Potential of repairing ischemically damaged kidneys ex vivo.
Therapies that would accelerate recovery from ischemic injury could positively impact the number of kidneys procured from non-heart-beating donors. An acellular warm (32 degrees C) perfusion was used to deliver growth factors to canine kidneys damaged by 2 hours of warm ischemia. Fibroblast growth factors 1 and 2 were selected for activation of the tyrosine kinases because of their known receptor-specific binding in the kidney, metabolic regulation, and mitogenic effect. During 24 hours of ex vivo perfusion at near-normothermia, oxidative metabolism was sufficiently restored to the ischemically damaged tissue to support upregulation of cellular processes dependent on new synthesis. The junctional integrity protein, ZO-1 was used to determine recovery of cytoskeletal integrity. The upregulation of proliferating cell nuclear antigen was used as a marker for recovery of synthetic functions. This modulation of both injury and repair proteins in the damaged kidneys was dependent on new synthesis. The observed modulation resulting in normalization of the cytoskeletal integrity correlated with outcomes in that when the "repaired" kidneys were reimplanted, they provided life-sustaining function. In contrast, when warm ischemically damaged control kidneys without treatment, with subsequent hypothermic perfusion or warm perfused in the absence of growth factors, were reimplanted the result was nonviability. The results of this study suggest that the administration of growth factors during 24 hours of near-normothermic, acellular perfusion, in the absence of concordant inflammation, triggers pathways for new synthesis leading to cellular recovery rather than resulting in cell death.
Brasile
L
L
University Hospital Utrecht, Utrecht, The Netherlands.
Stubenitsky
B
B
Haisch
C E
CE
Kon
M
M
Kootstra
G
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D004285:Dogs; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation / Q000473:pathology; D008565:Membrane Proteins / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D015427:Reperfusion Injury / Q000473:pathology / Q000628:therapy*; D062826:Zonula Occludens-1 Protein
D015415:Biomarkers; D008565:Membrane Proteins; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D062826:Zonula Occludens-1 Protein; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1