Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

Ischemia-reperfusion injury during kidney transplantation predisposes to delayed graft function, rejection, and premature graft failure. Exacerbation of tissue damage and alloimmune responses may be explained by necroinflammation: an autoamplification loop of cell death and inflammation, which is mediated by the release of damage-associated molecular patterns (eg, high-mobility group box-1; HMGB1) from necrotic cells that activate both innate and adaptive immune pathways. Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is upregulated on injured proximal tubular epithelial cells and enables them to clear apoptotic and necrotic cells. Here we show a pivotal role for clearance of dying cells in regulating necroinflammation in a syngeneic murine kidney transplant model. We found persistent KIM-1 expression in KIM-1(+/+) kidney grafts posttransplantation. Compared to recipients of KIM-1(+/+) kidneys, recipients of KIM-1(-/-) kidneys exhibited significantly more renal dysfunction, apoptosis and necrosis, tubular obstruction, and graft failure. KIM-1(-/-) grafts also had more inflammatory cytokines, infiltrating neutrophils, and macrophages compared to KIM-1(+/+) grafts. Most significantly, passive release of HMGB1 from apoptotic and necrotic cells led to dramatically higher serum HMGB1 levels and increased proinflammatory macrophages in recipients of KIM-1(-/-) grafts. Our data identify an endogenous protective mechanism against necroinflammation in kidney grafts that may be of therapeutic relevance in transplantation. In a murine model of kidney transplantation, KIM-1 in the donor kidney promotes tissue repair from transplant-related ischemia-reperfusion injury through the phagocytic clearance of dying cells, limiting the release of danger signals and reducing local and systemic inflammation.