BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Gaetano La Manna; Nicole Lanci; Elena Della Bella; Giorgia Comai; Maria Laura Cappuccilli; Katia Nisi; Paola Todeschini; Elisa Carretta; Maria Piera Scolari; Sergio Stefoni Journal: Am J Nephrol Date: 2011-10-26 Impact factor: 3.754
Authors: Xavier Tillou; Nicolas Poirier; Stéphanie Le Bas-Bernardet; Jeremy Hervouet; David Minault; Karine Renaudin; Fabio Vistoli; Georges Karam; Mohamed Daha; Jean Paul Soulillou; Gilles Blancho Journal: Kidney Int Date: 2010-03-24 Impact factor: 10.612
Authors: Markus J Harder; Nadine Kuhn; Hubert Schrezenmeier; Britta Höchsmann; Inge von Zabern; Christof Weinstock; Thomas Simmet; Daniel Ricklin; John D Lambris; Arne Skerra; Markus Anliker; Christoph Q Schmidt Journal: Blood Date: 2016-12-27 Impact factor: 22.113
Authors: Sri G Yarlagadda; Steven G Coca; Richard N Formica; Emilio D Poggio; Chirag R Parikh Journal: Nephrol Dial Transplant Date: 2008-12-22 Impact factor: 5.992
Authors: M Haas; A Loupy; C Lefaucheur; C Roufosse; D Glotz; D Seron; B J Nankivell; P F Halloran; R B Colvin; Enver Akalin; N Alachkar; S Bagnasco; Y Bouatou; J U Becker; L D Cornell; J P Duong van Huyen; I W Gibson; Edward S Kraus; R B Mannon; M Naesens; V Nickeleit; P Nickerson; D L Segev; H K Singh; M Stegall; P Randhawa; L Racusen; K Solez; M Mengel Journal: Am J Transplant Date: 2018-01-21 Impact factor: 8.086