International Society For Heart Transplantation Research Articles

Pre- and posttransplantation allosensitization in heart allograft recipients: Major impact of de novo alloantibody production on allograft survival

The involvement of humoral response in allograft rejection has been suggested by both immunologic and histochemistry studies. In the present study, we explored the role of alloantibodies in a large cohort of heart allograft recipients followed for 15 years. Sequential samples of sera were obtained from 950 recipients of heart allografts before and after transplantation at the time when protocol endomyocardial biopsies were performed. The presence of anti–human leukocyte antigen (HLA) antibodies was investigated using complement mediated cytotoxicity and solid phase assay (SPA). Our data reveal an inverse correlation between the development of alloantibodies after transplantation and heart allograft survival. The 15-year graft survival was highest in patients who never developed alloantibodies (70%) or who displayed them only before transplantation (71%); graft survival in recipients who showed antibodies both before and after transplantation (56%), or only after transplantation (47%), was lower. The deleterious effect of antibodies on graft survival started 8 years after transplantation, suggesting that the production of de novo antibodies may have been triggered by some later event. We found that patients with de novo antibodies appearing more than 1 year after transplantation had the poorest survival. Furthermore, the development of de novo antibodies was preceded in 76% of these patients by cellular rejection grade 3 or higher, according to the International Society for Heart Transplantation (ISHT) grading criteria. Development of antibody-mediated rejection (AMR) had a significant negative impact on graft survival (16% in AMR + vs 63% in AMR – patients, p = 0.0008). Of the 23 patients with AMR, 21 displayed cytotoxic donor-specific antibodies (DSA) at the time of diagnosis, and in 18 of these cases SPA showed that they were directed against the donors' HLA. The data demonstrate that the detection of alloantibodies permits a better definition of AMR in heart allograft recipients. Identification of patients at risk for developing AMR is of great importance for early treatment of rejection episodes.

Revision of the 1990 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Heart Rejection

In 1990, an international grading system for cardiac allograft biopsies was adopted by the International Society for Heart Transplantation. This system has served the heart transplant community well, facilitating communication between transplant centers, especially with regard to patient management and research. In 2004, under the direction of the International Society for Heart and Lung Transplantation (ISHLT), a multidisciplinary review of the cardiac biopsy grading system was undertaken to address challenges and inconsistencies in its use and to address recent advances in the knowledge of antibody-mediated rejection. This article summarizes the revised consensus classification for cardiac allograft rejection. In brief, the revised (R) categories of cellular rejection are as follows: Grade 0 R--no rejection (no change from 1990); Grade 1 R--mild rejection (1990 Grades 1A, 1B and 2); Grade 2 R--moderate rejection (1990 Grade 3A); and Grade 3 R--severe rejection (1990 Grades 3B and 4). Because the histologic sub-types of Quilty A and Quilty B have never been shown to have clinical significance, the "A" and "B" designations have been eliminated. Recommendations are also made for the histologic recognition and immunohistologic investigation of acute antibody-mediated rejection (AMR) with the expectation that greater standardization of the assessment of this controversial entity will clarify its clinical significance. Technical considerations in biopsy processing are also addressed. This consensus revision of the Working Formulation was approved by the ISHLT Board of Directors in December 2004.

Correlates of Myocardial Performance with Rejection in Pediatric Heart Transplant Patients † 80

In pediatric heart transplant patients, myocardial performance is an important determinant of outcome. However, correlates mediating systolic and diastolic function in these patients are incompletely understood. We determined left ventricular +dP/dtmax (an index of contractility);-dP/dtmax and Tau (measures of relaxation), and end diastolic pressure(EDP); and performed right ventricular endomyocardial biopsies, in 5 post-transplant patients undergoing 8 cardiac catheterizations. One patient(*) had 3, and another (†) 2 catheterizations because of severe rejection. Their ages ranged from 4 to 17 yrs., and the time from transplant to catheterization was 2.5 to 3 yrs. Mechanical parameters were determined from left ventricular pressure tracings recorded at 200 mm/sec, and sampled at 4.16 ms intervals. Tau, the relaxation time constant, was obtained by fitting the ventricular pressure data to the exponcntial function P(t) = Po e-t/Tau, where Po is the pressure at -dP/dtmax, and t the time. Myocardial rejection was classified as mild (open box), moderate (shaded box) or severe (black box), based upon the grading system of the International Society for Heart Transplantation. Positive- and -dP/dtmax were jointly evaluated to determine whether ventricular contraction and relaxation were coupled (Fig. 1). Tau and EDP were analyzed to examine the relationship between active relaxation and passive filling (Fig. 2). Both correlations were highly significant regardless of the patients' degree of rejection. In conclusion, for these pediatric heart transplant patients: 1) Contraction-relaxation coupling is preserved, 2) + and -dP/dtmax do not correlate with the degree of rejection, and 3) Tau and EDP correlate with each other, and, more importantly, with the degree of rejection.

Natural course of moderate cardiac allograft rejection (International Society for Heart Transplantation grade 2) early and late after transplantation.

The significance of International Society for Heart Transplantation (ISHT) grade 2 cardiac allograft rejection has been questioned, and the medical community is not in complete agreement as to its clinical management. We therefore retrospectively analyzed the follow-up of all available endomyocardial biopsy samples obtained from 161 transplant patients since introduction of the ISHT nomenclature at our institution. Of 2868 biopsies performed 3 days to 8.9 years after transplantation, 420 biopsies had no follow-up or were preceded by intensified immunosuppression and were excluded from analysis. Of the remaining 2448 biopsies, 374 (15.3%) were repeat biopsies performed 7 to 10 days after prior ISHT 2 rejection without change of treatment. Of these, 70 (18.7%) had progressed to > or = ISHT 3A, whereas 82 (21.9%) remained unchanged and 222 (59.4%) resolved. In contrast, follow-up of 2074 biopsies with lower-grade rejection showed graft rejection classified as > or = ISHT 3A in 153 (7.4%), ISHT 2 in 240 (11.6%), and < or = ISHT 1B in 1681 (81.1%) biopsy samples (P < .0001). In univariate analysis, the odds ratio (OR) of graft rejection > or = ISHT 3A after ISHT 2 rejection was 2.89. Other univariate predictors of rejection > or = ISHT 3A were time after transplantation (OR = 0.96 per month, P < .0001), blood group type B (OR = 1.62, P < .005), "Quilty" lesion on previous biopsy (OR = 1.70, P < .005), number of HLA mismatches (OR = 1.27 per mismatch, P < .005), female sex (OR = 1.55, P < .05), and serum creatinine level (OR = 0.93 per 10 mumol/L, P < .005). Young age of recipients was a risk factor during long-term (> or = 2 years) follow-up (P < .002), and lower cyclosporine level was a risk factor during the first month after transplantation (P < .01). In multivariate logistic regression analysis, ISHT 2 rejection on previous biopsy remained the strongest predictor of rejection > or = ISHT 3A (OR = 2.40, P < .0001). Several factors independently increase the risk of rejection classified as > or = ISHT 3A. The strongest predictor of a grade of > or = ISHT 3A was ISHT 2 rejection on the previous biopsy obtained 7 to 10 days earlier. Therefore, ISHT 2 graft rejection is of clinical significance, and short-term follow-up appears to be warranted even late after transplantation.

Working formulation nomenclature of heart transplant pathology: A retrospective evaluation of 1037 endomyocardial biopsies

Working Formulation (WF) was recently introduced by the International Society for Heart Transplantation to grade acute cellular rejection, as well as additional lesions observed in endomyocardial biopsies (EMBs). The aim of this study was to evaluate the actual advantages of this grading system in terms of feasibility and predictive value. To this purpose, we reclassified 1037 EMBs performed in our heart transplantation units according to the WF. Our results show that multifocal mild rejection (grade IA), when worsening, tends to progress to multifocal moderate (3A), whereas diffuse mild (1B) generally worsens to diffuse moderate (3B), thus following the same focal or diffuse pattern. Unifocal moderate rejection (grade 2) has a peculiar behavior, in that it almost always resolves, though in our units it is treated the same way as is grade 113. Finally, we found a significant relationship between Quilty B effect and chronic rejection. In conclusion, this retrospective study shows that WF is effective in using both qualitative and quantitative criteria and, particularly, in separating focal and diffuse forms of rejection and devoting a distinct grade to unifocal moderate rejection.

Evaluation of the International Society for Heart Transplantation (ISHT) grading of pulmonary rejection in 100 consecutive biopsies

Heart-lung and lung transplantation are accepted treatments for patients with end-stage pulmonary vascular disease or parenchymal lung disease [4, 5, 10]. Survival rates for heart-lung and lung transplantation are lower than those for heart transplantation alone. The 5-year actuarial survival for heart-lung transplantation has been 41% largely due to rejection and infection remaining as the limiting factors for long-term survival [3]. A standardized nomenclature for the histological grading of pulmonary rejection was formulated by the International Society for Heart Transplantation (ISHT) in July 1990 [12]. Infection, however, is a major problem in the histological assessment of lung recipient biopsies, potentially limiting the usefulnes of such a classification. In this study, 100 consecutive transbronchial biopsies (TBBs) from lung transplant recipients were analysed, together with microbiological and serological data, in order to evaluate the proposed ISHT grading system for pulmonary rejection and the importance of concomitant infections in the histological interpretation of TBBs.

Heart-Lung Transplantation in 1990 - Indications, Surgical Technique, Postoperative Complications and Outcome

Using cyclosporine A (CyA), long-term results after heart-lung transplantation became possible. Since 1981, 761 clinical heart lung transplantations have been registered at the International Society for Heart Transplantation. Candidates for this operation reveal signs of irreversible heart and lung diseases which are caused by cardiac lesions (e.g. valvular disease, Eisenmenger reaction due to congenital malformation) or pulmonary disorders (e.g. primary pulmonary hypertension, emphysema, fibrosis). The standard surgical procedure necessitates three anastomoses which combine donor and recipient tracheae, right atria and aortae. Immunosuppression consists of CyA (blood levels of 300-500 ng/ml), azathioprine (1-2 mg/kg/d) and rabbit antithymocyte globuline (RATG) (IgG: 2-4 mg/kg/d). After the first 2 postoperative weeks, RATG is replaced by low dose methylprednisolone (0.3-0.1 mg/kg/d). As an alternative, RATG may be omitted completely. Postoperatively, a variety of complications may evolve. Early problems (within the first month) comprise acute pulmonary rejection, bacterial pneumoniae, and multiorgan failure. Diagnosis of acute lung rejection proves difficult; it includes clinical signs, chest radiographic appearances and cytoimmunological monitoring of the peripheral blood. Transbronchial lung biopsies are for precise diagnosis of similar value to endomyocardial biopsies after heart transplantation. Late postoperative complications comprise viral, bacterial, fungal, and protozoal infections and chronic obliterative bronchiolitis. With increasing experience, the 30 day mortality fell to below 20% according to the International Society for Heart Transplantation. The one-year survival rate between 1986 und 1988 was reported to be 61%. The results of some individual groups are even better.

Clinical results of heart and heart-lung transplantation

T HE GREAT medical and social impact caused by the first human heart transplantation performed by Barnard 1 more than 20 years ago stimulated the sudden proliferation of centers performing heart transplantation. The poor results of 20% 1-year-survival rates in the late 1960s and early 1970s, 2 mainly due to early rejection and infection, rapidly discouraged this practice in practically all transplant centers. Nevertheless, notably at Stanford University, new efforts in the field of heart transplantation continued and their consistently improving survival statistics resulted in a renewed interest in heart transplantation in the late 1970s. 3 Although the first human lung transplantation was performed by Hardy 4 in 1963, 4 years prior to the first heart transplant, this clinical procedure did not achieve the same popularity as heart transplantation. In fact, little success and interest occurred in the following 20 years, during which approximately 38 patients underwent lung transplantation. Perhaps for this reason, successful thoracic organ transplantation went from cardiac to combined cardiopulmonary transplantation. The first human heart-lung transplantation was performed by Cooley 5 in 1968, and a clinical program was established at Stanford in 1981. 6 Until recently, cardiopulmonary transplantation was indicated for selected patients suffering from end-stage combined cardiopulmonary or pulmonary disease alone. With the promising clinical results obtained with single 7 and double lung g'9 transplantation, it is likely that lung disease without cor pulmonale can now be successfully managed by pulmonary transplantation alone. We present herein the current results of heart, heart-lung, and lung transplantation, discussing the options and specific needs of each patient and emphasizing the need for maximum use of organs available for transplantation. to the registry of the International Society for Heart Transplantation (ISHT), 1~ during the year 1987, 1,441 heart transplantations were performed in 109 centers in the United States with another 79 centers around the world performing approximately 700 transplants. It is estimated that each year in the United States more than 15,000 patients could benefit from heart transplantation. In contrast, each year only approximately 1,000 donor hearts are suitable for transplantation. It is clear that if not for current donor scarcity, the present experience with cardiac transplantation would be even more extensive.

Life after heart transplantation

CCORDING TO the 1988 report of the Registry of the International Society for Heart Transplantation,] approximately 2,200 heart transplantations were performed in 1987. There are 109 heart transplant programs in the United States and 79 in the rest of the world. Most patients are male, with an average age of 43 years. Cardiomyopathy and coronary artery disease are the most common indications. The frequency of transplantation increased almost exponentially from 1980 through 1986, slowing in 1987, perhaps because demand has caught up with readily available donor supply. The 30 day mortality rate for heart transplantation is about 7% to 10%. Recent reports indicate the 5 and 10 year survival of heart transplant patients to be over 72.5%, with five year survival for patients on a three-drug regimen as high as 84%.’ Infection, cardiac failure, and acute and chronic rejection remain the leading causes of death. Patients over 55 years old are increasingly recognized as viable candidates with survival equivalent to younger patients. 2*3 Recent experience, especially with the introduction of cyclosporine immunosuppression, has rendered earlier psychiatric observations4-9 obsolete, and improved long-term survival heightens the importance of issues of quality of life for heart transplant recipients.

The registry of the International Society for heart transplantation: Sixth official report—1989 : Heck CF, Shumway SJ, Kaye MP: J Heart Transplantation 8:271–276, 1989

The registry of the International Society for heart transplantation: Sixth official report—1989 : Heck CF, Shumway SJ, Kaye MP: J Heart Transplantation 8:271–276, 1989