Renal tubular cell binding of β-catenin to TCF1 versus FoxO1 is associated with chronic interstitial fibrosis in transplanted kidneys.

β-catenin is an important co-factor which binds multiple transcriptional molecules and mediates fibrogenic signaling pathways. Its role in kidney transplantation is unknown. We quantified binding of β-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, using a proximity ligation assay in 240 transplanted kidneys, and evaluated their pathological and clinical outcomes. β-catenin-FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, subsequent inflammation and inflammatory fibrosis (P<0.001). The relative binding of β-catenin/TCF1 versus β-catenin/FoxO1 (TF ratio) was the optimal biomarker, and abnormal in diverse 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 was associated with reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717) and moderate fibrosis (AUC 0.769) using receiver-operating-characteristic analysis. 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), however not with other oucomes or 10-year graft survival, which limits generalizabilty of these findings. In summary, differential binding of β-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys.