How UChicago Medicine became a leader in triple-organ transplants

When surgeons at the University of Chicago Medicine completed two, back-to-back heart-liver-kidney transplants in December 2018, it was assumed that it might be a while before they performed another.

After all, this marked the first time a U.S. hospital had ever transplanted these three organs in more than one patient within one year, let alone two in less than two consecutive days. And it was just the 16^th and 17^th time this type of triple-organ transplant had been performed in this country.

At the time, UChicago had performed six of these transplants — more than any other hospital in the world — with the most recent one in 2011 and the one before that in 2003. The chances of another any time soon seemed slim. Yet, in 2019, four more patients received successful heart-liver-kidney transplants at UChicago Medicine.

So, why such an extraordinary run at UChicago Medicine? Why the heart, liver and kidney? How does someone end up needing three new organs at once? It’s all about the right pieces of a complex puzzle coming together at the right time, with a little bit of serendipity and a lot of skill and experience.

Experience solving complicated medical puzzles

Multi-organ transplants of any kind are rare: They account for about 5% of the total number of organ transplants in the United States since 2004 (including just 12 heart-liver-kidney transplants in that time span). The most frequent combination, kidney-pancreas, averages about 820 per year, compared to nearly 15,000 kidney transplants a year.

That’s why very few hospitals have extensive experience with multi-organ transplants, and there isn’t a huge body of medical research or clinical trial data from which to draw expertise. Instead, because each patient in need of more than one organ presents a unique challenge to the transplant team, specialists for each organ contribute their talent and knowledge to build a coordinated game plan.

“You need the technical expertise to do the surgeries, but first you have to figure out the logistics to combine them,” said John Fung, MD, PhD, co-director of the UChicago Medicine Transplant Institute. “You need expertise on the immunology of the organs and the medical background to select patients. It’s truly a coordinated system.”

You need the technical expertise to do the surgeries, but first you have to figure out the logistics to combine them.

This builds institutional knowledge at a transplant center with experience at solving such complicated puzzles, requiring equal parts medical excellence, surgical skill, creativity and a tolerance for calculated risk. Over time, this culture of excellence and an eagerness to take on the toughest challenges builds a hospital’s reputation as a place that can pull off exceedingly rare, multi-organ transplants.

UChicago Medicine already has a long history of achievements in organ transplantation, from developing the technique for joining severed ends of blood vessels together to performing the first living-donor liver transplant in the U.S. Over the past year that reputation has grown — three organs at a time.

Understanding the series of events leading to organ failure

A crucial first step in helping these patients, Fung explained, is understanding the chain of events that led to multiple organ failures. The loss of function in one organ can have a downstream effect on others.

One of the 2018 triple-organ recipients, Sarah McPharlin, received a heart transplant in 2001 when she was 12 after contracting a rare condition called giant cell myocarditis that causes inflammation of the heart muscle. Over the next 17 years, her new heart developed circulatory issues that damaged her liver, and the continuous immunosuppressive drugs taken by all transplant recipients to prevent rejection wreaked havoc on her kidneys. Replacing any one of these organs individually wouldn’t have helped her.

Certain diseases can cause interrelated issues with organs that compound each other, too. The other 2018 triple transplant patient, Daru Smith, had sarcoidosis, a condition that causes abnormal clusters of inflammatory cells to form in organs and cause widespread damage.

Other patients may suffer from different conditions that can have a ripple effect on organs. One example that highlights the complex interaction among organs is called hyperoxalosis, which is caused by an enzyme defect in the liver that prevents the body from breaking down a molecule called oxalate. This leads to calcium-like deposits building up in the kidneys, which can cause their failure. In this case, transplanting a kidney alone wouldn’t solve the problem — these patients also need a new liver to prevent the problem from happening again.

In these cases, transplanting a liver first might allow the kidneys to recover, showing why understanding the close connections between organs can lead to different answers than just replacing the obviously malfunctioning component.

Overwhelming the immune system

The second part of any transplant story comes after the surgery.

The human body is built to fend off foreign invaders, be it virus, bacteria, allergen or even a lifesaving organ from a different person. The immune system monitors foreign proteins called antigens that may be present on the surface of cells of the transplanted organ. When the immune system detects these antigens, immune cells are mobilized and produce activated T and B cells (that make antibodies) to eliminate these cells.

While the role of the normal immune response is to protect us from infection, in the setting of transplantation, these responses can damage a new organ with foreign antigens.

To prevent rejection, one approach is to find a donor organ with antigens as similar as possible to the recipient. If multiple organs are needed, they must come from the same donor to limit the variety of foreign antigens introduced to the immune system. Nevertheless, no match is perfect (except for identical twins), so transplant recipients frequently have to take powerful immunosuppressive drugs the rest of their lives to tamp down their immune responses.

But what happens to the immune system when not one but two or three new organs are introduced to the body?

“There is very limited research on the impact of so many organs flooding the immune system with so much foreign antigen,” said Anita Chong, PhD, an immunologist at UChicago who studies transplant tolerance and rejection. “Does it overload the immune system so it plateaus? Does it shut down? No one really knows, but patients who receive multiple organs seem to have less rejection and do better.”

Taking advantage of the liver

The liver plays a special role in the context of multiple-organ transplants. In general, a liver transplant requires less immunosuppression than other organs. Normally, the liver acts as the body’s sponge, helping it digest, absorb and process food by filtering the blood coming from the digestive tract, detoxifying chemicals, metabolizing drugs and making other important proteins and enzymes. As it does these jobs, it encounters a lot of foreign proteins from foods and antigens from microbes in the gut — yet it doesn’t freak out and trigger a high-powered immune response.

After a certain stage, the response becomes less. There’s a switch from fighting back with a vigorous immune response to dialing back and just tolerating the transplanted organs.

So, the thinking goes, the liver must be a more tolerant organ with a higher threshold for responding to what truly poses an immune threat.

When a liver is transplanted along with other organs, it seems to protect them from damage as well. The transplanted organs will almost always need some level of immunosuppression, but when the liver is involved, the body tends to accept the rest of the organs with fewer issues. Since liver tissue can regenerate, it may repair itself from mild immune rejection damage. There is even some research data that suggests that the bigger the organ (the liver can be up to 5% of body mass), or the more tissue from multiple organs you transplant, the more tempered the immune system response.

“You cannot imagine a normal scenario in which the immune system has evolved to handle this amount of antigen,” Chong said. “So, for some paradoxical reason, after a certain stage, the response becomes less. There’s a switch from fighting back with a vigorous immune response to dialing back and just tolerating the transplanted organs.”

Leveraging UChicago Medicine’s strengths

All of these factors — highly-skilled medical staff, decades of experience and a deep understanding of the patient’s underlying conditions — are a hallmark of UChicago Medicine across all disciplines. But this unique combination of talent and knowledge combined with a history and culture of pushing the boundaries of patient care made all of these triple transplant procedures possible.

This past year may be an anomaly. It may be years before the University of Chicago Medicine performs another triple-organ transplant, let alone six in the same year. It was a stroke of luck that McPharlin and Smith were both on the waiting list in Chicago, that they both needed the same combination of organs, and that they both found matching donors on consecutive days. But it certainly wasn’t luck that UChicago Medicine was prepared to save them and the four patients who followed.