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

被引：23

作者：

Hameed, Ahmer M. ^{[1
,2
,3
]}

Lu, David B. ^{[2
]}

Burns, Heather ^{[2
]}

Byrne, Nicole ^{[2
]}

Chew, Yi Vee ^{[2
]}

Julovi, Sohel ^{[2
]}

Ghimire, Kedar ^{[2
]}

Zanjani, Negar Talaei ^{[2
]}

P'ng, Chow H. ^{[4
]}

Meijles, Daniel ^{[5
]}

Dervish, Suat ^{[2
]}

Matthews, Ross ^{[6
]}

Miraziz, Ray ^{[7
]}

O'Grady, Greg ^{[8
]}

Yuen, Lawrence ^{[1
,3
]}

Pleass, Henry C. ^{[1
,3
]}

Rogers, Natasha M. ^{[2
,3
,9
]}

Hawthorne, Wayne J. ^{[1
,2
,3
]}

机构：

[1] Westmead Hosp, Dept Surg, Sydney, NSW, Australia

[2] Westmead Inst Med Res, Sydney, NSW, Australia

[3] Univ Sydney, Sydney Med Sch, Sydney, NSW, Australia

[4] Westmead Hosp, Inst Clin Pathol & Med Res, Sydney, NSW, Australia

[5] St Georges Univ London, London, England

[6] Westmead Hosp, Dept Anim Care, Sydney, NSW, Australia

[7] Westmead Hosp, Dept Anesthesia, Sydney, NSW, Australia

[8] Univ Auckland, Dept Surg, Auckland, New Zealand

[9] Westmead Hosp, Dept Transplant Renal Med, Sydney, NSW, Australia

来源：

SCIENTIFIC REPORTS | 2020年 / 10卷 / 01期

关键词：

STATIC COLD-STORAGE; VIVO KIDNEY PERFUSION; COMPLEMENT INHIBITION; TRANSPLANTATION; DONATION; DEATH; CD47; PRESERVATION; LIVER; MODEL;

D O I：

10.1038/s41598-020-63687-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Normothermic machine perfusion (NMP) is an emerging modality for kidney preservation prior to transplantation. NMP may allow directed pharmacomodulation of renal ischemia-reperfusion injury (IRI) without the need for systemic donor/recipient therapies. Three proven anti-IRI agents not in widespread clinical use, CD47-blocking antibody (alpha CD47Ab), soluble complement receptor 1 (sCR1), and recombinant thrombomodulin (rTM), were compared in a murine model of kidney IRI. The most effective agent was then utilized in a custom NMP circuit for the treatment of isolated porcine kidneys, ascertaining the impact of the drug on perfusion and IRI-related parameters. alpha CD47Ab conferred the greatest protection against IRI in mice after 24hours. alpha CD47Ab was therefore chosen as the candidate agent for addition to the NMP circuit. CD47 receptor binding was demonstrated by immunofluorescence. Renal perfusion/flow improved with CD47 blockade, with a corresponding reduction in oxidative stress and histologic damage compared to untreated NMP kidneys. Tubular and glomerular functional parameters were not significantly impacted by alpha CD47Ab treatment during NMP. In a murine renal IRI model, alpha CD47Ab was confirmed as a superior anti-IRI agent compared to therapies targeting other pathways. NMP enabled effective, direct delivery of this drug to porcine kidneys, although further efficacy needs to be proven in the transplantation setting.

引用

页数：17

共 53 条

[1]

Adams TD, 2017, TRANSPLANT DIRECT, V3, DOI 10.1097/TXD.0000000000000655

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