Shorter kidney telomeres are associated with nephrosclerosis by an epigenetic signature.

Kidney telomere length showed a significant inverse association with chronological age.

• β = -0.029, confidence interval = -0.043 to -0.016, P = 0.00003
• Analysis was performed in 200 participants from the Human Kidney Tissue Resource (HKTR)
• Participants had matching information on kidney histology, renal function, blood leucocyte and kidney telomere length, and kidney genome-wide DNA methylation profiles

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 while kidney telomere length dropped simultaneously
• The associations were independent of demographic and clinical confounders
• 200 HKTR participants were included in the primary analysis

Leucocyte telomere length was not related to the extent of age-related changes in kidney function or structure.

• Blood leucocyte telomere length data was available for all 200 HKTR participants
• This contrasts with kidney telomere length, which was significantly associated with both renal structure and function
• The finding suggests tissue-specific relevance of telomere length in kidney ageing

Kidney CpGs, genes, pathways, and chromatin patterns associated with kidney telomere length are partly independent of those associated with chronological age.

• Genome-wide DNA methylation profiles from kidney tissue were analyzed
• The epigenomic associations with kidney telomere length were identified as partly distinct from those driven by chronological age
• An additional 71 HKTR individuals without telomere data were used in validation analyses

An epigenetic clock of kidney telomere length consisting of 57 CpGs showed predictive potential for nephrosclerosis independent of clinical cofounders, chronological age, and epigenetic age.

• The epigenetic clock was composed of 57 CpGs derived from kidney DNA methylation data
• Predictive potential for nephrosclerosis was demonstrated independently of clinical cofounders, chronological age, and epigenetic age
• This suggests that changes in the kidney epigenome may contribute to nephrosclerosis at least in part independently of chronological age