Kidney Week

Abstract: FR-PO237

Dapagliflozin Stabilizes the Tubulointerstitial Fibrosis Marker Urinary Dickkopf-3

Session Information

• Diabetic Kidney Disease: Advancing Treatment
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 602 Diabetic Kidney Disease: Clinical

Authors

• Pena, Michelle, University Medical Center Groningen, Groningen, Netherlands

Michelle Pena,

• Laverman, Gozewijn Dirk, ZGT Almelo, Almelo, Netherlands

Gozewijn Dirk Laverman,

• Wanner, Christoph, University Hospital, Wuerzburg, Germany

Christoph Wanner,

• Schunk, Stefan J., Saarland University Hospital, Homburg, Germany

Stefan J. Schunk,

• Speer, Thimoteus, Saarland University Hospital, Homburg, Germany

Thimoteus Speer,

• Fliser, Danilo, Saarland University Hospital, Homburg, Germany

Danilo Fliser,

• L Heerspink, Hiddo Jan, University Medical Center Groningen, Groningen, Netherlands

Hiddo Jan L Heerspink,

Background

Urinary Dickkopf-3 (DKK3) is a stress-induced tubular epithelia-derived profibrotic glycoprotein that induces tubulointerstitial fibrosis through its action on the canonical Wnt/β-catenin signaling pathway. A previous study showed that DKK3 concentrations are higher in patients with CKD than in the general population, and that a rise in urinary DKK3 was associated with significant eGFR decline. Prior experimental and clinical studies have suggested that SGLT-2 inhibition may reduce renal fibrosis. We therefore assessed the effect of the SGLT-2 inhibitor dapagliflozin on urinary DKK3.

Methods

24hr urine samples were used from a double-blind, randomized, placebo controlled crossover trial in 31 patients with type 2 diabetes and albumin:creatinine ratio (UACR) >100 mg/g on a stable dose of an ACE inhibitor or angiotensin receptor blocker. Patients were assigned to 6-week treatment periods with dapagliflozin 10 mg/d or placebo in random order. Urinary DKK3 was measured by ELISA at the start and end of each 6-week treatment period. A mixed effects repeated measures model was used to assess the effect of dapagliflozin on urinary DKK3.

Results

Dapagliflozin decreased UACR by 43.9% (95%CI: 30.3 to 54.8) and eGFR by 5.1 (2.0 to 8.1) mL/min/1.73m² compared to placebo. At baseline, urinary DKK3 concentration was 574.8 [1st, 3rd quartile: 304.3, 1223.7] ng/24hr. After 6 weeks placebo treatment, urinary DKK3 levels increased by 41.7% (95%CI: 2.2 to 96.4), p=0.0373, whereas they remained stable after dapagliflozin treatment (-1.2% (-29.3 to 38.2), p=0.9421). Accordingly, dapagliflozin lowered DKK3 compared to placebo by 30.3% (2.0 to 50.3), p=0.0384. After dapagliflozin, change in urinary DKK3 was significantly correlated with change in UACR (r=0.41, p=0.0309). No correlations with changes in other clinical markers (HbA1c, eGFR, SPB, Hb, Hct) were observed.

Conclusion

Dapagliflozin stabilized urinary DKK3 after 6 weeks of treatment in patients with type 2 diabetes and increased albuminuria, while an increase was observed during placebo treatment, suggesting that dapagliflozin may lessen tubular stress and fibrosis. Future studies of longer treatment duration and clinical outcomes are needed to confirm the clinical impact of these findings.