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Kidney Week

Abstract: TH-PO871

Urinary Kidney-Specific DNA Methylation Signature Correlates with Renal Function Decline in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Marumo, Takeshi, The University of Tokyo, Tokyo, Japan
  • Hoshino, Junichi, Toranomon Hospital, Tokyo, Japan
  • Kawarazaki, Wakako, The University of Tokyo, Tokyo, Japan
  • Nishimoto, Mitsuhiro, The University of Tokyo, Tokyo, Japan
  • Ayuzawa, Nobuhiro, The University of Tokyo, Tokyo, Japan
  • Hirohama, Daigoro, The University of Tokyo, Tokyo, Japan
  • Yamanouchi, Masayuki, Toranomon Hospital, Tokyo, Japan
  • Ubara, Yoshifumi, Toranomon Hospital, Tokyo, Japan
  • Sato, Atsuhisa, International University of Health and Welfare School of Medicine, Tokyo, Japan
  • Shimosawa, Tatsuo, International University of Health and Welfare School of Medicine, Tokyo, Japan
  • Fujita, Toshiro, The University of Tokyo, Tokyo, Japan
Background

Renal tubular injury contributes to the silent decline in kidney function in patients with diabetes. Cell type-specific DNA methylation patterns have been used to calculate proportions of particular cell types. In this study, we developed a method to detect renal tubular injury in diabetic patients based on tubule-specific DNA methylation patterns in urine sediment.

Methods

To identify gene loci exhibiting proximal tubule-specific DNA methylation in the human urinary system, we used two approaches: genome-wide DNA methylation analysis using the Infinium MethylationEPIC BeadChip Kit and extrapolation from mouse CpG data obtained in our previous study. We next determined the methylation levels of proximal tubule-specific loci in urine sediment of diabetic patients and analyzed correlation with clinical variables.

Results

Genomic loci in gene A and G6PC were selectively unmethylated in proximal tubular cells compared to other parts of micro-dissected tissues obtained from normal kidney and bladder epithelium. The methylation levels of gene A and G6PC in urine sediment, deemed to reflect the proportion of exfoliated proximal tubular cells, correlated well with each other. Multivariate analysis with classic tubular injury markers and known risk factors of renal insufficiency in diabetic patients revealed that lower eGFR and lower methylation levels of gene A were independently associated with larger annual decline in estimated glomerular filtration rate (eGFR). Moreover, addition of urinary gene A methylation to a model containing eGFR and urinary albumin/Cr improved discrimination of diabetic patients with faster eGFR decline, which were defined as those losing eGFR at a rate of more than the 25th percentile of annual eGFR decline, with c-statistics from 0.698 to 0.756 and a significant improvement in reclassification with category-free net reclassification improvement.

Conclusion

This study demonstrates that diabetic patients with continual loss in kidney function may be stratified by a specific DNA methylation signature and provides the approach for using kidney cells in the urine for the non-invasive diagnosis of kidney diseases through epigenetic urinalysis.

Funding

  • Government Support - Non-U.S.