Despite aggressive treatments, individuals with kidney disease often experience proteinuria, or excessive loss of protein in the urine, which increases kidney damage. A key factor in the development of proteinuria is endothelin, which by constricting blood vessels and raising blood pressure, causes the kidney''s filtering function to deteriorate. Researchers suspect that blocking the endothelin peptide could be a promising new treatment strategy for patients who develop proteinuria. Endothelin antagonists such as oral avosentan are already available and are prescribed for patients with cardiovascular conditions.
Johannes Mann, MD (Schwabing General Hospital and KfH Kidney Centre, in Munchen, Germany) and his colleagues examined the effects of avosentan on proteinuria and kidney function in patients with type 2 diabetes and kidney disease through a multicenter, multinational, double-blind, controlled trial. The Avosentan ASCEND study enrolled 1392 patients already being treated for kidney disease and randomized them to receive avosentan 25 mg, avosentan 50 mg, or placebo.
While avosentan at either dose lowered patients'' urinary protein excretion by 40%-50% (compared with less than 10% in patients taking placebo), individuals taking the drug experienced a high incidence of serious, sometimes life-threatening side effects. These included complications of fluid overload such as pulmonary edema, as well as congestive heart failure. In addition, there were more deaths in the groups taking avosentan (21 and 17) than in the group taking placebo (12).
Dr. Mann noted that the findings from the ASCEND trial highlight the risks and potential benefits of endothelin antagonists in kidney disease patients with proteinuria and will help investigators design future studies to test the drugs'' potential. Specifically, lower doses of avosentan may generate more positive results.
Speedel Pharma Ltd, Switzerland, sponsored the study and appointed the contract research organization Quintiles Ltd for study set-up, initiation, management, and analysis. Study co-authors include Damian Green (Quintiles Ltd, Strasbourg, France); Kenneth Jamerson, MD (University of Michigan); Luis Ruilope, MD (Hospital 12 de Octubre, Madrid, Spain); Susan Kuranoff, Thomas Littke, MD (Speedel Pharma Ltd, Basel, Switzerland); and Giancarlo Viberti, MD, FRCP (King''s College London School of Medicine, Guy''s Hospital, London, UK) for the ASCEND Study Group.
Disclosures: Susan Kuranoff and Thomas Littke were employees of the sponsor, and all other authors have consulting funds from Speedel Pharma Ltd.
The article, entitled "Avosentan for Overt Diabetic Nephropathy," will appear online at http://jasn.asnjournals.org/ on February 18, 2010, doi 10.1681/ASN.2009060593.
The American Society of Nephrology (ASN) does not offer medical advice. All content in ASN publications is for informational purposes only, and is not intended to cover all possible uses, directions, precautions, drug interactions, or adverse effects. This content should not be used during a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or other qualified health care provider if you have any questions about a medical condition, or before taking any drug, changing your diet or commencing or discontinuing any course of treatment. Do not ignore or delay obtaining professional medical advice because of information accessed through ASN. Call 911 or your doctor for all medical emergencies.
Founded in 1966, the American Society of Nephrology (ASN) is the world''s largest professional society devoted to the study of kidney disease. Comprised of 11,000 physicians and scientists, ASN continues to promote expert patient care, to advance medical research, and to educate the renal community. ASN also informs policymakers about issues of importance to kidney doctors and their patients. ASN funds research, and through its world-renowned meetings and first-class publications, disseminates information and educational tools that empower physicians.