Senescent Cells in Kidney Transplantation: Hidden Drivers of Graft Aging, Inflammation, and Long-Term Dysfunction

Abstract

Although kidney transplantation is the best option for ESRD, many issues have been identified that can affect long-term success, such as progressive graft aging and chronic allograft dysfunction. Persistent inflammation, decreased tissue repair and fibrotic remodeling have become clear mechanisms linking transplantation-associated injury to cellular senescence. Renal tissue senescent cells are generated via donor aging, ischemia–reperfusion injury, oxidative and mitochondrial stress, alloimmune response, and treatment-related insult. These cells, although permanently arrested in the cell cycle, continue to be metabolically active, and exhibit a senescence-associated secretory phenotype that can lead to propagation of inflammation, modification of immune-cell function, induce secondary senescence and promote extracellular matrix remodeling. In this review, the molecular mechanisms and transplant-specific mechanisms of renal senescence, its relationship to immune dysregulation, fibrosis, progressive graft dysfunction, and what methods are available to detect the presence of senescence in kidney allografts are discussed. It also reviews the predictive capacity of senescence markers and novel senolytic and senomorphic therapies. The ability to comprehend and therapeutically modulate graft senescence may offer novel means to maintain graft function and enhance long-term transplant survival.