Treating Ischemically Damaged Porcine Kidneys with Human Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stromal Cells During Ex Vivo Normothermic Machine Perfusion.

Merel B.F Pool,Henri G.D Leuvenink,Martin J Hoogduijn,Marlies E.J Reinders,Melissa Van Pel,Jaël Vos,Cyril Moers,Rutger J Ploeg,Marco Eijken,Bente Jespersen

doi:10.1089/scd.2020.0024

Abstract

Pretransplant normothermic machine perfusion (NMP) of donor kidneys offers the unique opportunity to perform active interventions to an isolated renal graft before transplantation. There is increasing evidence that mesenchymal stromal cells (MSCs) could have a paracrine/endocrine regenerative effect on ischemia-reperfusion injury. The purpose of this study was to determine which cytokines are secreted by MSCs during NMP of a porcine kidney. Viable porcine kidneys and autologous whole blood were obtained from a slaughterhouse. Warm ischemia time was standardized at 20 min and subsequent hypothermic machine perfusion was performed during 2-3 h. Thereafter, kidneys were machine perfused at 37°C during 7 h. After 1 h of NMP, 0, 107 cultured human adipose tissue-derived MSCs, or 107 cultured bone marrow-derived MSCs were added (n = 5 per group). In a fourth experimental group, 7-h NMP was performed with 107 adipose tissue-derived MSCs, without a kidney in the circuit. Kidneys perfused with MSCs showed lower lactate dehydrogenase and neutrophil gelatinase-associated lipocalin levels in comparison with the control group. Also, elevated levels of human hepatocyte growth factor, interleukin (IL)-6, and IL-8 were found in the perfusate of the groups perfused with MSCs compared to the control groups. This study suggests that MSCs, in contact with an injured kidney during NMP, could lead to lower levels of injury markers and induce the release of immunomodulatory cytokines.

Highlights

To date, kidney transplantation is regarded as the best treatment for patients with end-stage renal failure
We showed that A-mesenchymal stromal cells (MSCs) or BMMSCs that are infused during normothermic machine perfusion (NMP) are predominantly retained in glomerular capillaries and a proportion of those cells will remain viable and detectable after 7 h of ex vivo perfusion [21]
Based on previous work by other groups, we hypothesized that MSCs remain viable and functional during NMP and that they may lay a base for regenerative processes by inducing release of growth factors and cytokines

Summary

Introduction

Kidney transplantation is regarded as the best treatment for patients with end-stage renal failure. In an attempt to reduce the waiting time by increasing the deceased donor organ pool, the use of donor organs from donation after circulatory death donors and extended criteria donors plays an important role [1]. Many of these organs are older and of suboptimal quality, rendering kidneys more susceptible to ischemia-reperfusion injury (IRI) when compared to the organs derived from living donors [2]. Preserving the function of ischemically damaged allografts is of crucial importance for successful transplantation. Ex vivo cold (1°C–8°C) machine perfusion is considered to be the method of choice for preserving higher risk kidney allografts obtained from deceased donors [4]

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