Abstract Jeffrey Damman

The Acute Phase Response In Brain Dead Donors
¹J. Damman, ²W. van Oeveren, ³M.A. Seelen, ¹R.J. Ploeg, ¹T.A. Schuurs ¹Surgery Research Laboratory, Department of Surgery, University Medical Center Groningen, ²Department of BioMedical Engineering, University Medical Center Groningen, ³Department of Nephrology, University Medical Center Groningen (Netherlands)
Introduction
Organs derived from brain dead donors have poorer outcomes in survival rates compared to organs derived from living donors. Among other factors, highly elevated levels of interleukin 6 (IL-6) in the serum of brain dead humans and rats are seen. Upon injury and regulated by IL-6, the liver normally produces several acute phase proteins (APPs) which are secreted into the circulation. Recently, microarray and proteomics analyses have indicated increased expression of several APPs also in kidneys of brain dead rats.
Aim of this study was to investigate the acute phase response (APR) in donor livers and kidneys in a rat BD model.

Material and Methods
BD was induced in Fischer rats by inflation of a subdurally placed balloon catheter. The animals were sacrificed 0.5, 1 or 4 hours after BD induction. Sham-operated rats served as controls. APP gene expression for complement C3, fibrinogen, alpha-2-macroglobulin, haptoglobin and alpha-1-acid glycoprotein in liver and kidney was measured by Real Time PCR. APP expression was detected by immunohistochemistry. In addition, complement pathway activity was analysed by a CH50/AP50 assay.

Results
In general, the basal expression levels of genes encoding APPs were higher in the liver than in kidneys. Gene expression or complement C3 was significantly upregulated in the kidney (8 fold, P < 0.01) but not in the liver after 4 hours of BD when compared to sham-operated rats. Fibrinogen (liver 2.8 fold, kidney 54 fold, P < 0.01), alpha-2-macroglobulin (liver 21 fold, kidney 6.7 fold, P < 0.01) and haptoglobin (liver 1.7 fold, kidney 7.2 fold, P < 0.01) were significantly upregulated both in donor livers and kidneys after 4 hours of BD. Alpha-1-acid glycoprotein was significantly upregulated after 4 hours of BD only in the liver (3.6 fold, P < 0.01). Immunohistochemistry confirmed increased expression of fibrinogen and alpha-2-macroglobulin in liver after 4 hours of BD. Classical and alternative complement pathways were activated after 4 hours of BD (P < 0.01).

Conclusion
BD induces an inflammatory response resulting in enhanced expression of several APPs in the liver. Remarkably, also the kidney (locally) contributes to the APR induced by BD. The locally produced APPs might play an important role in the pathogenesis of injury found in renal tissue after BD. Intervention in APP expression during BD might be a promising approach to improve donor organ viability and therefore transplantation outcomes.

Keyword(s): Brain Death, Acute phase response