Investigating markers of injury and mitochondrial bioenergetics in kidneys from donors with acute kidney injury
One of the first research studies that QUOD supported was a project investigating markers of injury and mitochondrial bioenergetics in kidneys from donors with acute kidney injury (AKI). This study, led by Dr Flavia Neri and Dr Letizia Lo Faro at the University of Oxford, aimed to characterise whether kidneys from donors with an AKI have different molecular markers of injury and different mitochondrial bioenergetics to kidneys with no acute injury, and whether these markers associate with outcomes.
It has been shown clinically that the use of kidneys from deceased donors who have experienced AKI increases the risk of poorer long-term graft function, especially when older donors and higher degrees of AKI are included. The shortage of suitable donors has resulted in an increase in the use of higher-risk kidneys, which has led to interest in ways in which we can better predict which transplants will be successful and prevent unnecessary organ discard.
To identify molecular profiles or pathways in donors with AKI that could predict transplant outcome, samples were stratified according to good or poor outcomes in the recipient. QUOD kidney biopsies from 20 donors with and 20 donors without AKI were selected, then subdivided according to the post-transplant outcome defined as a threshold of 45 mL/min for the eGFR at 1 year. Frozen tissue samples were used for western blot analysis of a number of proteins selected for their potential involvement in AKI. FFPE tissue sections underwent histopathological and immunohistochemical assessment.
Samples from AKI kidneys with a poor outcome showed a fourfold increase in the levels of PPARg, a protein involved in mitochondrial and cellular metabolism, and twofold reduction of STAT1, involved in inflammation, compared to the other groups. Two antioxidant enzymes were increased in AKI kidneys with good outcomes.
These results suggest a specific molecular pattern in kidneys retrieved from donors with AKI that proceed towards worse function after transplantation. The importance of lipid metabolism (PPARg) and inflammatory signals (STAT1) in the function recovery of these kidneys hints to the therapeutical targeting of the involved pathways in the setting of organ reconditioning.
The study was published earlier this year in Nature Scientific Reports: Neri, F., Lo Faro, M.L., Kaisar, M. et al. Renal biopsies from donors with acute kidney injury show different molecular patterns according to the post-transplant function. Sci Rep 14, 6643 (2024). https://doi.org/10.1038/s41598-024-56277-x
This work has also led to the successful award of further funding. Letizia Lo Faro received small grant funding from NHSBT for a study to validate molecular profiles of donor kidney quality, including some of the markers identified in this study.