Targeting Complement Pathways During Ischemia and Reperfusion: Implications for the Prevention of Delayed Graft Function

Z. Yu,¹ S. Qi,² M. Lasaro,¹ K. Bouchard,¹ C. Dow,¹ K. Moore,¹ Z. Wu,² A. Barama,² J. Xu,² K. Johnson,¹ A. Marozsan,¹ Y. Wang.¹

¹Pre-Clinical Sciences, Alexion Pharmaceutical Inc., Cheshire, CT
²Department of Surgery, Hôpital Notre Dame and Université
de Montréal, Montréal, QC, Canada.

Meeting: 2015 American Transplant Congress

Abstract number: 188

Keywords: Efficacy, Graft survival, Kidney transplantation, Preservation solutions

Session Information

Session Name: Concurrent Session: Ischemia Reperfusion Injury: Basic Mechanisms

Session Type: Concurrent Session

Date: Monday, May 4, 2015

Session Time: 2:15pm-3:45pm

Presentation Time: 2:51pm-3:03pm

Location: Room 119-A

Complement system plays a critical role in ischemia-reperfusion injury (IRI), and contributes to DGF. The aim of this study was to evaluate the effects of inhibiting the complement alternative pathway (AP) and terminal pathway (TP) during cold ischemia (CI) and reperfusion on the development of DGF in a syngeneic rat model of kidney transplantation (tpx).

We first tested the effect of local blockade of the AP or TP in donor kidneys (DKs) prior to tpx. DKs were pretreated with either anti-rat C5 mAb, 18A10, a TP inhibitor or TT30, an AP inhibitor, during 28 hour CI. Pre-tpx treatment with either 18A10 or TT30 reduced ischemic injury to DKs and improved post-tpx graft function. 100% of 18A10-pretreated grafts (n=9) and 66.7% of TT30-pretreated grafts (n=9) survived beyond day 21 (end of study), whereas only 16.7% of isotype control mAb-pretreated grafts (n=12) and 22% of UW-pretreated grafts (n=9) survived beyond day 21 (P<.01). DKs pre-tpx treatment with either TT30 or 18A10 was also performed in the final 45 min of 28 hour CI. The 18A10 or TT30 pre-tpx treatment also increased graft survival from 0% to 67% (n=6, P<.01). To evaluate the effect of systemic inhibition of the AP or TP in recipient animals (RAs) after tpx, RAs, grafted with UW-pretreated DKs during CI, received iv administration of either 18A10 or TT30 immediately after tpx (q.d. for 7 days). 60% of RAs treated with 18A10 survived over 21 days, while RAs treated with TT30 survived for a median of 4 days (n=5). Additional studies, which achieved sustained systemic AP inhibition in RAs immediately before and after tpx , also showed that no RAs survived beyond 4 days.

Our results demonstrate that the AP plays a predominant role during CI in the DKs and that blocking either the AP or more effectively, the TP, prevents ischemic injury and the subsequent DGF. Complement activation during reperfusion appeared to be different from that during CI. Systemic AP inhibition in post-tpx RAs did not prevent IRI injury of ischemic organs and DGF, while systemic blockade of the TP with anti-C5 mAb in post-tpx RAs effectively enhanced graft survival. These results indicate that all three complement pathways may contribute to IRI injury during reperfusion and demonstrate the feasibility of using complement inhibitors for prevention of DGF in humans.

To cite this abstract in AMA style:

Yu Z, Qi S, Lasaro M, Bouchard K, Dow C, Moore K, Wu Z, Barama A, Xu J, Johnson K, Marozsan A, Wang Y. Targeting Complement Pathways During Ischemia and Reperfusion: Implications for the Prevention of Delayed Graft Function [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/targeting-complement-pathways-during-ischemia-and-reperfusion-implications-for-the-prevention-of-delayed-graft-function/. Accessed November 21, 2024.

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