Cardiac surgery and congenital heart disease: reflections on a modern revolution.

The success of cardiac surgery has transformed the prospects of children with congenital heart disease with over 90% now surviving to adulthood. The early pioneering surgeons took on significant risk, whilst current surgical practice emphasises safety and consistency. In this article we review important British contributions to the field and consider challenges for the future, specifically how to better manage and reduce the adverse sequelae of congenital cardiac surgery by continuing to innovate safely.

What are the predictors that affect the excellent long-term benefits of redo coronary artery bypass grafting?

OBJECTIVE: Recurrent angina refractory to medical therapy in patients having undergone prior coronary artery bypass grafting (CABG) is an indication for repeat surgical revascularisation. The primary aim of this retrospective study was to determine the benefit of redo surgery over the longer term with regards to survival and freedom from cardiac symptoms/events. Our secondary aim was to identify risk factors that compromise surgical efficacy of redo revascularisation. METHODS: Patients were identified through case note review. Survivors were interviewed by telephone according to a defined protocol. Actuarial freedom from cardiac symptoms/events and survival were determined. A composite outcome for cardiac symptoms/events was used and defined as angina class> or =2 or NYHA> or =2 or myocardial infarction or need for percutaneous intervention. Univariate and multivariate analysis was performed. Survival was assessed using a Kaplan-Meier method, and determinants of survival with the Cox proportional hazards model. RESULTS: Between January 1st, 1996 and February 1st, 2004, 101 consecutive patients underwent redo CABG at our institution under the care of a single surgeon. There were 91 men and 10 women, 64% (65/101) had an age> or =70 years. 30-Day mortality was 1.2% (2/101). Mean time to follow-up was 5.3+/-3.8 years. Poor left ventricular function and pre-operative NYHA> or =2 status were independent predictors of decreased survival with hazard ratios (HR) of 2.12 (1.042-4.31) and 3.98 (1.39-11.39) respectively. The use of a radial artery graft at re-operation was an independent predictor of peri-operative death OR=18 (1-346). Actuarial survival at 1, 5 and 8 years was 90.1%, 84.4% and 76.9% and freedom from cardiac symptoms/events was 100%, 95% and 68% respectively. CONCLUSION: This study shows acceptable short- and long-term survival and freedom from symptoms/events in patients undergoing redo coronary artery bypass grafting at a single institution. The apparent association between radial arterial grafts and impaired early clinical outcome warrants further investigation.

Combined heart-lung transplantation from a donation after circulatory death donor.

Combined heart-lung transplantation is the optimal treatment option for many patients with end-stage heart failure and fixed severe pulmonary hypertension. It offers the only possibility of long-term survival and a return to a normal quality of life. Unfortunately, it is rarely performed because of donor organ allocation policies. We present the case of a critically ill 24-year-old man, who after waiting for >100 days in-hospital on the urgent transplant list, deteriorated further and underwent the first successful heart-lung transplant with organs from a donation after circulatory death.

APT070 inhibits complement activation during in vitro cardiopulmonary bypass.

BACKGROUND: The proteins of the complement cascade play an important role in inflammation and the immune response. They have been shown to be activated during cardiopulmonary bypass (CPB), and may be responsible for the inflammatory response to CPB. We looked at the effect of APT070, an anti-complement agent, on human blood during in vitro CPB. MATERIALS AND METHODS: Four hundred millilitres of blood was venesected from healthy human volunteers and heparinised. To the blood was added either APT070 to a concentration of 50 microg/ml (n=5) or vehicle control (n=4). The blood was entered into an in vitro CPB circuit and circulated for 90 min. RESULTS: Our results showed that after 90 min of in vitro bypass APT070 significantly inhibited the activation of compliment as demonstrated by C3a (p=0.03) and sC5b-9 (p=0.01) levels, and reduced neutrophil stimulation as measured by CD11b expression (p=0.04 at 90 min). CONCLUSION: APT070 significantly inhibits complement and neutrophil activation. This result may have considerable implications, especially if it can be shown to decrease the inflammatory sequelae of CPB.

Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations, March 28-29, 2001, Crystal City, Va.

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to approximately 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond approximately 2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on "Maximizing Use of Organs Recovered From the Cadaver Donor" held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described.

Short- and long-term outcomes of using pulmonary allograft donors with low Po2.

BACKGROUND: The establishment of lung transplantation as a treatment modality for end-stage lung disease has led to an imbalance in the demand and supply for such a procedure. Increasingly marginal donors are being accepted for transplantation. We assessed the short- and long-term outcomes with the use of lung donors with low Po(2). METHODS: All heart-lung and double lung transplantations (n = 362) carried out between 1984 and 2001 were included. Recipients were divided according to the optimized donor Po(2) (on 100% Fio(2)): Po(2) = 30 to 40 kPa = low Po(2) donors (n = 50) and Po(2) >40 kPa = normal Po(2) donors (n = 312). There were no differences in the sex distribution, cytomegalovirus infection status, ischemic time, and intubation durations for the recipients and their respective donors between the 2 groups. The low Po(2) donors were older (38 vs 32 years, p = 0.01) and the allografts were transplanted into younger recipients (33 vs 38 years, p = 0.01). RESULTS: There was a trend toward an increase in the 30-day mortality between the 2 groups (22% vs 13%, odds ratio 1.92, 95% confidence interval 0.91-4.05 p = 0.08). The 1- and 5-year survival rates (standard error) were 66% (7%) and 52% (7%) for the low Po(2) group and 72% (3%) and 44% (3%) for the normal Po(2) group (p = 0.97). Similar infection rates were recorded for the groups. Although rejection rates were similar in the first 3 months, there was a lower rate of rejection in the low Po(2) group thereafter, (hazard ratio, 0.52; p = 0.05). Risk of bronchiolitis obliterans syndrome (BOS) onset was marginally increased in the borderline donors (hazard ratio 1.05, 95% confidence interval 0.68-1.62), although this was not statistically significant. CONCLUSIONS: Donor lung allograft, with optimized Po(2) between 30 and 40 kPa on 100% Fio(2), used for lung transplantation did compromise 30-day mortality, but the difference in mortality did not extend beyond 30 days in our patient group.

Early mortality after cardiac transplantation: should we do better?

BACKGROUND: According to International Society for Heart and Lung Transplantation (ISHLT) data, the 30-day survival after heart transplantation has continually improved from 84% (1979-85) to 91% (1996-2001). This has probably been achieved by better donor/recipient selection, along with improved surgical technique and immunosuppressive therapy. On the other hand, the data concerning the early causes of death after cardiac transplantation is incomplete, because in 25% of cases, an unknown cause is listed. This study investigated the incidence and causes of 30-day mortality (determined by postmortem studies) after cardiac transplantation and assessed the possibility of improvements. METHODS: A retrospective study of all patients who underwent heart transplantation at Papworth Hospital from 1979 to June 2001 (n = 879) and who died within 30 days of surgery was carried out. Postmortem examination data were available for all patients. RESULTS: The mean (standard deviation) recipient and donor ages were 46 (12) and 31 (12) years, respectively. Overall, the 30-day mortality was 8.5% (n = 75), 12.1% for the 1979 to 1985 period and 6.9% for the 1996 to 2001 period. The primary causes of death were graft failure (30.7%), acute rejection (22.7%) (1.3% for the 1996-2001 era), sepsis (18.7%) gastrointestinal problems (bowel infarction and pancreatitis; (9.3%), postoperative bleeding (6.7%), and other (12%). CONCLUSIONS: Our 30-day mortality compares favorably with the data from the ISHLT registry, with great improvement in the early mortality. Acute rejection is no longer a major cause of early mortality. Further reduction may be achieved by a better protection of the donor heart against the effects of brainstem death and ischemic injuries. However, the quest to improve early outcome should not be at the expense of needy patients by being overselective.

Angiogenesis occurs within the intimal proliferation that characterizes transplant coronary artery vasculopathy.

BACKGROUND: Vascular remodeling is central to the development of transplant coronary artery vasculopathy (CAV). For remodeling to occur, a sustained blood and nutrient supply is essential. Here we report on the presence of angiogenesis within the neointima of coronary arteries from cardiac transplant recipients. METHODS: Coronary arteries from 57 cardiac transplant recipients with CAV were analyzed. Immunocytochemistry with antibodies raised against endothelial cells (CD31, CD34, and vWF), vascular smooth muscle cells (SmA), and activated endothelial cells (MHC 2, P-SEL, E-SEL, and VCAM-1) was performed. RESULTS: A total of 89% of patients had significant angiogenesis. These vessels appeared as endothelial lined channels and were present in a concentric circumferential pattern within the mid portion of the neointima. These new vessels were present at an interface between an area of intimal hyperplasia and below an area of fibrous regeneration. These 2 distinct zones were present in 64% of the cases, and were clearly demonstrated with an elastic van Gieson (EVG) stain and are distinctly different from that seen in native atherosclerosis. Endothelial activation markers were strongly expressed by the endothelial cells lining new vessels, suggesting that they are functional and may aid in the recruitment of inflammatory cells. CONCLUSIONS: These data suggest that angiogenesis is present within the intima of CAV lesions and may contribute to the continued obliteration of the vessel lumen. The vessels appear to originate in the intima and may represent the location of the donor endothelium before transplantation. Inhibition of endothelial damage may provide therapeutic options to prevent the progression of CAV.

Comparison of survival by allocation to medical therapy, surgery, or heart transplantation for ischemic advanced heart failure.

BACKGROUND: To ascertain survival of ischemic advanced heart failure patients by treatment allocation, we examined the outcome of transplant assessment patients allocated to medical therapy, high-risk conventional surgery, or transplantation. METHODS: Patients were identified from the Papworth transplant database and excluded if primary etiology was not ischemic. Grouping was undertaken according to treatment allocation at initial assessment, and analysis was performed by intention to treat. Survival was computed from the time of assessment and Cox regression used to stratify patients according risk with the Heart Failure Survival Score. RESULTS: From May 1993 to September 2001, a total of 755 patients were admitted for transplant assessment, with 348 (46.1%) identified as having heart failure of ischemic origin. Variables required for calculation of the Heart Failure Survival Score was available in 273 patients (78.4%), and 20 patients (7.3%) were lost to follow-up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery, and 132 (52.2%) to transplantation. The relative risk (95% confidence limit) of death compared with medical therapy was 0.62 (0.28, 1.40) for surgery and 0.38 (0.24, 0.61) for transplantation in medium- to high-risk patients. For low-risk patients, the relative risks for death compared with medical therapy were 1.87 (0.63, 5.60) for surgery and 1.97 (0.79, 4.96) for transplantation. CONCLUSIONS: Transplantation improved survival of medium- and high-risk patients compared with medical therapy. In the low-risk group, this was not evident. However, repeated assessment of risk is required because the hazard for death rises steadily after the third year in these patients.

Diagnostic accuracy of coronary angiography and risk factors for post-heart-transplant cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is a common cause of death after heart transplantation. Coronary angiography is used to monitor the progress of recipients. Diagnostic accuracy of angiography and risk factors for CAV have not been clearly established. Between August 1979 and January 2002, 566 1-year survivors of heart transplantation underwent 2168 angiograms and were classified as having no CAV (0% stenosis), mild-moderate CAV (up to 70% stenosis), or severe CAV (>70% stenosis). We used serial measurements of stenosis to estimate the diagnostic accuracy of angiography and to assess the following risk factors for CAV onset, progression, and survival: recipient and donor age and sex, preoperative ischemic heart disease (IHD), acute rejection rates, cytomegalovirus (CMV) infection, and serologic status. CAV was diagnosed by angiography in 248 of 556 (45%) 1-year survivors, with a mean onset time of 8.6 years. Patients spent a mean of 3.4 years with mild-moderate disease and 3.4 years with severe disease before death. Angiography specificity was 97.8%, and sensitivity was 79.3%. The following variables were found to significantly increase the risk of CAV onset: recipient age relative rate (95% confidence interval) 1.16 (1.01-1.34), donor age by 1.27 (1.13-1.43), male recipient by 2.00 (1.11-2.57), pretransplant IHD by 1.75 (1.30-2.36), cumulative rejection by 1.13 (1.05-1.21), and CMV infection by 1.42 (1.06-1.92). Acute rejection increased risk of death by 1.48 (1.19-1.85). Angiography is highly specific and moderately sensitive for diagnosis of CAV. Risk of CAV onset is related to donor age and recipient history of pretransplant IHD and is further increased by immune-related insults of acute rejection and CMV infection.

Graft-versus-host disease in lung transplantation: 4 case reports and literature review.

Graft-versus-host disease (GVHD) is uncommon in lung transplant recipients despite the transfer of a significant amount of donor-derived lymphoid tissue and cells. It is associated with significant morbidity and a high mortality rate. We describe 4 cases of GVHD encountered over a 17-year period and review the literature about this peculiar pathology.

Cytomegalovirus antibody status of donor/recipient does not influence the incidence of bronchiolitis obliterans syndrome in lung transplantation.

BACKGROUND: We have previously reported that prophylaxis for cytomegalovirus (CMV) infection does not influence the incidence of bronchiolitis obliterans syndrome (BOS) at 2 years. The effect of CMV infection (without evidence of disease) on BOS is still not well understood. Moreover, the incidence and risk factors for development of BOS in CMV-antibody-negative donor/recipient matches in lung transplantation have not been described. The aim of this study is to determine the incidence of BOS in lung transplant patients with CMV-antibody-negative (-) donors (D) and recipients (R), and to evaluate the risk factors that predispose to BOS in this sub-group. METHOD: A retrospective study of data from the transplant database of our center was performed. All single-lung (SL), double-lung (DL) and heart-lung block (HL) transplant patients who survived >2 years post-transplant were included in the study group. They were grouped as follows: D(-)/R(-), n = 102; D(-)/R(+), n = 70; D(+)/R(-), n = 33, and D(+)/R(+), n = 92. RESULTS: The 3-year BOS-free survival rates were 65%, 56%, 58% and 67%, respectively, and the incidence rates of BOS at 5 years post-transplant in the different groups were 57%, 62%, 78% and 55% (p > 0.05). In the D(-)/R(-) group, the significant risk factor for developing BOS was three or more episodes of acute rejection (p = 0.02). The mean numbers of acute rejection episodes per 100 patients-days within the first 6 months were 1.28, 1.06, 0.50 and 1.11 (p < 0.001 overall) for the four groups, respectively. CONCLUSION: Although CMV is believed to be a risk factor for BOS, its absence did not affect the occurrence or incidence of BOS in lung transplant patients. The main risk factor for BOS in the CMV-antibody-negative population remains the number of acute rejection episodes within the first 6 months after transplantation.

Assessment of survival benefit after lung transplantation by patient diagnosis.

BACKGROUND: Lung transplantation has become an established procedure for treating patients with endstage lung disease, resulting in broadening criteria for recipient selection. The survival benefit for some patient groups has yet to be established. METHODS: We reviewed 653 patients accepted for lung transplantation at our center. Patients were categorized into 6 diagnosis groups: cystic fibrosis (174), obstructive lung disease (163), pulmonary fibrosis (100), Eisenmenger's syndrome (76), pulmonary hypertension (68), bronchiectasis (51), and other (21). Using Cox regression, we estimated the time at which early operative risk of death fell below pre-operative risk levels (crossover point) and the point at which early high post-operative risk was offset by later low risk (equity point). The relative benefits of single lung vs double lung/heart-lung transplantation were assessed for patients with obstructive lung disease and pulmonary fibrosis. RESULTS: Post-operative risk of death fell below pre-operative risk levels for all diagnosis groups, indicating a survival advantage. The equity point was achieved for all distinct diagnosis groups (except Eisenmenger's); this survival benefit was significant for patients with obstructive lung disease, cystic fibrosis, and pulmonary hypertension. Single lung vs double lung/ heart-lung comparisons showed no significant difference in survival benefit. CONCLUSION: All survival benefit patient groups achieve after lung transplantation, with the exception of patients with Eisenmenger's syndrome, who may have prolonged survival while listed. Differences in survival benefit between single lung and double or heart-lung transplantation are not significant for patients with obstructive lung disease or pulmonary fibrosis.

Risk factors for bronchiolitis obliterans: a systematic review of recent publications.

BACKGROUND: Obliterative bronchiolitis remains the major limitation to long-term survival after lung transplantation. A thorough understanding of the factors that confer high risk of developing obliterative bronchiolitis or its physiologic surrogate bronchiolitis obliterans syndrome is important to help define therapeutic strategies. METHODS: We performed a systematic review of studies published since the beginning of 1990. The review excluded non-human studies, publications before 1990, small (less than 25 patients) studies that were predominantly concerned with investigating the pathogenesis of obliterative bronchiolitis, studies solely concerned with diagnosis or treatment of obliterative bronchiolitis, and overlapping studies from the same center. Onset of bronchiolitis obliterans syndrome or obliterative bronchiolitis was the outcome of interest. RESULTS: Acute rejection plays an important role in obliterative bronchiolitis and bronchiolitis obliterans syndrome onset, and late rejection is a significant risk factor. Lymphocytic bronchitis/bronchiolitis is also a risk factor, with some evidence that late onset is associated with greater risk. The effects of cytomegalovirus, other infectious organisms, and human leukocyte antigen matching are less clear and require further confirmation. There is little evidence that recipient and donor characteristics play a major role. CONCLUSIONS: This systematic review supports the view that obliterative bronchiolitis arises from alloimmunologic injury marked by clinically apparent acute rejection episodes and that inflammatory conditions, including viral infections or ischemic injury, may also play a role. Implications for therapy are discussed.

Acute and chronic onset of bronchiolitis obliterans syndrome (BOS): are they different entities?

BACKGROUND: Bronchiolitis obliterans syndrome (BOS), defined as an irreversible, staged decline in forced expiratory volume in 1 second (FEV(1)), is an established marker of obliterative bronchiolitis. Potential causes of BOS include sub-clinical chronic rejection and/or exaggerated healing response following acute injury. BOS may thus result from two or more distinct processes, both acute and chronic. METHODS: A total of 5,916 measurements of FEV(1) from 204 lung transplant recipients surviving at least 6 months after transplantation were analyzed. Follow-up ranged from 6 months to 13 years. By adjusting for the acute effects of rejection, pulmonary infection and measurement variation on FEV(1) trace, patients either had a linear decline characterized by a single acute drop in FEV(1) of >15% at BOS onset, or a chronic linear decline in FEV(1). The fraction having acute onset was estimated. Acute events occurring within the first 6 months were assessed as risk factors for acute onset BOS. RESULTS: Of the 204 patients, 8% died before BOS onset and 18% were BOS-free at analysis. For 18% of patients, BOS onset followed a chronic linear decline in FEV(1) of 3.7% per year, with a median time of BOS onset >99 months. For 56% of patients, BOS onset followed an acute drop in FEV(1) of median 33.8% (95% CI 19.1% to 39.7%), with median onset time of 52 months. During the first 6 months, acute rejection was significantly and independently associated with acute onset of BOS (relative risk = 1.15 per episode, 95% CI [1.03 to 1.29], p = 0.01), whereas pulmonary infection and cytomegalovirus (CMV) infection were not. Acute BOS onset followed a documented acute event in the previous 6 months in 38 of 114 (33%) of cases. CONCLUSIONS: BOS likely reflects more than one process. Compared with those who had a slow linear decline in lung function, acute BOS onset was associated with acute rejection in the first 6 months, was often triggered by an acute event and had poor prognosis, with obliterative bronchiolitis (OB) the main cause of death.

Microvascular changes in small airways predispose to obliterative bronchiolitis after lung transplantation.

BACKGROUND: There is strong evidence that obliterative bronchiolitis (OB) in lung transplant recipients is related to acute rejection as graded by parenchymal perivascular infiltrates. OB (chronic rejection) is a small airways, rather than a parenchymal, scarring process. Moreover, there has been no study of the microcirculation in the small airways in lung transplantation. This study assesses the microvasculature around small airways (SA) in post-mortem lung allograft specimens. METHODS: The microvasculature of SA (n = 19) from 5 patients who died within 24 hours of lung transplantation (Group A) and SA in OB lungs (11 patients, median post-transplant survival 1,371 days) was assessed by the use of monoclonal antibodies to the vascular endothelium, namely von Willebrand factor (vWF) and CD31. The second group was further sub-divided into Group B (airways not obliterated, n = 18), Group C (sub-total airways obliteration, n = 21) and Group D (airways with total luminal obstruction, n = 14). RESULTS: The measured median circumference of the SA in the 4 groups was 2.1, 2.1, 2.5 and 2.3 mm, respectively (p = 0.66). Using CD31 as the endothelial marker, the median number of blood vessels per unit length of airway circumference (BVPL) was 3.5 vessels/mm for Group A, 0.8 for Group B, 1.3 for Group C and 2.8 for Group D, (p < 0.001). Large blood vessels (circumference >0.20 mm) were present in 95%, 11%, 14% and 21% of each group, respectively (p < 0.001). Similar trends were confirmed with the vWF endothelial antibodies. CONCLUSIONS: OB after lung transplantation is associated with a decrease in microvascular supply to the small airway. This ischemic event may lead to airway damage or increase the tendency to repair by scarring. The small airways then appear to respond to this insult by angiogenesis, which may either occur too late to prevent permanent airway damage or be inadequate in restoring adequate blood supply to the airway.

Does cytomegalovirus status influence acute and chronic rejection in heart transplantation during the ganciclovir prophylaxis era?

BACKGROUND: The effect of cytomegalovirus (CMV) status on acute rejection in heart transplantation is not well understood. Furthermore, there is some evidence to suggest that CMV antibody positivity is associated with cardiac allograft vasculopathy (CAV). METHODS: This study compared the effect of CMV antibody status in heart transplant donors (D) and recipients (R) on acute and chronic rejection episodes during the ganciclovir prophylaxis era. RESULTS: All heart transplant recipients at Papworth Hospital during the ganciclovir prophylaxis era were included (n = 374). They were grouped according to recipients and their respective donor CMV serology: R(-)/D(-) (n = 82); R(+)/D(-) (n = 114); R(-)/D(+) (n = 73); and R(+)/D(+) (n = 105). Ganciclovir prophylaxis was administered to the R(-)/D(+) group. The mean (SD) recipient and donor ages were 46 (11), 51 (9), 47 (11) and 52 (8) years (p < 0.001), and 32 (11), 33 (14), 36 (12) and 38 (14) years (p = 0.01), respectively, for the CMV groups. The mean number of acute rejection episodes (as confirmed by cardiac biopsy) per 100 patient-days was 0.13 (0.36), 0.11 (0.34), 0.12 (0.34) and 0.12 (0.34), respectively (p > 0.05) There was no statistical difference in the development of CAV as assessed by angiography (p = 0.92). At 2 years, the "freedom from CAV" rates were 96%, 97%, 97% and 98%, respectively. The 5-year post-operative survival rates were 83%, 79%, 67% and 73% (p = 0.08 overall). CONCLUSIONS: CMV status of heart transplant recipients and their respective donors does not influence acute or chronic rejection in terms of cardiac allograft vasculopathy.

Short- and long-term outcomes of combined cardiac and renal transplantation with allografts from a single donor.

Coexisting end-stage heart and kidney failure can be treated by combined cardiac and renal transplantation. This study reviews the short- and long-term outcomes after such a procedure over a 16-year period at a single institution. All patients who underwent single-donor simultaneous heart and kidney transplantation during the period of March 1986 to April 2002 (including heart retransplantation) were included (n = 13). They were listed for combined heart and kidney transplantation as they fulfilled our criteria for irreversible end-stage organ failure. Retrospective review of patient data from the transplant database, patient case notes and post-mortem reports were carried out. The mean (SD) recipient age was 45 (12) years and there were 2 females. The mean pre-operative creatinine level was 724 (415) micromol/liter with 9 patients (69.2%) on continuous ambulatory peritoneal dialysis and 2 patients (15.4%) on hemodialysis prior to transplantation. The 30-day mortality rate was 15.4% (2 of 13). For surviving patients the mean creatinine level at hospital discharge was 158 (93) micromol/liter. The mean number of acute cardiac rejection episodes per 100 patient-days was significantly lower (p = 0.01) than that for the heart-only transplant group (n = 760) during the same period. The median (interquartile range) post-operative survival was 1,969 (620 to 3,468) days. The actuarial survival rates (95% confidence interval) at 1 and 10 years were 77% (54% to 100%) and 67% (40% to 94%), respectively, and were not significantly different from the isolated heart transplant population (p = 0.68). Only 1 episode of acute renal rejection was diagnosed on clinical grounds, which was treated accordingly. There was no renal allograft loss in the long-term survivors. Combined cardiac and renal transplantation with allografts from the same donor has acceptable short- and long-term outcomes for patients with coexisting end-stage cardiac and renal failure. This group of patients may also experience fewer acute rejection episodes post-operatively.

Histopathology of cardiac xenograft rejection in the pig-to-baboon model.

BACKGROUND: The use of pig organs transgenic for human decay accelerating factor (hDAF) has largely overcome the problems of hyperacute rejection. With improved immunosuppressive protocols, life supporting grafts are showing greater survival times bringing the possibility of clinical xenotransplantation closer. Examination of the histopathology of the rejection process provides insight into the underlying mechanism and may suggest ways in which new immunosuppressive strategies should be directed. METHODS: 44 baboons (Papio anubis) underwent heart transplants of which 39 were from transgenic donors. The transplanted organs were examined histologically and stained for evidence of immunoglobulin and complement deposition as well as cellular infiltrates. RESULTS: In the transgenic animals survival times were 2 to 99 days (mean 23.5) and the heterotopic group and 1 to 39 days (mean 11.7) in the orthotopic group. There were 3 cases of hyperacute rejection between the 2 groups. Rejected organs showed areas of old and recent myocardial infarction associated with vascular thrombosis. There was widespread deposition within vessels of immunoglobulins IgM and IgG together with complement fractions C3 and C5b to 9 in those organs that were rejected. The amount of complement positive in the longer surviving organs was less than those rejecting early. Cellular infiltate was predominantly macrophage with some later appearing T or natural killer cells. CONCLUSIONS: The histopathological changes support the importance of immunoglobulin and complement in delayed xenograft or acute vascular rejection. With time there is an increase in cellular infiltrate predominantly macrophages and these findings suggest an increasingly important role for the cells and the rejection process. The presence of areas of infarction and underlying vascular thrombosis is in keeping with endothelial activation and the establishment of procoagulant phenotype which may be due to immunoglobulin, complement, secreted cytokines and direct cellular effects.