Kidney Week

Abstract: SA-PO308

Effects of Bardoxolone Methyl on Urinary Proximal Tubular Markers: A Subanalysis of the TSUBAKI Study

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

• Kuwahara, Shoji, Laboratory of Clinical Nutrition, Department of Nutrition, Graduate School of Human Cultures, The University of Shiga Prefecture, Hikone, Japan

Shoji Kuwahara, 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

• Kinoshita, Shunji, Development Division, Kyowa Kirin Co., Ltd, Tokyo, Japan

Shunji Kinoshita

• Ichikawa, Tomohiro, Development Division, Kyowa Kirin Co., Ltd, Tokyo, Japan

Tomohiro Ichikawa, MS, MBA

• 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

Bardoxolone methyl (BARD) activates nuclear factor erythroid 2-related factor 2, exhibiting antioxidative and anti-inflammatory properties. BARD has been developed as a therapeutic agent for diabetic kidney disease (DKD). Previous clinical trials have demonstrated that BARD increases the estimated glomerular filtration rate (eGFR) and albuminuria. Animal experiments have suggested that the increase in albuminuria induced by BARD is associated with a decrease in the expression of megalin, a proximal tubule endocytic receptor involved in the reabsorption, metabolism, and degradation of glomerular filtrate proteins. However, the specifics of these effects require further elucidation. This study aimed to measure the urinary concentrations of markers associated with megalin in the proximal tubules using urine samples collected from the TSUBAKI study, a phase II clinical trial of BARD administration in DKD patients conducted in Japan, and to examine changes in these markers and their independent effects on eGFR.

Methods

In the TSUBAKI study, urine samples were collected at baseline and at 4, 8, 12, 16, and 4 weeks after administration. The urinary concentrations of A-megalin (megalin ectodomains), C-megalin (full-length megalin), α₁-microglobulin (α₁-MG), and N-acetyl-β-D-glucosaminidase (NAG) were measured. Statistical analyses were performed using mixed-effects models for repeated measures.

Results

Compared with the placebo group, the BARD group showed significantly increased urinary α₁-MG/creatinine (Cr) and A-megalin/Cr at all time points after the start of administration. However, this increase disappeared after the completion of administration. Similar results were found in urinary α₁-MG/Cr/eGFR and A-megalin/Cr/eGFR. In contrast, there were no changes in urinary C-megalin/Cr and NAG/Cr.

Conclusion

BARD administration resulted in changes in urinary proximal tubule markers. The increase in α₁-MG, a ligand of megalin, following BARD administration was consistent with the reduction in megalin expression observed in animal studies. The increase in urinary A-megalin levels suggests that BARD may stimulate the recycling and shedding of megalin, independent of its effect on increasing eGFR.