Kidney Week

Abstract: SA-PO151

Effects of Senolytic Agents on Blood- and Urine-Borne Extracellular Vesicles from Senescent Cells in Diabetic Kidney Disease: A Pilot Study

Session Information

• Diabetic Kidney Disease: Clinical - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Hickson, LaTonya J., Mayo Clinic, Rochester, Minnesota, United States

LaTonya J. Hickson,

• Kirkland, James L., Mayo Clinic, Rochester, Minnesota, United States

James L. Kirkland,

• Sanjay, Kumar, Mayo Clinic, Rochester, MN, Rochester, Minnesota, United States

Kumar Sanjay,

• Tchkonia, Tamara, Mayo Clinic, Rochester, Minnesota, United States

Tamara Tchkonia,

• Textor, Stephen C., Mayo Clinic, Rochester, Minnesota, United States

Stephen C. Textor,

• Lerman, Lilach O., Mayo Clinic College of Medicine, Rochester, Minnesota, United States

Lilach O. Lerman,

• Jayachandran, Muthuvel, Mayo Clinic, Rochester, Minnesota, United States

Muthuvel Jayachandran,

Background

Cellular senescence, from DNA damages leading to cell cycle arrest and increased expression of p16, contributes to the pathogenesis of diabetic kidney disease (DKD). Affected blood and kidney cells generate pro-inflammatory cytokines causing kidney injury. Extracellular vesicles (EV) shed by cells represent novel biomarkers of disease and disease activity. We tested the hypothesis that clearance of senescent cell abundance via senolytic agents would decrease markers of senescence, inflammation and kidney injury which could be identified through EV examination.

Methods

DKD subjects were randomized to senolytic drugs (n=5; a single 3-days oral regimen) vs “no treatment” (n=2). EVs were characterized and quantified in platelet-free plasma and cell-free urine sampled at Days 0, 14, and 120 by standardized digital flow cytometer methods using fluorophore conjugated preselected markers specific antibodies: senescence (p16), inflammation (CD45), kidney injury (KIM-1, NGAL). A non-EV (soluble) plasma biomarker of DKD progression, tumor necrosis factor receptor-1 (TNFR-1), was also measured.

Results

Of 7 male subjects, mean age was 71±6 years and eGFR 29±10 mL/min/1.73m². Over 120 days, treated subjects had decreased levels of inflammatory and senescent cell-derived EVs in plasma while untreated subjects showed progressive increases (Figure). Plasma TNFR1 biomarker levels did not differ. Similarly, senescent cell-derived urinary EVs and kidney injury marker (KIM-1 and NGAL) positive urine EVs tended to fall over time in treated while EVs rose in untreated subjects.

Conclusion

These early pilot study findings suggest that senolytic agents may attenuate progression of senescent cell abundance, inflammation, and kidney injury in patients with DKD.

Inflammatory and senescent-cell derived EVs in DKD subjects by senolytic-treated and untreated groups

Funding

• NIDDK Support