An Analysis of Strategies Targeting Early Clinical and Immunological Events to Improve Kidney Transplant Outcomes

Background: Kidney transplantation is an essential treatment for patients with end-stage renal failure. The long-term fate of the transplant often depends on early events, including the development of delayed graft function (DGF) and rejection. However, there are barriers to targeting these risk factors to improve outcomes. First, DGF is associated with an increased incidence of acute rejection, but there is a lack of consensus around how to diagnose DGF. Second, despite growing recognition of the role of inflammatory monocytes (MΦ) in rejection, no clinically available treatment specifically targets MΦ. Previous work of our group has shown the efficacy of an immune-modifying nanoparticle (IMP) in preventing ischaemia-reperfusion injury; however, the role of IMP in rejection is unknown. This thesis, therefore, aims to evaluate potential strategies targeting early clinical and immunological events to improve transplant outcomes. Methods: A systematic review of all adult and paediatric clinical trials on diagnostic tests for DGF is presented in Chapter 4. All clinical studies evaluating novel methods performed post-transplant to diagnose DGF in both living and deceased donor kidney transplantation recipients were identified through a comprehensive search strategy. The risk of bias for each study was assessed using the quality assessment of studies-2 tool. A fully major histocompatibility complex (MHC)-mismatched kidney transplantation model was used to evaluate the therapeutic potential of IMP in transplantation. The role of IMP in attenuating acute rejection was first explored in Chapter 5, where mice were sacrificed on day 14 post-transplant. The long-term effects of IMP on kidney survival and allograft function were further evaluated in Chapter 6. Results: Thirty-seven studies were included in the systematic review, including 1916 kidney transplant recipients. There was marked heterogeneity among studies, and the reporting quality was generally low. Among the 20 biomarkers studied, the most frequently evaluated were serum neutrophil gelatinase-associated lipocalin (NGAL) (8 studies; 357 participants), urine NGAL (7 studies; 387 participants), and serum cystatin C (4 studies; 297 participants). No superior biomarker was found, but serum NGAL has the greatest potential as an objective diagnostic test. In the mouse model of transplantation, mice treated with IMP, compared to those without, exhibited superior survival with less acute rejection at day 14. IMP prevented the infiltration of MΦ in the allograft and diverted them to the spleen. At day 100 post-transplantation, treated mice exhibited reduced macrophage responses but were not protected from chronic rejection. Conclusions: This thesis provides further insight into the diagnostic tests for DGF and the nanoparticle-based treatment for rejection. Although the systematic review has not identified a superior biomarker, we have identified that serum NGAL has the greatest potential as a diagnostic test. Further assessment and validation are essential through larger-scale studies. By targeting MΦ, IMP improved allograft survival and prevented acute allograft rejection, proving its therapeutic role as an induction agent in transplantation