Kidney Week

Abstract: FR-PO449

Cathepsin D: A Potential Biomarker for Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Clinical - I
  October 26, 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

• Drel, Viktor, University of Texas Health San Antonio, San Antonio, Texas, United States

Viktor Drel,

• Vaisar, Tomas, University of Washington, Seattle, Washington, United States

Tomas Vaisar,

• Kim, Jiwan John, University of Texas Health San Antonio, San Antonio, Texas, United States

Jiwan John Kim,

• Valo, Erkka A., Folkhälsan Research Center, Helsinki, Finland

Erkka A. Valo,

• Zhang, Jing, University of California San Diego, La Jolla, California, United States

Jing Zhang,

• Ahluwalia, Tarunveer S., Steno Diabetes Center Copenhagen, Gentofte, Denmark

Tarunveer S. Ahluwalia,

• Snell-Bergeon, Janet, University of Colorado Denver , Aurora, Colorado, United States

Janet Snell-Bergeon,

• Rossing, Peter, Steno Diabetes Center Copenhagen, Gentofte, Denmark

Peter Rossing,

• Groop, Per-Henrik, Folkhälsan Research Center, Helsinki, Finland

Per-Henrik Groop,

• Natarajan, Loki, University of California San Diego, La Jolla, California, United States

Loki Natarajan,

• Hoofnagle, Andrew N., University of Washington, Seattle, Washington, United States

Andrew N. Hoofnagle,

• de Boer, Ian H., University of Washington, Seattle, Washington, United States

Ian H. de Boer,

• Darshi, Manjula, University of Texas Health San Antonio, San Antonio, Texas, United States

Manjula Darshi,

• Sharma, Kumar, University of Texas Health San Antonio, San Antonio, Texas, United States

Kumar Sharma,

Background

Cathepsins are lysosomal proteases that play important roles in a wide range of physiological and pathological processes. Recent studies have suggested that dysregulation of cathepsin D (Cat D) can lead to development of fibrosis and induce apoptosis in the podocytes and tubular cells in acute kidney injury murine models. In the current study we analyzed if changes in Cat D are associated with the development and progression of diabetic kidney disease (DKD) in type I diabetic mouse models and in humans.

Methods

Cat D protein levels in urine were measured by liquid-chromatography mass spectroscopy in four diverse cohorts (CACTI, EDC, Finn-Diane, and Steno) with long-standing type I diabetes and normal kidney function (eGFR≥60ml/min/1.73m²). Subjects were classified into slow decliners/controls with eGFR decline ≤1ml/min/1.73m²/yr or rapid progressors/cases with eGFR decline of ≥3ml/min/1.73m²/yr. Cat D activity in urine samples of patients with established kidney disease (eGFR<40ml/min/1.73m²) and in type 1 DKD mouse model (Akita) was measured biochemically. Immunohistochemistry in mouse kidney tissues were performed with FFPE embedded kidney sections.

Results

Baseline mean eGFR and median ACR in controls (n=351) and cases (n=270) were 91.97 (sd 18.68) and 9.44 (IQR 30), and 98.37 (sd 25.44) and 33.49 (IQR 283.01), respectively. Cat D protein levels in urine were significantly elevated in cases as compared to controls [mean 1.18 au (1.07-1.3) in controls vs 1.56 au (1.37 to 1.57) in cases, p<001, FDR q=0.01). Immunohistochemical analysis identified predominant localization of Cat D to tubules in akita kidney sections and increased as compared to controls. Cat D activity was significantly elevated in urine (p<0.001) samples of of akita mice (n=6 each WT and akita, p<0.001) and in patients with established DKD (n=10 each control and DKD, p<0.0001). Cat D activity also correlated significantly (R²: 0.855, p<0.0001) with albumin/creatinine in akita mouse urine.

Conclusion

The current data indicate that Cathepsin D may play vital role in the pathogenesis of diabetic kidney disease and its level as well as activity in urine can serve as biomarker of the diabetic nephropathy.

Funding

• Private Foundation Support