Abstract: PO0410
Defects in KIM-1-Mediated Phagocytosis Do Not Predispose to AKI in Humans
Session Information
- AKI: Repair and Progression
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Suri, Rita, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Lee, Ji Yun, Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
- Ban, Matthew, Robarts Research Institute, London, Ontario, Canada
- Shrum, Bradly, Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
- Ismail, Ola Ziyad, Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
- Xu, Qingyong, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Hegele, Robert A., Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
- Gunaratnam, Lakshman, Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
Background
Phagocytosis of dying cells is critical for homeostasis and tissue repair. During renal injury, upregulation of kidney injury molecule-1 (KIM-1) transforms kidney epithelial cells into phagocytes which engulf apoptotic and necrotic cells. A mutation that impairs KIM-1 phagocytic function (mucin domain deletion) resulted in worse kidney dysfunction after ischemia-reperfusion-injury (IRI) in mice, but this has not been studied in humans.
Methods
We expressed three common mucin domain nonsynonymous variants (rs12522248, rs45439103, rs6149307) of the human KIM-1 gene (HAVCR1) in human kidney cells. To test if impaired KIM-1-mediated phagocytosis predisposes to kidney dysfunction after IRI, we genotyped 627 consecutive kidney donors and assessed risk of delayed graft function in recipients.
Results
Cells expressing these variants exhibited markedly reduced phagocytosis of apoptotic and necrotic cells, compared to cells expressing wild type KIM-1; rs6149307 showed the most severe defects (<5% phagocytosis vs. wild type). Surprisingly, the risk of delayed graft function in recipients of donor kidneys homozygous for rs6149307 was not significantly increased compared to recipients of donor kidneys with one or no copies (adjusted relative risk 1.0 [0.7-1.3]). Analysis of rs12522248 and rs45439103 yielded similar resutls.
Conclusion
Contrary to murine models, these results suggest severe defects in KIM-1-mediated phagocytosis do not predispose to acute kidney dysfunction after IRI in humans.
Funding
- Government Support – Non-U.S.