Combined Heart and Liver Transplantation

A50-year-old Caucasian female with arrhythmogenic right ventricular (RV) dysplasia presented with 2 years of progressive RV heart failure (New York Heart Association class IV), recurrent ascites, and peripheral edema in spite of optimal medical therapy. Liver biopsy demonstrated advanced liver cirrhosis. Left ventricular chamber size and systolic function were normal. Right heart catheterization was consistent with severe RV dysfunction (RV dP/dt<200 mm Hg/ms). The patient had had three pregnancies. Surgical history included surgical disarticulation of the right ventricle for recurrent syncope, and a cholecystectomy a few months before presentation, requiring transfusion of blood products. She was found to have a large number of anti–human leukocyte antigen (HLA) antibodies with very high titers (Fig. 1A). The cytotoxic panel reactive antibody (PRA) was positive at 98%. The “calculated” PRA based on existing anti-HLA antibodies with levels above 8000 mean fluorescence intensity was 95%. She was blood group A, Rh positive. It was thought that an appropriate donor for cardiac transplantation was not likely and that usual desensitization protocols would be insufficient in the context of very high PRA and very high antibody titers. Based on our experience with renal transplantation in recipients with donor-specific antibody (DSA) (1, 2), we planned to proceed with liver followed by heart transplantation with the use of a single local donor (<200 miles) to minimize cardiac ischemic time and perform a prospective flow-mediated crossmatch accepting a positive T-cell crossmatch with a channel shift less than 350 or a positive complement-dependent cytotoxicity crossmatch up to a dilution of 1:8. The plan also consisted of performing preoperative plasmapheresis and intravenous eculizumab (3), intended to protect the heart until the liver had time to reduce the DSA levels.FIGURE 1: A, all anti-HLA antibodies and titers with and without dilution. B, summary of DSA titers since the day of surgery up to 3 weeks afterward. DSA were for A34, B45, DR11, and DR15 antigens. Before transplantation, the patient demonstrated very high DSA titers to A34, B45, and DR11. Immediately after liver transplantation, there was significant decrease in antibody levels that were maintained stable in the following weeks. DSA, donor-specific antibody; HLA, human leukocyte antigen.The donor was an 18-year-old African-American male who suffered a gunshot wound to the head. The heart and liver were felt suitable for transplantation. Donor and recipient HLA types are shown in Table S1 (see SDC, https://links.lww.com/TP/A739). DSA are shown in Figure 1B (pre-Tx). Prospective cytotoxic crossmatch was negative. Flow crossmatch was positive with channel shifts for B-cell FCXM 358 and T-cell FCXM 279. Preoperative plasmapheresis was performed, methylprednisolone (360 mg) was given intravenously, and the first dose of eculizumab (1200 mg) was administered after which DSA titers were rechecked (Fig. 1B, post-PP). To minimize cardiac ischemic time and to allow cardiopulmonary bypass to be initiated at the time of liver reperfusion, the initial step of the surgical procedure was median sternotomy and dissection of aorta and superior and inferior vena cava. The liver transplant team then performed the abdominal incision and dissection for the liver transplantation. Before reperfusion of the liver, heparin was administered, cannulas were placed in the vena cavas and ascending aorta, and cardiopulmonary bypass was initiated to reduce hepatic venous pressure for the liver (set at 2.4 L/min/m2). The patient was cooled to 32°C, and mean systemic blood pressure was maintained at above 70 to 80 mm Hg to adequately perfuse the liver. After hepatic reperfusion, methylprednisolone (250 mg) was given and blood was drawn for repeat crossmatch (Fig. 1B, post-liver). A second dose of eculizumab (1200 mg) was administered. Cardiac dissection and cardiectomy were performed and cardiac implantation was performed in a standard fashion with bicaval anastomoses. The cardiac ischemic time was 4 hr 17 min. After weaning from cardiopulmonary bypass and giving protamine to reverse the heparin, methylprednisolone (500 mg) was administered followed 30 min later by rabbit anti-thymocyte globulin (110 mg; our standard immunosuppression for heart transplantation). A third dose of eculizumab (900 mg) was given 9 hr after the second dose and after the patient had arrived in the intensive care unit. Flow crossmatch was repeated with donor serum and blood was drawn from the recipient immediately after the transplantation and was negative for both B and T cells (channel shift <52 for B cells and <106 for T cells). Anti-HLA antibody titers were monitored daily, showing a significant decrease immediately after liver transplantation, and stabilization since then (Fig. 1B). Based on this, no additional doses of eculizumab were given and no additional plasmapheresis (just one time preoperatively) was performed. Immunosuppression was managed routinely with induction therapy using daily anti-thymocyte globulin (seven doses) until initiation of tacrolimus (based on renal function) and until therapeutic levels were achieved. The first cardiac biopsy was at the time of chest closure 2 days after transplantation and was negative for cell- and antibody-mediated rejection. In the 15 months after surgery, she has had more than 10 sequential cardiac biopsies that were all negative for cell- or antibody-mediated rejection. Anti-HLA antibodies were monitored routinely twice a week and have remained stable (Fig. 1B). At 15 months after transplantation, she has done very well clinically with no other complications and regained normal functional status with no recurrent edema or ascites. All tests of liver and cardiac function have been normal since hospital dismissal. Her immunosuppression has consisted of tacrolimus, mycophenolate mofetil, and prednisone following our standard cardiac transplant protocol. Potential transplant recipients with multiple pretransplantation antibodies (sensitized) often remain on the waiting list for long periods of time waiting for a crossmatch-negative graft, and those that are transplanted in the presence of donor-specific anti-HLA antibodies (DSA) are at increased risk for early acute rejection, have a lower graft survival (4, 5), are at increased risk for recurrent antibody-mediated rejection, and accelerated cardiac allograft vasculopathy (6). A positive crossmatch against the donor can become negative after liver transplantation, suggesting that the DSA may be absorbed or neutralized by the liver allograft (7). We hypothesized that a combined heart and liver transplant, with the liver implanted first followed by the heart (the heart is implanted first in combined heart-liver transplant cases because the heart has a much lower tolerance to ischemia), may protect the heart from antibody-mediated rejection in patients with multiple pretransplant DSA by rapidly absorbing these antibodies before cardiac graft implantation. We report that heart transplantation can be successfully performed, despite the presence of very high titers of DSA, and preoperative positive T- and B-cell flow cytometric crossmatches, when combined with a liver graft, implanted immediately before the heart, from the same donor. There are numerous reports of successful renal transplantation in sensitized patients using various preoperative and postoperative desensitizing treatments (3, 8–12). These reports indicate two major requirements for a successful outcome. The DSA titers have to be sufficiently low at the time of grafting to avoid an immediate hyperacute rejection and the levels must be kept low during the first postoperative weeks, minimizing the risk of humoral rejection due to rebound in antibody synthesis. These objectives may be possible in many patients, but there are also cases in which such treatments fail or result in significant side effects. It seems to be relatively easy to reduce HLA antibodies for planned living-donor kidney transplantation into recipients with lower degrees of sensitization (13). On the other hand, heart transplant recipients, waiting for organs from deceased donors, with broadly reacting DSA, seem to be more difficult to desensitize. One reason for this may be the logistic problems regarding timing and allocation of organs to patients undergoing desensitizing protocols. Such problems are avoided if a liver graft is used as the only desensitizing tool, which may make it a suitable option for patients on the waiting list. The mechanism of protection induced by the transplanted liver is debatable. Few animal experiments suggest that donor alloantibodies and complement may be absorbed by nonparenchymal hepatic cells (14). The results of the antibody analyses in our patient support this hypothesis (Fig. 1B). Obviously, the liver graft had a protective role, not only in the initial phase but also in the midterm maintenance of the heart graft function, as implicated by the absence of cell- or antibody-mediated rejection, and the continued suppression of DSA titers during the follow-up period. At the present time, combined heart and liver transplantation is indicated only for patients with end-stage liver and cardiac disease or familial amyloidosis, limiting its clinical use. Recent reports have described the use of a partial auxiliary liver in the context of kidney transplantation (15, 16), demonstrating that the auxiliary liver may offer a protective effect when transplanted together with a kidney from the same donor, despite a positive crossmatch between the donor and the recipient. The results of the antibody analyses in these reports have supported the hypothesis that even smaller liver grafts protect the transplanted kidneys by reducing the levels of specific DSA reactivity. Whether such partial auxiliary liver transplants may be performed in the context of heart transplantation in patients with high titers of DSA is speculative. In conclusion, transplantation of a liver graft immediately before heart transplantation can achieve profound and sustained decrease in DSA and protect the transplanted heart for cell- and antibody-mediated rejection, even in the presence of preformed high titers of such antibodies. Combined heart and liver transplantation in “reversed order” may become a therapeutic option for highly sensitized patients waiting for a heart transplant. Richard C. Daly1 Yan Topilsky2 Lyle Joyce1 Tal Hasin2 Manish Gandhi3 Charles Rosen4 Julie Heimbach4 Brooks S. Edwards2 Naveen Pereira2 John M. Stulak1 Christopher J. Arendt5 Soon J. Park1 Sudhir S. Kushwaha2 1 Division of Cardiovascular Surgery Mayo Clinic Rochester, MN 2 Division of Cardiovascular Disease Mayo Clinic Rochester, MN 3 Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN 4 Division of Transplant Surgery Mayo Clinic Rochester, MN 5 Division of Pharmacy and Therapeutics Mayo Clinic Rochester, MN ACKNOWLEGMENTS The authors thank Lucian Durham, M.D., Paul Henke, Michael Timmons, Scott Suddenforf, and Simon Maltais, M.D.