Intra-Renal Delivery of Drugs Targeting Ischemia-Reperfusion Injury of the Kidney using Normothermic Machine Perfusion. (July 2018)

• Record Type: Journal Article
• Authors: Hameed, Ahmer; Rogers, Natasha; Pleass, Henry; Lu, Bo; Miraziz, Ray; Hawthorne, Wayne
• Is Part Of: Transplantation. Volume 102(2018)Supplement 7S-1
• Publication Date: 2018-07
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/01.tp.0000543660.39716.78
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Introduction: The ongoing donor kidney shortage has necessitated the increasing use of higher Kidney Donor Profile Index (KDPI) kidneys. Our aim was to investigate machine perfusion (MP) as a strategy to optimise outcomes from these grafts, in particular through the pharmacologic targeting of ischaemia-reperfusion injury (IRI). Materials/Methods: (i) A systematic review/meta-analysis was conducted to compare renal transplantation outcomes after hypothermic (HMP) and normothermic (NMP) MP in comparison to static cold storage (CS) using both clinical and experimental data, and thence identify areas for further investigation using animal experimental models. (ii) Directed drug delivery to the kidney, delivered using MP and targeting IRI, was identified as an important area for further research. Three different IRI targets (CD47 antibody, soluble complement receptor 1 [sCR1], and recombinant thrombomodulin [rTM]), delivered intra-renally, were therefore compared in a rodent model of kidney IRI. (iii) NMP was identified as a promising preservation modality for further clinical implementation; therefore a NMP system was developed/optimised using a porcine donation after cirulatory death (DCD) model. The impact of CD47 and sCR1 on NMP parameters was subsequently investigated. Results: (i) Hypothermic MP (HMP) reduces kidney delayed graft function in comparison to CS (RR 0.77, 95% CI 0.69 to 0.87), but there is no cumulative study evidence for an improvement in longer-term outcomes. NMP evidence is largely limited to the experimental setting and indicates that NMP is superior to HMP with regards to subsequent renal function (mean difference of peak creatinine -1.66; 95% CI -3.19 to -0.14). Drug delivery targeting IRI is under-explored in MP studies. (ii) A rodent renal IRI model was established, and preliminary evidence (day 1 and 7 renal function and histopathology) indicates intra-renal delivery of CD47 and/or soluble complement receptor 1 may ameliorate IRI. (iii) A clinically translatable NMP system was developed and tested using a porcine kidney donation after circulatory death model. Pressure-controlled perfusion, using a leukocyte-depleted, colloid-containing perfusate produced ideal baseline conditions. Addition of CD47 to the perfusion circuit impacts on perfusion and biochemical parameters, including intra-renal resistance, urine output, and creatinine clearance. Discussion: Renal HMP does not seem to modulate longer-term graft outcomes. IRI of the kidney can be ameliorated by the intra-renal delivery of pharmocotherapies such as CD47 blocking antibody. NMP presents the ideal opportunity to deliver such IRI-targeting drugs to the kidney and simultaneously assess kidney function and may enhance the impact of this preservation modality. Conclusion: Modification of perfusion conditions using NMP in combination with drug(s) targeting IRI may further improve transplantation outcomes, and avoids systemic treatment of the donor or recipient.