Inhibitory monoclonal antibody to factor B attenuates brain death-induced renal injury and inflammation

N.M. Jager, F. Poppelaars, M. Subías, H.G.D. Leuvenink, M.R. Daha, S.R. de Córdoba, M.A. Seelen

Thursday 14 march 2019

11:10 - 11:20h at Tropentheater

Categories: Best abstracts, Parallelsessie

Parallel session: Parallelsessie XII – Best abstracts III

Background: The majority of organs used for transplantation are retrieved from brain-dead organ donors. Brain death is characterized by irreversible loss of all brain function resulting in hemodynamic instability, hormonal changes, and immunological activation. Recently, brain death has been shown to cause activation of the complement system. Furthermore, complement activation in brain-dead donors is adversely associated with renal allograft outcome. Modulation of the complement system in the brain-dead donor might therefore form a promising strategy to improve organ quality prior to transplantation. This study investigated the effect of an inhibiting antibody against factor B on brain death-induced renal inflammation and injury.

Methods: Brain death was induced in male Fisher rats by inflating a subdural placed balloon catheter. Anti-factor B (anti-FB) or saline was administered intravenously thirty minutes prior to the induction of brain death (n=8/group). Sham-operated rats served as controls (n=4). After 4 hours of brain death, renal function, injury, inflammation and complement activation was assessed.

Results: Pretreatment with anti-FB resulted in significantly less local and systemic complement activation in brain-dead rats. Moreover, anti-FB treatment improved renal function, reflected by significantly reduced serum creatinine levels in anti-FB treated rats (saline: 60μM, anti-FB: 45μM, sham: 30μM). Furthermore, anti-FB significantly attenuated histological injury as seen by the reduced tubular injury score and lower renal gene expression of kidney injury marker-1 (KIM-1). More specifically, KIM-1 mRNA expression was reduced by more than 75% in anti-FB treated brain-dead rats. In addition, anti-FB treated rats had significantly less influx of neutrophils compared to controls, while no effect was seen on macrophage influx. In accordance, renal gene expression of IL-6, MCP-1 and VCAM-1 were also significantly reduced after anti-FB treatment, while a trend was seen for lower expression of IL-1βand P-selectin.

Conclusions: Altogether, this study shows that donor treatment with anti-FB significantly improved renal function, reduced renal damage and inflammation prior to transplantation. Therefore, inhibition of the alternative pathway, more specifically anti-FB, might be a promising strategy to reduce brain death-induced renal injury in organ donors.