Early renal ischemia-reperfusion injury in humans is dominated by IL-6 release from the allograft.
The pathophysiology of ischemia/reperfusion (I/R) injury is complex, and current knowledge of I/R injury in humans is incomplete. In the present study, human living-donor kidney transplantation was used as a highly reproducible model to systematically study various processes potentially involved in early I/R injury. Unique, direct measurements of arteriovenous concentration differences over the kidney revealed massive release of interleukin (IL)-6 in the first 30 minutes of graft reperfusion and a modest release of IL-8. Among the assessed markers of oxidative and nitrosative stress, only 15(S)-8-iso-PGF(2alpha) was released. When assessing cell activation, release of prothrombin factor 1 + 2 indicated thrombocyte activation, whereas there was no release of markers for endothelial activation or neutrophil activation. Common complement activation complex sC5b-9 was not released into the bloodstream, but was released into urine rapidly after reperfusion. To investigate whether IL-6 plays a modulating role in I/R injury, a mouse experiment of renal I/R injury was performed. Neutralizing anti-IL-6 antibody treatment considerably worsened kidney function. In conclusion, this study shows that renal I/R in humans is dominated by local IL-6 release. Neutralization of IL-6 in mice resulted in a significant aggravation of renal I/R injury.
de Vries
D K
DK
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Lindeman
J H N
JH
Tsikas
D
D
de Heer
E
E
Roos
A
A
de Fijter
J W
JW
Baranski
A G
AG
van Pelt
J
J
Schaapherder
A F M
AF
D000328:Adult; D000818:Animals; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000293:injuries*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009500:Neutralization Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous; D000093242:Interleukin-6 Inhibitors
D015938:Complement Membrane Attack Complex; D015850:Interleukin-6; D012333:RNA, Messenger; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human