Plasma endotrophin, reflecting tissue fibrosis, is associated with graft failure and mortality in KTR: results from two prospective cohort studies

BACKGROUND: Fibrosis is a suggested cause of graft failure and mortality among kidney transplant recipients (KTR). Accumulating evidence suggests that collagen type VI is tightly linked to fibrosis, and may be a marker of systemic fibrosis and ageing. We studied whether plasma endotrophin, a pro-collagen type VI fragment, is associated with graft failure and mortality among KTR.

METHODS: In cohort A, we measured plasma endotrophin in 690 prevalent KTR ≥ 1 year after transplantation (cohort A, 57% male, age 53 ± 13y). The non-overlapping cohort B included 500 incident KTR with serial endotrophin measurements before and after kidney transplantation, to assess trajectories and intra-individual variation of endotrophin.

RESULTS: In cohort A, endotrophin was higher in KTR compared to healthy controls. Concentrations were positively associated with female sex, diabetes, cardiovascular disease, markers of inflammation and kidney injury. Importantly, endotrophin was associated with graft failure (HR per doubling: 1.87; 95%CI: 1.07 to 3.28) and mortality (HR per doubling: 2.59; 95%CI: 1.73 to 3.87) independent of potential confounders. Data from cohort B showed that endotrophin concentrations strongly decrease after transplantation, and remain stable during post-transplantation follow-up (intra-individual coefficient of variation: 5.0% [3.7%-7.6%]).

CONCLUSIONS: Plasma endotrophin is strongly associated with graft failure and mortality among KTR. These findings suggest a key role of abnormal extracellular matrix turnover and fibrosis in graft and patient prognosis among KTR, and highlight the need for (interventional) studies targeting the pro-fibrotic state of KTR. The intra-individual stability after transplantation indicates potential use of endotrophin as a biomarker and outcome measure of fibrosis.