Order is everything: New procedure for heart-liver transplant averts rejection risk

Aug. 17, 2021

Mayo Clinic transplant specialists have found that a procedure reversal — transplanting the liver first and then the heart in a dual heart-liver transplant — profoundly lowers rejection rates for a select group of highly sensitized patients who have elevated antibody levels. This effect occurs because preceding with the liver significantly decreases the individual's donor-specific alloantibody (DSA) levels, thereby intervening to avoid negative immunological responses when the heart is transplanted afterward. The Journal of the American College of Cardiology published these novel findings in March 2021.

"A dual heart-liver transplant in this order hasn't been done before," says Sudhir S. Kushwaha, M.D., a cardiologist at Mayo Clinic's campus in Rochester, Minnesota, and the study's senior author. "It deals with a problem with no other obvious solution — avoiding rejection in highly sensitized patients who have trouble getting a transplant at all."

Turning the paradigm on its head

The standard procedure for a heart-liver transplant involves heart transfer first, followed by the liver. This order originated from an attempt to address the heart upfront in a significantly ill patient with heart failure, to avoid circulatory compromise.

Mayo Clinic innovated the new dual-transplant sequence called heart-after-liver transplant (HALT) with a seven-patient group. All of these patients were listed for both organs, and transplant specialists determined that they would encounter elevated rejection risk or long waitlist time because of their DSA levels. In the HALT protocol, Dr. Kushwaha and team found that the liver absorbed a significant amount of the recipient's antibody load, creating an environment in which the body would accept the two new organs and prevent antibody-mediated rejection.

Though investigators determined positive flow cytometric T cell crossmatch in all patients studied and positive B cell crossmatch in five of seven patients, postoperatively they found that retrospective B cell and T cell crossmatch became negative in all patients. They observed that DSA dropped to less than 2,000 mean fluorescence antibody. Over a median four-year follow up, no patients experienced graft rejection, though one patient died due to metastatic cancer, unrelated to the graft.

The need for both a heart and a liver is uncommon. However, Mayo Clinic sees a number of patients requiring both organs referred by other medical centers. A frequent reason for patients needing a dual transplant is congenital heart disease resulting in cirrhotic liver disease. For example, two frequent indications for transplant of both organs are transthyretin amyloid cardiomyopathy (ATTR-CM) and hemochromatosis. However, these patients, because they are not generally heavily sensitized, can be transplanted using the usual approach of heart transplant first. Thus far, Mayo Clinic has performed combined heart-liver transplant in 40 patients with ATTR-CM.

From this experience with combined organ transplantation, Dr. Kushwaha and colleagues developed the concept of reverse-order heart-liver transplants based on the observation that patients undergoing liver transplant generally experience low rejection rates due to the liver's so-called immunological privilege. The investigators noted a mechanism whereby the liver, a highly vascular organ, acts like a sponge, soaking up antibodies.

"Many patients, when they reach the end of the road with a congenital heart disease, need a transplant," says Dr. Kushwaha. "They often have liver disease as well and have had many surgeries and multiple blood transfusions over the years.

"The heart is very sensitive, whereas the liver appears to tolerate exposure to high levels of circulating antibodies. If we put the heart in first, we know the circulating antibodies will attack the heart."

In a dual transplant, the heart and liver grafts must be from the same donor. Although clinician-researchers have reported liver rejections, they are uncommon in a dual heart-liver transplant.

Dr. Kushwaha says the first patient who received a dual heart-liver transplant at Mayo Clinic, a woman from North Carolina, experienced severe heart failure, cirrhosis of the liver and high antibody levels prior to transplant. Dr. Kushwaha says she is doing well now, 12 years later. Another patient who underwent a dual transplant at Mayo Clinic spent five years in the hospital pretransplant with complex congenital heart disease. Specialists found it challenging to locate organ matches for her due to her antibody levels. Though she has encountered a few problems since transplant, she also is currently doing fine, he says.

Though Dr. Kushwaha says his team was highly selective with the sensitized patient group transplanted with a heart and a liver, he considers the concept generalizable to many sensitized patients. He indicates that this is one step toward reducing high waitlist mortality for those at this sensitization level who need both a heart and a lung.

Next steps

Dr. Kushwaha and colleagues are now looking at transplant possibilities for patients who need a heart transplant but have no liver cirrhosis. In other words, these patients don't need a liver transplant at all, but they are at high risk if they undergo a heart transplant due to elevated antibodies. "You can't take a liver out of circulation if the patient doesn't need a liver transplant," says Dr. Kushwaha.

Other potential solutions for these patients include:

  • In a domino transplant, the liver is taken from the sensitized patient to donate to another patient, then the sensitized patient receives both a new heart and a new liver.
  • In a segmental transplant, a segment of the liver is removed from the donor, which the donor's body will regenerate. The surgeon leaves the recipient's native liver but makes space for the donated segment. The transplanted segment then provides the antibody-absorbing action needed to safely transplant a heart.

Dr. Kushwaha notes that Julie K. Heimbach, M.D., chair of Transplantation Surgery at Mayo Clinic in Minnesota, has successfully performed segmental transplants. Dr. Kushwaha also anticipates that he may publish results of longer term follow-up with the highly sensitized patient group.

Most transplant centers don't take on heart-liver transplants or even dual transplants at all, says Dr. Kushwaha. Mayo Clinic transplant surgeons, however, are willing to take on this high-risk, technically difficult task to make dual transplants possible for patients with high antibody levels, and they welcome referrals for this surgery.

"One of the main reasons for success of the program is the high level of teamwork that we take for granted at Mayo Clinic but without which such a procedure would not be possible," says Dr. Kushwaha.

For more information

Daly RC, et al. Heart-after-liver Transplantation attenuates rejection of cardiac allografts in sensitized patients. Journal of the American College of Cardiology. 2021;77:1331.