Transplant for Life - Advancing HLA Matching in Paediatric Kidney Transplantation using Molecular Assessment of HLA Immunogenicity

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The first successful kidney transplant was performed in 1954 and was made possible due to the perfect tissue match (or HLA match - the proteins that allow the body to tell the difference between itself and others) from identical twins, the Herrick brothers. Since then, kidney transplantation has become the best treatment for thousands of patients with end stage kidney disease. This overwhelming success is largely due to better understanding of the HLA system, improved techniques to detect antibodies which attack donor tissue proteins, and improvements in anti-rejection medication. However, long term outcomes have largely remained unchanged and the majority of transplants are lost due to rejection at an average time of 12 years. This is mainly due to incompatibilities between donor and recipient HLA proteins. Paediatric recipients have benefitted from research that has been done in adult transplantation. Nevertheless, there are fundamental differences between adults and children. The main causes of kidney failure in children are different compared to adults who often suffer from chronic ill health such as diabetes and cardiovascular disease. Therefore, children come into transplantation healthier. They need transplants that last longer and when the first transplant stops working, they will need a second, third or more. Children gain the most 'added life years' from transplantation. A child who has a transplant at age 5 years is expected to live many decades. Thus, benefits and risks related to transplantation are magnified over a larger time horizon. HLA typing is currently done as broad groups called serotypes and recorded as a one field HLA type. For example, the most common HLA type for group A is HLA-A2. But we now know there are many different types of HLA-A2. This is recorded as a two field HLA type, e.g. HLA-A*02:01, HLA-A*02:02 etc. Thus, when matching is only done at the serology level, the match (and mismatch) between donor and recipient might not be entirely precise. The two field HLA type can be used for more detailed assessment of matching by using modern computational approaches, often referred to as molecular HLA matching. This is akin to using a microscope rather than a magnifying glass to compare the HLA molecules. Our team has developed new ways to assess the difference between donor and recipient HLA molecules based on our research into their 3D structure and surface charge. The tool is able to tell if there is a big difference which can cause rejection (immunogenicity) or if the difference is actually quite small. Therefore the benefits of molecular HLA matching work both ways - by improving confidence in selecting a good mismatch, and increasing the chances of finding a suitable donor by allowing low immunogenicity HLA mismatches to be used. This study aims to assess the effectiveness of molecular HLA matching in children and young adults with kidney transplants, i.e. to determine the risk of developing anti-HLA antibodies and rejection, and to predict the risk of deteriorating kidney function. We will develop the risk prediction model using a contemporaneous dataset of paediatric patients from 2010-2015. The model will be tested for validity and reliability in a similar cohort of patients from Australia and New Zealand. The individual risk model will then be tested retrospectively in the group of paediatric patients in the UK Transplant Registry (2000-2015) to predict the risk of kidney transplant failure. We aim to derive a molecular donor-recipient HLA matching score which can be used in the national kidney allocation scheme to provide children with better HLA matched kidneys; and to allow individualised treatment of children by enabling adjustments to their anti-rejection medication according to their risk of rejection.