Kidney Week

Abstract: SA-PO321

Unraveling the Mechanism of SGLT2 Inhibitors Using Urinary Proteomics in Patients with Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Clinical Pathology, Diagnostic and Treatment Advances
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 702 Diabetic Kidney Disease: Clinical

Authors

• De la Rambelje, Mark Andre, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Mark Andre De la Rambelje, MSc

• Nair, Viji, University of Michigan Department of Internal Medicine, Ann Arbor, Michigan, United States

Viji Nair, PhD

• Jongs, Niels, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Niels Jongs, PhD

• Hansen, Michael K., Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Michael K. Hansen, PhD

• Voors, Adriaan A., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Adriaan A. Voors, MD

• Kretzler, Matthias, University of Michigan Department of Internal Medicine, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• Ju, Wenjun, University of Michigan Department of Internal Medicine, Ann Arbor, Michigan, United States

Wenjun Ju, PhD

• Heerspink, Hiddo Jan L., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Hiddo Jan L. Heerspink, PhD

Background

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) confer kidney protection in patients with diabetic kidney disease (DKD). We studied the effect of the SGLT2i canagliflozin (CANA) on the urinary proteome, aiming to identify biological pathways involved in its protective effect.

Methods

We performed a post-hoc analysis in a subgroup of 392 participants with DKD from the phase 3 randomized placebo controlled CREDENCE trial. A total of 5284 proteins were quantified using the SomaScan platform in urine samples collected at baseline and week 52. Change in protein abundance was evaluated in patients receiving CANA after 1 year of treatment. Pathways were identified using ingenuity pathway analysis (IPA). Single-cell RNA expression of genes coding for proteins found to be affected by CANA was assessed in proximal tubule (PT) cells and thick ascending limb (TAL) cells in kidney biopsies from young patients with type 2 diabetes receiving either standard care + SGLT2i or only standard care.

Results

Placebo and CANA groups were well matched based on age (62 years), gender 141 (34.7%) female, albuminuria (median 1016 mg/g), eGFR (mean 60.4 mL/min/1.73m²). After one year of treatment, 103 proteins were up-regulated (FDR < 0.05), these proteins are enriched in pathways related to gluconeogenesis, carbon metabolism, and hypoxia-inducing factor-1 signaling (Figure). Single cell analysis of young adults with T2D using SGLT2 inhibitors showed that more genes linked to these urinary proteins were upregulated in TAL cells compared to PT cells, suggesting that these urinary proteins more likely originate from TAL cells.

Conclusion

These results suggest that CANA treatment causes an increase in energy-demand in the distal tubule, possibly reflecting compensatory sodium reabsorption following sodium inhibition in the proximal tubule.

Funding

• Commercial Support – Janssen