Age-related changes in DNA methylation affect renal histology and post-transplant fibrosis

During ageing, kidney function decreases due to renal tubular atrophy, interstitial fibrosis, glomerulosclerosis and arteriosclerosis. Recently, changes in DNA methylation were shown to contribute to various ageing processes. However, it is unknown whether such changes also contribute to age-related kidney dysfunction. To assess this, we profiled genome-wide changes in DNA methylation (over 800 000 CpG sites) in 95 renal biopsies obtained prior to kidney transplantation from donors aged 16 to 73 years. Donor age significantly associated with the methylation of 92 778 CpGs (false discovery rate under 0.05), corresponding to 10 285 differentially methylated regions. These regions were most frequently located in genes involved in the Wnt/beta-catenin signaling pathway. Using an independent cohort of 67 biopsies, we autonomously validated these findings. Interestingly, the methylation status of these 92 778 age-related CpGs was associated with glomerulosclerosis (34.4% of CpGs at a false discovery rate under 0.05) and interstitial fibrosis (0.9%) and graft function at one year after transplantation, but not with tubular atrophy and arteriosclerosis. No association was observed with any of these pathologies at the time of transplantation (0% at a false discovery rate under 0.05). Thus, age-associated changes in DNA methylation at the time of transplantation predict future injury of transplanted kidneys. Specifically, our epigenome-wide association study demonstrates that epigenetic renal ageing is implicated in progressive fibrosis in both the glomerulus and the interstitium.