After receiving a new kidney, transplant patients need to undergo painful biopsies for years to monitor their condition. Together with European partners, VITO searched for and found a set of biomarkers that are easily measurable in urine and that provide an accurate and rapid indication of rejection. It’s now a matter of putting the test into clinical practice as quickly as possible, including at Leuven University Hospital.

After performing an organ transplant, there is always a risk of the donor organ being rejected by the receiver’s immune system. That is why doctors always look for the best possible match with an organ donor for transplant patients who are waiting for a new organ. Despite this, rejection still occurs quite frequently. In the case of kidney transplants, it happens in more than 30 percent of patients over a period of 10 years following the transplant. If the kidney is rejected, the patient needs to go back on dialysis, which has a huge impact on their quality of life – not to mention being very expensive for the healthcare services.

Therapy against rejection

That is why transplant patients are carefully monitored after receiving a new organ. This is done by means of biopsies, where a long needle is used to remove part of the organ tissue, which is then tested in the medical lab. If the tissue shows signs of rejection, additional immunosuppressive therapy is started up straight away. During the first year after their transplant, those receiving kidneys undergo two to three biopsies a year.

These biopsies are extremely unpleasant. Furthermore, the rejection symptoms are often already at an advanced stage when they are discovered, so therapy will make little difference and it will no longer be possible to save the kidney. For years, medical researchers have therefore been looking for an alternative method that is not only more comfortable for the patient, but can also detect so-called subclinical (‘early’) symptoms of rejection.

Panel of proteins

For the kidneys – which play a key role in the removal of waste products from our body – it would seem obvious for such a non-invasive test to use a patient’s urine. That is why a group of European health and knowledge organisations set up a project in 2013 to develop a diagnostic test for this. VITO and Leuven University Hospital were also involved in this project, together with three transplant centres abroad. In the course of this Biomargin project (which was carried out under the European FP7 funding programme, the predecessor to Horizon 2020), the urine of transplant patients was analysed to search for proteins that could indicate kidney rejection. “In recent years, thousands of proteins were screened in this way,” says Inge Mertens of VITO. “We did this both for transplant patients without complaints and for patients with complaints, distinguishing three types of rejection.” The efforts paid off, as the researchers were able to identify no fewer than ten proteins that together provide a good indication of whether a kidney is being rejected – including in the subclinical phase. “This set of proteins gives us clear biomarkers for rejection, allowing to detect this subclinically by means of a simple urine test.”

The Biomargin project ended in 2018. The test method has now been patented. VITO and its partners are currently working on the development of an initial prototype of a urine test that is just as quick and user-friendly as a pregnancy test. But is that not the task of the pharmaceutical industry? “We have noticed that the full development of the test is still too expensive for companies,” says Mertens. “The annual number of kidney transplants is just too low for this (in Belgium, about 450 people receive a new kidney every year). It’s now a matter of continuing the development of this new urine test in the initial phase, after which we can try and get businesses more interested.”

Fast implementation in practice

But in the meantime, transplant surgeons are the ones asking for the test method to be introduced as soon as possible. This is also required to judge the value of the test better and to determine the extent to which it can replace invasive procedures like biopsies. As part of a follow-up process, the test will therefore (probably) be introduced soon by Gasthuisberg University Hospital in Leuven. “We are currently trying to find funding for this,” says Maarten Naesens, a nephrologist and transplant surgeon at Leuven University Hospital. “The test may have been developed on a platform that is available in hospital labs, but it still needs to be translated into a routine protocol that we can use here.”

According to Naesens, who participated in the Biomargin project, the best benefit of the test is the highly accurate determination of rejection – or more precisely: the lack of this. “If the results are negative, the risk of actual rejection is very low,” says Naesens. “So we’re hopeful that this will allow us to strongly reduce the number of biopsies.” And the test works in two directions. “If subclinical indications for rejection are found, it will be possible to perform a biopsy at the right time.”

“It’s now a matter of making this urine test clinically available as soon as possible,” says Inge Mertens. "We want to be able to quickly convert the scientific results (which have been published in Kidney International Reports) into a usable test. After that, we can get to the market introduction.”

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