Prompt Thrombo-Inflammatory Response to Ischemia-Reperfusion Injury and Kidney Transplant Outcomes

Gabriel Strandberg; Carl M Öberg; Anna M Blom; Oleg Slivca; David Berglund; Mårten Segelmark; Bo Nilsson; Ali-Reza Biglarnia

doi:10.1016/j.ekir.2023.09.025

Prompt Thrombo-Inflammatory Response to Ischemia-Reperfusion Injury and Kidney Transplant Outcomes

Kidney Int Rep. 2023 Sep 24;8(12):2592-2602. doi: 10.1016/j.ekir.2023.09.025. eCollection 2023 Dec.

Authors

Gabriel Strandberg¹, Carl M Öberg², Anna M Blom³, Oleg Slivca¹, David Berglund⁴, Mårten Segelmark², Bo Nilsson⁴, Ali-Reza Biglarnia¹

Affiliations

¹ Department of Surgery, Department of Clinical Sciences Malmö, Skåne University Hospital, Lund University, Malmö, Sweden.
² Department of Nephrology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden.
³ Department of Translational Medicine, Lund University, Malmö, Sweden.
⁴ Department of Immunology, Genetics, and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.

Abstract

Introduction: In kidney transplantation (KT), the role of the intravascular innate immune system (IIIS) in response to ischemia-reperfusion injury (IRI) is not well-understood. Here, we studied parallel changes in the generation of key activation products of the proteolytic cascade systems of the IIIS following living donor (LD) and deceased donor (DD) transplantation and evaluated potential associations with clinical outcomes.

Methods: In a cohort study, 63 patients undergoing LD (n = 26) and DD (n = 37) transplantation were prospectively included. Fifteen DD kidneys were preserved with hypothermic machine perfusion (HMP), and the remaining were cold stored. Activation products of the kallikrein-kinin, coagulation, and complement systems were measured in blood samples obtained systemically at baseline and locally from the transplant renal vein at 1, 10, and 30 minutes after reperfusion.

Results: DD kidneys exhibited a prompt and interlinked activation of all 3 cascade systems of IIIS postreperfusion, indicating a robust and local thrombo-inflammatory response to IRI. In this initial response, the complement activation product sC5b-9 exhibited a robust correlation with other IIIS activation markers and displayed a strong association with short-term and mid-term (24-month) graft dysfunction. In contrast, LD kidneys did not exhibit this thrombo-inflammatory response. The use of HMP was associated with reduced thromboinflammation and preserved mid-term kidney function.

Conclusion: Kidneys from DD are vulnerable to a prompt thrombo-inflammatory response to IRI, which adversely affects both short-term and long-term allograft function. Strategies aimed at minimizing graft immunogenicity prior to reperfusion are crucial to mitigate the intricate inflammatory response to IRI.

Keywords: delayed graft function; intravascular innate immune system; ischemia-reperfusion injury; kidney transplantation; organ preservation; thromboinflammation.