Telomere Length of Recipients and Living Kidney Donors and Chronic Graft Dysfunction in Kidney Transplants

Autor: Arthur J. Matas, Pamala A. Jacobson, David P. Schladt, Bharat Thyagarajan, Ajay K. Israni, Weihua Guan, Jennifer Becker, Winston Wildebush, William S. Oetting
Rok vydání: 2014
Předmět:
Zdroj: Transplantation. 97:325-329
ISSN: 0041-1337
Popis: The identification of biomarkers that can measure the biological age of an allograft could aid in optimizing the allocation of the allograft to specific recipients to maximize the life of each transplanted organ. Older kidneys have been shown to be more susceptible to chronic graft dysfunction (CGD) and graft failure (GF) when compared with younger kidneys after transplantation (1, 2). Older kidneys have a faster progression of tubular atrophy and tubular loss when compared younger kidneys (3) as well as having an increased incidence of delayed graft function (4), and this is felt to be an intrinsic feature of the older donated kidney. This has become an important issue, as older kidney allografts are increasingly being used in transplantation along with the poorer outcomes associated with these older kidneys, especially when transplanted into young recipients (5). Cellular replicative senescence, due to aging, is thought to play an important role in loss of graft function and this senescence may be linked to telomere length (TL) (6). Additionally, it has been suggested that younger recipients have a higher risk of acute rejection (AR) events than older recipients (7, 8), although these results are controversial (9). This reduced risk for AR in older recipients may be due to an older immune system that is less responsive, resulting in a lower risk of AR. Progressively shorter TL in immune cells due to aging in recipients may be a reason reduced immune response potentially making TL a better predictor of AR than chronological age. The aging of tissues and organs is a controlled biological process. Somatic cells have been shown to have a limited replicative capacity (10) and this is thought to be associated, in part, with the reduction in TL as chromosome replication occurs with each cell division (11). Telomeres consist of multiple copies (100s–1000s) of short (6 nucleotide) repeats at the end of all chromosomes, playing a protective role against chromosome deterioration. With every round of DNA replication in somatic cells, TL is reduced and this progressive shorting is thought to have a fundamental role in cell senescence. TL is thought to reflect the remaining replicative potential of a population of cells (10). TL is heritable and shortens throughout life, making TL a potential marker for the “biological age” of a tissue (12). The analysis of TL as a predictive marker of transplant outcome has been previously reported. It has been shown that TL may be a marker of treatment-related mortality in hematopoietic stem cell transplantation (13). A study by Bansal et al. (14) found that reduced TL was associated with reduced kidney function, but the significance was lost after adjustment for age. A modest significance associating TL and variation in serum creatinine levels in transplanted kidneys has also been reported (15). Using senescence-associated β-galactosidase (SA-β-Gal) enzyme as a marker, donor age appeared to be the major determinant factor in replicative senescence, as seen in higher expression of SA-β-Gal in donor kidneys with chronic allograft nephropathy (16). It was found that TL was significantly shorter in SA-β-Gal–expressing cells. Additionally, ischemia-reperfusion during transplantation of primate kidneys was associated with a more rapid decrease in TL (17). It has also been shown that TL shortens more rapidly in transplanted human liver allografts than in untransplanted livers resulting in a shorter than expected life for liver allografts, as would be predicted by the chronological age of the donor (18). Because of this progressive decrease in the TL, individuals who obtain a kidney from a donor with shorter than normal telomeres may be at greater risk for reduced graft survival and more susceptible to age associated disease, including allograft dysfunction. The DeKAF Genomics study contains a large number of recipient/living donor pairs along with clinical outcomes (19). We hypothesized that the biological age of the allograft, as estimated using TL from peripheral blood DNA, would be more reflective of risk for transplant outcomes than the chronological age of the allograft. We investigated if TL, in either the recipient or the donor, is associated with kidney allograft outcome.
Databáze: OpenAIRE
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