Can the immunological risk be better defined in renal transplant recipients, enabling a tailored approach to patient monitoring and treatment; improving efficiency and outcomes?

Abstract

End stage kidney disease (ESKD) affects a growing number of people, with transplantation being the treatment of choice offering improved prognosis, quality of life and cost efficiency. Allograft survival rates have improved due to general advances in immunosuppression, surgery, antibody definition and post-transplant management. Despite this, antibody mediated rejection remains the leading cause of graft loss and consequently, prevention of rejection and mitigation of risk factors is essential. The main focus of this thesis was on improving risk stratification in renal transplant recipients to reduce the risk of rejection and improve long term outcomes. This was addressed by refining the definition of HLA matching using molecular algorithms, determining the risk of preformed HLA antibodies detected by sensitive solid phase assays alone, and by assessing the use of stratified immunosuppression protocols for higher risk patients. The stated aims were achieved by performing a group of studies. The first study looked at the clinical relevance of preformed donor specific antibodies (DSA) in crossmatch (XM) negative transplanted patients. Here, it was determined that patients receiving a DSA+XM- living donor transplant had superior survival compared to patients remaining on the waitlist, and comparable outcomes to patients receiving a compatible deceased donor transplant. A second study looked at the impact of the introduction of the 2019 kidney offering scheme (KOS2019) on transplantation rates and outcomes in highly sensitised and long waiting patients. It was determined that the scheme benefited highly sensitised patients (HSP) and that recipients of poorly matched kidneys, permissible in the new offering scheme, were at increased risk of developing de novo DSA. A third study evaluated the introduction of a two-tier immunosuppression protocol introduced to coincide with the KOS2019. HSPs were given mycophenolate mofetil (MMF) as an additional maintenance therapy. This group saw increased levels of cytomegalovirus when compared to HSPs given the standard tacrolimus monotherapy, though had reduced incidence of post-transplant diabetes. The use of modified immunosuppression provided improved one-year rejection free survival compared to the patients receiving tacrolimus monotherapy. A better definition of the patient group to receive the enhanced immunosuppression protocol was proposed. Finally, the use of in silico assays was assessed for their ability to predict de novo DSA development at three months post-transplant. It was determined that the molecular mismatch (MolMM) algorithms were superior at predicting de novo DSA when compared to the current whole antigen mismatch definition. The B cell algorithms (HLA Matchmaker and HLA-EMMA) were superior to the T cell algorithm (PIRCHE-II) for this prediction, as the T cell algorithm was not found to be associated with HLA class I de novo DSA development. It was also determined that intermediate resolution HLA typing data could be used in the MolMM algorithms for one half of the transplant pair, as may be the case for offer types produced for deceased donor transplants, successfully with minimal impact on the scores obtained. Recommendations from this thesis include the early assessment of transplant options for highly sensitised patients to identify and limit predictable long waits, the implementation of a delisting process to enable acceptable risk DSA+XM- transplants to occur, and the use of MolMM scores and B cell flow crossmatch to better define risk, thus enabling enhanced immunosuppression targeted to the correct patients.

Date of Award	9 May 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Judith Worthington (Main Supervisor) & Karen Cosgrove (Co Supervisor)