August 8, 2011
Mahesh’s Top Reads August 2011
Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes
Authors: Pablo E. Pergola, Philip Raskin, Robert D. Toto, Colin J. Meyer, J. Warren Huff, Eric B. Grossman, Melissa Krauth, Stacey Ruiz, Paul Audhya, Heidi Christ-Schmidt, Janet Wittes, and David G. Warnock, for the BEAM Study Investigators*
Journal Citation: N Engl J Med 2011;365:327-36.
Summary: For patients with chronic kidney disease (CKD), diabetes mellitus is both a major cause of the disease and a contributing factor to complications can lead to kidney failure. Particularly, diabetes in patient with CKD can be associated with chronic inflammation and oxidative stress, in turn leading to glomerular endothelial dysfunction, mesangial-cell contraction, glomerular fibrosis, and mesangial expansion. These deteriorations ultimately manifest into kidney failure. Bardoxolone methyl is an antioxidant inflammation modulator that activates the Keap1 Nrf2 pathway associated with the maintenance of kidney function and structure. Bardoxolone methyl resembles the cyclopentenone prostaglandins structurally and is thought to exert anti-inflammatory effects by inhibiting the proinflammatory NFκB pathway.
In this phase 2, double-blind, randomized, placebo-controlled trial, Pergola and colleagues from the BEAM trial studied whether or not bardoxolone methyl can affect kidney function in patients with CKD. 227 adult patients with CKD (eGFR = 20 to 45 ml/min/1.73 m2 BSA) were assigned to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily (1:1:1:1 ratio). The investigators found that patients who received bardoxolone methyl had significant increases (compared with placebo patients) in the mean (±SD) eGFR at 24 weeks: 25 mg group = 8.2±1.5 ml/min/1.73 m2; 75 mg group = 11.4±1.5 ml/min/1.73 m2; 150 mg group = 10.4±1.5 ml/min/1.73 m2; P<0.001). These increases continued through Week 52 of the study. Adverse events commonly associated with bardoxolone methyl, including muscle spasms, were generally mild and dose-related; however, hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were found to be more common among patients receiving bardoxolone methyl.
These results suggest that bardoxolone methyl administration was associated with significant improvement in the eGFR in patients with advanced CKD and type 2 diabetes and may be an effective treatment in this patient population.
The Effects of Frequent Nocturnal Home Hemodialysis: The Frequent Hemodialysis Network Nocturnal Trial
Authors: Michael V. Rocco, Robert S. Lockridge Jr, Gerald J. Beck, Paul W. Eggers, Jennifer J. Gassman, Tom Greene, Brett Larive, Christopher T. Chan, Glenn M. Chertow, Michael Copland, Christopher D. Hoy, Robert M. Lindsay, Nathan W. Levin, Daniel B. Ornt, Andreas Pierratos, Mary F. Pipkin, Sanjay Rajagopalan, John B. Stokes, Mark L. Unruh, Robert A. Star, Alan S. Kliger, and the Frequent Hemodialysis Network (FHN) Trial Group
Journal Citation: Kidney International Advance online publication, 20 July 2011; doi:10.1038/ki.2011.213
Summary: The mortality rates among patients on maintenance hemodialysis remain a significant problem, with an annual average mortality of ~20% over the past 2 decades. Previous studies, including the NCDS and HEMO studies, have presented conflicting results on this issue. There are inconclusive data as to whether factors such as dialysis dose and/or frequency of dialysis are associated with morbidity and mortality. In the current study, Rocco et al set out to determine if an increased hemodialysis frequency could lead to improved patient outcomes, as the increased frequency can result in both an increased clearance of solutes and a reduced interdialytic change in volume. This increased frequency can be achieved through a short, daily schedule or a longer nocturnal schedule.
Power calculations in designing the study indicated that 250 patients needed to be randomized. However recruitment was difficult and only 87 patients were randomized: 42 enrolled in the conventional hemodialysis arm (3 times/week) and 45 in the frequent nocturnal dialysis arm (6 times/week). The primary endpoints across both groups included death, change in left ventricular (LV) mass, and the physical health composite (PHC) score. There was not a significant effect of nocturnal hemodialysis for death or (LV) mass with a hazard ratio of 0.68, or of death or a PHC score with a hazard ratio of 0.91. The co-primary outcome of combined decrease in mortality and decrease in LV mass did show a positive trend, with a p-value of 0.095. However, here was also a trend for increased vascular access events in patients receiving nocturnal dialysis.
Thus, based on their findings, the investigators concluded that “the results of the FHN Nocturnal Trial neither prove nor disprove the hypothesis that frequent nocturnal dialysis leads to clinically important reductions in LV mass”.