Title: Bardoxolone Methyl and Kidney

Name: Aimee Kristene M. Carpio BSN IV-A/ SGC

Function in CKD with Type 2 Diabetes Source: The New England Journal of Medicine/ http://www.nejm.org Author: Pablo E. Pergola, M.D., Ph.D Year: July 28, 2011

Diabetes mellitus is a major cause of chronic kidney disease (CKD) worldwide. The complications of CKD (e.g., cardiovascular disease and death) occur before kidney failure develops and are independent of known risk factors (i.e., hypertension and proteinuria). Although CKD progression is slowed by the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), in many patients, the condition progresses to kidney failure. CKD in patients with diabetes is associated with chronic inflammation and oxidative stress. Effects of these processes result in glomerular endothelial dysfunction and mesangial-cell contraction and, with time, glomerular fibrosis and mesangial expansion. These effects result in a decline in kidney function. Bardoxolone methyl, an antioxidant inflammation modulator, activates the Keap1Nrf2 pathway, which plays an important role in maintaining kidney function and structure. The chemical and biologic characteristics of bardoxolone methyl, a derivative of the natural product oleanolic acid, have been reviewed recently (see Figure 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Bardoxolone methyl interacts with cysteine residues on Keap1, allowing Nrf2 translocation to the nucleus and subsequent up-regulation of a multitude of cytoprotective genes. The structure and activity profile of bardoxolone methyl resemble those of the cyclopentenone prostaglandins, endogenous Nrf2 activators that promote the resolution of inflammation. Like cyclopentenone prostaglandins, bardoxolone methyl exerts antiinflammatory effects by inhibiting the proinflammatory nuclear factor B pathway. In a previous phase 2 trial, we found that daily administration of bardoxolone methyl for 8 weeks significantly increased the estimated glomerular filtration rate (GFR). In the randomized, placebo-controlled 52-Week Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) study, the results of which are reported here, we assessed the effects of three doses of bardoxolone methyl on the estimated GFR at 24 and 52 weeks in patients with CKD and type 2 diabetes.

Reactions/Comment: Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes

Diabetes is the most common cause of kidney failure, accounting for nearly 44 percent of new cases. Even when diabetes is controlled, the disease can lead to CKD and kidney failure. Most people with diabetes do not develop CKD that is severe enough to progress to kidney failure. Nearly 24 million people in the United States have diabetes, and nearly 180,000 people are living with kidney failure as a result of diabetes. People with kidney failure undergo either dialysis, an artificial blood-cleaning process, or transplantation to receive a healthy kidney from a donor. Diabetic kidney disease takes many years to develop. In some people, the filtering function of the kidneys is actually higher than normal in the first few years of their diabetes. Over several years, people who are developing kidney disease will have small amounts of the blood protein albumin begin to leak into their urine. This first stage of CKD is called microalbuminuria. The kidney's filtration function usually remains normal during this period. As the disease progresses, more albumin leaks into the urine. This stage may be called macroalbuminuria or proteinuria. As the amount of albumin in the urine increases, the kidneys' filtering function usually begins to drop. The body retains various wastes as filtration falls. As kidney damage develops, blood pressure often rises as well. Overall, kidney damage rarely occurs in the first 10 years of diabetes, and usually 15 to 25 years will pass before kidney failure occurs. For people who live with diabetes for more than 25 years without any signs of kidney failure, the risk of ever developing it decreases. Adults with moderate-to-severe CKD and type 2 diabetes were eligible for study enrollment if they had an estimated GFR of 20 to 45 ml per minute per 1.73 m2 of body-surface area, calculated as the mean of two measurements (differing by 25%) in blood samples collected less than 5 days apart within a 3-week screening period. Treatment with a stable dose of an ACE inhibitor, an ARB, or both for at least 8 weeks before screening was required, unless such therapy was not tolerated. Major exclusion criteria were 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.

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Submitted by: Aimee Kristene M. Carpio BSN IV-A Submitted To : Mr. Rejell Nugent R. Cichon Clinical Instructor