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J Am Soc Nephrol. Mar 2010; 21(3): 527–535.
PMCID: PMC2831858

Avosentan for Overt Diabetic Nephropathy

Abstract

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

Data from animal studies and observational data from humans suggest that proteinuria is not simply a biomarker of renal disease but also contributes to progressive renal damage, ultimately leading to ESRD.1 Proteinuric nephropathies are a leading cause of ESRD, and, despite current available treatments, most patients still exhibit residual proteinuria and disease progression.14 In controlled trials, 15 to 20% of patients who had type 2 diabetes and overt diabetic nephropathy and had been intensively treated still reached ESRD after only 2.5 to 3.5 years.2,3 Clearly, there is a need for the development of new strategies to reduce further and perhaps arrest the rate of loss of renal function.

Endothelin 1, via the activation of the endothelin type A (ETA) receptor, seems to have a central role in the pathogenesis of proteinuria.5,6 In short-term (up to 12 weeks) proof-of-concept clinical studies, avosentan, a predominant ETA receptor antagonist, reduced proteinuria in people who had diabetes and were on maximal dosages of inhibitors of the renin-angiotensin system.79 This antiproteinuric effect was achieved without significant changes in BP.

We therefore examined the effect of avosentan on time to doubling of serum creatinine, ESRD, or death (A Randomised, Double Blind, Placebo Controlled, Parallel Group Study to Assess the Effect of the Endothelin Receptor Antagonist Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death in Patients With Type 2 Diabetes Mellitus and Diabetic Nephropathy [ASCEND]) and evaluated, as secondary outcomes, changes in urine albumin excretion and in estimated GFR (eGFR), as well as cardiovascular outcomes in people with type 2 diabetes and overt diabetic nephropathy. Safety aspects were monitored throughout the study.

Results

The Steering Committee terminated the trial prematurely on the recommendation of the Data Safety and Monitoring Board (DSMB) because of an excess of cardiovascular events with avosentan, mainly congestive heart failure (CHF) and fluid overload. The median treatment period was 4 months with avosentan 25 and 50 mg and 5 months with placebo. At study termination, 3523 patients had been screened and 1402 randomly assigned. Of the latter, seven did not receive any trial medication, and no follow-up information was available for three, leaving 1392 patients for the intention-to-treat analysis (Figure 1). Treatment exposure was 183, 192, and 224 patient-years for avosentan 25 and 50 mg and placebo, respectively. Baseline characteristics were similar between groups (Table 1) and typical for stages 3 to 4 chronic kidney disease (CKD) and overt diabetic nephropathy.

Figure 1.
Screen failure was almost exclusively due to an ACR below the inclusion criterion of 35 mg/mmol or a serum creatinine outside the inclusion criteria. For definitions and details of primary and secondary outcomes, see Table 2 and the Concise Methods section. ...
Table 1.
Baseline demographic, clinical, and biochemical characteristics

Primary and Secondary Outcomes

The proportion of patients who met the primary composite end point of doubling of serum creatinine, ESRD, or death was not significantly different among the three groups (Table 2, Figure 2). Fewer patients on avosentan experienced ESRD, but more died compared with placebo. These differences were NS. The reason for death could be ascertained in 29 of the 46 adjudicated cases; death was due to cardiovascular causes in 74%. After the trial had ended and participants stopped trial medication, four additional deaths were reported with avosentan 25 mg/d (see Table 2). Cardiovascular outcomes were more frequent with avosentan, specifically CHF (Table 2).

Table 2.
Occurrence of the adjudicated primary composite outcome of doubling of serum creatinine, ESRD, or death and its individual components and of secondary outcomes
Figure 2.
Kaplan-Meier plot shows time to doubling of serum creatinine, ESRD, or death in patients who had type 2 diabetes and diabetic nephropathy and were treated with avosentan 25 mg/d, avosentan 50 mg/d, or placebo (n = 1392). There were no significant differences ...

The eGFR declined during the study in all three groups by 2.5 to 4 ml/min per 1.73 m2 during 6 months (Table 3). The decrease in eGFR was slightly greater in the avosentan 50-mg group compared with placebo at both 3 months (P = 0.030) and 6 months (P = 0.018) with no significant difference for avosentan 25 mg. The median albumin-to-creatinine ratio (ACR) significantly declined similarly by 40 to 50% in both avosentan groups (NS between the two avosentan groups) and by 8 to 10% with placebo (P < 0.0001 versus both avosentan groups, adjusted for changes of BP; Figure 3, Table 3). When the changes in ACR were corrected for the changes in eGFR, these differences persisted (see Supplemental Appendix 1).

Table 3.
Change in eGFR (ml/min per 1.73 m2) and in ACR (mg/mmol)
Figure 3.
Urine ACR changed significantly (P < 0.0001; see Table 3) in the avosentan (av)-treated groups during the first 6 months of the trial. Medians and interquartile ranges are given. Similar differences were found for fractional excretion of urine ...

Changes of Body Weight and BP

Mean ± SD body weight increased by 0.4 ± 3.0, 0.3 ± 2.9, and 0.0 ± 2.7 kg, respectively, at 3 months and then remained stable up to 6 months. BP declined by 0.0 to −0.5 mmHg systolic and diastolic with placebo and by −4.1 to −6.1 mmHg systolic and by −3.0 to −4.4 mmHg diastolic in both avosentan groups (P = 0.003 to 0.118 for placebo versus avosentan; range of mean values for systolic and diastolic BP and of P values at 3 and 6 months, for details see Supplemental Appendix 2). After 3 months, the proportion of patients who achieved target BP was 66.9% with avosentan 25 mg, 62.6% with avosentan 50 mg, and 50.0% with placebo.

Adverse Events

Serious adverse events occurred more often with avosentan as did adverse events leading to premature discontinuation of trial medication (Tables 4 and and5).5). Signs and symptoms of fluid overload were significantly more frequent with avosentan (Figure 4). In particular, there were more reports of pulmonary edema and of CHF with avosentan (Tables 2 and and5).5). Of participants who permanently discontinued trial medication as a result of adverse events, the most common reason was symptoms of fluid overload, reported by 44 of 89, 38 of 87, and eight of 53 participants with avosentan 25 mg, 50 mg, and placebo, respectively, followed by worsening of renal function in 18 of 89, 20 of 87, and 18 of 53, respectively.

Table 4.
Occurrence of adverse events
Table 5.
Frequency of adverse events relating to fluid overload as reported by the clinical investigators on adverse event forms (not adjudicated)
Figure 4.
Fluid overload occurred in the avosentan-treated groups. Fluid overload was not defined by the trial protocol but taken from the adverse event reports of the local investigators. All participants were followed at monthly intervals and examined for adverse ...

Mean ± SD hemoglobin levels decreased in patients who were taking avosentan 25 mg by 11.4 ± 11.7 g/L, avosentan 50 mg by 11.0 ± 12.6 g/L, and placebo by 0.1 ± 9.0 g/L from baseline to 3 months (P < 0.001 for both avosentan groups versus placebo) and remained stable thereafter (data not shown). Anemia was reported as an adverse event more frequently with avosentan than with placebo (Table 4). The incidence of an increase in any liver function test above the upper limit of normal was not different between avosentan and placebo groups (65 [14.2%], 80 [16.7%], and 96 [20.9%] with avosentan 25 and 50 mg and placebo, respectively). A small proportion of patients who exhibited an increase in one or more liver function tests had increases up to twice the upper limit of normal of these tests.

Discussion

Although ASCEND was terminated prematurely because of safety concerns, it provides new information about the effects of a predominant ETA receptor antagonist in patients with type 2 diabetes and stages 3 to 4 CKD. At the dosages used, avosentan induced a major decrease in proteinuria but also symptoms of fluid overload with serious consequences in some patients that led to the discontinuation of the trial. Of particular concern was a trend to a higher mortality with avosentan. eGFR fell to a greater extent with avosentan 50 mg/d, and anemia, hypoglycemia, and hypotension were reported more frequently by the investigators in patients who received avosentan.

Avosentan reduced albuminuria by 40 to 50% in patients who had an average baseline albuminuria close to 1.5 g/g creatinine; exhibited reasonable BP control8,9; and received extensive treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), other antihypertensive drugs, diuretics, and statins. In another study on diabetic nephropathy, a 50% reduction in albuminuria was associated with a relative risk reduction for ESRD of approximately 50%.10 In people with less albuminuria, the association of albuminuria reduction and reduction of ESRD risk may be less pronounced.11 Our findings on proteinuria confirm previous observations in shorter small-scale studies over several weeks with avosentan in patients with overt diabetic nephropathy but with less advanced renal insufficiency9 and in acute studies with infusion of BQ-123, another ETA receptor antagonist.12 The effect on albuminuria is likely due to inhibition of the renal ETA receptor, because other researchers have found that the mixed type ETA/B receptor antagonists have a weaker or no effect on proteinuria.1214 The slightly greater decrease in eGFR that was observed with avosentan does not seem to explain the substantial difference in albuminuria between placebo and avosentan,15 because this persisted after correction for the changes in eGFR.

It is generally thought that additional lowering of albuminuria in diabetic nephropathy may protect the kidney from progressive loss of function; however, because of the early termination of ASCEND, the number of primary outcomes was insufficient to test the latter hypothesis with avosentan. Primary outcomes occurred at approximately the same rate with avosentan and placebo, and the decrease in eGFR, a secondary outcome, seemed to be slightly faster with avosentan. Whether the faster fall in eGFR was the result of avosentan-induced lower intraglomerular pressure, an effect that could translate into long-term benefit,1,15 remains a moot point. ESRD seemed to occur less frequently with avosentan, and we cannot exclude that a beneficial effect on the kidney was outweighed by increased early mortality. Avosentan caused a moderate decrease in systolic BP by 3 to 6 mmHg, compared with <0.5 mmHg with placebo, that does not fully explain a change of proteinuria by approximately 40 to 50%.15,16 ETA receptor antagonists can lower BP17 and more so in combination with ACEIs18 and in those with CKD.13

The administration of avosentan at the dosages of 25 and 50 mg/d was associated with symptoms of fluid overload that led to life-threatening complications in some patients. The modest weight gain in ASCEND of approximately 0.5 kg during 6 months with avosentan may be explained by fluid retention but also fluid redistribution. Edema formation has been observed before with ETA and mixed type ETA/B receptor antagonists.1719 For avosentan, a predominant type A antagonist, these effects were seen mainly at dosages of ≥5 mg/d, but they were not found to be life threatening in shorter term studies of patients with less advanced renal disease.8,9 It may be that at dosages of 25 to 50 mg, avosentan is less selective for the ETA receptor and thus caused sodium and water retention and peripheral vasodilation with a potential fluid shift from the intravascular to extravascular space.20,21 The assumption of ETB receptor blockade with higher dosages of avosentan is further supported by data that showed a natriuretic effect of selective ETA receptor blockade in people who were treated with ACEIs.13 The ETA receptor mediates vasoconstriction, cellular proliferation, and matrix deposition and also renal sodium retention, whereas the function of ETB is mainly vasodilatory, depending on its anatomic location, and also mediates action on endothelin clearance and on renal sodium handling. The action of a given endothelin antagonist will depend on its selectivity and on the activation of ETA versus ETB receptors in a given clinical situation. In healthy individuals, only minor effects on fluid shifts were found at avosentan dosages of ≤5 mg/d.21

In long-term trials of patients who had advanced heart failure and received endothelin receptor antagonists (either ETA/B or ETA), peripheral edema but not pulmonary edema was observed.1719 In some heart failure studies, such as Heart Failure ETA Receptor Blockade Trial (HEAT), ETA Receptor Antagonism Trial in Heart Failure (EARTH), Research on Endothelin Antagonism in Chronic Heart Failure (REACH-1), and Lowering Cardiac Events in Heart Failure (ENABLE), short-term hemodynamic benefit of endothelin antagonism was noted but no benefit on hard outcomes, and even more adverse events, including death, were reported.18,19 It is important to note that patients who enrolled in ASCEND were prone to fluid retention by the very nature of their disease, and, indeed, edema was noted in approximately 15% of the participants at baseline physical examination, but participants with New York Heart Association stage III or IV CHF, the predominant population of the heart failure trials mentioned, were excluded.

Some endothelin receptor antagonists have also been associated with hepatic dysfunction and anemia. In our trial, no signal of hepatic toxicity was detected with monthly monitoring, but hemoglobin levels declined by approximately 10 g/L. This decline may be due to hemodilution. A reduction in hemoglobin has been reported with other endothelin receptor antagonists.17

The major limitation of this study was the short treatment exposure time, which precludes conclusions for the primary outcome. Despite its potent albuminuria-lowering effect, it is clear that avosentan at the doses of 25 and 50 mg/d in a population of patients with type 2 diabetes and 3 to 4 CKD stage is not a viable therapeutic option. The clear dosage dependence of the renal and hemodynamic effects of avosentan shown in other studies7 raises the question as to whether lower dosages of avosentan would maintain the antialbuminuric effect, thereby affording a significantly more favorable risk-benefit ratio, especially at earlier stages of CKD and with more strict control of sodium balance.

Concise Methods

Design Overview

ASCEND was an international, multicenter, randomized, double-blind study of people with type 2 diabetes and overt nephropathy that started in July 2005 and was prematurely discontinued in December 2006 on recommendation of the DSMB because of an excess of cardiovascular events. After a 2-week screening phase to check eligibility, a 42-month treatment phase was scheduled with three randomized treatments, either placebo or avosentan tablets at 25 or 50 mg once daily, as add-on to existing treatment. Tablets were identical in shape, color, and taste. All participants gave written informed consent. Approval from all local and central ethics committees and by regulatory authorities was obtained consistent with the principles of the Declaration of Helsinki.

Setting and Participants

In 551 clinical centers in 36 countries worldwide, men and women who had type 2 diabetes and overt nephropathy and were aged between 21 and 80 years were recruited. Clinical centers were selected, on the basis of their previous experience with clinical trials, by members of the steering committee and by Quintiles, the contract research organization involved. Diabetes had to be known for at least 3 years and had to be treated by oral antidiabetic drugs and/or insulin. Overt nephropathy was defined as urine ACR ≥35 mg/mmol (≥309 mg/g) and a serum creatinine level between ≥115 and 265 mmol/L (≥1.3 to 3.0 mg/dl) in men and between ≥106 and 265 mmol/L (≥1.2 to 3.0 mg/dl) in women. Standard treatment for diabetic nephropathy had to include ACEIs or ARBs or their combination for at least 6 months before screening, but participants who were intolerant of ACEIs or ARBs were not excluded. Exclusion criteria were type 1 diabetes, proteinuria of nondiabetic origin, renal transplant, previous nephrectomy, eGFR ≤15 ml/min, sitting BP ≥160/100 mmHg with or without antihypertensive medication, or New York Heart Association stage III or IV CHF, glycosylated hemoglobin >12%, prolonged QT or QTc >500 ms with normal sinus rhythm; recent (60 days) history of acute myocardial infarction, unstable angina, stroke or transient ischemic attack, percutaneous transluminal coronary angioplasty, percutaneous coronary intervention, coronary artery bypass grafting, or any other major surgical intervention; history of life-threatening arrhythmias including those at high risk for QT/QTc prolongation such as a family history of long QT syndrome, severe hypokalemia, hepatitis B surface antigen or hepatitis C antibody positivity and abnormal liver function (specifically alanine aminotransferase/aspartate aminotransferase >1× upper limit of normal); treatment with spironolactone, eplerenone, or amiodarone; and women who were of child-bearing potential and not using adequate contraception.

Randomization and Interventions

Participants were randomly assigned 2 weeks after the screening visit to avosentan 25 or 50 mg/d or matching placebo on a 1:1:1 basis by an automated interactive voice recognition system in blocks of six. Treatment allocation was not known to patients or their physicians or anybody within or outside the study except a statistician who was not involved in the study and reported exclusively to the DSMB. During the study, a goal BP of <130/80 mmHg was recommended by the trial protocol. When BP was higher at any given visit, investigators were instructed to increase ACEIs or ARBs to maximal tolerated dosages, then to add diuretics followed by calcium antagonists or β blockers. Further recommended drugs were peripheral α blockers, central α agonists, and other agents according to local guidelines of antihypertensive therapy. Renal elimination of avosentan is <1%.

Outcomes and Measurements

The primary outcome was defined as the composite of time to doubling of serum creatinine, ESRD, or death. ESRD was defined as need for dialysis or renal transplantation or an eGFR <15 ml/min per 1.73 m2. Both doubling of serum creatinine and eGFR ≤15 ml/min per 1.73 m2 had to be confirmed by a second measurement within 4 ± 1 weeks. Secondary outcomes were changes in eGFR and in urine ACR and cardiovascular outcomes that were defined as the composite of coronary or peripheral vascular revascularization, amputations (except from trauma), nonfatal acute myocardial infarction, stroke, and CHF. For an event to be qualified as CHF, the patient had to have typical signs and/or symptoms of heart failure and receive new therapy for CHF and be admitted to hospital for at least 24 hours. For myocardial infarction, two of three criteria had to be met (ischemic symptoms, typical electrocardiogram changes, and cardiac enzymes two-fold above upper limit of normal); for stroke, there had to be a focal neurologic deficit for >24 hours and a computed tomography or magnetic resonance scan was strongly recommended. Death was classified as cardiovascular or noncardiovascular. All primary and secondary outcomes, except for eGFR and ACR, were adjudicated by an independent clinical end point committee that was unaware of treatment allocation.

Because the trial was terminated early, all adverse event reports were examined for evidence of fluid overload. The following items in those reports were grouped as indicating fluid overload: Heart failure, edema, fluid overload, fluid retention, hypervolemia, dyspnea, pleural and pericardial effusions, ascites, weight increase, pulmonary rales, and pulmonary edema.

All laboratory parameters were measured centrally. Creatinine in blood and urine was measured by the Jaffe method and urine albumin by the Roche Tinaquant turbidimetric method on Roche Modular analyzers (Roche, Basel, Switzerland). For each urine measurement, first-void morning sample was collected on 3 consecutive days, and the geometric mean albumin concentration value was recorded in the database. From the serum creatinine concentration, eGFR was calculated using the six-variable Modification of Diet in Renal Disease (MDRD) formula that includes age, race, gender, serum albumin, and serum urea.22,23

Follow-up Procedures and Monitoring

Participants were followed up at monthly intervals. At each visit, sitting BP after 10 minutes of rest, body weight, and blood for liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin) were taken, and adverse events were recorded. Electrocardiogram and serum creatinine and potassium were measured at baseline, at 1 and 3 months after randomization, and every 3 months thereafter. Urine ACR and glycosylated hemoglobin were measured at baseline and every 3 months thereafter.

Statistical Analysis

A sample size of 2364 patients and 747 primary outcomes were calculated to provide a 90% power at the 5% level (two-sided) to detect a 7% (25-mg dose) and 10% (50-mg dose) absolute reduction of the primary outcome compared with the placebo group, assuming a placebo cumulative incidence of 40% at 36 months for the primary outcome. This calculation incorporated two interim analyses of the DSMB, a 1% loss to follow-up, and a constant enrollment over 18 months. Because the study terminated early, most results are presented for the first 3 and 6 months of the trial, for which follow-up data were available for a substantial number of participants.

Continuous data are given as mean ± SD and categorical data as actual frequencies and percentages. The primary analysis used a time-to-event approach using the Kaplan-Meier method and included all randomly assigned participants who received at least one dose of randomized treatment and had at least one postbaseline visit (intention-to-treat population). Treatment comparisons with regard to time-to-event–related data (based on Cox regression of time to occurrence of first event) are displayed as hazard ratio with 95% confidence interval. All P values are two-sided and not adjusted for multiplicity. Treatment group comparisons for categorical data were performed using the Cochran-Mantel-Haenszel χ2 test controlling for investigator center. Comparisons for continuous variables, eGFR, and ACR between treatment groups were analyzed by a repeated measures ANOVA, with the values at 3 and 6 months being the response variables and treatment group the effect variable, with baseline as a covariate. Urine ACRs were not normally distributed; therefore, median and interquartile range are reported. For statistical comparisons between groups, ACR was log-transformed.

Disclosures

Speedel Pharma Ltd., Switzerland, sponsored the study and appointed the contract research organization, Quintiles Ltd., for study set-up, initiation, management, monitoring, laboratory analyses, data management, and statistical analysis. The contract research organization housed all blinded data during the treatment phase of the study and performed data analyses according to a prespecified statistical plan developed with and approved by the Steering Committee. The Steering Committee members had access to all data analyses, wrote the manuscript, and made the decision to publish, with no restrictions imposed by the sponsor.

All authors contributed to the design, conduct, analysis, and reporting of this study and approved the final draft. S.J.K. and T.L. were employees of the sponsor; all other authors report receiving honoraria for consultancy with the sponsor.

Supplementary Material

[Supplemental Data]
[Press Release]

Acknowledgments

We thank the many trial coordinators, national coordinators, local investigators, and patients for support of ASCEND. Influence Medical Communication, UK, provided support with the tabulation and graphs but had no influence on the scientific content of this report. Three independent committees were appointed before initiation of the study to supervise the conduct of the study and undertake specific functions: The Steering Committee, the Data Safety and Monitoring Board, and the Clinical Endpoint Committee. The composition of these committees is reported in Supplemental Appendix 1.

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

This trial has been registered at http://www.clinicaltrials.gov (identifier NCT00120328).

See related editorial, “Endothelin Receptor Antagonists in Proteinuric Renal Disease: Every Rose Has Its Thorn,” on pages 392–394.

Supplemental information for this article is available online at http://www.jasn.org/.

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