Finding hope for patients with high antibodies in need of a kidney transplant
To mark Organ Donation Week, we have caught up with one of our researchers, Dr Siân Griffin, a consultant nephrologist in Cardiff, to find out how she is striving to improve the transplant options for patients with very high antibody levels.
Certain antibodies can complicate kidney transplantation
Antigens are molecules that can trigger an immune response. When our immune systems encounter antigens on foreign cells like bacteria and viruses, they produce antibodies against them.
Most of our cells have proteins on their surface called human leukocyte antigen (HLA). HLA help to tell the immune system which cells belong to our own bodies and therefore shouldn’t be attacked. But they can also make organ transplantation more complicated.
The problems arise if a patient who needs an organ transplant has been exposed to foreign tissue types, perhaps during pregnancy or if they have had a blood transfusion or an organ transplant.
These patients develop HLA-specific antibodies against the tissue types that are different from their own, making it harder to find a suitable match for transplantation. They are likely to be on dialysis and waiting for a transplant for a long time.
When a patient joins the transplant waiting list, they have their HLA antibodies measured and compared with those of the general population. If a patient has antibodies against the tissue types found in more than 85% of the population, they are referred to as ‘highly sensitised’. Managing these patients is arguably one of the biggest hurdles in kidney transplantation, and it’s a common problem – about 1 in 4 people joining the transplant waiting list has significant levels of HLA antibodies.
Our dedicated researchers are tackling the problem
Dr Siân Griffin is committed to improving highly sensitised patients’ chances of successful transplant. Like many researchers, Siân was inspired by a particular patient who highlighted the urgency of the problem.
“About 10 years ago I met a patient who was about to start dialysis and needed a transplant. She was about the same age as me and our lives were very similar. She had many responsibilities and being able to maintain these was very important – this would have been difficult if she was on dialysis. Although a living donor had come forward for her, they were incompatible as she was very highly sensitised. Her situation resonated with me so much – what if this was me? I really felt, and still do feel, that there is more work to be done to overcome the barrier of sensitisation.”
The Increasing Transplant Opportunities for Sensitised Patients (ITOPS) trial
With our funding, Siân is leading the ITOPS trial – a UK-wide collaborative programme to test a strategy to lower highly sensitised patients’ antibodies and increase their chances of having a successful transplant.
The team recruited patients who had antibodies against more than 85% of the population, and who had already been on the transplant waiting list for three years – the approximate average waiting time for a donor kidney.
The team enrolled 26 patients across three sites (Cardiff, Leeds and Bristol) and patients were either given standard care – three-monthly monitoring of HLA antibodies – or a combination therapy to try to decrease antibody levels.
Antibodies are made by immune cells called plasma cells, which develop from B cells. If you remove a patient’s antibodies, their plasma cells will just make more. Patients in the ITOPS trial were given a combination therapy to target each bit of this pathway to antibody production, so as well as removing a patient’s antibodies by a process called ‘plasmapheresis’, patients were given the drug rituximab to reduce the number of B cells and the drug bortezomib to target the plasma cells that release antibodies.
Patients in the treatment group had their antibody levels measured at intervals after completing treatment. The aim was to reduce the proportion of the donor population that were incompatible due to the presence of HLA antibodies (referred to as the calculated reaction frequency). If this proportion is reduced, more donors are compatible and the chance of receiving an offer is increased. If the treatment had not decreased the antibody levels enough, patients were given a second cycle of treatment.
“We are primarily looking at whether the treatment made the patients less sensitised as this will make the biggest difference to whether a patient receives the offer of a transplant,” Siân explained. “But we also looked at how long the change in antibodies lasted, whether there was a pattern in the type of antibodies that were sensitive to treatment and whether the patients went on to have a transplant.”
The team also took samples from these patients for another study to investigate other factors that could increase a patient’s chance of organ rejection.
The results from the trial have all been collected and are now being analysed by a team of statisticians and will be ready to share later in the year.
“This trial wouldn’t have been possible without funding from Kidney Research UK,” Siân said. “The grant enabled us to use a clinical trials unit so I was able to continue with my clinical responsibilities at the same time, and the drugs that the patients received were all funded by the charity.”
Hope on the horizon for highly sensitised kidney patients
As well as the ITOPS trial, some further developments in the field offer hope for highly sensitised patients in need of a kidney transplant.
Firstly, at the end of 2019, the deceased donor allocation scheme changed to give more priority to difficult to match patients, meaning more highly sensitised patients have a chance of receiving an offer of a kidney sooner.
Secondly, a new antibody-busting treatment from Swedish company Hansa Biopharma called imlifidase has been approved for clinical use in the EU and is currently being reviewed by NICE for use in England. Whereas all current options for reducing a patient’s antibodies work over weeks or months, imlifidase is effective in a matter of hours so holds huge potential for enabling highly sensitised patients to have a transplant from a deceased donor when the transplant must take place within hours. Antibodies may rebound after treatment with imlifidase with a risk of rejection, so these patients will still need careful monitoring and possibly additional treatment, but new options for patients are welcome.
Find out more about Organ Donation Week.
Read about Paula, mum of five, who is holding out hope for a kidney transplant after her potential donor – another mum of five – couldn’t donate her kidney when it was discovered she also had kidney disease.
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