Kidney Injury Molecule-1 Mediated Phagocytosis and Its Therapeutic Application in Ameliorating Renal Transplant Ischemia Reperfusion Injury
Abstract
Renal transplantation is a life-saving procedure for patients with end-stage renal disease. Persistent graft inflammation and fibrosis due to injury from repeated insults - both alloantigen-dependent and -independent - lead to chronic allograft dysfunction and long-term graft loss. Ischemia-reperfusion injury (IRI) to the graft is an inescapable consequence of transplantation and can result in significant delayed graft function (DGF). Tissue damage and graft dysfunction resulting from transplant-associated IRI have been correlated with acute rejection and long-term graft loss. During IRI, dying renal proximal tubular epithelial cells (TECs) release pro-inflammatory mediators, worsening tissue damage and further potentiating injury by initiating an auto-amplification loop of inflammation and cell death. Therefore, therapies that curtail this auto-amplification loop may mitigate graft dysfunction and extend the lifespan of grafts. Kidney injury molecule-1 (KIM-1) is a phagocytic receptor specifically upregulated on TECs during renal injury, enabling them to engulf apoptotic and necrotic cells during acute kidney injury. While KIM-1 can directly bind to apoptotic cells via phosphatidylserine, the clearance of necrotic cells is enhanced by the opsonin, Apoptosis Inhibitor of Macrophage (AIM) protein. The extent to which KIM-1 in the donor kidney contributes to renal transplantation has not been well-studied. In this thesis, we studied the role of KIM-1 in the donor kidney on graft outcomes following renal transplantation. We assessed the therapeutic potential of exogenous recombinant AIM (rAIM) in mitigating transplant-associated IRI. Finally, we explored the association between polymorphisms of the KIM-1 gene and DGF. Using a syngeneic murine renal transplant model, we found that KIM-1 in the donor kidney protects against renal dysfunction, inflammation, graft damage and death. Moreover, the protective effect of KIM-1 was further enhanced with the administration of rAIM. Finally, we found that common genetic variations of the coding region of human KIM-1 gene suppressed the phagocytic ability in vitro compared to wild-type KIM-1. However, none of the variations were associated with increased risk of DGF in our patient cohort. In summary, the findings reported in this thesis provide further evidence of the protective properties of KIM-1 in transplant-related IRI and the viable therapeutic potential of rAIM in renal transplantation.