Heylen L, et al. - Given that oxygen shortage in tumors reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression, researchers investigated if ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury. In this study, a novel epigenetic basis for ischemia-induced chronic allograft injury with biomarker potential was highlighted.

Methods

• Genome-wide DNA methylation was profiled in three cohorts of brain-dead donor kidney allograft biopsy specimens:
• A longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n=13), after implantation and reperfusion (postischemia; n=13), and at 3 or 12 months after transplant (n=5 each);
• A cross-sectional cohort with preimplantation biopsy specimens (n=82); and
• A cross-sectional cohort with postreperfusion biopsy specimens (n=46).

Results

• Analysis of the paired preischemia and postischemia specimens indicated that in all allografts, methylation increased drastically on ischemia.
• Loss of 5-hydroxymethylcytosine, the product of TET activity, caused hypermethylation, and it was stable 1 year after transplant.
• CpG hypermethylation was noted to have direct correlation with ischemia time in the preimplantation cohort and for some CpGs, increased 2.6% per additional hour of ischemia.
• The expression of genes involved in suppressing kidney injury and fibrosis was preferentially affected and reduced in association with hypermethylation.
• Moreover, CpG hypermethylation in preimplantation specimens predicted chronic injury, particularly fibrosis and glomerulosclerosis, 1 year after transplant.
• In the independent postreperfusion cohort, in which hypermethylation also predicted reduced allograft function 1 year after transplant, outperforming established clinical variables, the finding was validated.