Effects of donor age and cell senescence on kidney allograft survival.
The biological processes responsible for somatic cell senescence contribute to organ aging and progression of chronic diseases, and this may contribute to kidney transplant outcomes. We examined the effect of pre-existing donor aging on the performance of kidney transplants, comparing mouse kidney isografts and allografts from old versus young donors. Before transplantation, old kidneys were histologically normal, but displayed an increased expression of senescence marker p16(INK4a). Old allografts at day 7 showed a more rapid emergence of epithelial changes and a further increase in the expression of p16(INK4a). Similar but much milder changes occurred in old isografts. These changes were absent in young allografts at day 7, but emerged by day 21. The expression of p16(INK4a) remained low in young kidney allografts at day 7, but increased with severe rejection at day 21. Isografts from young donors showed no epithelial changes and no increase in p16(INK4a). The measurements of the alloimmune response-infiltrate, cytology, expression of perforin, granzyme B, IFN-gamma and MHC-were not increased in old allografts. Thus, old donor kidneys display abnormal parenchymal susceptibility to transplant stresses and enhanced induction of senescence marker p16(INK4a), but were not more immunogenic. These data are compatible with a key role of somatic cell senescence mechanisms in kidney transplant outcomes by contributing to donor aging, being accelerated by transplant stresses, and imposing limits on the capacity of the tissue to proliferate.
Melk
A
A
Division of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany. melk.anette@mh-hannover.de
Schmidt
B M W
BM
Braun
H
H
Vongwiwatana
A
A
Urmson
J
J
Zhu
L-F
LF
Rayner
D
D
Halloran
P F
PF
D000375:Aging / Q000276:immunology*; D000818:Animals; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D006085:Graft Survival; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger