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.

Public Health Relevance

There are 80,000 patients on a kidney transplant list in the US and the number is growing, while donations remained flat for years. To solve this enduring shortage and prolong lives of waiting list candidates who would otherwise die before receiving a transplant, clinicians are attempting to identify kidneys from older donors that would perform well during and after transplant. Current approaches to judge organ quality are based on chronological age and as a result most kidneys from donors over the age of 65 are discarded. However, while aging is associated with decline in kidney function, some older donor organs perform just as well as donations form younger donors suggesting that age is not a reliable predictor of kidney function. In general, aging is associated with diminished functional capacity and the ability to recover from treatments and surgeries. While precise mechanisms of age-induced decline are unknown, accumulation of cells, referred to as senescent cells is a big factor. Senescent cells are normal cells that our organs are made of but these senescent cells reached the end of their ability to divide and stop. Although they are not dividing and not contributing to tissue regeneration required to heal after surgeries, senescent cells remain in tissues making them 'old'. While senescence occurs as a normal process of aging, external factors can accelerate senescence, smoking and physical inactivity to name a few. Therefore, as we age our 'molecular age'will vary form the molecular age of our peers. These differences are often what people refer to when they describe someone as a young 80- year old or old 80- year old. Given those differences exist, if measured they can help us identify donated kidneys that will perform well. HealthSpan Diagnostics is evaluating a biomarker of aging and senescence, a gene called 16INK4a. In this proposal, we will determine if levels of 16INK4a can predict kidney function after transplant. If successful, we can assess quality of kidneys available for transplant better than the current methods and identify 'molecularly young'organs that can be successfully used in transplants.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Murthy, Mahadev
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Healthspan Diagnostics, LLC
Chapel Hill
United States
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