Pretransplant endotrophin predicts delayed graft function after kidney transplantation

Martin Tepel,Morten A Karsdal,Bente Jespersen,Qais Saleh,Stephan J L Bakker,Marie B Nielsen,Jacob Van Den Born,Olivier Thaunat,Firas F Alkaff,Stefan P Berger,Daan Kremer,Subagini Nagarajah,Nicoline V Krogstrup,Federica Genovese,Nadja Sparding,Rikke Nørregaard,Daniel G K Rasmussen

doi:10.1038/s41598-022-07645-y

Abstract

Delayed graft function after kidney transplantation is common and increases morbidity and health care costs. There is evidence that endotrophin, a specific fragment of pro-collagen type VI, promotes the inflammatory response in kidney diseases. We tested the hypothesis that pretransplant endotrophin in kidney transplant recipients may be associated with the risk of delayed graft function. Pretransplant plasma endotrophin was assessed using an enzyme-linked immunosorbent assay in three independent cohorts with 806 kidney transplant recipients. The primary outcome was delayed graft function, i.e., the necessity of at least one dialysis session within one-week posttransplant. In the discovery cohort median pretransplant plasma endotrophin was higher in 32 recipients (12%) who showed delayed graft function when compared to 225 recipients without delayed graft function (58.4 ng/mL [IQR 33.4–69.0]; N = 32; vs. 39.5 ng/mL [IQR 30.6–54.5]; N = 225; P = 0.009). Multivariable logistic regression, fully adjusted for confounders showed, that pretransplant plasma endotrophin as a continuous variable was independently associated with delayed graft function in both validation cohorts, odds ratio 2.09 [95% CI 1.30–3.36] and 2.06 [95% CI 1.43–2.97]. Pretransplant plasma endotrophin, a potentially modifiable factor, was independently associated with increased risk of delayed graft function and may be a new avenue for therapeutic interventions.

Highlights

Inflammatory mechanisms during ischemia and reperfusion together with immigration of cells, e.g., neutrophils, macrophages, and T lymphocytes, are hallmarks in the pathogenesis of DGF7–9
We investigated whether pretransplant plasma endotrophin in incident kidney transplant recipients was associated with Delayed graft function (DGF) after kidney transplantation
We investigated the association between pretransplant endotrophin and DGF after incident kidney transplantation with recipients who obtained living as well as deceased donors

Summary

Introduction

Inflammatory mechanisms during ischemia and reperfusion together with immigration of cells, e.g., neutrophils, macrophages, and T lymphocytes, are hallmarks in the pathogenesis of DGF7–9. Factors linked to influx of cells into the graft after ischemia reperfusion injury could be new targets for therapy and prevention. One factor that may promote this immigration of cells is endotrophin, which is a Pro-collagen type VI fragment. Endotrophin is part of the inflammatory response. Endotrophin acts as a chemoattractant on macrophages, aggravates reperfusion injury, and increases inflammation. Using a doxycycline-inducible mouse model, overexpression of endotrophin increased the inflammatory response in m acrophages. A prospective study in patients with type 2 diabetes and microalbuminuria showed that doubling of plasma endotrophin levels significantly increased the risk for progression of kidney disease and deterioration of glomerular filtration r ate. Since reperfusion injury is the main contributor to DGF, it is biologically plausible that pretransplant endotrophin may aggravate DGF. We investigated whether pretransplant plasma endotrophin in incident kidney transplant recipients was associated with DGF after kidney transplantation

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Conclusion