Effect of Bardoxolone Methyl on Kidney Function in Patients with T2D and Stage 3b–4 CKD

Abstract

Background/Aims: Bardoxolone methyl, a novel synthetic triterpenoid, induces Nrf2, a transcription factor known to play a key role in decreasing oxidative stress and the production of pro-inflammatory molecules. Methods: This exploratory multi-center, open-label study assessed the clinical activity and safety of bardoxolone methyl in 20 patients with moderate to severe chronic kidney disease and type 2 diabetes. Patients received 25 mg of bardoxolone methyl daily for 28 days, followed by 75 mg daily for another 28 days. Results: The study achieved its primary efficacy endpoint, as demonstrated by a significant increase from baseline in estimated glomerular filtration rate (eGFR) of 7.2 ml/min/1.73 m² (p < 0.001). Improvements were seen in approximately 90% of patients and showed a dose- and time-dependent increase in eGFR. The eGFR change paralleled a significant reduction in serum creatinine (–0.3 mg/dl) and blood urea nitrogen (–4.9 mg/dl), along with an increase in creatinine clearance (+14.6 ml/min/1.73 m²), without a change in the 24-hour creatinine excretion rate. Markers of vascular injury and inflammation were improved by treatment with bardoxolone. No life-threatening adverse events or drug-related serious adverse events were reported. Conclusions: The results describe an apparent increase in kidney function following relatively short-term treatment with bardoxolone methyl, a promising new agent that warrants placebo-controlled studies to define its long-term effects on renal function.

Cysteamine Modulates Oxidative Stress and Blocks Myofibroblast Activity in CKD

“…5,32,33 Prior studies centered on the reduction of oxidized macromolecules as the critical component to limiting disease progression, 34,35 rather than the specific redoxsensitive pathways or target cells that are directly modulated by antioxidants. 36,37 We found that cysteamine bitartrate treatment resulted in a substantial reduction in protein oxidation (.50%) despite no change in total thiol levels at advanced time points. These results, combined with our in vitro studies, suggest that the cysteamine-dependent antioxidant mechanism was not simply due to a drug-derived increase in the free thiol cellular pool; rather, its downstream modulatory effects on oxidantgenerating pathways attenuated tissue damage.…”

Neutrophil-to-Lymphocyte Ratio as a Predictor of Worsening Renal Function in Diabetic Patients (3-Year Follow-Up Study)

“…[17][18][19] Some medications were found to slow down the progression of DN through suggested antiinflammatory actions. [20][21][22][23][24][25][26] Neutrophil to lymphocyte ratio (NLR) rather than other white cell parameters (e.g., total white cell, monocyte count, and absolute neutrophil count) was found to be a useful inflammatory marker that predicts adverse outcomes in many medical and surgical conditions. [27][28][29][30] This finding was found not only in acute conditions but also in stable and preoperative medical conditions.…”

Bardoxolone Methyl: A Targeted Antioxidant

“…4 A recent, phase 2a, multicenter, openlabel study in 20 patients with moderate to severe diabetic CKD showed an apparent increase in kidney function following relatively short-term treatment with bardoxolone methyl with no life-threatening adverse events. 5 Apart from diabetes, SO have been used favorably in experimental animal models of kidney injury caused by toxic agents, cystic fibrosis, and emphysema induced by cigarette smoke, disease states characterized by hyperactivity of the immune system, cancer, including prevention and treatment, Parkinson's disease, Huntington's disease, and Alzheimer's disease. 6 To conclude, bardoxolone methyl and other SO could form the basis of therapies halting the progression of CKD and may be even reversing them.…”