Abstract: SA-PO0268
Role of Casts in Proximal Tubule Injury and Atrophy
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Faivre, Anna, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Kristensen, Anders Meldgaard, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Zheng, Xiang, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Wu, Qi, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Berg, Peder, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Sjøgaard, Camilla Tanderup, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Lukianchenko, Iryna, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Kidmose, Hanne, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Fenton, Robert A., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Schiessl, Ina M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
Background
Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), but mechanisms driving failed repair remain unclear. Granular casts accumulate within injured tubules during AKI and correlate with disease severity, yet whether they promote tubular injury and fibrosis is unknown. We hypothesized that granular casts drive tubular damage and that enhancing cast clearance attenuates maladaptive repair after ischemic AKI.
Methods
Unilateral ischemia–reperfusion injury (uIRI) was induced in male C57BL/6J mice by 30-min renal pedicle clamping. Spatial proteomics of granular casts and tubular epithelium at day 7 post-uIRI was performed after laser microdissection. Longitudinal in vivo 2-photon microscopy in PDGFRβCreERT2 x Salsa6F mice tracked cast formation, tubular injury, and myofibroblast recruitment over 3 weeks. Cast removal was promoted by osmotic diuresis with mannitol (1 g/kg i.p. twice daily for 4 days and 20% in drinking water for 7 days), reducing urine osmolarity by 30% in controls. Fibrosis and tubular function were assessed by Picrosirius Red staining and Urine Ammonium-pH-Score (AP-score, PMID: 39485702).
Results
Spatial proteomics from n=5 mice demonstrated enrichment of damage-associated molecular patterns (DAMPs) in granular casts, suggesting a role in injury signaling. Serial in vivo imaging revealed early intratubular debris by day 2 after uIRI and mature granular casts by day 7. Mannitol treatment reduced luminal casts by 77% (p<0.0001) and attenuated tubular atrophy and fibrosis. Mannitol also reduced tubular VCAM1 expression and fibrosis by 83% (p<0.0001) and 40% (p<0.05) at 6 weeks, alongside improved AP-score (p<0.05), indicating preserved tubular function.
Conclusion
Granular casts may not only reflect injury but also exacerbate proximal tubular damage and maladaptive repair through obstruction and direct signaling to epithelium. Enhancing cast clearance with osmotic diuretics reduced tubular atrophy and may represent a strategy to prevent AKI-to-CKD transition.