This week in NEJM, there is a major article with results from a new study BEAM, showing efficacy of a medication, Bardoxolone methyl (BARD) an oral antioxidant, in chronic kidney disease due to diabetes. We have always known of medications that decrease renal function. This would be the first medication that improves renal function. It works by inhibiting renal injury by oxidative stress and inflammation in diabetic kidney disease. However, Its role in other conditions with the same pathophysiology has not been tested, yet. Type 2 Diabetes being the most common cause of CKD (chronic Kidney disease) this new drug (if tested safe and effective in long term studies), might give the much needed major turn in management of diabetic kidney disease.
Summary from the NEJM article:
Sponsored by Reata pharmaceuticals, an employee of the sponsor wrote the first draft of the manuscript. study design by first author and representatives of the sponsor.
Glomerular Filtration Rate GFR estimated using the four variable (Modification of diet in Renal disease) MDRD equation
Patient characteristics: similar in all four groups. mean age 67 y, well controlled blood sugars, 98% were receiving ACE, ARB or both. Mean GFR was about 32 +/- 7 ml/min/1.73m2. Albumin to creatinine ratio (ACR) was distributed almost in thirds.
Exclusion criteria: type 1 diabetes, nondiabetic kidney disease, a glycated hemoglobin level of more than 10%, hepatic dysfunction, or a cardiovascular event within the previous 3 months.
Primary outcome: Change from baseline of estimated GFR Bardoxolone methyl vs placebo at 24 wks –> upto 12ml/min/1.73 m2 difference in eGFR between placebo and the BARD group
Secondary outcome: change in eGFR at 52 weeks–> upto 10 ml/min/1.73 m2 difference in eGFR between placebo and BARD group
a) Cumulative changes in estimated GFR from baseline to 52 wks –>54% in placebo group. ~ 20 % in 25 mg group and 75 mg groups, 27% in 150 mg group
b) Time to and percentage of patients with > 25% reduction in eGFR 13% in placebo vs 2% in BARD group
c) Slight but significant increase in ACR in 75 & 150 mg BARD group at 24 & 52 wks.
d) Significant decreases in levels of blood urea nitrogen, serum phosphorus, uric acid, and magnesium, as compared with placebo at 24 wks
Adverse events: more in bardoxolone group 18% vs > 50%
1. muscle spasm most common in first 12 wks, resolved spontaneously with continuation of drug
2. Hypomagnesemia (not related temporally to 1.)
3. Alanine amino transferase elevation, mild and transient
4. GI side effects (nausea, vomiting, decreased appetite)
5. Last but not least : The BARD group had slight but significant increases in ACR. Authors explain it by attributing it to increased GFR but decreased tubular reabsorption.
Discussion: Oxidative stress and inflammation is the final common pathway for chronic kidney disease in diabetic nephropathy. Bardoxolone activates the Keap1-nrf 2 (kelch like ECH associated protein1– nuclear factor E2 related factor) pathway thus ameliorating damage, hence preventing deterioration the pathogenic agents. It interacts with cysteine residues in keap1, causing translocation of Nrf2 to nucleus and upregulation of several cytoprotective genes. Bardoxolone activates nrf2 expression in glomerular endothelial cells and peritubular capillaries, increased hemoxygenase 1 in tubules and interstitial leucocytes. BARD also exerts inhibitory effect on nuclear factor kB pathway. This leads to decreased inflammation, BUN, and amelioration of both glomerular and tubular injury
Side note: Nrf2 deletion causes inflammation/oxidative stress.
Treatment with BARD lead to sustained and significant improvement in GFR in patients with CKD due to diabetes. The effect was sustained after 4 weeks after discontinuation of the drug.
Increases in the estimated GFR was independent of changes in albumin excretion
The absence of a significant decline in the estimated GFR among patients receiving placebo may reflect the fact that most patients did not have macroalbuminuria at baseline and their important risk factors (e.g., blood pressure and glycated hemoglobin levels) were well controlled with standard medical care
However, bringing skepticism to the table: we know that proteinuria is a not only a major marker for renal function but also mediates injury. If the glomerulus is in some way protected by BARD, it has to be reflected by decrease in albuminuria. or there might be a possibility that the protection conferred by BARD might be negated by increased proteinuria.
Important questions that pop up:
The GFR was estimated by creatinine based equations. Does BARD have any effect on serum creatinine itself outside of its reported protective effect, either in laboratory measurements or in its production or secretion. In any of such situations, it can lead to a falsely higher GFR on calculations. There is reference (Number 28) that says no.
By excluding patients with poorly controlled diabetes, with higher glycated hemoglobin levels is there a selection bias where only patients with better predicted outcomes were studied. Note that the placebo group
But being optimistic, if it works out, this medication could potentially play a major role in many disease processes that are mediated by the Keap1-Nrf2 pathway.