A biomarker of aging as a predictor of kidney transplant function

摘要

ABSTRACT The number of kidney transplant candidates on the waiting list continues to increase each year, while the number of kidney donations remains stagnant. The enduring donor shortage compels clinicians to use kidneys from marginal donors, referred to as expanded criteria donors (ECD). ECD kidneys, obtained primarily from older donors, have a higher risk of delayed graft function and graft loss. While ECD kidneys are thought to carry increased risks, retrospective studies suggest that the existing system to evaluate kidney quality has low predictive power resulting in a large variability in ECD graft functions and the associated patient survival. Identification of new factors that can assess ECD graft quality and predict graft function, would allow to expand donor pool and to minimize organ discard without compromising patient outcomes. A decline in the replicative capacity of certain self-renewing cells and accumulation of senescent cells appears to broadly contribute to tissue aging. Senescent cells lack replicative capacity and, therefore, cannot contribute to tissue repair and homeostasis. This defect in tissue regenerative potential is further accelerated by stresses associated with kidney transplant surgeries, leading to an earlier graft failure. Moreover, senescent cells remain metabolically active and secrete a myriad of pro-inflammatory cytokines, contributing to tissue inflammation. Therefore, measuring the accumulation of senescent cells in vivo has been suggested to provide a means of measuring 'molecular aging'. In 2004, the Sharpless lab proposed using expression of p16INK4a, a key effector of cellular senescence, as an in vivo marker of molecular aging in humans. Intellectual property around this marker was issued in 2012 and is the core technology of HealthSpan Diagnostics. The p16INK4a marker, measured in blood, has been evaluated in a number of clinical scenarios in >1,000 human patients and appears to offer several significant technical advantages over other approaches to measuring senescence in vivo. The p16INK4a diagnostic could be especially useful in kidney graft assessment as p16INK4a levels in the kidney at the time of organ harvest are the best known predictor of renal allograft function 6 months to 1 year after surgery. The finding that renal p16INK4a expression is a better predictor of graft function than donor age further supports our theory that p16INK4a diagnostic could greatly improve graft assessment and allow older patients to donate kidneys for transplantation, markedly expanding the donor pool and decreasing organ discard. In this proposal, we will determine if p16INK4a blood test correlates with graft function similarly to kidney p16INK4a expression. The availability of inexpensive, easy to use blood test would increase chances of adoption into the clinic. Completion of this Phase I proposal will allow us to seek Phase II funding to conduct large scale clinical trials and further develop our p16INK4a assay for commercialization.