Kidney Week

Abstract: SA-PO136

Type 1 Interferon Is Associated with Kidney Dysfunction in Type 2 Diabetes

Session Information

• Diabetic and Obesity Induced Kidney Disease - Experimental
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Diabetes

• 503 Diabetes Mellitus and Obesity: Translational

Authors

• Conway, James, MedImmune, Gaithersburg, Maryland, United States

James Conway,

• Eichinger, Felix H., University of Michigan, Ann Arbor, Michigan, United States

Felix H. Eichinger,

• Godfrey, Brad A., University of Michigan, Ann Arbor, Michigan, United States

Brad A. Godfrey,

• Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States

Viji Nair,

• Reznichenko, Anna, AstraZeneca, Molndal, Sweden

Anna Reznichenko,

• Slidel, Tim, MedImmune, Gaithersburg, Maryland, United States

Tim Slidel,

• Cohen, Clemens D., Klinikum Munchen, Munchen, Germany

Clemens D. Cohen,

• Higgs, Brandon W, MedImmune, Gaithersburg, Maryland, United States

Brandon W Higgs,

• Moreno Quinn, Carol Patricia, MedImmune, Gaithersburg, Maryland, United States

Carol Patricia Moreno Quinn,

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler,

Background

Type I interferon (IFN) is linked to the pathogenesis of autoimmune and inflammatory diseases known as interferonopathies. A portion of patients show aberrant type I IFN signaling, which can be measured by a gene expression signature composed of IFN-inducible genes (IFNGS). Chronic kidney disease (CKD) is characterized by chronic inflammation and interstitial fibrosis, yet little is known regarding type I IFN signaling in type 2 diabetics (T2D) with diabetic nephropathy (DN). Here we evaluated a type I IFNGS in these patients and identified an association with immune response and kidney dysfunction.

Methods

Tissue from human glomeruli (DN, n₁=12), tubulointerstitium from two independent patient sets (DN; n₁=17, n₂=31), and living donors (n₁=46) were obtained from the European Renal cDNA Bank and profiled by Affymetrix array. Gene-set variation analysis (GSVA) quantified a 21-gene type I IFNGS identified by Yao Y et al (PMID: 20948567) and other function-specific signatures. Patients were assigned to type I IFN-low or IFN-high groups based on median GSVA score. Gene signatures for which IFN-high patients differed from IFN-low were identified. P-values were adjusted for sex and age. A Fisher’s combined probability was applied to summarize both studies (p_chi).

Results

Type I IFNGS was elevated in the tubulointerstitium (p_chi=1.3x10^-4), but not the glomeruli of DN patients compared to living donors. IFN-high patients associated with lower glomerular filtration rate (GFR) compared to IFN-low patients (p_chi=0.02). Although a high collagen signature associated with decreased GFR (p_chi=0.001), it did not correlate with type I IFNGS, suggesting an independent mechanism. IFN-high patients displayed increased T cell activation (p_chi=6.6x10^-6), TLR4 signaling (p_chi=5.7x10^-5) and innate immune response (p_chi=1.9x10^-5).

Conclusion

A significant decrease in GFR was observed in T2D patients with elevated Type I IFN signaling, which was also linked to increases in immune response signatures. This link between type I IFN signaling and kidney dysfunction may inform on patient selection for therapies targeting immune response pathways. This hypothesis should be confirmed in an independent study.

Funding

• Commercial Support –