Abstract: TH-PO640
Metabolic Profiling of Kidney Grafts: A Novel Approach for Allograft Monitoring in Transplantation
Session Information
- Transplantation: Basic
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2001 Transplantation: Basic
Authors
- Clotet Freixas, Sergi, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- McEvoy, Caitríona M., Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Kawamura, Masataka, Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Kotlyar, Max, Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada
- Boshart, Alexander, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Saha, Aninda Dibya, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Kim, Joseph, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- John, Rohan, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Robinson, Lisa, Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Konvalinka, Ana, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
Background
Kidney transplantation is the optimal treatment for end-stage kidney disease, but kidney grafts are often lost prematurely. In transplanted organs, ischemia reperfusion injury (IRI) predisposes to inferior graft outcomes. Delayed graft function (DGF) is the manifestation of severe IRI in kidney transplantation. DGF is manifested as acute tubular necrosis (ATN), and injury to the peritubular and glomerular vasculature, features of acute kidney injury (AKI). Increasing evidence suggests that altered metabolism in the graft mediates AKI and is the major cause of DGF. Deciphering the metabolic underpinnings of IRI will improve our capacity to diagnose, prevent, and treat AKI.
Methods
We studied the tubulointerstitial and glomerular proteome of kidney transplant patients that developed ATN (n=12) and compared them to cases with antibody-mediated rejection (n=7) or acute cellular rejection (n=11). In addition to kidney graft proteome, we studied metabolic function of biopsy-derived kidney cell suspensions, and the urinary excretion of lactate, in a pig kidney auto-transplantation model.
Results
Patients with ATN showed increased expression of 8 glycolytic enzymes in the tubulointerstitium (ALDOA, ALDOC, GPI, LDHA, PFKP, PGM2, PKM, and TALDO1) and 5 in the glomeruli (ALDOA, G6PD, HK1, LDHA, and TALDO1), at the time of rejection. ATN was also linked to altered levels of mitochondrial proteins (P<0.05). In our pig model, ischemia followed by cold storage led to significantly reduced mitochondrial respiration in cells derived from the kidney graft, in comparison to the ‘healthy’ contralateral kidney. Functional changes after cold storage were linked to significantly reduced levels of kidney mitochondrial proteins (e.g., CPT2, ETFB; n=10; P<0.05), and significantly increased lactate levels in urine (n=10; P<0.05).
Conclusion
Our work shows that increased glycolysis and reduced mitochondrial function may contribute to post-transplant AKI and solidifies the importance of monitoring metabolism in kidney transplantation. Our next goal is to delineate a glycolytic signature that identifies ‘high risk allografts’, facilitating early diagnosis of DGF in kidney transplantation. Such signature could facilitate future clinical interventions targeting the highest risk grafts.