Extra‐corporeal normothermic machine perfusion of the porcine kidney: working towards future utilization in Australasia

Hameed, Ahmer; Miraziz, Ray; Lu, David B.; Warwick, Neil; El-Ayoubi, Ali; Burns, Heather; Chew, Yi Vee; Matthews, Ross; O’Grady, Greg; Yuen, Lawrence; Rogers, Natasha M.; Pleass, Henry; Hawthorne, Wayne J.

doi:10.1111/ans.14321

Cited by 8 publications

(6 citation statements)

References 21 publications

(17 reference statements)

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“…Existing renal NMP devices have differed in perfusion settings and constituents. 1,3,17,18,21 Therefore, parameters such as RBF, IRR, and UO may not be readily compared between different studies in terms of significance and predictive potential. Nevertheless, our use of NMP in discarded human kidneys enhanced RBF and IRR in all but one kidney, possibly suggesting good immediate graft function, as evidenced by early work from Nicholson and Hosgood 16 where kidneys with high flows had lower delayed graft function rates upon transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…The NMP system was assembled as previously described; a schematic diagram of the perfusion set-up can also be found in this reference. 21 A continuous supply of oxygen, delivered as 95% oxygen/5% carbon dioxide, was delivered to the oxygenator at a flow rate of 1.5 L/min. Creatinine was added to the circuit (Merck, Darmstadt, Germany) to enable subsequent quantification of creatinine clearance (CrCl).…”

Section: Methodsmentioning

confidence: 99%

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Brief Normothermic Machine Perfusion Rejuvenates Discarded Human Kidneys

Hameed

Patrick

et al. 2019

Transplantation Direct

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Brief Normothermic Machine Perfusion Rejuvenates Discarded Human Kidneys

Hameed

Patrick

et al. 2019

Transplantation Direct

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“…Porcine kidney retrieval -DCD model. Kidney retrieval and a DCD model was established as previously described 40 . All operative procedures were performed under general anesthetic, including pre-medication with intramuscular 1 mg/kg Ilium Xylazil (Xylazine, Troy Laboratories Pty Ltd, Sydney, Australia), 25 mg/kg Tiletamine combined with 25 mg/kg Zolazepam (Zoletil 100, Virbac Australia Pty Ltd, Sydney, Australia), and 1 mg/kg Azaperone (Stresnil, Boehringer Ingelheim Pty Ltd, Sydney, Australia).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Normothermic machine perfusion. Kidney NMP was performed using a modified cardio-pulmonary bypass circuit, as described previously 40 . In brief, packed red blood cells (PRBCs) were isolated from autologous whole blood, and leucocyte-depleted using a leucocyte filter (Imugard III-RC, Terumo, Tokyo, Japan).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Pharmacologic targeting of renal ischemia-reperfusion injury using a normothermic machine perfusion platform

Hameed

Burns

et al. 2020

Sci Rep

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(NMP) is especially promising, and is now the subject of a multi-center randomized control trial (RCT) comparing it to CS alone in DCD kidneys 10-13. Most pharmacotherapeutics shown to ameliorate renal IRI have been unable to bridge the 'valley of death' (translational gap) to the clinic. This is at least partly attributable to the inherent difficulties and ethical considerations associated with the systemic use of such therapies in donors or recipients 14,15. NMP can serve as a bridge across this valley by providing a platform for direct, non-systemic drug treatment of the kidney whilst it is undergoing normal metabolic processes 15,16. Amongst the multiple anti-IRI agents tested in pre-clinical models, CD47-blocking antibody (αCD47Ab), recombinant thrombomodulin (rTM), and soluble complement receptor 1 (sCR1) are especially translatable as they have been safely employed for other clinical applications 17-25. However, the comparative efficacy of these agents has not been established. αCD47Ab ameliorates thrombospondin (TSP)-1 mediated IRI signaling, including inhibition of nitric oxide and promotion of oxidative stress 21. sCR1 is an inhibitor of the classical and alternative complement pathways, activation of which is important in IRI 26. rTM is an anti-coagulant molecule involved in the generation of activated protein C, although its efficacy in IRI may be more attributable to anti-inflammatory effects 17,27. Because IRI is characterized by the activation of multiple intersecting pathways 28,29 , it is also plausible that synergistic anti-IRI effects may be derived by delivering two or more of these agents together. The aims of this study were to directly compare the acute effects of αCD47Ab, sCR1, and rTM in a murine model of renal IRI and to establish the combined efficacy of two of the best agents. We then show that the chosen drug could be directly delivered to porcine DCD kidneys using NMP to enhance renal perfusion parameters and ameliorate IRI. The primary focus of this study is the immediate phase of IRI, which correlates to the immediate post-transplant setting and the risk of delayed graft function in higher risk renal allografts. Methods Animal work-ethics. All protocols were approved by the Western Sydney Local Health District Animal Ethics Committee, in accordance with the Australian code for the care and use of animals for scientific purposes (8 th Ed., 2013), developed by the National Health and Medical Research Council. Animal experiments adhere to the ARRIVE guidelines.

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“…Our NMP set-up has been described previously [5]. We initially used a custom-designed metal chamber, however this was difficult to clean/re-sterilize, and did not adequately collect and funnel all residual blood into the reservoir.…”

mentioning

confidence: 99%