial in five transplant centers in the United States. Given the high negative predictive value for the VERA, this approach may provide a screen to determine if individual patients require more invasive procedures such as endomyocardial biopsy and may aid in reducing the number of biopsies needed.     

Biopsy-negative cardiac transplant rejection: etiology, diagnosis, and therapy

PURPOSE OF REVIEW: As the frequency of cellular rejection after heart transplantation is decreasing, biopsy-negative episodes of rejection are being recognized more often. This article reviews the features of humoral rejection, which we believe is responsible for most episodes of biopsy-negative rejection. Hemodynamic compromise, in the absence of acute cellular rejection, called biopsy-negative rejection occurs in 10 to 20% of cardiac allograft recipients. These episodes of rejection are often more severe, and more difficult to treat, than classical acute cellular rejection. Histologic, immunofluorescence, and immunoperoxidase studies of endomyocardial biopsies from such patients often reveal intravascular macrophages, and immunoglobulin and complement deposition in capillaries, in the absence of lymphoid infiltrates, suggesting an antibody-mediated or humoral form of rejection. RECENT FINDINGS: Humoral rejection is associated with increased graft loss, accelerated transplant coronary artery disease, and increased mortality. Severely ill patients require intense therapy, which includes high-dose corticosteroids, cytolytic agents, intravenous heparin, intravenous gamma globulin, plasmapheresis, and/or antiproliferative agents. SUMMARY: Currently, our knowledge of the pathogenesis, diagnostic criteria, and optimal therapy for biopsy-negative rejection is incomplete, and evolving.     

Cytomegalovirus-associated allograft rejection in heart transplant patients

PURPOSE OF REVIEW: Modern antiviral strategies are effective in controlling the clinical syndromes associated with acute cytomegalovirus infection in heart transplant recipients. Despite this effectiveness, subclinical cytomegalovirus infection is a common finding in these patients and its impact on long-term graft outcome is currently underestimated. RECENT FINDINGS: Recent studies provide evidence implicating subclinical cytomegalovirus infection in the pathogenesis of allograft rejection and cardiac allograft vasculopathy. In this process, cytomegalovirus interacts with local inflammatory pathways, and systemic immune-regulation mechanisms, which may lead to graft damage, even in the absence of cytomegalovirus replication within the graft. Consequently, in addition to pharmacologic strategies that inhibit viral replication, immune-based therapies that abrogate host immune response may provide an effective tool to prevent the indirect impact of cytomegalovirus on graft function. SUMMARY: Current evidence suggests that subclinical cytomegalovirus infection plays an important role in the pathogenesis of long-term graft dysfunction in heart transplant recipients and in other solid organ transplant recipients. Pending the availability of definitive data from randomized trials, we propose that the use of pharmacologic and immune-based approaches, directed at complete suppression of cytomegalovirus infection, represents the best strategy for prevention of cytomegalovirus-induced rejection, cardiac allograft vasculopathy and chronic allograft damage.     

Arterio-venous shunting in renal transplant rejection.

The angiographic appearance of arterio-venous shunting has been reported in one previous case of a patient with acute severe transplant rejection. Two additional cases are presented here. In the first the arteriovenous shunting is massive, and the venous filling is within the first second of the study. In the second the shunting is less severe, and the venous filling occurs later in the arterial phase. Shunting is probably caused by multiple microscopic arterio-venous fistulae secondary to the vasculitis of rejection. We propose that the presence of arterio-venous shunting suggests renal transplant rejection and may indicate a poor prognosis for reversal of this rejection.     

Acute humoral rejection of renal transplant

Acute humoral rejection (AHR) is a rare complication which often results in the loss of kidney graft. The objective of this retrospective monocentric study was to evaluate two different approaches to AHR. Documentation of 730 patients was analysed, who underwent renal transplantation between 2002 and 2005. From 2002 to 2003, patients with AHR were treated with 5 plasmaphereses (PF group, n = 13), and from 2004 to 2005 with a combination of 5 PF and intravenous immunoglobulins (PF + IVIG, 0.5 g/kg, n = 8). Data for the period of one year post-transplant was analysed. AHR occurred in 21 out of 730 patients (2.9%). Survival of grafts in the 6th month and in the 1st year was significantly higher for the PF + IVIG group than for the PF group only (p < 0.05). Patient survival was similar in both groups. The incidence of infectious complications was similar in both groups. There was a higher incidence of acute cellular rejections in the PF group (46.2 vs. 14.3%) in control rebiopsies (performed due to deteriorated graft function or in order to check the efficiency of the treatment). It can be concluded that acute humoral rejection of transplanted kidney is a rare complication which can be treated by the combination of plasmaphereses and intravenous immunoglobulins.     

Graft rejection following HLA matched T-lymphocyte depleted bone marrow transplantation

Bone marrow graft rejection following HLA-matched bone marrow transplantation (BMT) for leukaemia has been a rare problem. However, with the introduction of T-lymphocyte depleted BMT, graft rejection is recognized as a new complication. At the Royal Free Hospital (RFH) in London T-depletion is achieved using two monoclonal antibodies with complement mediated lysis. The methodology was extended to other centres and in total 56 patients have received T-depleted, HLA matched BMT. Twelve of 56 patients have had graft rejection. At the RFH three of 41 (7%) patients have had rejection whereas at collaborating centres nine of 15 (60%) patients have had rejection. We have investigated these rejections in order to identify factor(s) responsible. Rejection was not restricted by patient or donor characteristics, nor disease status. Patient management, chemotherapy conditioning, efficiency of T-depletion, graft versus host disease (GvHD), and infection post BMT, were not consistently implicated. The major difference between the RFH and all other centres was in the radiotherapy (RT) conditioning: The RFH prescribed a single fraction of 7.5 Gy total body irradiation (TBI) whilst collaborating centres gave 10 or 12 Gy fractionated TBI. We conclude that the different incidence of rejection (7% v. 60%) relates primarily to the RT conditioning although the mechanisms(s) of rejection remain unknown. We conclude that where T-depleted BMT is used, compensation by more intensive RT conditioning is required in order to avert graft rejection.     

Age-associated decline in cardiac allograft rejection

The influence of age on cardiac allograft rejection was studied in 57 consecutive recipients. Twenty-one subjects were 54 years of age or older (mean, 57.7 +/- 0.6 years [+/- SEM]; range, 54 to 63 years) and 36 subjects were 52 years of age or younger (mean, 39.9 +/- 1.8 years; range, 16 to 52 years; p less than 0.001). The older recipients had fewer rejection episodes during the first four months following cardiac transplantation (0.24 +/- 0.05 episodes per month versus 0.72 +/- 0.09 episodes per month; p less than 0.001) and during the total duration of follow-up (0.20 +/- 0.03 episodes per month versus 0.40 +/- 0.07 episodes per month; p = 0.045), and experienced their first rejection episode later (50.4 +/- 4.0 days versus 27.7 +/- 8.5 days; p = 0.008). Younger age was found to add significantly as a predictor of rejection in a multivariate analysis that controlled for sex, immunosuppressive agents, cause of heart failure, and pretransplantation lymphocyte cross-match status (r = 0.64, p less than 0.05). Decreased rejection frequency occurred without a concomitant increase in the serious infection rate (67 percent in both groups). The 12-month actuarial survival was 100 percent in the older group and 94 percent in the younger group (p = NS). Decreased rejection in the older recipients is likely a manifestation of an age-associated decline in immune function and might represent an advantage in transplantation for carefully selected older patients.     

Arteritis in cardiac rejection after transplantation

During a 4-year experience with cardiac transplantation, 33 hearts were obtained by autopsy or surgical resection for retransplantation. Arteritis was a feature common to all rejected hearts (14 of 14), but was absent in explanted hearts without rejection (0 of 19) (p = 0.001). Monitoring of acute cardiac rejection by endomyocardial biopsy (863 biopsies) was also reviewed, with special reference to the incidence of arteritis. Among the 16 patients with arteritis on 1 or more biopsies, 44% (7 patients, confidence limits 29 to 60%) suffered fatal rejection or underwent retransplantation because of irreversible rejection. Arteritis was seen in the small vessels obtained by endomyocardial biopsy in 4 of 5 persons who underwent biopsy within 3 days of death or retransplantation due to rejection and on none of the 6 persons who underwent biopsy within 3 days of death or retransplantation for causes other than rejection. Thus, arteritis is an important indicator for severe acute rejection, and although often reversible, may identify patients at higher risk for fatal rejection. Arteritis occurred in transplanted hearts subjected to varying combinations of cyclosporine, azathioprine and steroid therapy and could not be correlated with any drug regimen.