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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.

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

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  • Media type: E-Article
  • Title: Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation
  • Contributor: 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.
  • imprint: Ovid Technologies (Wolters Kluwer Health), 2022
  • Published in: Transplantation
  • Language: English
  • DOI: 10.1097/tp.0000000000003754
  • ISSN: 0041-1337
  • Keywords: Transplantation
  • Origination:
  • Footnote:
  • Description: <jats:sec> <jats:title>Background.</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods.</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results.</jats:title> <jats:p>Of vehicle-treated recipients, 80% (4 of 5) developed DGF versus 12.5% (1 of 8) rhC1INH-treated recipients (<jats:italic toggle="yes">P</jats:italic> = 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions.</jats:title> <jats:p>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.</jats:p> </jats:sec>