Abstract: FR-PO1063
Identification of Surrogate Biomarkers Reflecting Tubular Failed Repair in CKD
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Bohnenpoll, Tobias, Evotec International GmbH, Göttingen, Germany
- Lo, I-Ju, Evotec International GmbH, Göttingen, Germany
- Ragan, Seamus, Chinook Therapeutics Inc, Seattle, Washington, United States
- Badal, Shawn S., Chinook Therapeutics Inc, Seattle, Washington, United States
- Radresa, Olivier, Evotec International GmbH, Göttingen, Germany
- Kuo, Jay, Chinook Therapeutics Inc, Seattle, Washington, United States
- Cox, Jennifer H., Chinook Therapeutics Inc, Seattle, Washington, United States
- Andag, Uwe, Evotec International GmbH, Göttingen, Germany
- King, Andrew J., Chinook Therapeutics Inc, Seattle, Washington, United States
- Olson, N. Eric, Chinook Therapeutics Inc, Seattle, Washington, United States
Background
Interstitial fibrosis, tubular atrophy and inflammation (IFTA) are common final pathways to end-stage kidney disease (ESKD), contributing to progressive nephron loss and functional decline in most chronic kidney diseases (CKD), including those typically glomerular in origin. Disease-associated failed repair proximal tubule cells (FR-PTs) have been described in rodent models and are characterized by a proinflammatory and profibrotic phenotype that contributes to IFTA severity. We have recently demonstrated that accumulation of FR-PTs in humans predicts reduced event-free survival in multiple CKD etiologies. Here we used multi-omics analysis of patient-matched kidney biopsies and biofluids from the NURTuRE CKD cohort to discover biomarkers associated with an accumulation of FR-PTs to non-invasively identify patients at risk for progression.
Methods
Serum (n = 99) and urine samples (n = 22) from multiple etiologies from the NURTuRE biobank were assayed using Olink and SomaScan proteomics platforms, respectively. Patient-matched kidney biopsies for each of the samples were analyzed via RNA-Seq and scored for a gene signature reflecting FR-PTs. Correlation analysis of biofluid protein abundance with kidney mRNA expression and FR-PTs signature scores suggested candidate non-invasive biomarkers for further validation (r ≥ 0.4 and p ≤ 0.05).
Results
Proteomic analysis identified 78 serum and 79 urine proteins significantly correlated with the kidney biopsy FR-PT score in CKD patients. Strong positive correlation of 14/78 serum and 9/79 urine proteins with kidney mRNA expression suggests these proteins originate from the kidney or share a common regulatory mechanism. Importantly, expression of the respective genes was negatively correlated with eGFR and enriched in FR-PTs and immune cells, likely reflecting the kidney inflammatory and fibrotic microenvironment.
Conclusion
This study identified potential surrogate biomarkers associated with the accumulation of FR-PTs in subjects with different CKD etiologies from the NURTuRE cohort. These may aid in identifying patients with a disease-relevant phenotype and at risk for progression and will complement our target identification and validation focused on maladaptive tubular repair.
Funding
- Commercial Support – Chinook Therapeutics, Evotec SE