Shorter kidney telomeres are associated with nephrosclerosis by an epigenetic signature

Ageing leads to a progressive loss in structural integrity and a functional decline of human organs, alongside telomere attrition and alterations in DNA methylation patterns. Their relationships in the human kidney in the context of ageing remain elusive.

We analysed 200 participants from the human kidney tissue resource (HKTR) with matching information on kidney histology, renal function, blood leucocyte and kidney telomere length, as well as kidney genome-wide DNA methylation profiles. Additional 71 HKTR individuals without telomere data were used in validation analyses. Kidney telomere length showed a significant inverse association with age (β = -0.029, confidence interval = -0.043 to -0.016, P = 0.00003). Shorter kidney telomeres were strongly associated with both renal structure and function, independent of demographic and clinical confounders. Nephrosclerosis score showed a gradual increase with age categories, whilst kidney telomere length dropped simultaneously. Leucocyte telomere length was not related to the extent of age-related changes in kidney function or structure. Kidney DNA methylation analysis revealed that kidney CpGs, genes, pathways, and chromatin patterns associated with kidney telomere length are partly independent of these associated with chronological age. Consisted of 57 CpGs, epigenetic clock of kidney telomere length showed a predictive potential for nephrosclerosis, independent of clinical cofounders, chronological, and epigenetic age.

Our study revealed that gradual age-related structural involution of human kidney and a decline in its filtration capacity are accompanied by shortening of telomeres in renal cells and that changes in the kidney epigenome (i.e. DNA methylation) may contribute to nephrosclerosis (at least in part) independently of chronological age.