Abstract
Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC® ) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC-treated kidneys demonstrated improved urine output (P=.009), decreased expression of injury biomarker NGAL (P=.012), improved microvascular perfusion on contrast-enhanced ultrasound (cortex P=.019, medulla P=.001), downregulation of interleukin (IL)-1β (P=.050), and upregulation of IL-10 (P<.047) and Indolamine-2, 3-dioxygenase (P=.050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (P<.001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.
Highlights
The UK kidney transplant waiting list stands at over 5000 patients and the average waiting time is 3 years[1]
The donors included represent a heterogeneous cohort with ages ranging from 52 to 77 years, but all were from either donation after circulatory death (DCD) donors or had characteristics consistent with extended criteria donors (ECD) status
These were compared between the pairs of kidneys, control vs Multipotent Adult Progenitor Cells (MAPC) treated, and demonstrated equivalent organ physiology associated with MAPC cell infusion
Summary
The UK kidney transplant waiting list stands at over 5000 patients and the average waiting time is 3 years[1]. The organ shortage has led to increased use of organs from donation after circulatory death (DCD) and extended criteria donors (ECD) to bridge the gap between supply and demand 2. Concerns regarding inferior transplant outcomes from DCD & ECD organs can lead to under utilization of this valuable resource [3, 4]. DCD & ECD organs are more susceptible to damage from ischaemia reperfusion injury (IRI) manifesting as delayed graft function (DGF) and this can diminish graft survival [5, 6]. IRI is an unavoidable consequence of solid organ transplantation and results in DGF in up to 50% of kidney transplants 8. As the transplant community becomes increasing reliant on marginal donors, new therapeutic approaches to reduce IRI and optimise utilisation of ECD kidneys are leading to a greater focus on improving organ preservation
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