Introduction: Donor brain death (BD) triggers a complement-mediated inflammatory response linked to renal injury which has been associated to delayed graft function (DGF) and the development of antibody-mediated rejection (ABMR) post-transplant. We hypothesized that BD donor pretreatment with recombinant human C1 inhibitor (C1-INH) would prevent progression to DGF and ABMR in a translatable non-human primate (NHP) model of renal allotransplantation.

Methods: BD was induced and maintained for 20 hours and recovered kidneys were cold-stored for a 44-hour period. These were then transplanted into ABO-compatible, MHC fully mismatched recipients. Donor animals were divided into three groups: G1) Vehicle (n=3 donors, 6 recipients), G2) C1INH 500 U/kg/dose + heparin (n=3 donors, 6 recipients) and G3) Heparin only (n=2 donors, 3 recipients). Animals were followed for a 90-day period and underwent interval biopsies. The main end-points of the study were: 1) Incidence of DGF and 2) development of ABMR within 90 days of transplant.

Results: Donor pretreatment with C1-INH prevented progression to DGF in 6/6 (100%) recipients of G2 donor kidneys. In contrast, 4/6 (66.6%) animals receiving kidneys from G1 donors and 3/3 (100%) from G3 donors developed DGF (p= 0.008). In addition, recipients of G2 kidneys showed a statistically significant decrease in creatinine levels in the first post-operative week (p <0.01) along with a significant reduction in the activation of the donor classical pathway of complement and effectors of the contact system. Furthermore, recipients of G2 kidneys expressed markedly reduced urinary NGAL levels. In tissue, macrophage and neutrophil infiltration was limited in renal grafts from G2 C1-INH treated donors. All recipients of G1 (4/4) and G2 (6/6) donor grafts surviving beyond one week post-transplant progressed to ABMR as evidenced by deteriorating renal function, positive C4d staining, peritubular capillaritis and glomerulitis and sustained DSA levels.

Conclusion: Our data supports the use of C1-INH as an innovative approach for the prevention of DGF in grafts from BD donors with prolonged cold-ischemia time. We did not identify a role for donor complement blockade in the progression to ABMR in this study.

CITATION INFORMATION: Danobeitia J., Zens T., Zitur L., Chlebeck P., Torrealba J., Burguete D., Van Amersfoort E., Relan A., D'Alessandro A., Fernandez L. Targeted Donor Complement Blockade after Brain-Death Prevents Delayed Graft Function but Not Progression to Antibody-Mediated Rejection in a Non-Human Primate Model of Kidney Allo-Transplantation Am J Transplant. 2017;17 (suppl 3).

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