Blood-Derived DNA Methylation Biomarkers Predict Diabetic Kidney Disease and Map to Epigenomic Remodeling in Renal Cells

We undertook this study because albuminuria and estimated glomerular filtration rate often identify diabetic kidney disease risk only after substantial kidney injury in type 1 diabetes. We asked whether blood DNA methylation patterns could predict future DKD progression and improve clinical risk stratification. Genome-wide leukocyte methylation sequencing identified hypomethylated regions and a four-locus methylation risk score (SLC4A4, FSTL4, ICA1, and PTK2) that improved prediction beyond clinical risk models and was validated in 330 participants. Podocyte multiomics showed concordant hyperglycemia-induced hypomethylation and gene activation, supporting the biological plausibility of the blood-derived risk score.