During the progression of chronic kidney disease (CKD), opportunities exist for interventions to slow kidney damage. These include smoking cessation, weight loss, periodontal care, dietary reductions in fructose, sodium, and, for patients with stages 4 and 5 disease, protein intake (J Intern Med 2010;268:456-467). These interventions are low cost and easily implemented. The full impact of these interventions, however, is difficult to determine.
Pharmacologic interventions, in contrast, are easy to monitor and the effects are well documented in studies. Additionally, funding for these interventions may be more readily available. New and/or novel interventions to slow disease progression are beginning to emerge. As mentioned in past articles, sodium bicarbonate, weight loss, and low or very low protein or vegetarian diets have slowed the progression of kidney damage.
However, few interventions have demonstrated the ability to improve kidney function as shown by increasing glomerular filtration rate (GFR).
Recently, a moderately sized study published recently online ahead of print by Pergola et al in the New England Journal of Medicine (NEJM) showed that bardoxolone methyl may be effective an a primary intervention to improve kidney function (see article on page XX).
It is well known that patients with CKD die from cardiovascular disease (CVD) at much higher rates than the general population. This higher death rate is thought to be due to calcium deposits in soft tissue and inflammation, among other things. In addition, protein energy wasting is an extremely strong indicator of mortality in CKD patients. The connection between these two etiologies for mortality is inflammation.
The role of inflammation
Much effort has been put into understanding the inflammatory process in CKD, and recent review articles have been published summarizing this topic. Carrero and Stenvinkel published an excellent review in Seminars in Dialysis (2010;23:498-509) that provides a comprehensive outline of the knowledge gained in the past 10 years on inflammation in CKD.
They propose a three-step process to manage inflammation in dialysis patients. The first step is to identify and treat clinical conditions (called intercurrent events in the review article). This could mean, for example, identifying periodontal disease in a hemodialysis patient and referring the patient to a dentist for treatment.
The second step is evaluation and, if possible, removal of sources of inflammation caused by the dialysis process (e.g., identifying an infection in the vascular access of a hemodialysis patient and treating it with antibiotics). The third step is consideration of anti-inflammatory interventions for treating persistent inflammation.
This step-by-step management plan could be extrapolated to predialysis patients by just using steps one and three. Bardoxolone methyl would be part of step three—an anti-inflammatory treatment. According to NEJM report by Pergola et al, bardoxolone methyl works by activating the Keap1-Nrf2 pathway by interacting with cysteine residues on Keap1. This allows Nrf2 to translocate into the nucleus. The process triggers up-regulation of many cytoprotective genes and inhibits the pro-inflammatory nuclear factor kappa B pathway similar to prostaglandins.
The BEAM trial was designed to determine whether bardoxolone methyl would significantly improve the estimated GFR (eGFR) in patients with moderate-to-severe CKD (GFR 20-45 mL/min/1.73m2) and reasonably stable type 2 diabetes (hemoglobin A1c less than 10%).
The study enrolled 227 patients. Unfortunately, no baseline or subsequent dietary data was collected nor were any dietary instructions provided the patients. The study was a 52-week randomized clinical trial conducted by the manufacturers of bardoxolone methyl. The treatment group had three levels of drug dose (25, 75, and 150 mg). By the end of 24 weeks, the researchers observed a statistically significant increase in eGFR from baseline in the treatment groups compared with placebo recipients. This landmark trial demonstrated not just the maintenance of kidney function, but actual improvement in kidney function.
Additional research needed
More studies should be conducted to examine the synergistic impact of low protein or vegetarian diets, weight loss, and bardoxolone methyl on kidney function. In addition, other anti-inflammatory interventions need to be more thoroughly tested, such as omega-3 fatty acids, hydrogen infused dialysate, low-dose insulin infusions, and carnitine.
In summary, the evaluation and treatment of inflammation is an important approach for potentially lowering mortality rates from CVD and protein energy wasting. Bardoxolone methyl is an anti-inflammatory drug shown to increase eGFR in patients with moderate-to-severe CKD and type 2 diabetes.