Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse

Sofia Nordling,Jos Buijs,Fredrik Carlsson,Alkwin Wanders,Johan Brännström,Sergio Estrada,Evelyn Salvaris,Peetra U Magnusson,Tomas Lorant,Bo Lu,Peter J Cowan,Vladimir Tolmachev

doi:10.1038/s41598-018-21463-1

Abstract

Ischemia reperfusion injury is one of the major complications responsible for delayed graft function in kidney transplantation. Applications to reduce reperfusion injury are essential due to the widespread use of kidneys from deceased organ donors where the risk for delayed graft function is especially prominent. We have recently shown that coating of inflamed or damaged endothelial cells with a unique heparin conjugate reduces thrombosis and leukocyte recruitment. In this study we evaluated the binding capacity of the heparin conjugate to cultured human endothelial cells, to kidneys from brain-dead porcine donors, and to murine kidneys during static cold storage. The heparin conjugate was able to stably bind cultured endothelial cells with high avidity, and to the renal vasculature of explanted kidneys from pigs and mice. Treatment of murine kidneys prior to transplantation reduced platelet deposition and leukocyte infiltration 24 hours post-transplantation, and significantly improved graft function. The present study thus shows the benefits of enhanced protection of the renal vasculature during cold storage, whereby increasing the antithrombotic and anti-adhesive properties of the vascular endothelium yields improved renal function early after transplantation.

Highlights

Transplantation of kidneys from brain-dead donors impeded in up to 40% of cases due to delayed graft function (DGF), commonly defined as the need for dialysis during the first week after transplantation[1,2]
The kinetics of Corline Heparin Conjugate (CHC) binding was further evaluated by real-time measurement of the interaction with Human Dermal Microvascular EC (HDMEC)
We investigated a strategy of suppressing the harmful effects of an activated vascular endothelium with the aim of reducing the reperfusion damage of donated kidneys posttransplantation

Summary

Introduction

Transplantation of kidneys from brain-dead donors impeded in up to 40% of cases due to delayed graft function (DGF), commonly defined as the need for dialysis during the first week after transplantation[1,2]. DGF remains a major hurdle when transplanting kidneys from diseased donors[2], as it increases the risk of acute rejection[4] and reduces the overall graft survival[1]. In addition to inflammatory cues originating from damaged tubular cells, triggers EC activation, resulting in a more pro-coagulant and pro-inflammatory phenotype of the renal vasculature[13]. The consequent disruption of the blood flow, and increased leukocyte infiltration, triggers a further decline in kidney function[16]. With the aim of reducing inflammatory and thrombotic interactions between the renal vascular endothelium and the blood compartment, we have utilized a heparin-based macromolecule, Corline Heparin Conjugate (CHC). We have previously shown that CHC binds cultured EC and reduces recruitment of leukocytes and platelets in addition to reducing the thrombogenicity of hypoxic EC19. We have shown that CHC binds the vascular lining of porcine kidneys when added to the perfusion fluid during hypothermic machine perfusion[20]

Methods

Results

Conclusion