Recombinant Apoptosis Inhibitor of Macrophage Protein Ameliorates Transplant Ischemia-Reperfusion Injury
1Department of Microbiology and Immunology, Western University, London, ON, Canada, 2Matthew Mailing Centre for Translational Transplant Studies, London Health Sciences Centre, London, ON, Canada, 3Matthew Mailing Centre for Translational Transplant Studies, London Health Sciences Centre, Lodnon, ON, Canada, 4Department of Pathology, Western University, London, ON, Canada, 5Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo, Japan, 6Department of Medicine, Western University, London, ON, Canada
Meeting: 2019 American Transplant Congress
Abstract number: A116
Keywords: Graft function, Inflammation, Ischemia, Kidney
Session Information
Session Name: Poster Session A: Ischemia Reperfusion & Organ Rehabilition
Session Type: Poster Session
Date: Saturday, June 1, 2019
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall C & D
*Purpose: Ischemia-reperfusion injury (IRI) during kidney transplantation is associated with acute rejection and long-term graft loss. During IRI, pro-inflammatory mediators (e.g. HMGB1) released from necrotic and uncleared apoptotic renal tubular epithelial cells (TECs) can not only worsens tissue damage, but can potentiate alloimmune injury. We uncovered that mice deficient in Kidney Injury Molecule-1 (KIM-1) are more prone to renal dysfunction and death after native and transplant kidney IRI than wild-types. KIM-1 is a transmembrane glycoprotein specifically upregulated on proximal TECs during renal injury, enabling them to engulf apoptotic and necrotic cells, protecting against tissue damage as well as local and systemic inflammation. Apoptosis Inhibitor of Macrophage Protein(AIM) is a circulating serum protein produced by macrophages that is freely filtered by the glomerulus during IRI and accumulates on necrotic cell debris within proximal renal tubules in humans and in mice. We further revealed administration of intravenous recombinant AIM (rAIM) after reperfusion facilitated native kidney recovery via KIM-1-dependent clearance of necrotic cells/debris. Here we tested if rAIM can be used to ameliorate transplant-associated IRI in a murine model of syngeneic kidney transplantation where the graft is exposed to both cold and warm ischemia.
*Methods: We performed single syngeneic kidney transplants (cold ischemia time 35 mins) from C57BL/6 donor mice into C57BL/6 mice, followed by bilateral native nephrectomy. We evaluated serum creatinine, serum HMGB1 and graft acute tubular necrosis (ATN) after 48 hours after administration of rAIM (200mg/ml) or PBS (n=4 per group).
*Results: Compared to recipients treated with PBS, recipients treated with rAIM had significantly less renal dysfunction (creatinine = 181+/-52 vs. 33+/-11 μmol/L, p=0.0315) and tissue damage (tissue injury score = 3.5/5 vs. 1.5/5, p=0.029). There was no significant difference in serum HMGB1 levels between the groups.
*Conclusions: Our data suggest that administration of rAIM to kidney transplant recipients can improve graft function by mitigating transplant-related IRI. Therefore, rAIM may be used as a therapeutic strategy to improve graft outcomes in kidney transplant patients.
To cite this abstract in AMA style:
Lee JY, Zhang X, Lian D, Haig AR, Miyazaki T, Gunaratnam L. Recombinant Apoptosis Inhibitor of Macrophage Protein Ameliorates Transplant Ischemia-Reperfusion Injury [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/recombinant-apoptosis-inhibitor-of-macrophage-protein-ameliorates-transplant-ischemia-reperfusion-injury/. Accessed May 9, 2025.« Back to 2019 American Transplant Congress