Abstract: PO2386
Tubular Cell Binding of β-Catenin to TCF1 or FoxO1 Associates with Chronic Fibrosis and Adverse Outcomes in Transplanted Kidneys
Session Information
- What's Hot, What's New in Transplantation: Basic and Translational
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 1902 Transplantation: Clinical
Authors
- Zheng, Guoping, University of Sydney, Sydney, New South Wales, Australia
- Yang, Ying, University of Sydney, Sydney, New South Wales, Australia
- Nankivell, Brian John, Westmead Hospital, Westmead, New South Wales, Australia
- Rao, Padmashree, University of Sydney, Sydney, New South Wales, Australia
- Ren, Xiaojun, University of Sydney, Sydney, New South Wales, Australia
- Yu, Hong, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Chen, Titi, University of Sydney, Sydney, New South Wales, Australia
- Cao, Qi, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Wang, Yiping, University of Sydney, Sydney, New South Wales, Australia
- Wang, Yuan Min, Children's Hospital at Westmead, Westmead, New South Wales, Australia
- Lee, Vincent W.S., Westmead Hospital, Westmead, New South Wales, Australia
- Alexander, Stephen I., Children's Hospital at Westmead, Westmead, New South Wales, Australia
- Rogers, Natasha M., Westmead Hospital, Westmead, New South Wales, Australia
- Harris, David, University of Sydney, Sydney, New South Wales, Australia
Background
β-catenin is a key transcription factor via which multiple fibrogenic pathways converge. Importantly, it binds to multiple transcription co-factors mediating diverse signaling pathways. Its role in kidney transplantation is unknown.
Methods
A proximity ligation assay was used to assess binding of β-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, in 240 transplanted kidneys. Their correlation with pathological and clinical outcomes was evaluated.
Results
β-catenin-FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, and subsequent inflammation and inflammatory fibrosis (P<0.001). The relative binding of β-catenin/TCF1 verus β-catenin/FoxO1 (TF ratio) was the optimal prognostic biomarker compared with individual components, and abnormal in a diverse range of fibrotic transplant diseases. A high 1-month TF ratio was followed by greater tubular atrophy and interstitial fibrosis scores, cortical inflammation, renal impairment, and proteinuria at one year (n=131, all P<0.001). TF ratio predicted reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717) and moderate fibrosis (AUC 0.769) using receiver-operating-characteristic analysis, exceeding conventional clinical and predictors including baseline fibrosis. An independent validation cohort (n=76) confirmed 1-month TF was associated with 12-month moderate fibrosis (15.8% versus 2.6%, P=0.047), but not with 10-year graft survival.
Conclusion
In conclusion, differential binding of β-catenin to TCF1 rather than FoxO1 is predictive of a fibrogenic response in transplanted kidneys.
Funding
- Government Support - Non-U.S.