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Kidney Week

Abstract: PO2029

Urinary Proteomics and Effects of Dapagliflozin Treatment in Persons with Type 2 Diabetes and Kidney Disease

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Ahluwalia, Tarunveer S., Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Rönkkö, Teemu K. E., Steno Diabetes Center Copenhagen, Gentofte, Denmark
  • Eickhoff, Mie K., Mosaiques Diagnostics Gmbh, Hanover, Germany
  • Mischak, Harald, Mosaiques Diagnostics Gmbh, Hanover, Germany
  • Rossing, Peter, Kobenhavns Universitet, Kobenhavn, Denmark
  • Persson, Frederik, Steno Diabetes Center Copenhagen, Gentofte, Denmark
Background

About 40% of persons with type 1 (T1D) or type 2 diabetes (T2D) develop diabetic kidney disease (DKD) posing a major economic burden on health care systems. Sodium Glucose Co Transporter 2 inhibitors (SGLT2i) have emerged as a novel treatment option for T2D and DKD. Albeit the kidney-protective effects of SGTL2i are well documented, the mechanisms remain unclear. The current study aims to investigate SGTL2i function through urinary proteomics.

Methods

A double-blinded, randomized, placebo-controlled, crossover trial comprising 36 persons with T2D was treated with 10 mg of dapagliflozin for 12 weeks or matching portion of placebo on top of their standard diabetes treatment at the Steno Diabetes Center Copenhagen, Denmark. All participants had albuminuria (UACR ≥ 30 mg/g) and received RAAS medication. Clinical factors like BMI, blood pressure (BP), estimated glomerular filtration rate (eGFR), LDL and HDL cholesterol, were measured at baseline, and after trial. Changes in clinical factors were modelled using linear mixed effects model adjusting for relevant clinical covariates. Urinary proteomics data in pre and post treatment groups (n=32) were analyzed using paired Mann Whitney U test. Multiple testing correction was performed and p < 0.05 was considered significant. We further verified whether identified peptide levels differed significantly between T1D DKD vs. healthy controls (n=210) and performed pathway enrichment analysis with STRING database.

Results

Trial participants had a mean (SD) age of 63 (8) years, 88% males, diabetes duration 15.9 (4.7) years, BMI 33.7 (5.4) kg/m2, HbA1c 8.8 (1.2)%, median (IQR) UACR 154 (94–329), eGFR 85.5(19.1) ml/min/m2, respectively. 19 proteins significantly changed after treatment. Type I and III collagen α (I), (II), and (III) chains, α-2-HS-glycoprotein, and polymeric immunoglobulin receptor peptides increased while albumin, α–1–antitrypsin, and α–1B–glycoprotein peptides decreased multifold. This was reflected in the DKD–control cohort.

Conclusion

We identified differential urinary peptide patterns in response to SGLT2i (Dapagliflozin) treatment on individuals with T2D and DKD. Extracellular matrix organization, inflammation, coagulation, renal fibrosis, and wound healing pathways were enriched. We suggest the involvement of expected and novel proteins.