Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation

• Published in: Transplantation Vol. 106; no. 1; p. 60
• Main Authors: Eerhart, Michael J, Reyes, Jose A, Blanton, Casi L, Danobeitia, Juan S, Chlebeck, Peter J, Zitur, Laura J, Springer, Megan, Polyak, Erzsebet, Coonen, Jennifer, Capuano, Saverio, D'Alessandro, Anthony M, Torrealba, Jose, van Amersfoort, Edwin, Ponstein, Yolanda, van Kooten, Cees, Burlingham, William, Sullivan, Jeremy, Pozniak, Myron, Zhong, Weixiong, Yankol, Yucel, Fernandez, Luis A
• Format: Journal Article
• Language: English
• Published: United States 01.01.2022
• Subjects: Animals; Delayed Graft Function - etiology; Delayed Graft Function - prevention & control; Graft Rejection - prevention & control; Graft Survival; Humans; Kidney; Kidney Transplantation - adverse effects; Primates; Tissue Donors
• ISSN: 1534-6080
• DOI: 10.1097/TP.0000000000003754

Complement activation in kidney transplantation is implicated in the pathogenesis of delayed graft function (DGF). This study evaluated the therapeutic efficacy of high-dose recombinant human C1 esterase inhibitor (rhC1INH) to prevent DGF in a nonhuman primate model of kidney transplantation after brain death and prolonged cold ischemia. Brain death donors underwent 20 h of conventional management. Procured kidneys were stored on ice for 44-48 h, then transplanted into ABO-compatible major histocompatibility complex-mismatched recipients. Recipients were treated with vehicle (n = 5) or rhC1INH 500 U/kg plus heparin 40 U/kg (n = 8) before reperfusion, 12 h, and 24 h posttransplant. Recipients were followed up for 120 d. Of vehicle-treated recipients, 80% (4 of 5) developed DGF versus 12.5% (1 of 8) rhC1INH-treated recipients (P = 0.015). rhC1INH-treated recipients had faster creatinine recovery, superior urinary output, and reduced urinary neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2-insulin-like growth factor-binding protein 7 throughout the first week, indicating reduced allograft injury. Treated recipients presented lower postreperfusion plasma interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and IL-18, lower day 4 monocyte chemoattractant protein 1, and trended toward lower C5. Treated recipients exhibited less C3b/C5b-9 deposition on day 7 biopsies. rhC1INH-treated animals also trended toward prolonged mediated rejection-free survival. Our results recommend high-dose C1INH complement blockade in transplant recipients as an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes.