More organs on the way

“We have had a slowly growing supply of organs in Sweden, a positive development going back several years. Now, important changes are underway that will provide additional organs. You could liken it to a plug that has been released slowly,” says Annika Tibell, transplant surgeon and professor of Ethics at the Department of Learning, Informatics, Management and Ethics at Karolinska Institutet.

The first project involves a donation process known as DCD, Donation after Circulatory Death. It involves donations from those who died in a different situation compared to previous donors. In Sweden, only those who die during ongoing respiratory care used to be eligible as donors. One example of such a situation is a traffic accident, where someone suffers head trauma, which causes the brain to swell to the point that the circulation in the brain stops. This causes a total cerebral infarction, brain death, and the person is declared dead. Since the death takes place during respiratory care, the organs are still receiving oxygen. A donation can be performed for up to 24 hours after death.

New possibilities

But there are very few who die in this fashion. This leads to the number of potential donors being very low. This is an important explanation as to why there are so few donations in Sweden even though the willingness to donate is high. There were around 19 organ donors per one million inhabitants in Sweden in 2019. Compare this to Spain, where the corresponding number is around 49, according to Mer Organdonation, MOD.

But now, the possibility of using organs from patients who die in other situations is spreading. It could be someone who suffers a cardiac arrest but has their heart restarted with a defibrillator. The patient is then brought to a hospital and placed in an intensive care unit, where they are treated with a ventilator. The examination shows that the brain has suffered severe damage as a result of being deprived of oxygen, to the point that they are incompatible with a continued life.

In situations like this, it is common practice to end life support treatment. In more concrete terms, the ventilator is disconnected. This is because the life support treatment will not bring the patient back to life, only prolong the death process. The patient’s closest relatives are consulted on when the ventilator should be turned off so they can be present when it is done.

Greg Nowak explains that the liver is a very complex organ with many tasks. It is an organ where some substances are broken down, others are formed and additional ones are being stored. This means that there are no ways of artificially managing its tasks in case of a failure. Livers have no equivalent of kidney dialysis or a cardiopulmonary bypass. A transplanted kidney can be allowed a certain recovery period to regain its function after a transplant. During this period, the recipient can receive support through dialysis. But a liver must be able to manage most of its functions immediately after the transplant, as there are no machines that can help it.

The liver is sensitive to lack of oxygen

 “It makes the liver very sensitive to damage that may be caused by a lack of oxygen, since it needs to function immediately. If we are to use livers through DCD donations, we need to do something extra to ensure the organ is of sufficiently high quality for transplantation,” says Greg Nowak.

This extra care will be provided in a special device, known as a perfusion machine. This machine will allow the vessels in the liver to be continuously flushed with fluid, a process that mimics blood circulation. It provides the liver with a more gentle storage and also makes it possible to more thoroughly check the quality before the transplant itself. In a perfusion machine, the liver can, in simplified terms, “carry on as usual”, which keeps its functions more intact. As such, perfusion machines are very commonly used abroad in DCD donations.

But in both Sweden and other countries, the aim is not just that the liver should be stored in the perfusion machine. The goal is that they should be trimmed up and healed from the damages they already had, when they were in the donor’s body. Simply put, the livers will receive treatment. The goal is for livers to recover more quickly in the donor’s body or provide clearer signs that they are unfit for transplantation.

If the method is successful, the plan is not just to treat DCD livers, but also others. Greg Nowak explains that there is a problem with the quality of donated livers deteriorating over time, meaning more and more have to be turned down. According to Greg Nowak, these livers can be treated using perfusion to improve their condition.

“After just 24 hours of flushing, we can remove fat from the liver. But we want to achieve a procedure where we provide each donated liver with an individual treatment, based on the condition of the liver. We want to take everything we know about the liver and the recipient into account and achieve even more targeted selection processes. A liver with a high degree of fattening could undergo perfusion treatment, but even if a certain degree of fatty tissue remains, this normally heals inside the recipient if they lead a healthy lifestyle,” he says.

He describes a whole repertoire of possible treatments that he is looking into in his research. Most of them are centred around adding various medicines to the fluids in the perfusion machine. Some of them are already used to treat certain liver diseases, such as omega-3 fatty acid. It also appears valuable to add oxygen to the perfusion fluids, especially for DCD donations. Additionally, perfusion can be performed using cold of body temperature fluids, with different advantages and disadvantages.

But the tricky part is assessing the condition of the liver, since it has multiple tasks. Lungs that can handle a certain amount of gas exchange can be transplanted, much like a heart that pumps a certain volume. There are no such simple and clear values for livers. Today, they are assessed by the surgeon prior to the surgery using some laboratory values, but also their appearance. A good liver is reddish brown while a fatty liver takes on a yellowish colour.

Identify deficiencies before the transplant

A more comprehensive test kit is another contribution from Greg Nowak and his colleagues. They have developed a new method that combines the laboratory tests already available with new elements, such as measuring the presence of certain substances in the perfusion fluid. This makes it possible to quickly and more objectively get a more accurate image of the condition of the donated liver. The test will start seeing use at the same time as the perfusion machine. The hope is that this way of handling livers will lead to better long-term results for transplants. The one-year survival rate has been significantly improved over the last decades, but the risk of long-term complications, after around maybe ten years, is roughly the same.

“We know that some of the complications that arise in the long term are caused by the liver being damaged in the donation process. These damages might go undetected for many years. We hope to be able to identify deficiencies before the actual transplant, while the liver is in perfusion fluid, and to be able to treat the damages. The goal is for transplanted livers to be in better conditions generally, which would reduce long-term complications,” says Greg Nowak.

In other words, DCD is one of the major projects that will increase the number of organs in Sweden. The other focuses on kidneys - and extremely advanced matching theory. The project background includes a Nobel Prize on this topic, awarded in the field of economics in 2012 to two Americans. In Sweden, the award ceremony led to economist Tommy Andersson, professor at Lund University and the Stockholm School of Economics, writing an article in the Swedish journal “Läkartidningen”. His proposal was to also use the calculation models, which had previously been used in other countries to help the right kidney find the right recipient, in Swedish donation activities.

 “We do not know what the results of such matchings would look like until we try. We also do not know how any kidney exchanges would look in practice, but that is something we perhaps could work out. We will deal with these issues when we get there, if we get there,” says Lars Wennberg.

He does not know how many new kidney exchanges STEP might bring about. In 2019, a total of 476 kidneys were transplanted in Sweden. 147 of these came from living donors. The additional 17 kidneys supplied by STEP constitute a 10 per cent increase to the Swedish supply of living donors. A good result for something that is still in its infancy, according to Lars Wennebrg: “We are aiming for 20 per cent this year. We are taking one step at a time and it is difficult to make predictions for this”.

Another way of addressing organ shortages is to reduce the number of people who need a second new organ, retransplantations. Some of those currently waiting for a new kidney have ended up in their situation due to a previous transplant, possibly of an organ different from a kidney. A tough nut to crack in the world of transplant is the side effects caused by the immunosuppressive drugs that prevent the new organ from being rejected. Drugs are tough, not least for the kidneys. Long-term side effects of the drugs can include kidney failure, causing the person to need a new kidney.

Completely freed from immunosuppressants

One person trying to find paths around these drugs is Bo Göran Ericzon, transplant surgeon at Karolinska University Hospital in Huddinge, and also professor at the Department for Clinical Science, Intervention and Technology at Karolinska Institutet. A study conducted in Japan a few years ago has caught his eye. In the study, patients who received a new liver also received a specially prepared cell mixture. Out of ten treated patients, seven became completely freed from immunosuppressants. This turned out to hold up during a follow-up conducted five years after the transplant.

“We are going to conduct a similar study here and treat 18 patients in roughly the same way as the Japanese patients. We are now ready to get started after years of preparations. We will start asking patients on the waiting list if they would like to participate in the study.”

The true magic is in the cell mixture. It includes cells from the immune system, taken from both the donor and recipient. In somewhat simplified terms, a number of cells from the donor, three, four, five billon give or take, get to hang out with an equal number of cells from the recipient. They are to get along for two weeks in a bath along with a specific antibody which provokes certain behaviours in the immune system cells. The idea is that the recipient’s cells learns to view the donor cells as their own and not to try to reject them, and by extension, the donated organ.

Using an antibody bath

The researchers, led by Bo Göran Ericzon, are not entirely sure what happens when the cells spend time together. They also do not know exactly what will happen when the freshly bathed and trained cells are given to transplanted patients. But they do now that the treatment has worked in the Japanese study and in animal trials before that.

Regulatory t-cells, or “Treg”, are of particular importance in the cell mixture. Their usual role in a healthy body is to cool down their overheated colleagues, who become too active in their immunological defence. As such Treg are important for preventing autoimmune diseases, where some immune system cells run amok and attack healthy tissue.

What appears to be happening when the cells interact in an antibody bath is that the recipient's regulatory T-cells starts behaving like the donor’s. They start defending the donor’s liver and hold off other immune system cells looking to attack it.

After two weeks of antibody baths, the cell mixture is given to the recipient. The patient take immunosuppressants according to standard transplant care procedure. But after six months, attempts are made to scale back the treatment. The aim is for patients to not need immunosuppressants at all after one and a half years.

“My hope is that half of the patients will get there, so that they can be free of immunosuppressants after one and a half years. If we get there, we have certainly come a long way,” says Bo Göran Ericzon.

He believes that they will have tested the cell mixture on some of the 18 patients participating in the study as early as 2020. The aim is then to conduct an expanded study, which includes around 60 to 80 patients or so. The hope is that it will work and be incorporated into the healthcare system.

 “The vision is that only a small minority of patients will need lifelong immunosuppressive medication. This should, theoretically speaking, apply for all organ transplantations,” he says.

Text: Annika Lund, first published in Swedish in the magazine Medicinsk Vetenskap no. 2/2020.