Urinary Endotrophin as a Biomarker for T-cell Mediated Rejection-associated Fibrogenesis in Kidney Transplant Recipients

Background Endotrophin, the C-terminal pro-collagen type VIα3 fragment, has been shown to correlate with kidney interstitial fibrosis, kidney outcome measures, and survival in various kidney diseases and kidney transplantation. In this study, we investigated whether endotrophin is associated with fibrogenesis in T-cell-mediated rejection (TCMR), allowing its use as a non-invasive biomarker. Method Plasma endotrophin and urinary endotrophin (indexed for creatinine) were measured in samples from a cross-sectional study among kidney transplant recipients (KTR) who underwent indication biopsy after transplantation and enrolled in TransplantLines Biobank and Cohort Study. Endotrophin was measured using the nordicPRO-C6TM enzyme-linked immunosorbent assay. Blood and urine were collected on the day of biopsy. In a subset of patients, the biopsy was stained for endotrophin and T-cells. Results A total of 149 KTR were included in the analyses. Of them, 48 (32.2%) had TCMR (either borderline, acute, chronic, or mixed). Higher urinary endotrophin levels were associated with increased odds of TCMR, and the association remained significant after adjustment for other potential confounders, including plasma endotrophin (adjusted odds ratio [95% confidence intervals] per doubling = 1.38 [1.11-1.72], p = 0.004). In contrast, higher plasma endotrophin levels were not associated with increased odds of TCMR. T-cell density in the biopsy was associated with endotrophin-positive myofibroblasts (ρ = 0.61; p = 0.045), urinary endotrophin (ρ = 0.67; p = 0.017), and interstitial fibrosis/tubular atrophy (ρ = 0.61; p = 0.048). Conclusion These data indicate the potential use of urinary endotrophin as a non-invasive biomarker for fibrogenesis in the context of TCMR.