Effects of Donor Age and Cell Senescence on Kidney Allograft Survival

Abstract

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 p16INK4a 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 p16INK4a . The measurements of the alloimmune response-infiltrate, cytology, expression of perforin, granzyme B, IFN-c 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 p16INK4a , 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.

Cellular Senescence Limits Regenerative Capacity and Allograft Survival

“…Human transplant biopsy studies have shown that periand post-transplantation stresses (such as ischemia-reperfusion injury, 24,28,29 acute rejection, 30 or hypertension 31 ) lead to an increased p16…”

Th-17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell–Mediated Rejection

“…In addition, the kidney allograft from old mice is highly susceptible to transplant stress (20). Moreover, both the function and integrity of epithelial barriers decrease with age (21).…”

Biomarkers to identify and isolate senescent cells

“…A reliable readout that identifies senescent cells would facilitate high-throughput screens as well as allow quantification of aging in various animal models. Most importantly, therapeutic techniques would benefit from robust markers to enable removal of senescent cells from tissues (such as blood filtering, Figure 3), stem cell preparations from aged autologous donors (Melk et al, 2009) and identification of replicative exhaustion in stem cell expansions. One example of how such markers could be used is a strategy using selectively-lytic viruses, which are already used in oncology (Elsedawy and Russell, 2013).…”