{"doi":"10.1111/ajt.15777","title":"Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation","abstract":"Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 - vehicle, G2 - rhC1INH+heparin, and G3 - heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase–associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation. Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 - vehicle, G2 - rhC1INH+heparin, and G3 - heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase–associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation.","journal":"American Journal of Transplantation","year":2020,"id":98255,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9583,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":484960,"name":"Tiffany Zens","orcid":"0000-0003-0213-6940","position":1,"is_corresponding":false},{"id":484961,"name":"Peter J. 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D’Alessandro","orcid":"0000-0003-4946-0713","position":8,"is_corresponding":false},{"id":484964,"name":"José Torrealba","orcid":"0000-0001-6018-927X","position":9,"is_corresponding":false},{"id":484965,"name":"Daniel Burguete","orcid":"0000-0002-3819-6112","position":10,"is_corresponding":false},{"id":484966,"name":"Kevin Brunner","orcid":"0000-0003-2620-2666","position":11,"is_corresponding":false},{"id":485771,"name":"E. van Amersfoort","orcid":null,"position":12,"is_corresponding":false},{"id":484967,"name":"Yolanda Ponstein","orcid":"0000-0002-5003-321X","position":13,"is_corresponding":false},{"id":484968,"name":"Cees van Kooten","orcid":"0000-0002-6257-0899","position":14,"is_corresponding":false},{"id":257144,"name":"Ewa Jankowska−Gan","orcid":null,"position":15,"is_corresponding":false},{"id":255412,"name":"William J. Burlingham","orcid":"0000-0002-2653-6044","position":16,"is_corresponding":false},{"id":255404,"name":"Jeremy A. Sullivan","orcid":"0000-0001-7290-0399","position":17,"is_corresponding":false},{"id":390548,"name":"Arjang Djamali","orcid":"0000-0001-7675-6128","position":18,"is_corresponding":false},{"id":485772,"name":"Myron A. Pozniak","orcid":null,"position":19,"is_corresponding":false},{"id":484969,"name":"Yücel Yankol","orcid":"0000-0002-4427-9096","position":20,"is_corresponding":false},{"id":484970,"name":"Luis A. Fernandez","orcid":"0000-0002-8785-6041","position":21,"is_corresponding":false},{"id":425913,"name":"Juan S. 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