Ms Xiangju Wang1,2, Mr Benjamin Adams1,2,3, Prof Chang Seong Kim1,2,4,5, Dr Monica Suet Ying Ng1,2,3, A/Prof Helen Healy1,2,3, Dr Andrew Kassianos1,2,3
1Pathology Queensland, Brisbane, Australia, 2Royal Brisbane and Women’s Hospital, Brisbane, Australia, 3University of Queensland, Brisbane, Australia, 4Chonnam National University Hospital, Gwangju, Republic of Korea, 5Chonnam National University Medical School, Gwangju, Republic of Korea
Biography:
Dr Andrew Kassianos is a Senior Scientist at the Conjoint Kidney Research Laboratory, Queensland Health, with expertise in nephrology and immunology. He has 53 career publications (h-index 29; >2,600 citations), and over $2.5M in grant funding, including two NHMRC Grants as CIA. He has delivered 50+ conference presentations, five keynotes, and received awards from ISEV (2024) and the ANZSN (2022, 2024). His research program focuses on cell-cell communication mechanisms (i.e., extracellular vesicle signalling) between kidney and immune cells, exploring checkpoint-based therapeutic strategies to modulate this cross-talk and stop disease progression.
Aim:
To establish microRNAs (miRNAs) as prognostic biomarkers for acute kidney injury (AKI) progression.
Background:
Up to 40% of AKI survivors progress to chronic kidney disease (CKD), increasing their risk of premature mortality. We have previously shown that AKI progression is driven by tubular ferroptosis (↑ACSL4, ↓SLC7A11) propagated via extracellular vesicles (EVs) along the urinary space. Here, we assess the prognostic utility of ferroptosis-associated miRNAs (↑miR-25-3p, ↓miR-155-5p) in kidney tissue and urinary EVs.
Methods:
Kidney biopsies and matched urine samples were obtained from people with (i) baseline eGFR≥60ml/min/1.73m², (ii) KDIGO-defined AKI and (iii) histologically confirmed acute tubular injury without CKD (i.e., no scarring). Individuals were stratified at 3 months post-AKI into ‘AKI recovery’ (≥95% return to baseline eGFR) or ‘AKI progressors’ (≤75% baseline eGFR). Spatial miRNA expression was mapped using miRNAscope in situ hybridization, while urinary EV miRNA profiles were analysed via sequencing. Functional validation was performed in patient-derived proximal tubular epithelial cells (PTECs) and tubular organoids (tubuloids).
Results:
Biopsies from ‘AKI progressors’ showed increased tubular ferroptosis (↑ACSL4) and a distinct miRNA signature (↑miR-25-3p, ↓miR-155-5p) compared to ‘AKI recovery’ and control kidney tissue. Urinary EVs from ‘AKI progressors’ mirrored this signature, with network analysis mapping the differentially expressed miRNAs from these EVs to ferroptotic pathways of cell death and lipid dysregulation. In functional studies, urinary EVs from ‘AKI progressors’ induced ferroptosis in PTECs and tubuloids (↑ACSL4), while miR-25-3p transfection of PTECs downregulated SLC7A11 and promoted ferroptotic injury.
Conclusions:
Ferroptosis-associated miRNA signatures identify patients at highest risk of AKI progression to CKD. These findings support the development of non-invasive prognostic tools and targeted therapeutics to enable earlier intervention and improve long-term kidney outcomes.