Kidney Week

Abstract: SA-PO309

Effects of Empagliflozin on Urinary Megalin and Its Ligand α1-Microglobulin 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

• Hosojima, Michihiro, Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Michihiro Hosojima, MD, PhD

• Kabasawa, Hideyuki, Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Hideyuki Kabasawa, MD, PhD

• Saito, Akihiko, Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Akihiko Saito, MD, PhD

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially marketed as oral hypoglycemic agents acting on proximal tubules (PTs) but have also begun to be used worldwide as renoprotective agents. However, the detailed mechanisms underlying these renoprotective effects remain unclear. Megalin is highly expressed in the apical membranes of PTs and serves as an endocytic receptor for various glomerular-filtered proteins, peptides, and drugs. Previous studies have demonstrated that megalin could play a role in the progression of renal injury as a "gateway molecule" for nephrotoxic substances. Furthermore, measuring urinary megalin excretion may help evaluate the severity and pathophysiology of diabetic kidney disease. In particular, A-megalin (megalin ectodomains) may serve as a novel urinary biomarker of the metabolic load in PTs. Therefore, this study aimed to explore whether measuring the excretion of A-megalin helps evaluate the efficacy of SGLT2 inhibitors, including the evaluation of other PT markers such as α₁-microglobulin (α₁-MG), an endocytic ligand of megalin.

Methods

Forty-seven adult patients with type 2 diabetes and mild to moderate renal dysfunction (HbA1c 7.6±1.2%, eGFR 65.8±17.9 mL/min/1.73 m², albuminuria 153.6±305.6 mg/g creatinine (Cr)) were enrolled (UMIN000023902). Urinary excretion of megalin, albumin, and PT markers such as α₁-MG was measured at baseline, one month after starting empagliflozin, and then every three months for 36 months, along with evaluation of changes in eGFR.

Results

There were no significant changes in urinary albumin levels at six months compared to baseline. Urinary α₁-MG showed an increasing trend from 9.2±8.7 mg/g Cr at baseline to 12.1±9.2 mg/g Cr at three months and 12.0±9.3 mg/g Cr at six months, and urinary α₁-MG/g Cr/eGFR exhibited a similar trend. Urinary A-megalin, which was 90.0±62.6 pmol/g Cr at baseline, showed a decreasing trend to 64.3±71.2 pmol/g Cr at three months and 56.3±43.1 pmol/g Cr at six months, and urinary A-megalin/g Cr/eGFR exhibited a similar trend.

Conclusion

Administration of empagliflozin led to decreased urinary A-megalin and increased α₁-MG in patients with diabetic kidney disease, even when considering changes in eGFR. Further detailed evaluations are needed to elucidate the relationship between the renal protective effects and megalin function.