Abstract: FR-OR001
A Light-Chain Amyloidosis Model in Kidney Organoids Demonstrates That Attenuation of CDK1-Mediated Epithelial-Mesenchymal Transition (EMT) Resolves Podocytopathy and Tubulointerstitial Fibrosis
Session Information
- Advancing Onconephrology Precision: Biomarkers, Therapeutic Targets, and Patient Outcomes
October 23, 2026 | Location: Room 401, Convention Center
Abstract Time: 04:30 PM - 04:40 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Afrin, Humayra, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Robichaud, Jielu Hao, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Mohan, Arjunmohan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Imtiaz, Zeeshan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Khan, Muhammad Ibrahim, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Dick, Christopher J., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Kourelis, Taxiarchis, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Leung, Nelson, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Gupta, Navin R., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
Renal AL amyloidosis involves the deposition and aggregation of insoluble light chain fibrils in the kidney, leading to a multicompartmental injury characterized by proteinuria, podocyturia, and tubulointerstitial fibrosis. Current treatment focuses on a hematologic response, i.e. reducing the burden of circulating soluble light chains, but does not address the toxicity of previously deposited fibrils. Strategies that improve the renal response are not supported by existing models, as transgenic and humanized animal models lack glomerular amyloid deposition and multicompartmental kidney injury.
Methods
hPSC-derived kidney organoids were exposed to human recombinant amyloidogenic κ and λ light chains (LCs), and their soluble controls. GFP-tagging of LCs permitted tandem and longitudinal live brightfield and epifluorescent microscopy for fibril deposition. Using non-GFP tagged LCs, multicompartmental injury was investigated with transmission electron microscopy (TEM), confocal microscopy, and mesoscale discovery. Analysis of the glomerular proteome of >1075 AL-λ and 412 AL-κ clinical samples revealed CDK1 as a leading upregulated target specific to AL-k disease, to prompt a mechanistic study of CDK1 inhibition.
Results
TEM confirms that renal AL amyloid deposits as 9nm wide, non-branching, haphazardly arranged fibrils in the extracellular space of podocytes, which manifest foot process effacement and cytoplasmic vascuolization. Immunostaining displayed progressive loss of slit diaphragm proteins, NPHS1 and NPHS2. AL fibrils were additionally detected in the tubular lumen, where TEM reflected the loss of brush border. Supernatants were enriched for tubule-derived proinflammatory cytokines of IL-1β, TNF-α, IL-6, and TGF-α. Confocal microscopy demonstrated that acute podocytopathy and tubulopathy were followed by a progressive αSMA+COL1A1+ tubulointerstitial fibrosis. CDK1 inhibition was found to prevent podocyte and tubule epithelial-to-mesenchymal transition to preserve podocyte structure and number, prevent tubular atrophy, and limit interstitial fibrosis.
Conclusion
Kidney organoids are a complex human in vitro system of requisite complexity to model the near-exclusively human disease, renal AL amyloidosis, serving as a translational platform to evaluate innovative therapeutic strategies and identify novel druggable targets.
Acknowledgment
Amyloidosis Foundation; Mayo Clinic Amyloid Interest Group
Funding
- Private Foundation Support