Effect of bardoxolone methyl on the urine albumin-to-creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease

Abstract

Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor kB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebocontrolled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-tocreatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-tocreatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: L0.035 [95% confidence interval L0.031 to L0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

Predicting the protein composition of human urine in normal and pathological states: Quantitative description based on Dent1 disease (CLCN5 mutation)

“…Furthermore, acute changes in eGFR may be associated with altered albumin excretion. Recent examples include the acute impact of SGLT2 inhibitors (Cherney et al 2017;Pollock et al 2019) and bardoxolone (Rossing et al 2019), where a decreased eGFR was associated with reduced albumin excretion and an increased eGFR with worsening albuminuria, respectively. Our model anticipates these outcomes if SNGFR changes in proportion to eGFR in such acute treatment situations.…”

Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice

“…A post-hoc analysis showed an association between albuminuria and increases in eGFR. 15 An explanation for an increase in glomerular filtration rate (GFR) may be increased glomerular surface area 16 but concerns persist for increased renal plasma flow or intraglomerular pressure, which may be deleterious in chronic disease. 17,18 Bardoxolone methyl is currently in clinical trials for Alport's Syndrome (CARDINAL, NCT03019185), IgA nephropathy, type 1 diabetic nephropathy, focal segmental glomerulosclerosis, and autosomal dominant polycystic kidney disease (PHOENIX, NCT03366337).…”

The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer

“…CDDO-methyl ester (CDDO-Me), a semi-synthetic triterpenoid derived from oleanolic acid, is a promising chemotherapeutic and anti-inflammatory agent in clinical development ( Couch et al, 2005 ; Celentano et al, 2019 ; Rossing et al, 2019 ; Tian et al, 2019 ). The structure of CDDO is comprised of two α , β -unsaturated carbonyl moieties, which are accessible for nucleophilic addition.…”