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Abstract: TH-OR060

Inflammasome Priming and Activation Glomerular Gene Expression Scores Associate with Poor Outcome in Nephrotic Syndrome

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Hodgin, Jeffrey B., University of Michigan, Ann Arbor, Michigan, United States
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
  • Luo, Jinghui, University of Michigan, Ann Arbor, Michigan, United States
  • Yang, Yingbao, University of Michigan, Ann Arbor, Michigan, United States
  • Hartman, John R., University of Michigan, Ann Arbor, Michigan, United States
Background

Recent studies have shown that the inflammasome, a cytoplasmic protein complex that processes interleukins IL-1beta and IL-18, is functional in resident cells of the glomerulus, such as the podocyte. Before activation of the NLRP3 inflammasome, a priming step occurs consisting of upregulation of NLRP3, pro-IL-1beta, and other genes. Here we interrogate glomerular mRNA of patients with nephrotic syndrome to test our hypothesis that gene expression profiles of inflammasome priming and activation (IL-1beta-regulated genes) correlate with eGFR and proteinuria at time of biopsy and outcome measures.

Methods

Using the Nephrotic Syndrome Study Cohort (NEPTUNE), a prospective longitudinal cohort study enrolling patients at time of biopsy, we correlated glomerular gene expression Z-scores of inflammasome priming (5 genes) and activation (100 genes) with clinical characteristics at enrollment (Pearson for eGFR; Spearman for UPCR). Linear GEE models of eGFR and urine protein to creatinine ratio (UPCR) were fit to associate baseline inflammasome Z-scores with disease status over time.

Results

97 patients with NS (50 FSGS, 47 MCD) were available for analysis. At time of biopsy, both the priming (r=-0.33, p<0.001) and activation (r=-0.45, p<0.001) Z-scores negatively correlated with eGFR. Priming (r=0.23, p=0.02) and activation (r=0.28, p=0.01) Z-scores positively correlated with UPCR as well. Over a follow-up time of 45 months, baseline inflammasome priming and activation Z-scores were associated with lower eGFR over time (-12.6 mg/dL, p=0.028 and -55.4 mg/dL, p<0.001 respectively) in unadjusted models. After adjusting for baseline eGFR and UPCR, diagnosis, age, black race, immunosuppression and time, only the activation Z-score association was significant (-17.4 mg/dL, p=0.05). The inflammasome priming and activation Z-scores did not associate with UPCR over time in adjusted models.

Conclusion

Inflammasome priming and activation Z-scores based on glomerular gene expression profiles significantly correlate with eGFR and UPCR at time of biopsy and associate with lower eGFR, but not UPCR, over time. This approach offers the opportunity to discover novel molecular tests to predict outcome in nephrotic syndrome and highlight pathways for therapeutic intervention.

Funding

  • NIDDK Support