Pig-to-baboon heterotopic heart transplantation--exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens.

BACKGROUND: Three costimulation blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb. METHODS: All pigs were on an α1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n=4) expressed additional CD55, and those into Group B (n=3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n=2) or abatacept (Regimen 2: n=2) or anti-CD40mAb+belatacept (Regimen 3: n=2). Regimens 1 and 2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy. RESULTS: Group A baboons survived 15 to 33 days, whereas Group B survived 52, 99, and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4 m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T-cell response was documented only in baboons receiving Regimen 2. CONCLUSIONS: The combination of anti-CD40mAb+belatacept proved effective in preventing a T-cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.

Lung transplant, double valve repair, and pulmonary artery aneurysm resection.

Up to 66% of giant pulmonary artery aneurysms are associated with severe pulmonary hypertension. For these patients, lung or heart-lung en bloc transplantation is the only definitive therapy available. To date, there have been only two reports of concomitant double lung transplant and resection of a giant pulmonary artery aneurysm. We report a case of combined mitral and pulmonary valve repair, resection of a giant pulmonary artery aneurysm, and double lung transplant in a patient with primary pulmonary hypertension.

Combining tricuspid valve repair with double lung transplantation in patients with severe pulmonary hypertension, tricuspid regurgitation, and right ventricular dysfunction.

BACKGROUND: Concomitant tricuspid valve repair (TVR) and double lung transplantation (DLTx) has been a surgical option at our institution since 2004 in an attempt to improve the outcome of DLTx for end-stage pulmonary hypertension, severe tricuspid regurgitation, and right ventricle (RV) dysfunction. This study is a review of that single institutional experience. METHODS: Consecutive cases of concomitant TVR and DLTx performed between 2004 and 2009 (TVR group, n = 20) were retrospectively compared with cases of DLTx alone for severe pulmonary hypertension without TVR (non-TVR group, n = 58). RESULTS: There was one in-hospital death in the TVR group. The 90-day and 1- and 3-year survival rates for the TVR group were 90%, 75%, and 65%, respectively, which were not significantly different from those for the non-TVR group. The TVR group required less inotropic support and less prolonged mechanical ventilation in the ICU. Follow-up echocardiography demonstrated immediate elimination of both volume and pressure overload in the RV and tricuspid regurgitation in the TVR group. Notably, there was a significantly lower incidence of primary graft dysfunction following transplantation in the TVR group (P < .05). Pulmonary functional improvement shown by an FEV(1) increase after 6 months was also significantly better in the TVR group (40% vs 20%, P < .05). CONCLUSIONS: Combined TVR and DLTx procedures were successfully performed without an increase in morbidity or mortality and contributed to decreased primary graft dysfunction. In our experience, this combined operative approach achieves clinical outcomes equal or superior to the outcomes seen in DLTx patients without RV dysfunction and severe tricuspid regurgitation.

Pitfalls in donor lung procurements: how should the procedure be taught to transplant trainees?

OBJECTIVE: The current trend in lung transplantation has led to liberalized lung donor selection criteria and use of marginal donors, with a corresponding requirement for improved procurement techniques to obtain high-quality donor grafts. Few reports, however, have provided recommendations for successful lung procurement procedures. METHODS: We retrospectively studied 47 lung procurements performed by the University of Pittsburgh Medical Center team from January 2007 to December 2007. From those findings, we compared outcomes, as well as technical errors encountered, between procurements performed by trainees with limited transplant experience and by experienced transplant surgeons. RESULTS: Twenty-two of the procurements (47%) were performed by experienced transplant surgeons and 25 (53%) by supervised trainees. Patient characteristics and technical difficulties were comparable between the two groups. The trainees took more time to complete the procedure than did the experienced surgeons, although the difference was not significant. Furthermore, 21 of the cases performed by trainees (84%) had one or more technical errors in the sequential steps of the procurement, including inadequate placement of the perfusion cannula in the main pulmonary artery (60%), insufficient topical cooling (56%), and inadequate timing of the start of pulmonary artery perfusion (44%). CONCLUSION: Donor lung procurements performed by beginners with limited transplant experience included frequent technical errors with regard to adequate graft preservation, which may lead to serious complications after transplant. Sequential steps in lung procurement techniques and better understanding of organ preservation should be an integral part of a lung transplant training program.

The innate immune response and activation of coagulation in alpha1,3-galactosyltransferase gene-knockout xenograft recipients.

BACKGROUND: The role of the innate immune system in the development of thrombotic microangiopathy (TM) after alpha1,3-galactosyltransferase gene-knockout (GTKO) pig organ transplantation in primates is uncertain. METHODS: Twelve organs (nine hearts, three kidneys) from GTKO pigs were transplanted into baboons that received no immunosuppressive therapy, partial regimens, or a full regimen based on costimulation blockade. After graft failure, histologic and immunohistologic examinations were carried out. RESULTS: Graft survival of less than 1 day was prolonged to 2 to 12 days with partial regimens (acute humoral xenograft rejection) and to 5 and 8 weeks with the full regimen (TM). Clinical or laboratory features of consumptive coagulopathy occurred in 7 of 12 baboons. Immunohistochemistry demonstrated IgM, IgG, and complement deposition in most cases. Histopathology demonstrated neutrophil and macrophage infiltrates, intravascular fibrin deposition, and platelet aggregation (TM). Grafts showed expression of primate tissue factor (TF), with increased mRNA levels, and TF was also expressed on baboon macrophages/monocytes infiltrating the graft. CONCLUSIONS: Our data suggest that (1) irrespective of the presence or absence of the adaptive immune response, early or late xenograft rejection is associated with activation of the innate immune system; and (2) porcine endothelial cell activation and primate TF expression by recipient innate immune cells may both contribute to the development of TM.

Lung and heart-lung transplantation at University of Pittsburgh: 1982-2009.

The Lung Transplantation program at the University of Pittsburgh began in 1982. From the beginning to December 31, 2009, 1347, lung and heart lung transplantations have been done. (674 double-lung, 310 left single-lung, 227 right single-lung and 130 heart-lung transplantations. University of Pittsburgh maintains a data base, from the time of the inception of the program, of all recipients and donors. There is an increasing trend to do double-lung transplantation, as 5- and 10-year survival is better with double than single lungs. Our experience with heart-lung transplantation is considerable. The 4 most common indications for lung transplantation are: chronic obstructive disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF) and pulmonary arterial hypertension. (PAH). Potential recipients are evaluated over 2 weeks. There is also a pathway for accelerated evaluation of sicker patients. Our recipient criteria are expanded and flexible; as many patients, who have been denied lung transplantation, at other major centers have been successfully transplanted by us with good outcomes. The median waiting time on the list in 2009 was 37 days. Our altruistic flexibility in recipient selection, balanced with respect to the altruistic gift of donor families, has been described in considerable detail. To solve the problem of shortage of donor lungs, we have expanded our donor selection criteria beyond the historic ideal donor, without comprising on outcomes. These selection criteria and our donor-lungs management protocol are also described in reasonable detail. We started using lungs from donors after cardiac death (DCD) in January 2007. Recently we reviewed our experience and literature, and devised a protocol; which is given in a robust table. We also participate as faculty in the educational program initiated by the Organ Procurement Organizations (OPO) of Pennsylvania. During procurement we use 500 microg of prostaglandin E-1 into the pulmonary artery just before X clamp, Perfedex infusion after X-clamp, at 70 ml/kg, with 500 microg of prostaglandin and 50 mg of nitroglycerine in the first bag, and retrograde flush of 500 ccs in each pulmonary vein. We have refined our recipient operation, from clam shell incision to bilateral antero-axillary incisions, preserving the sternum and internal mammary arteries, for both double and single-lung transplantation, with good outcomes. This technique and results have been described in generous detail. We use pneumoplegia, similar to cardioplegia, to protect the allograft from ischemic and reperfusion injury (Appendix III). Our technique of bronchial anastomosis and intraoperative management of septic lung disease has remained unchanged. Post-operatively we continue to use the ventilatory management of low FiO2 and high PEEP. Our immunosuppression and infection prophylaxis protocol is the same since 2003, when we started using Alemtuzumab (Campath) for induction, with minimization of the use of steroids. For maintenance, we use Tacrolimus and Mycophenolate Mofetil. Now, we also monitor the functional activity of the T cell by Cylex ImmuKnow. Lowered activity (< 100 ng/ml) suggests an increased risk of infection; and higher activity (> 200 ng/ml) suggests greater risks for rejection. Although we have expanded our recipient and donor pools, our outcomes have continued to improve. The overall survival of double-lung transplantation from 2003-2009 was 82.8% at one year and 56.8% at 5 years. This compares well with the international data which shows an overall survival rate of 80% at one year and 56% at 5 years. Results of lung transplantation will continue to improve, with our increasing understanding of mechanisms and management of ischemic-reperfusion injury, acute rejection and bronchiolitis obliterans syndrome.

Long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension.

BACKGROUND: The survival after lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension has been reportedly the lowest among the major diagnostic categories of lung transplant recipients. METHODS: Retrospective analysis was performed for lung and heart-lung transplant recipients for idiopathic pulmonary arterial hypertension from 1982 to 2006. The patients were divided into 2 groups, based on the era; group 1: 1982 to 1993, and group 2: 1994 to 2006. Since 1994, we have introduced our current protocols including prostaglandin E1 and nitroglycerin for donor lung preservation, and lung protection with cold and terminal warm blood pneumoplegia as well as immunosuppression with alemtuzumab induction. These modifications were introduced in different years over a wide span of time (1994 to 2003). RESULTS: Group 1 had 59 patients (35 +/- 1 years old, ranging 15 to 53, 20 male and 39 female) with 7 single lung, 11 double lung, and 41 heart-lung, whereas group 2 had 30 (43 +/- 2 years old, ranging 17 to 65, 9 male and 21 female) with 2 single, 20 double, and 8 heart-lung transplantations. The recipient age was significantly (p = 0.004) higher in group 2, and group 2 had significantly older (35 +/- 3 vs 26 +/- 1, p = 0.002) and more female donors (73% vs 41%, p = 0.007) compared with group 1. The actuarial survival was significantly (p = 0.004) better in group 2 with 86% at 1 year, 75% at 5 years, and 66% at 10 years compared with group 1 with 58% at 1 year, 39% at 5 years, and 27% at 10 years. CONCLUSIONS: With our current pulmonary protection and immunosuppression, the long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension is excellent.