Effects of Oxygen During Long-term Hypothermic Machine Perfusion in a Porcine Model of Kidney Donation After Circulatory Death

Venema, Leonie H; Brat, Aukje; Moers, Cyril; Hart, Nils A 't; Ploeg, Rutger J.; Hannaert, Patrick; Minor, Thomas; Leuvenink, Henri G. D.

doi:10.1097/tp.0000000000002728

Cited by 57 publications

(77 citation statements)

References 26 publications

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“…Proteomics analysis also suggests that RIC leads to altered energy metabolism in kidney tissue 6 days after transplantation. This is consistent with other reports in experimental models that suggested reduced IRI in kidney after RIC, although it was mainly attributed to reduced oxidative stress [ 1 , 28 , 29 ], while re-oxygenation leads to similar benefits [ 30 , 31 ].…”

Section: Discussionsupporting

confidence: 93%

Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics

et al. 2020

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Background Remote ischaemic conditioning (RIC) is currently being explored as a non-invasive method to attenuate ischaemia/reperfusion injuries in organs. A randomised clinical study (CONTEXT) evaluated the effects of RIC compared to non-RIC controls in human kidney transplants. Methods RIC was induced prior to kidney reperfusion by episodes of obstruction to arterial flow in the leg opposite the transplant using a tourniquet (4 × 5 min). Although RIC did not lead to clinical improvement of transplant outcomes, we explored whether RIC induced molecular changes through precision analysis of CONTEXT recipient plasma and kidney tissue samples by high-resolution tandem mass spectrometry (MS/MS). Results We observed an accumulation of muscle derived proteins and altered amino acid metabolism in kidney tissue proteomes, likely provoked by RIC, which was not reflected in plasma. In addition, MS/MS analysis demonstrated transient upregulation of several acute phase response proteins (SAA1, SAA2, CRP) in plasma, 1 and 5 days post-transplant in RIC and non-RIC conditions with a variable effect on the magnitude of acute inflammation. Conclusions Together, our results indicate sub-clinical systemic and organ-localised effects of RIC.

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Section: Discussionsupporting

confidence: 93%

Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics

et al. 2020

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“…Formalin fixed paraffin embedded biopsies of the upper, lateral and lower renal cortex and medulla (t = -10; t = 240 and t = 420) were stained with haematoxylin and eosin (HE) to assess changes in tissue morphology. The biopsies were examined and a damage scoring system was developed, based on previously reported scoring systems [15], and validated by an experienced renal pathologist. As differences in histology between upper, lateral and lower pole were very minimal, per experiment three cortical biopsies of only the upper pole at t = -10, t = 240 and t = 420 were scored, by two independent blinded examiners.…”

Section: Histologymentioning

confidence: 99%

Normothermic machine perfusion of ischaemically damaged porcine kidneys with autologous, allogeneic porcine and human red blood cells

et al. 2020

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In porcine kidney auto-transplant models, red blood cells (RBCs) are required for ex-vivo normothermic machine perfusion (NMP). As large quantities of RBCs are needed for NMP, utilising autologous RBCs would imply lethal exsanguination of the pig that is donor and recipient-to-be in the same experiment. The purpose of this study was to determine if an isolated porcine kidney can also be perfused with allogeneic porcine or human RBCs instead. Porcine kidneys, autologous and allogeneic blood were obtained from a local slaughterhouse. Human RBCs (O-pos), were provided by our transfusion laboratory. Warm ischaemia time was standardised at 20 minutes and subsequent hypothermic machine perfusion lasted 1.5-2.5 hours. Next, kidneys underwent NMP at 37˚C during 7 hours with Williams' Medium E and washed, leukocyte depleted RBCs of either autologous, allogeneic, or human origin (n = 5 per group). During perfusion all kidneys were functional and produced urine. No macroscopic adverse reactions were observed. Creatinine clearance during NMP was significantly higher in the human RBC group in comparison with the allogeneic group (P = 0.049) but not compared to the autologous group. The concentration of albumin in the urine was significantly higher in the human RBC group (P <0.001) compared to the autologous and allogeneic RBC group. Injury marker aspartate aminotransferase was significantly higher in the human RBC group in comparison with the allogeneic group (P = 0.040) but not in comparison with the autologous group. Renal histology revealed glomerular and tubular damage in all groups. Signs of pathological hyperfiltration and microvascular injury were only observed in the human RBC group. In conclusion, perfusion of porcine kidneys with RBCs of different origin proved technically feasible. However, laboratory analysis and histology revealed more damage in the human RBC group compared to the other two groups. These results indicate that the use of allogeneic RBCs is preferable to human RBCs in a situation where autologous RBCs cannot be used for NMP.

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“…In vivo, high fractional sodium excretion (FeNa) (usually >1%) is suggestive of tubular necrosis [80]. Several normothermic perfusion models, making use of pig kidneys or kidneys found not suitable for transplantation, report FeNa with a high variability and a wide range (5%-200%) [81][82][83][84][85]. Extrapolating in vivo findings, it seems logical that the lower the FeNa during normothermic perfusion, the better tubular function is preserved.…”

Section: Nephron Functionmentioning

confidence: 99%

“…Therefore, measuring oxygen consumption could be a potential viability marker. Indeed, oxygen consumption is measured in different models as a marker of kidney metabolic activity [81,84,85,88]. What limits direct comparison between studies is the use of a multitude of formulas to calculate oxygen consumption.…”

Section: Nephron Functionmentioning

confidence: 99%

Kidney Perfusion as an Organ Quality Assessment Tool—Are We Counting Our Chickens Before They Have Hatched?

Beule

Jochmans

2020

JCM

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The final decision to accept an organ for transplantation remains a subjective one. With “poor organ quality” commonly cited as a major reason for kidney discard, accurate, objective, and reliable quality assessment is essential. In an era of increasingly higher-risk deceased donor kidneys, the catch is to accept those where the risk–benefit scale will tip in the right direction. Currently available assessment tools, such as risk-scores predicting outcome and zero-time biopsy, perform unsatisfactory, and assessment options during static cold storage are limited. Kidney perfusion technologies are finding their way into clinical practice, and they bring a new opportunity to assess kidney graft viability and quality, both in hypothermic and normothermic conditions. We give an overview of the current understanding of kidney viability assessment during ex situ kidney perfusion. A pragmatic framework to approach viability assessment is proposed as an interplay of three different compartments: the nephron, the vascular compartment, and the immune compartment. Although many interesting ways to assess kidney injury and function during perfusion have been proposed, none have reached the stage where they can reliably predict posttransplant outcome. Larger well-designed studies and validation cohorts are needed to provide better guidance.

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Effects of Oxygen During Long-term Hypothermic Machine Perfusion in a Porcine Model of Kidney Donation After Circulatory Death

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Cited by 57 publications

References 26 publications

Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics

Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics

Normothermic machine perfusion of ischaemically damaged porcine kidneys with autologous, allogeneic porcine and human red blood cells

Kidney Perfusion as an Organ Quality Assessment Tool—Are We Counting Our Chickens Before They Have Hatched?

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