Complement Mediated Renal Inflammation Induced by Donor Brain Death: Role of Renal C5a-C5aR Interaction

Abstract

Kidneys retrieved from brain-dead donors have impaired allograft function after transplantation compared to kidneys from living donors. Donor brain death (BD) triggers inflammatory responses, including both systemic and local complement activation. The mechanism by which systemic activated complement contributes to allograft injury remains to be elucidated. The aim of this study was to investigate systemic C5a release after BD in human donors and direct effects of C5a on human renal tissue. C5a levels were measured in plasma from living and brain-dead donors. Renal C5aR gene and protein expression in living and braindead donors was investigated in renal pretransplantation biopsies. The direct effect of C5a on human renal tissue was investigated by stimulating human kidney slices with C5a using a newly developed precisioncut method. Elevated C5a levels were found in plasma from brain-dead donors in concert with induced C5aR expression in donor kidney biopsies. Exposure of precision-cut human kidney slices to C5a induced gene expression of pro-inflammatory cytokines IL-1 beta, IL-6 and IL-8. In conclusion, these findings suggest that systemic generation of C5a mediates renal inflammation in brain-dead donor grafts via tubular C5a-C5aR interaction. This study also introduces a novel in vitro technique to analyze renal cells in their biological environment.

Complement as a multifaceted modulator of kidney transplant injury

“…Whole genome expression profiling of 53 human renal allograft protocol biopsies obtained at implantation confirmed significantly higher expression levels of complement genes in deceased donor kidneys (29). Extending these findings prior to surgical removal of the donor organ, van Werkhoven et al found that brain death initiates systemic complement activation, upregulates C5aR expression in renal tubular cells (30), and is associated with induction of intrarenal inflammatory cytokines. The authors hypothesized that complement activation that occurs in the donor accounts in part for the poorer outcomes of grafts harvested from deceased compared with living donors.…”

The Critical Role of Innate Immunity in Kidney Transplantation

“…In the brain-deceased donor, the intracranial hypertension triggers a massive release of cytokines and growth factors with consequent activation of cell-adhesion molecules and leukocyte infiltration in the kidney [34]. Another consequence of brain death is local upregulation and the activation of complement that can contribute to create an inflammatory environment [35]. The manipulation of the kidney during removal may also produce mechanical injury.…”

The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis

“…In a similar study, Damman et al reported that high levels of the terminal MAC in the plasma of brain-dead donors was strongly associated with acute rejection within the first year post-transplantation [57]. Additionally, activation of the C5a-C5aR axis in kidney donors plays an important role in the amplification of the inflammatory response to brain death [58]. …”

“…As described earlier, anaphylatoxin C5a and signaling through the C5aR play pivotal roles in mediating IRI and the dysregulated inflammatory response in the brain-dead donor [38,58]. Furthermore, the use of C5a receptor antagonists has been effective in attenuating the extent of IRI in small animal models and limiting fibrogenic responses after acute kidney injury [39,78,104].…”