Acute kidney injury (AKI) is a serious syndrome that encompasses a spectrum of disorders that lead to an abrupt decline in kidney function. AKI most often results from severe or prolonged hypoperfusion (ischemia) or nephrotoxicant-induced injury. It affects about 5-10% of all hospitalized patients and is associated with increased mortality risk. Unfortunately, there has been no improvement in mortality rates with current therapies.
AKI is characterized by tubular cell death and inflammation. The efficient removal of apoptotic cells by phagocytes is essential for resolution of inflammation and tissue repair. Phagocytes that ingest apoptotic cells actively suppress local inflammation while preventing the release of immunogenic contents from apoptotic cells that can undergo secondary necrosis. Kidney injury molecule-1 (KIM-1) is cell-surface receptor for phosphatidylserine (PS), an “eat me” signal displayed on the surface of apoptotic cells and necrotic cells. KIM-1 is highly upregulated on proximal tubular epithelial cells (PTECs) after AKI and transforms surviving PTECs into phagocytes for clearance of apoptotic and necrotic cells.
Our recent work proposed a protective role for KIM-1 in ischemic AKI. We showed that Kim-1-/- mice sustained more severe and prolonged kidney dysfunction, tissue damage and mortality after bilateral renal artery clamping AKI leads to systemic inflammation and distant organ injury. Whether the relationship between AKI and mortality is causal is unclear, but emerging experimental evidence suggests that AKI directly contributes to systemic inflammation and multi-organ (e.g. cardiac, lung, etc.…) dysfunction. An exciting question is whether systemic inflammation and/or distant effects caused by AKI directly contribute to the mortality observed clinically.
Major research goals:
- Uncover novel injury and repair mechanisms in AKI
- Develop novel therapeutic strategies for AKI.
- Determine the mechanism(s) of distant organ injury and mortality during AKI
- This may lead us to identify novel therapeutic targets for AKI.
Applied and Translational Research
Unavoidable ischemic injury to the graft at the time of retrieval and implantation continues to adversely affect long-term graft survival in transplantation. Delayed graft function (DGF) is associated with prolonged hospitalization, acute rejection, and poor long-term graft outcomes. While DGF is thought to be primarily a consequence of ischemia-reperfusion injury (IRI) caused by perfusion of warm blood into a cold asanguineous organ, growing evidence suggests that IRI and immune injury may also interact to worsen renal damage early after transplantation, predisposing to long-term graft loss. Initial cellular injury is caused by ATP depletion and generated reactive oxygen species which lead to apoptosis or necrosis of the tubular epithelial cells.
Subsequent activation of immune pathways can lead to secondary graft damage. Release of damage-associated molecular patterns (DAMPs) from uncleared apoptotic and necrotic cells activate renal parenchymal and innate immune cells via pattern recognition receptors, trigger the production of pro-inflammatory cytokines and mediators that further propagate tissue damage by initiating an auto-amplification loop. Work from our lab and others have demonstrated that upregulation of Kim-1 on PTECs protects against warm IRI in non-transplanted mice, decreasing renal damage and mortality. However, the role of Kim-1 in renal transplantation where unavoidable IRI results, is not known.
Major research goal: Decipher the role of KIM-1 in renal transplant IRI and develop strategies to prolong graft survival.
More to come...