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Abstract: TH-PO547

Differentiating Lupus Nephritis Classes Using Peripheral Blood DNA Methylation

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Bakhoum, Christine Y., Yale University, New Haven, Connecticut, United States
  • Faulkner, Sophia, Yale University, New Haven, Connecticut, United States
  • Ix, Joachim H., University of California San Diego, La Jolla, California, United States
  • Moledina, Dennis G., Yale University, New Haven, Connecticut, United States
  • Bakhoum, Mathieu F., Yale University, New Haven, Connecticut, United States
Background

Approximately 60% of patients with systemic lupus erythematosus (SLE) develop nephritis. Histologically-determined disease classification provides clinically actionable information including administration of kidney-specific immunosuppression. Given the pivotal role of autoimmunity in SLE, we hypothesized that DNA methylation patterns of immune cells could distinguish between the different lupus nephritis classes.

Methods

We identified 25 participants from the Yale Kidney Biobank with biopsy-confirmed lupus nephritis. DNA was extracted from blood buffy coat. DNA methylation was analyzed using Illumina MethylationEPIC V2.0, surveying > 935,000 CpG loci. β-values (percent methylation) were derived using the R Sesame package. KEGG pathway enrichment and differential methylation analyses were performed, comparing class II participants to those with more advanced nephritis (III, IV, V).

Results

We identified 3 participants with class II disease, and 22 participants with classes III, IV, or V disease. Enrichment analysis identified differential methylation in Rap1 signaling, focal adhesion, and MAPK signaling pathways between the two groups (q-values < 0.001). Participants with advanced lupus nephritis exhibited ERK hypermethylation and RAP1 hypomethylation compared to those with class II. We identified 5 CpG loci that were differentially methylated between the two groups (adjusted p-values < 0.05). Unbiased hierarchical clustering based on the top 25 differentially methylated loci revealed that those with class II nephritis have distinct methylation profiles as compared to those with more advanced nephritis (Figure 1).

Conclusion

Our findings suggest that DNA methylation patterns in immune cells may distinguish between lupus nephritis classes, potentially guiding the decision to conduct a kidney biopsy. The observed methylation differences in ERK and RAP1 pathways, which have been implicated in SLE pathophysiology, among advanced lupus nephritis classes may provide valuable insights into disease pathogenesis.

Funding

  • NIDDK Support