Improving methods to test kidney transplant compatibility

Improving methods to test kidney transplant compatibility

The Evelyn Trust has funded an award-winning researcher to look at ways in which we can improve the allocation of donated kidneys for transplantation.

This is a key challenge as, despite efforts to improve levels of organ donation and the transplant of about 3,200 kidneys from donors each year, the demand is growing and the transplant waiting list is long.

Lead researcher Dr Vasilis Kosmoliaptsis, NIHR Clinical Lecturer in Transplant Surgery at Addenbrooke’s Hospital, explains the causes of this challenging situation.

“Typically about 30% of donated kidneys fail within 10 years, although kidneys donated by a living donor may function for longer. Transplant kidneys often develop what we call ‘chronic rejection’ where the recipient’s immune system develops antibodies against histocompatibility proteins expressed on the transplanted organ. These proteins are called HLAs – Human Leukocyte Antigens. The risk of chronic rejection can be reduced by pre-transplant matching for HLAs: where the donor and the recipient share more HLAs, there’s less chance of antibody development and of subsequent organ rejection. The problem is that the current method for determining HLA compatibility isn’t adequate – we’re just counting HLA differences without being able to take into account molecular, or structural, differences between the HLA proteins in the donor and patient. We know that matching for HLA is vitally important, for example kidneys donated by siblings with identical HLA proteins to the patient lead to the best clinical outcomes. But HLA proteins vary widely between individuals, making a ‘perfect match’ very difficult to achieve with current methods.”

When a kidney fails, there’s a further complication as most patients who need a repeat transplant have developed donor-specific antibodies, called alloantibodies. Explained simply, the less well-matched the first kidney was to the patient, the more likely it is that the patient develops alloantibodies against potential future donors, dramatically reducing the chances of re-transplantation. Less well-matched kidneys also mean that stronger drugs must be used to suppress the immune system. Long term use of heavy immunosuppression can be very harmful to the patient, as it increases the risk of infections and cancer. This is also a key problem in other transplant treatments: HLA compatibility is critical for a successful bone marrow transplant, but finding a fully-compatible donor is difficult and methods for selecting the best possible graft for a particular patient are urgently needed.

To tackle this challenge, and improve the long term outcomes for transplant patients, Dr Kosmoliaptsis and his team have been studying the structure of HLA proteins using advanced computational molecular modelling and they have been successful in showing that structural and physicochemical differences between the HLA proteins are indeed fundamental to compatibility. They have moved on recently to develop a new computerised algorithm that can quantify these differences and indicate a rating of donor and recipient ‘matchability’.

The team is working closely with NHS Blood and Transplant to establish two large, national clinical studies to prove that the new algorithm is a better way to determine HLA matching and so improve the long-term survival of transplanted organs.

“The funding from the Evelyn Trust has helped us to produce the evidence we needed to secure the national clinical studies, so it has been essential to our work to improve organ allocation and the quality of life for patients with renal failure,” adds Vasilis.

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