Original Article
Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes
N Engl J Med 2011; 365:327-336July 28, 2011
- Abstract
Background
Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined.
Methods
In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 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) 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. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks.
Results
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). The increases were maintained through week 52, with significant differences per minute per 1.73 m2 of 5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl.
Conclusions
Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.)
Media in This Article
Figure 1
Effects of Bardoxolone Methyl on the Estimated Glomerular Filtration Rate (GFR).Table 1
Demographic and Clinical Characteristics of the Patients.Article Activity
- Article
Diabetes mellitus is a major cause of chronic kidney disease (CKD) worldwide.1,2 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).3,4 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.5-9
CKD in patients with diabetes is associated with chronic inflammation and oxidative stress.10-12 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.13-17
Bardoxolone methyl, an antioxidant inflammation modulator, activates the Keap1–Nrf2 pathway, which plays an important role in maintaining kidney function and structure.18-22 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).23 Bardoxolone methyl interacts with cysteine residues on Keap1, allowing Nrf2 translocation to the nucleus and subsequent up-regulation of a multitude of cytoprotective genes.18,22,23 The structure and activity profile of bardoxolone methyl resemble those of the cyclopentenone prostaglandins, endogenous Nrf2 activators that promote the resolution of inflammation.24 Like cyclopentenone prostaglandins, bardoxolone methyl exerts antiinflammatory effects by inhibiting the proinflammatory nuclear factor κB pathway.25-27
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).28 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.
Methods
Patients
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.
Study Design
We screened 573 patients at 43 sites in the United States. Of these patients, 227 were randomly assigned in a 1:1:1:1 ratio to receive placebo or oral bardoxolone methyl at a dose of 25, 75, or 150 mg once daily for 52 weeks (Fig. 2 in the Supplementary Appendix). The study had four periods: a 21-day screening period; an 8-week period of dose adjustment (every 4 weeks) that could be extended up to 20 weeks if needed to reach the randomly assigned dose of bardoxolone methyl; dose maintenance from the end of the dose-adjustment period through week 52; and follow-up for 4 weeks after the last dose. Patients were stratified at randomization according to the estimated GFR (<30 ml or ≥30 ml per minute per 1.73 m2), the urinary albumin-to-creatinine ratio (ACR, ≤300 or >300 [with albumin measured in milligrams and creatinine in grams]), and the glycated hemoglobin level (<7% or ≥7%). The use of concomitant medications, including antihypertensive agents, was adjusted by the treating physician according to established guidelines. Patient safety was assessed at each visit and monitored by an independent data and safety monitoring board. The study protocol (which is available at NEJM.org) was approved by the institutional review board associated with each study center. All patients provided written informed consent.
Study Oversight
This study was sponsored by Reata Pharmaceuticals and was designed by the first author and representatives of the sponsor. Study investigators and coordinators jointly managed the study with the sponsor. The main database was held by a contract research organization (Numoda). Employees of Statistics Collaborative performed the statistical analyses. Data were reviewed by the data and safety monitoring board during the study. An employee of the sponsor wrote the first draft of the manuscript. All the authors participated in manuscript revision, made the decision to submit the manuscript for publication, agreed to maintain data confidentiality pending publication, and vouch for the completeness and accuracy of the data.
Procedures and Outcomes
Measurement of the estimated GFR and routine laboratory testing were performed during screening and every 4 weeks by a central laboratory. Creatinine assays were calibrated to an isotope-dilution standard for mass spectrometry. The GFR was estimated with the use of the four-variable equation used in the Modification of Diet in Renal Disease study.29 No dietary interventions were included, and 24-hour urine collections were not obtained.
The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. Exploratory outcomes included the cumulative distribution of the change in the estimated GFR from baseline to 52 weeks; the time to and percentage of patients with a reduction in the estimated GFR of 25% or more; the change in the estimated GFR 4 weeks after the last administration of the study drug; and the changes from baseline in the ACR and in levels of serum creatinine, blood urea nitrogen, serum phosphorus, uric acid, magnesium, potassium, bicarbonate, glycated hemoglobin, and intact parathyroid hormone with bardoxolone methyl, as compared with placebo, at 24 and 52 weeks.
Statistical Analysis
We calculated that 55 patients per group in a longitudinal analysis would provide a power of approximately 90% to determine a mean (±SD) difference in the change from baseline in the estimated GFR of 4.33±5.77 ml per minute per 1.73 m2 between any dose of bardoxolone methyl and placebo. Our calculations assumed a rate of dropout (permanent discontinuation of a study drug before 24 weeks) of 25%. The type I error rate was controlled at 0.05 through Dunnett–Tamhane tests at 0.019 for three comparisons with placebo.30
We used a repeated-measures model to analyze the primary and secondary outcomes, with monthly measurement of the estimated GFR through 52 weeks as the response and with the baseline estimated GFR, ACR, and glycated hemoglobin level as continuous covariates. The model included all measurements up to the time of withdrawal from the study, regardless of the status of study-drug administration and categorical variables for treatment, week, and treatment-by-week interaction. Within-patient correlation was modeled with a Toeplitz structure.31 We used Kaplan–Meier methods to estimate the proportion of patients remaining event-free at time points of interest. The study groups were compared with the use of unstratified log-rank tests with unadjusted two-sided type I error rates.
Results
Patients
Dose increases to achieve the randomly assigned dose occurred during the first 20 weeks. Among patients receiving bardoxolone methyl, the proportions who received the randomly assigned dose at 52 weeks were 81% in the 25-mg group, 42% in the 75-mg group, and 25% in the 150-mg group. The four study groups were similar with respect to baseline variables (Table 1Table 1
Demographic and Clinical Characteristics of the Patients.); the mean age was 67 years. Blood glucose levels were generally well controlled. A total of 98% of patients were receiving an ACE inhibitor, an ARB, or both; the remaining patients could not tolerate such medications. The mean estimated GFR was 32.4±6.9 ml per minute per 1.73 m2. The ACR was less than 30 (normoalbuminuria) in 37% of patients, 30 to 300 (microalbuminuria) in 29%, and more than 300 (macroalbuminuria) in 34%.Primary and Secondary End Points
The estimated GFR increased within 4 weeks after the initiation of treatment in the three bardoxolone methyl groups. The value peaked at 12 weeks and remained relatively stable through 52 weeks (Figure 1AFigure 1
Effects of Bardoxolone Methyl on the Estimated Glomerular Filtration Rate (GFR).). At 24 weeks, there was significant improvement in the primary end point (change from baseline in the estimated GFR) in all bardoxolone methyl groups, as compared with the placebo group, with mean 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 for all comparisons). The difference in the change between the 25-mg group and the 75-mg group was significant (P=0.04), but the difference between the 75-mg group and the 150-mg group was not significant (P=0.54). At 52 weeks, differences in the changes in the estimated GFR, as compared with placebo (the secondary end point), continued to favor the bardoxolone methyl groups, with differences per minute per 1.73 m2 of 5.8±1.8 ml in the 25-mg group (P=0.002), 10.5±1.8 ml in the 75-mg group (P<0.001), and 9.3±1.9 ml in the 150-mg group (P<0.001). There were no significant changes from baseline in the estimated GFR in the placebo group at 24 or 52 weeks (Figure 1A).Exploratory Outcomes
The cumulative distribution of changes in the estimated GFR at 52 weeks in patients completing 52 weeks of therapy showed decreases in 54% of patients in the placebo group but in only 20% of those in the group receiving 25 mg of bardoxolone methyl, 21% of those in the 75-mg group, and 27% of those in the 150-mg group (Figure 1B). The proportion of patients with a reduction in the estimated GFR of 25% or more at 24 weeks was 13% (95% confidence interval [CI], 6 to 25) in the placebo group and 2% (95% CI, 1 to 6) in the combined bardoxolone methyl groups (P=0.05) (Figure 1C). Four weeks after the last administration of the study drug (at 56 weeks), the estimated GFR remained above the baseline value in patients receiving bardoxolone methyl, with differences from baseline per minute per 1.73 m2 of 0.7±1.6 in the 25-mg group, 2.5±1.6 ml in the 75-mg group, and 2.3±1.7 ml in the 150-mg group. In the placebo group, patients had a modest decrease of 0.6±1.1 ml per minute per 1.73 m2 from baseline (Figure 1D). The change in the estimated GFR at 56 weeks was significantly correlated with the change at the end of treatment, at 52 weeks (r=0.84, P<0.001) (Figure 1E).
In a post hoc sensitivity analysis that was based on the dose of bardoxolone methyl that was actually received at 52 weeks rather than the randomly assigned dose, increases in the estimated GFR were sustained for 52 weeks in the 75-mg and 150-mg groups but not in the 25-mg group (Fig. 3 in the Supplementary Appendix).
At 24 weeks in all three bardoxolone methyl groups, there were significant decreases in levels of blood urea nitrogen, serum phosphorus, uric acid, and magnesium, as compared with placebo; these decreases had an inverse correlation with changes in the estimated GFR (Table 1 in the Supplementary Appendix). At 52 weeks, changes in these solutes continued to have an inverse correlation with changes in the estimated GFR (Fig. 4 in the Supplementary Appendix). In the 75-mg and 150-mg groups, there was a slight but significant increase in the ACR at 24 and 52 weeks (Table 1 in the Supplementary Appendix). Changes in the ACR and estimated GFR were positively correlated at 52 weeks (Fig. 5A in the Supplementary Appendix). At 56 weeks, the ACR generally returned to the baseline level (Fig. 5B in the Supplementary Appendix). Changes in the levels of potassium, bicarbonate, intact parathyroid hormone, and glycated hemoglobin did not differ significantly among the study groups (Table 1 in the Supplementary Appendix).
Adverse Events
Adverse events were more frequent in the bardoxolone methyl groups than in the placebo group (Table 2Table 2
Most Common Adverse and Serious Adverse Events by Week 56., and Table 2 in the Supplementary Appendix). Most of the adverse events were mild to moderate in severity. The most common adverse event among patients receiving bardoxolone methyl was muscle spasm, with an incidence of 42% in the 25-mg group, 61% in the 75-mg group, and 59% in the 150-mg group, as compared with 18% in the placebo group. Muscle spasms, which were most frequent during the first 12 weeks of the study, primarily involved the calf and generally resolved without discontinuation of the study drug. Levels of lactate dehydrogenase were not significantly increased. Although hypomagnesemia was more common among patients receiving bardoxolone methyl than among those receiving placebo, hypomagnesemia was not present before or at the time of the spasms in 70% of the patients in the bardoxolone methyl groups who had muscle spasms (data not shown).Other adverse events that were more common in patients receiving bardoxolone methyl were mild elevations in alanine aminotransferase levels and gastrointestinal effects. Of the 170 patients who received bardoxolone methyl, 120 (71%) had transient aminotransferase elevations that peaked within 2 to 4 weeks after the initiation of treatment or an increase in the dose and generally resolved while the patients continued to take the drug. A total of 18 patients (11%) had an alanine aminotransferase elevation of more than three times the upper limit of the normal range. Persistent elevations at such levels were not observed, and such elevations did not recur once they had resolved. Total bilirubin levels were unchanged in patients with aminotransferase elevations, except in one patient with a posthepatic obstruction that was deemed to be unrelated to the study drug. Signs and symptoms of hepatic injury (i.e., severe, persistent, and concomitant pain in the right upper quadrant, jaundice, rash, vomiting, or malaise) were not observed.
There was no clear dose-related trend in blood pressure; blood-pressure values were variable, and doses of antihypertensive medications were adjusted during the study in most patients. Despite increases in blood pressure that were noted in some patients, there was no correlation between a change in blood pressure and the estimated GFR (Fig. 6 in the Supplementary Appendix). Weight reduction was observed in all the study groups (Table 1 in the Supplementary Appendix) and was more pronounced in patients with an increased body-mass index at baseline than in other patients (Table 3 in the Supplementary Appendix). Among patients receiving bardoxolone methyl, reductions in weight were independent of the magnitude of change in the estimated GFR (Table 4 in the Supplementary Appendix).
The total incidence of serious adverse events was similar in all study groups (Table 2, and Table 5 in the Supplementary Appendix). Discontinuations and withdrawals occurred primarily during the first 24 weeks of the study (Fig. 7 in the Supplementary Appendix). Sixteen patients discontinued bardoxolone methyl because of adverse events or changes in their medical status, with nine patients having more than one event. Events leading to discontinuation that were adjudicated to be possibly related to bardoxolone methyl included muscle spasms in six patients (4%), nausea and vomiting in three patients (2%), weight change in three patients (2%), and decreased appetite in two patients (1%) (Table 6 in the Supplementary Appendix). These events resolved after the discontinuation of bardoxolone methyl in all patients. One death occurred after cardiac-bypass surgery in a patient in the 75-mg group.
Discussion
Therapeutic interventions that suppress inflammation and oxidative stress may address both short-term (dynamic) and long-term (structural) contributors to a decline in the GFR in patients with CKD and could possibly stabilize or even improve kidney function.12 Bardoxolone methyl activates the Keap1–Nrf2 pathway, which regulates inflammation and oxidative stress.18 The deletion of Nrf2 in murine models results in structural and functional kidney defects that are associated with increased inflammation and oxidative stress.19-21,32,33 In a model of acute kidney injury, bardoxolone methyl induced Nrf2 expression (messenger RNA and protein), as well as its activity, which was measured indirectly through the expression of heme oxygenase 1, which is known to decrease the amount of reactive oxygen species and decrease inflammation.34 In this model, the use of bardoxolone methyl led to increased Nrf2 expression in glomerular endothelial cells and cortical peritubular capillaries, as well as to increased expression of heme oxygenase 1 in kidney tubules and interstitial leukocytes. A concomitant reduction in inflammation, decrease in the blood urea nitrogen level, and amelioration of both glomerular and tubular injury was observed.34
In our study, treatment with bardoxolone methyl for 52 weeks led to sustained, significant improvements in the estimated GFR among patients receiving standard medical care for CKD and type 2 diabetes. The estimated GFR increased in most patients receiving bardoxolone methyl but in less than half the patients in the placebo group. The time course of changes in the estimated GFR among patients receiving bardoxolone methyl suggests that there was a short-term effect during the first 12 weeks, which was followed by a longer-term effect. The estimated GFR remained above baseline levels 4 weeks after the discontinuation of bardoxolone methyl (i.e., approximately 17 half-lives of the drug). Although additional analyses are necessary, we speculate that such sustained increases in the estimated GFR after the discontinuation of bardoxolone methyl could be due to a decrease in the inflammation and oxidative stress associated with CKD. Moreover, increases in the estimated GFR occurred independently of changes in albumin excretion, a finding similar to that reported for patients with diabetic nephropathy who were treated with pirfenidone, a drug that inhibits inflammatory cytokines.35 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.
In a previous study, therapy with bardoxolone methyl was not associated with a short-term increase in biomarkers of renal injury (i.e., N-acetyl-β-D-glucosaminidase and neutrophil gelatinase-associated lipocalin), nor did it alter creatinine production or excretion.28 We did not assess these biomarkers in our study. Concurrent, correlated improvements in levels of blood urea nitrogen, uric acid, phosphate, and magnesium suggest that bardoxolone methyl has effects on multiple blood chemical values. Among these measures, blood urea nitrogen, which is not actively secreted by the kidney tubules, had the highest correlation with the estimated GFR. Although we did not directly assess tubular function, the decreased correlation between the estimated GFR and levels of uric acid, phosphate, and magnesium (which are handled by the kidney tubules) indicate that bardoxolone methyl may have a direct effect on solute transport in the tubules. Patients receiving bardoxolone methyl had slight but significant increases in the mean ACR, for which the mechanism is unknown. We speculate that such increases may result from increased glomerular filtration and decreased tubular resorption of protein due to an increased rate of tubular transit. Decreases in the ACR 4 weeks after the discontinuation of bardoxolone methyl may indicate that changes in the ACR are reversible.
There was no correlation between changes in the estimated GFR and in blood pressure. In addition, some patients had an increase in the estimated GFR without an increase in blood pressure. Although increases in blood pressure may have partly accounted for the increase in the estimated GFR in some patients, we believe it was not the predominant mechanism. This lack of correlation between blood-pressure changes and estimated GFR changes does not support the possibility of a short-term change in glomerular hemodynamics (hyperfiltration), followed by an accelerated decline in the GFR. Our study did not assess muscle mass, but the changes in the estimated GFR do not appear to be dependent on changes in body weight among patients receiving bardoxolone methyl.
Several of the most common adverse events were consistent with known pharmacologic effects of bardoxolone methyl. Because Nrf2 expression is ubiquitous, multiple physiological and biochemical changes may be observed in response to bardoxolone methyl and may be explained, at least in part, by the presumed mechanism of action. Transient, self-limited elevations in aminotransferase levels in patients receiving bardoxolone methyl resolved without drug withdrawal and were asymptomatic. Liver biopsies were performed in two patients on the basis of increased alanine aminotransferase levels; each patient had chronic disease that was deemed to be unrelated to the use of bardoxolone methyl (data not shown). Nrf2 has been shown to increase alanine aminotransferase levels transcriptionally.36 In preclinical studies in a model of hepatic injury, mild increases in aminotransferase levels that were caused by both genetic and bardoxolone methyl analogue–mediated Nrf2 activation were not associated with hepatic toxic effects. Nrf2 activation, in fact, inhibits acute inflammatory hepatic injury, despite the increase in aminotransferase levels.37
Among patients receiving bardoxolone methyl, muscle spasms were not associated with increases in lactate dehydrogenase levels, a marker of muscle damage, or with hypomagnesemia. The most common site of muscle spasms was the calf. Preclinical data showed that bardoxolone methyl increased glucose uptake in the calf muscle in mice with diabetes.38 Furthermore, insulin-mediated glucose uptake is associated with muscle spasms in humans. We hypothesize that muscle spasms in patients receiving bardoxolone methyl may be associated with a similar mechanism.
Our study has several limitations. The dose-adjustment design and the intention-to-treat analysis precluded a full assessment of dose-related efficacy, since many patients did not reach the target dose. Another limitation is the surrogate primary end point (the change in the estimated GFR). Measurement of the GFR to validate these results would be important. The confirmation of clinical benefit will require a larger, long-term study involving the assessment of clinical outcomes.
In conclusion, patients with advanced CKD and type 2 diabetes who received treatment with bardoxolone methyl had sustained increases in the estimated GFR throughout the 52-week study period, a finding that is consistent with an improvement in kidney function. Thus, bardoxolone methyl appears to be an attractive therapeutic candidate for further study in patients with CKD.
Supported by Reata Pharmaceuticals.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article (10.1056/NEJMoa1105351) was published on June 24, 2011, at NEJM.org.
We thank Drs. Michael Sporn, Gordon Gribble, Tadashi Honda, Nanjoo Suh, and Karen Liby for their discovery and characterization of bardoxolone methyl; and Dr. Edmund Doherty, Danielle Wrolstad, and Ritu Rajan for their assistance in the preparation of the manuscript.
Source Information
From Renal Associates, San Antonio, TX (P.E.P.); the Department of Medicine, University of Texas Southwestern, Dallas (P.R., R.D.T.); Reata Pharmaceuticals, Irving, TX (C.JM., J.W.H., E.B.G., M.K., S.R., P.A.); Statistics Collaborative, Washington, DC (H.C.-S., J.W.); and the Department of Medicine, University of Alabama at Birmingham, Birmingham (D.G.W.).
Address reprint requests to Dr. Pergola at Renal Associates, 215 E. Quincy, Suite 610, San Antonio, TX 78215, or at ppergola@raparesearch.com.
The investigators in the 52-Week Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) study are listed in the Supplementary Appendix, available at NEJM.org.
- References
References
1
Kidney Disease Outcomes Quality InitiativeKDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 2007;49:Suppl 2:S12-S154
CrossRef | Web of Science | Medline2
Stenvinkel P . Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 2010;268:456-467
CrossRef | Web of Science | Medline3
Go AS ,Chertow GM ,Fan D ,McCulloch CE ,Hsu C . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305
Full Text | Web of Science | Medline4
National Kidney Foundation
Web of Science | Medline5
Barnett AH ,Bain SC ,Bouter P , et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952-1961[Erratum, N Engl J Med 2005;352:1731.]
Full Text | Web of Science | Medline6
Mann JF ,Schmieder RE ,McQueen M , et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-553
CrossRef | Web of Science | Medline7
Navaneethan SD ,Nigwekar SU ,Sehgal AR ,Strippoli GF . Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;4:542-551
CrossRef | Web of Science | Medline8
Onuigbo MA . Can ACE inhibitors and angiotensin receptor blockers be detrimental in CKD patients? Nephron Clin Pract 2011;118:c407-c419
CrossRef | Web of Science | Medline9
Rahman M ,Pressel S ,Davis BR , et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005;165:936-946
CrossRef | Web of Science | Medline10
Garrido AM ,Griendling KK . NADPH oxidases and angiotensin II receptor signaling. Mol Cell Endocrinol 2009;302:148-158
CrossRef | Web of Science | Medline11
Marrero MB ,Fulton D ,Stepp D ,Stern DM . Angiotensin II-induced signaling pathways in diabetes. Curr Diabetes Rev 2005;1:197-202
CrossRef | Medline12
Cachofeiro V ,Goicochea M ,de Vinuesa SG ,Oubina P ,Lahera V ,Luno J . Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease. Kidney Int Suppl 2008;111:S4-S9
CrossRef | Medline13
Lemley KV ,Abdullah I ,Myers BD , et al. Evolution of incipient nephropathy in type 2 diabetes mellitus. Kidney Int 2000;58:1228-1237[Erratum, Kidney Int 2000;58:2257.]
CrossRef | Web of Science | Medline14
Hayashi H ,Karasawa R ,Inn H , et al. An electron microscopic study of glomeruli in Japanese patients with non-insulin dependent diabetes mellitus. Kidney Int 1992;41:749-757
CrossRef | Web of Science | Medline15
Mauer SM ,Steffes MW ,Ellis EN ,Sutherland DE ,Brown DM ,Goetz FC . Structural-functional relationships in diabetic nephropathy. J Clin Invest 1984;74:1143-1155
CrossRef | Web of Science | Medline16
Fioretto P ,Caramori ML ,Mauer M . The kidney in diabetes: dynamic pathways of injury and repair: the Camillo Golgi Lecture 2007. Diabetologia 2008;51:1347-1355
CrossRef | Web of Science | Medline17
Raptis AE ,Viberti G . Pathogenesis of diabetic nephropathy. Exp Clin Endocrinol Diabetes 2001;109:Suppl 2:S424-S437
CrossRef | Web of Science | Medline18
Dinkova-Kostova AT ,Liby KT ,Stephenson KK , et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci U S A 2005;102:4584-4589
CrossRef | Web of Science | Medline19
Li J ,Stein TD ,Johnson JA . Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice. Physiol Genomics 2004;18:261-272
CrossRef | Web of Science | Medline20
Yoh K ,Itoh K ,Enomoto A , et al. Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 2001;60:1343-1353
CrossRef | Web of Science | Medline21
Ma Q ,Battelli L ,Hubbs AF . Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am J Pathol 2006;168:1960-1974
CrossRef | Web of Science | Medline22
Yates MS ,Tauchi M ,Katsuoka F , et al. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther 2007;6:154-162
CrossRef | Web of Science | Medline23
Sporn MB ,Liby KT ,Yore MM ,Fu L ,Lopchuk JM ,Gribble GW . New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 2011;74:537-545
CrossRef | Web of Science | Medline24
Levonen AL ,Landar A ,Ramachandran A , et al. Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem J 2004;378:373-382
CrossRef | Web of Science | Medline25
Ahmad R ,Raina D ,Meyer C ,Kharbanda S ,Kufe D . Triterpenoid CDDO-Me blocks the NF-{kappa}B pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem 2006;281:35764-35769
CrossRef | Web of Science | Medline26
Straus DS ,Pascual G ,Li M , et al. 15-Deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci U S A 2000;97:4844-4849
CrossRef | Web of Science | Medline27
Serhan CN ,Chiang N ,Van Dyke TE . Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008;8:349-361
CrossRef | Web of Science | Medline28
Pergola P ,Krauth M ,Huff JW , et al. Effect of bardoxolone on kidney function in patients with T2D and stage 3b-4 CKD. Am J Nephrol 2011;33:469-476
CrossRef | Web of Science | Medline29
Levey AS ,Coresh J ,Greene T , et al. Using standardized serum creatinine values in the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247-254[Erratum, Ann Intern Med 2008;149:519.]
Web of Science | Medline30
Dunnett CW ,Tamhane ACA . Step-up multiple test procedure. J Am Stat Assoc 1992;87:162-170
CrossRef | Web of Science31
Woflinger R . Covariance structure selection in general mixed models. Comm Statist Simulation Comput 1993;22:1079-1106
CrossRef | Web of Science32
Itoh K ,Mochizuki M ,Ishii Y , et al. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). Mol Cell Biol 2004;24:36-45
CrossRef | Web of Science | Medline33
Kobayashi M ,Yamamoto M . Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 2005;7:385-394
CrossRef | Web of Science | Medline34
Wu QQ ,Wang Y ,Senitko M , et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPAR{gamma}, and HO-1. Am J Physiol Renal Physiol 2011;300:F1180-F1192
CrossRef | Web of Science | Medline35
Sharma K ,Ix JH ,Mathew AV , et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol 2011;22:1144-1151
CrossRef | Web of Science | Medline36
Osburn WO ,Yates MS ,Dolan PD , et al. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci 2008;104:218-227
CrossRef | Web of Science | Medline37
Malhotra D ,Portales-Casamar E ,Singh A , et al. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 2010;38:5718-5734
CrossRef | Web of Science | Medline38
Saha PK ,Reddy VT ,Konopleva M ,Andreeff M ,Chan L . The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent antidiabetic effects in diet-induced diabetic mice and Lepr(db/db) mice. J Biol Chem 2010;285:40581-40592
CrossRef | Web of Science | Medline
- Citing Articles (28)
Citing Articles
1
L. Gnudi. (2012) Cellular and molecular mechanisms of diabetic glomerulopathy. Nephrology Dialysis Transplantation
CrossRef2
B. N. Chorley, M. R. Campbell, X. Wang, M. Karaca, D. Sambandan, F. Bangura, P. Xue, J. Pi, S. R. Kleeberger, D. A. Bell. (2012) Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Research
CrossRef3
Suqing Zheng, Y. R. Santosh Laxmi, Emilie David, Albena T. Dinkova-Kostova, Katherine H. Shiavoni, Yanqing Ren, Ying Zheng, Isaac Trevino, Ronald Bumeister, Iwao Ojima, W. Christian Wigley, James B. Bliska, Dale F. Mierke, Tadashi Honda. (2012) Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents(1). Journal of Medicinal Chemistry120507094643009
CrossRef4
N. Suh, S. Paul, H.J. Lee, T. Yoon, N. Shah, A.I. Son, A.H. Reddi, D. Medici, M.B. Sporn. (2012) Synthetic triterpenoids, CDDO-Imidazolide and CDDO-Ethyl amide, induce chondrogenesis. Osteoarthritis and Cartilage 20:5, 446-450
CrossRef5
Jade S. Hiramoto, Ronit Katz, Carmen A. Peralta, Joachim H. Ix, Linda Fried, Mary Cushman, David Siscovick, Walter Palmas, Mark Sarnak, Michael G. Shlipak. (2012) Inflammation and Coagulation Markers and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA). American Journal of Kidney Diseases
CrossRef6
Brian Shepler, Christy Nash, Cory Smith, Abbey DiMarco, Josie Petty, Stephanie Szewciw. (2012) Update on Potential Drugs for the Treatment of Diabetic Kidney Disease. Clinical Therapeutics
CrossRef7
Subodh J. Saggi, Michael Allon, Judith Bernardini, Kamyar Kalantar-Zadeh, Rachel Shaffer, Rajnish Mehrotra. (2012) Considerations in the optimal preparation of patients for dialysis. Nature Reviews Nephrology
CrossRef8
James T. Handa. (2012) How does the macula protect itself from oxidative stress?. Molecular Aspects of Medicine
CrossRef9
Sadagopan Magesh, Yu Chen, Longqin Hu. (2012) Small Molecule Modulators of Keap1-Nrf2-ARE Pathway as Potential Preventive and Therapeutic Agents. Medicinal Research Reviewsn/a-n/a
CrossRef10
Basem Azab, Jacques Daoud, Fahad Ben Naeem, Rabih Nasr, Jennifer Ross, Pratima Ghimire, Ayesha Siddiqui, Nadine Azzi, Nancy Rihana, Marie Abdallah, Nassif Azzi, Parishram Patel, Morton Kleiner, Suzanne El-Sayegh. (2012) Neutrophil-to-Lymphocyte Ratio as a Predictor of Worsening Renal Function in Diabetic Patients (3-Year Follow-Up Study). Renal Failure1-6
CrossRef11
Erwin Tschachler, Leopold Eckhart, Florian Gruber. (2012) ‘Don't be so over-protective!’. EMBO Molecular Medicinen/a-n/a
CrossRef12
Richard Steel, Jonathan Cowan, Estelle Payerne, Maria A. O'Connell, Mark Searcey. (2012) Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction. ACS Medicinal Chemistry Letters120314110725002
CrossRef13
Daniel Merk, Manfred Schubert-Zsilavecz. (2012) New hope or drawbacks: will chronic kidney disease be treatable with small molecules in the near future?. Future Medicinal Chemistry 4:3, 269-271
CrossRef14
Miklos Z. Molnar, Akinlolu O. Ojo, Suphamai Bunnapradist, Csaba P. Kovesdy, Kamyar Kalantar-Zadeh. (2012) Timing of dialysis initiation in transplant-naive and failed transplant patients. Nature Reviews Nephrology
CrossRef15
Tonibelle N. Gatbonton-Schwager, John J. Letterio, Gregory P. Tochtrop. (2012) Bryonolic Acid Transcriptional Control of Anti-inflammatory and Antioxidant Genes in Macrophages in Vitro and in Vivo. Journal of Natural Products120216110549005
CrossRef16
Shinji Hagiwara, Phillip Kantharidis, Mark E. Cooper. (2012) What Are New Avenues for Renal Protection, in Addition to RAAS Inhibition?. Current Hypertension Reports
CrossRef17
Sarah Crunkhorn. (2012) Deal watch: Abbott boosts investment in NRF2 activators for reducing oxidative stress. Nature Reviews Drug Discovery 11:2, 96-96
CrossRef18
Jaime Uribarri, Man S Oh. (2012) The key to halting progression of CKD might be in the produce market, not in the pharmacy. Kidney International 81:1, 7-9
CrossRef19
Bing Li, Shujun Liu, Lining Miao, Lu Cai. (2012) Prevention of Diabetic Complications by Activation of Nrf2: Diabetic Cardiomyopathy and Nephropathy. Experimental Diabetes Research 2012, 1-7
CrossRef20
Tej K. Pareek, Abdelmadjid Belkadi, Sashi Kesavapany, Anita Zaremba, Sook L. Loh, Lianhua Bai, Mark L. Cohen, Colin Meyer, Karen T. Liby, Robert H. Miller, Michael B. Sporn, John J. Letterio. (2011) Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Scientific Reports 1,
CrossRef21
Jeffrey M Turner, Carolyn Bauer, Matthew K Abramowitz, Michal L Melamed, Thomas H Hostetter. (2011) Treatment of chronic kidney disease. Kidney International
CrossRef22
Adeera Levin. (2011) Nondialysis chronic kidney disease in 2011: Progression, prediction, populations and possibilities. Nature Reviews Nephrology
CrossRef23
(2011) Bardoxolone Methyl, Chronic Kidney Disease, and Type 2 Diabetes. New England Journal of Medicine 365:18, 1745-1747
Full Text24
Andrew A. House, Matthew A. Weir. (2011) Sulodexide for Diabetic Nephropathy: Another One Bites the Dust. American Journal of Kidney Diseases 58:5, 692-694
CrossRef25
Erik Ames, Salif Harouna, Colin Meyer, Lisbeth A. Welniak, William J. Murphy. (2011) The Triterpenoid CDDO-Me Promotes Hematopoietic Progenitor Expansion and Myelopoiesis in Mice. Biology of Blood and Marrow Transplantation
CrossRef26
Michele B. Kaufman. (2011) New approvals. Dialysis & Transplantation 40:9, 422-423
CrossRef27
Brooks M. Hybertson, Bifeng Gao, Swapan K. Bose, Joe M. McCord. (2011) Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation. Molecular Aspects of Medicine 32:4-6, 234-246
CrossRef28
R. Garrick. (2011) Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes. Yearbook of Medicine 2011, 213-214
CrossRef
- Letters
