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@article{Hamaoui:2016:10.1097/TP.0000000000001437,
author = {Hamaoui, K and Gowers, S and Boutelle, M and Cook, TH and Hanna, G and Darzi, A and Smith, RA and Dorling, A and Papalois, V},
doi = {10.1097/TP.0000000000001437},
journal = {Transplantation},
pages = {e128--e139},
title = {Organ pre-treatment with cytotopic endothelial localising peptides to ameliorate microvascular thrombosis & perfusion deficits in ex-vivo renal haemo-reperfusion models},
url = {http://dx.doi.org/10.1097/TP.0000000000001437},
volume = {100},
year = {2016}
}

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TY - JOUR
AB - Background: Hypothermic machine organ perfusion (HMP) offers opportunity to manipulate grafts with pharmacological agents prior to transplantation. Pre-treating organs with novel cytotopic anti-coagulant peptides that localise to endothelial cell membranes could ameliorate microvascular thrombotic sequelae post-transplantation. We describe experiments testing Thrombalexin (TLN), a novel cell binding thrombin-inhibitor, using porcine and unused human kidneys in a series of ex-vivo normothermic haemo-reperfusion models. Methods: 38 porcine kidneys were utilised. Control kidneys underwent pretreatment via HMP with either unmodified perfusion solution (n=15) or solution with Inactive-TLN (absent anticoagulant effect, n=4). Test kidneys were perfused with TLN treated solution (n=19). All kidneys then underwent haemo-reperfusion. Two unused human kidneys underwent a similar protocol.Results: HMP pretreatment facilitated delivery and tethering of TLN in the organ microvasculature. Haemo-reperfusion challenge demonstrated improved perfusion in TLN-treated kidneys compared to controls: 26.4% superior flow (30.6 vs.23.1 ml/min/100g,p=0.019) and 28.9% higher perfusion flow indices (0.43 vs.0.32 ml/min/100g/mmHg,p=0.049). Orthogonal polarisation spectral imaging demonstrated superior microvascular capillary perfusion in TLN-treated organs vs. controls (9.1 vs. 2.8pl/s/mm2,p=0.021). Rapid-sampling microdialysis for cortical [lactate] as a marker of tissue ischaemia/metabolism detected lower levels in TLN-treated kidneys. Perfusate analysis demonstrated reduced fibrin generation in TLN-treated kidneys correlating with perfusion data. Conclusion: Our data suggest HMP graft pretreatment with cytotopic anticoagulants is feasible and ameliorates perfusion deficits seen in ex-vivo haemo-reperfusion models. There is potential for further development and application of this translational strategy to deliver locally-active anti-coagulants directly within grafts and decrease microvascular
AU - Hamaoui,K
AU - Gowers,S
AU - Boutelle,M
AU - Cook,TH
AU - Hanna,G
AU - Darzi,A
AU - Smith,RA
AU - Dorling,A
AU - Papalois,V
DO - 10.1097/TP.0000000000001437
EP - 139
PY - 2016///
SN - 1534-6080
SP - 128
TI - Organ pre-treatment with cytotopic endothelial localising peptides to ameliorate microvascular thrombosis & perfusion deficits in ex-vivo renal haemo-reperfusion models
T2 - Transplantation
UR - http://dx.doi.org/10.1097/TP.0000000000001437
UR - http://hdl.handle.net/10044/1/39433
VL - 100
ER -

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