Effect of brain death on gene expression and tissue activation in human donor kidneys.
BACKGROUND
After kidney transplantation, decreased graft survival is seen in grafts from brain dead (BD) donors compared with living donors. This might result partly from a progressive nonspecific inflammation in the graft. In this study, we focused on the effects of BD on inflammatory response (adhesion molecules, leukocyte invasion, gene expression) and stress-related heat shock proteins in the human kidney. Research outcomes and clinical donor parameters were then linked to outcome data after transplantation.


METHODS
Kidney biopsy specimens and serum were obtained during organ retrieval from BD and living organ donor controls. Immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction were performed on the biopsy specimens. Clinical and laboratory parameters from BD donors were recorded and connected to outcome data of the recipients of the kidneys studied.


RESULTS
After brain death, immunohistochemistry showed an increase of E-selectin (P<0.01) and interstitial leukocyte invasion (P<0.05) compared with controls. Also, reverse transcriptase-polymerase chain reaction showed a threefold increased heme oxygenase-1 (P<0.05) and Hsp70 (P<0.01) gene expression after BD. Levels of monocyte chemotactic protein-1 and transforming growth factor-beta were twice as high after brain death but did not reach significance. Transplantation outcome was influenced by several donor variables: positively most notably by donor treatment with desmopressin and negatively by high serum urea levels during brain death and by high intercellular adhesion molecule and vascular cell adhesion molecule expression in the kidney. Heme oxygenase-1 proved to have a protective function, but only in kidneys from living donors.


CONCLUSIONS
The presence of interstitial leukocytes and the early adhesion molecule E-selectin in BD donor kidneys indicates an early-phase inflammatory process during organ retrieval. Elevated levels of monocyte chemotactic protein-1 and transforming growth factor-beta suggest a role for monocytes/macrophages in this phase. We suggest that BD causes a stress-related response against which protective heat shock proteins are formed in the future graft. This stress response may be too severe to be fully counteracted by elevated heat shock proteins. Which systemic and/or local factors trigger brain death-related graft injury is currently under investigation.
Surgery Research Laboratory, University Hospital Groningen, Groningen, The Netherlands. w.n.nijboer@chir.azg.nl
Willemijn N
WN
Nijboer
Theo A
TA
Schuurs
Joost A B
JA
van der Hoeven
Susan
S
Fekken
Janneke
J
Wiersema-Buist
Henri G D
HG
Leuvenink
Sijbrand
S
Hofker
Jaap J
JJ
Homan van der Heide
Willem J
WJ
van Son
Rutger J
RJ
Ploeg
D000328:Adult; D000368:Aged; D001926:Brain Death / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D018932:Chemokine CCL2; D018840:HSP70 Heat-Shock Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1