Since the end of 2015, all deceased donor kidneys that are transplanted within the Netherlands are placed on a cold perfusion machine. This gold standard among preservation methods, however, is not good enough for all deceased donor kidneys. Transplant surgeon at the Erasmus Medical Centre Rotterdam, dr. Robert Minnee, is investigating whether warm perfusion could be a helping hand. “We cannot yet determine how well the kidney exactly works during and after warm perfusion. It is kind of a black box."
For various reasons, the filters in our kidneys can gradually break down. Due to high blood pressure for instance, or due to diabetes. This makes the kidney less and less able to filter the toxins from our body. In the Netherlands, 12 percent of the entire population has chronic kidney damage and of this group, approximately 18,000 people have end-stage renal failure, requiring dialysis. For those people, a kidney transplant is the best solution.
“Chronic renal failure is an underexposed problem”, Minnee emphasizes. “Of all patients that start their dialysis treatment, half of them die within five years. That is a very large group. It may be hard to imagine, but most cancers – such as breast, bladder or colon cancer – have a better five-year survival rate than end-stage renal failure.”
A transplanted kidney can filter out about 70 percent of waste, while dialysis can only filter up to 10 percent. “Patients are sent to the transplant centre when kidney function is around 20 percent”, Minnee says. “Here, the transplant nephrologist, together with the surgeon and anaesthetist, checks whether a transplant is possible. In addition, a suitable living donor is sought, even before the patient really has to start dialysis.”
“People on the waiting list are still dying”
Charging the battery
But the number of suitable donor kidneys is too low. “In the Netherlands, approximately 900 patients receive a new kidney every year. In 50 to 60 percent of these cases it is a living donor. This is far too little. People on the waiting list are still dying, or we are forced to remove them from the waiting list because they are simply too sick”, Minnee says.
To increase the number of suitable donors, improving the quality of suboptimal deceased donor kidneys could be a solution. These suboptimal donor kidneys come from older deceased donors or from donations after a so-called circulatory death. “If it is not a living donor, you have two types of donors: brain death and circulatory death. In the latter group, the kidney has suffered more damage due to oxygen deficiency.”
Research into a better perfusion method could mean a breakthrough for optimizing these suboptimal donor kidneys. “You can compare organ perfusion to an iPhone that you put on a charger”, Minnee explains. “In this case, you provide oxygen and nutrients instead of electricity. This allows the kidney to dispose of its waste materials before the transplant and for its battery to be fully charged.”
Old for old
Currently, the standard storage method used is cold perfusion, also known as hypothermic machine perfusion. Before the transplant starts, the kidney is given a storage solution at a temperature of four degrees, which lowers the metabolism by 90 percent.
“But the kidneys that are placed on the cold pump”, Minnee says, “do not do well enough in a certain population. At least this is apparent in the old for old group. Patients and donors are matched based on age. So, for example, if the patient is aged 65 or older, the patient can also expect a donor kidney from someone aged 65 or older.”
80 donor kidneys
And this is where Minnee's research on warm renal perfusion, also known as normothermic machine perfusion, could offer a helping hand. Sufficient oxygen, nutrients and medicines are given to the donor kidneys at a temperature of 37 degrees. This allows the kidney's metabolism to return to its former glory and immediately initiate its own recovery.
“We are not yet at the stage where we can say that warm perfusion is better than cold perfusion”, Minnee emphasizes. “There are preliminary indications that it could be better. In a pilot study with 11 donor kidneys within the old for old group, we were able to demonstrate that a donor kidney stored with two hours of warm perfusion can be transplanted safely and feasible.”
To gather more evidence in support of the warm perfusion method, Minnee is currently conducting a randomized study that involves 80 donor kidneys. “The study consists of two groups. The first 40 donor kidneys are treated with cold perfusion before transplantation, and the other 40 receive an extra two hours of warm perfusion on top of the cold perfusion.”
“Just like an iPhone charger, but then this system would say: ‘the kidney needs eight more minutes to be fully charged'”
A first step
But to see whether the warm perfusion is effective, the kidney must first be checked for quality. “We are still at an early stage when it comes to these quality checks”, Minnee says. “Currently, we determine the quality of the kidney based on a couple of rough measurements. We check whether the kidney is urinating, whether the kidney looks pink and whether the renal flow is good.”
According to Minnee, there is no system that can measure the condition of the kidney in real time. “During the perfusion we take various samples. For example, we collect urine, we take biopsies from the kidney, and we have a special camera that monitors the oxygen level. But the results of these samples are not available immediately, and therefore we cannot immediately undertake the proper adjustments.”
“On the one hand, we need a system that is able to indicate how long the kidney needs to be on the machine. Just like an iPhone charger, but then this system would say: 'the kidney needs eight more minutes to be fully charged. On the other hand, it would be ideal if this same system could provide constant feedback. Do all the regulatory mechanisms in the kidney function optimally or do certain drugs still need to be administered? Or should the temperature be lowered?”
Together with other colleagues from the Erasmus Medical Centre, Omnigen and various partners in Europe, Minnee has drawn up plans for such a system. The team is currently putting out European applications to secure funding. Once the funding is received, the first step in understanding the quality of the kidney during and after warm perfusion can be taken: the unravelling of the black box.