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

Daan Kremer; Firas F Alkaff; Adrian Post; Tim J Knobbe; Martin Tepel; Olivier Thaunat; Stefan P Berger; Jacob van den Born; Federica Genovese; Morten A Karsdal; Daniel G K Rasmussen; Stephan J L Bakker

doi:10.1093/ndt/gfac332

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

Nephrol Dial Transplant. 2023 Mar 31;38(4):1041-1052. doi: 10.1093/ndt/gfac332.

Authors

Affiliations

¹ Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
² Division of Pharmacology and Therapy, Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia.
³ Odense University Hospital, Department of Nephrology, Odense, Denmark.
⁴ Institute of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
⁵ Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Transplantation, Néphrologie et Immunologie Clinique, Lyon, France.
⁶ Nordic Bioscience, Herlev, Denmark.

Abstract

Background: Fibrosis is a suggested cause of graft failure and mortality among kidney transplant recipients (KTRs). 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 KTRs.

Methods: In cohort A (57% male, age 53 ± 13 years), we measured plasma endotrophin in 690 prevalent KTRs ≥1 year after transplantation. The non-overlapping cohort B included 500 incident KTRs 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 KTRs compared with 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 {hazard ratio [HR] per doubling 1.87 [95% confidence interval (CI) 1.07-3.28]} and mortality [HR per doubling 2.59 (95% CI 1.73-3.87)] 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% (95% CI 3.7-7.6)].

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

Trial registration: ClinicalTrials.gov NCT02811835.

Keywords: collagen; extracellular matrix; fibrosis; inflammation; kidney transplantation; mortality.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Collagen Type VI*
Female
Fibrosis
Humans
Kidney* / pathology
Male
Middle Aged
Prospective Studies
Risk Factors

Substances

endotrophin
Collagen Type VI

Associated data

ClinicalTrials.gov/NCT02811835