Circulating Levels of Endotrophin Are Prognostic for Long-Term Mortality after AKI

Background: Acute kidney injury (AKI) is a rapid decrease in kidney function that may be associated with structural damage. Early markers predicting AKI are emerging, but tools to assess patients' long-term health risks after AKI are still lacking. Endotrophin (ETP) is a bioactive molecule released during formation of collagen type VI. We evaluated the potential of circulating ETP as a prognostic biomarker of adverse outcome following AKI. Methods: We measured ETP in plasma samples collected 1 year after an episode of AKI, using the PRO-C6 ELISA in 801 patients (393 AKI and 408 controls) from the prospective AKI Risk in Derby (ARID) study ( ISRCTN25405995 ), who were then followed until year 3. Kidney disease progression was defined as ≥25% decline in eGFR combined with a decline in CKD stage. Results: ETP levels were significantly higher in the AKI group compared to controls (P<0.001). In the AKI group, ETP could discriminate patients with kidney disease progression at year 3 (AUC=0.67, P<0.01), whereas eGFR could not (AUC=0.51, P=0.57). In logistic regression including common risk factors, ETP was independently associated with kidney disease progression in patients with AKI (OR=1.10, P<0.01). ETP could discriminate survivors from non-survivors at year 3 (AUC=0.64, P<0.01). In a Cox proportional hazards regression for mortality after AKI that included common risk factors, only ETP (HR=1.05, P<0.001) and age (HR=1.06, P<0.01) were retained in the final model. Conclusions: Patients in the AKI group had higher levels of plasma ETP at year 1 as compared to those who had not had AKI. In the AKI group, ETP levels predict kidney disease progression and mortality. Since endotrophin is a pro-fibrotic molecule, our findings may indicate that ETP identifies patients with active fibrogenesis after AKI suggestive of long-term renal remodeling, which is associated with patient outcome.