Early Activation of the Complement System After Brain Death in Clinical Kidney Donation and Transplantation

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Abstract
Background.: Brain death (BD) results in an inflammatory response, including complement activation. The clinical impact of prolonged BD duration on the graft-to-be is still unclear. We investigated how BD duration impacts complement activation levels, both systemically and locally within donor kidneys. Methods.: EDTA plasma samples and kidney biopsies were obtained from the Quality in Organ Donation biobank (n = 120). Samples were routinely taken at 3 fixed points during BD management and donors were grouped according to short (≤14 h), medium (15–22 h), or long (≥23 h) duration of BD. ELISAs were used for quantification of complement in plasma, and immunohistochemistry was performed to determine complement activation at tissue level. Results.: Plasma levels of C4d, Bb, C3c, and C5b-9 were significantly elevated compared with living donor samples taken at similar timepoint. Complement activation was already observed at the start of donor management and remained elevated. Prolonged BD duration was associated with reduced complement activation, with significantly lower levels of C4d and Bb, and trends toward lower C3c. Elevated levels of Bb were associated with increased delayed graft function (DGF), while increased C4d levels showed trends toward higher DGF and lower eGFR at 3 mo posttransplantation. Also, renal biopsies taken just before reperfusion, showed local complement activation, with more intense complement staining (C3d and C5b-9) in the vascular pole in kidneys that developed DGF. Conclusions.: The complement system is already activated in BD donors early on during donor management. Prolonged BD duration was associated with reduced systemic complement activation. Increased systemic and local complement activation appears to negatively impact short-term kidney function.

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