UKidney Nephrology News and Insights

Bardoxolone in Chronic Kidney Disease: A major breakthrough?

In this week's New England Journal of Medicine, Pergola et al report the results of a phase 2 randomized trial of an antioxidant inflammation modulator, bardoxolone, in patients with type 2 diabetes and chronic kidney disease (CKD). Over a period of 52 weeks, 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m2 of body-surface area) were randomized in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. Primary outcome was a change from baseline in the estimated GFR with bardoxolone, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. The results were quite surprising.

Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m2 of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P<0.001). Muscle spasms were the most frequent side of effect reported in the treatment group. The increases weremaintained through week 52, with significant differences per minute per 1.73 m2 of5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively.

Most pivotal trials in CKD evaluate doubling of serum creatinine, ESRD or death as their outcomes. However, in the current trial, sample size ad follow-up length preclude realistic chance of significant change in these outcomes. In a trials of smaller size and shorter follow-up, change in creatinine and/or proteinuria are often used as surrogate outcomes. Bardoxolone actually led to a higher GFR over the course of this study. While this is a promising outcome, one must also consider that short-term increases in GFR may not translate to long-term prevention of end-stage renal disease (ESRD), the most important outcome of an intervention trial in nephrology. Short term increases in GFR may in fact be hemodynamic in nature, and may in fact lead to long term harm, especially in diabetes, where hyperfiltration and early increases in GFR are halmarks of this disorder. In fact, in patients with diabetic nephropathy, those who ever experience increases in GFR early in the course of their illness have the worst prognosis. An intervention that leads to increased filtration but without modulating the underlying disease pathogenesis, might then actually be harmful.

Nevertheless, the present study is fascinating and one of the first of its kind to show not only renal function preservation, but improvement over the course of the study. While many questions remain, notably the long-term impact of this intervention, bardoxolone may well become and important tool in the management of CKD.

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