avosentan and Renal-Insufficiency--Chronic

Chronic kidney disease (CKD) is a worldwide health problem. Despite remarkable headway in slowing the progression of kidney diseases, the incidence of end-stage renal disease (ESRD) is increasing in all countries with a severe impact on patients and society. The high incidence of diabetes and hypertension, along with the aging population, may partially explain this growth. Currently, the mainstay of pharmacological treatment for CKD, aiming to slow progression to ESRD are ACE inhibitors and angiotensin II receptor blockers for their hemodynamic/antihypertensive and anti-inflammatory/antifibrotic action. However, novel drugs would be highly desirable to effectively slow the progressive renal function loss.. Through the search engines, PubMed and ClinicalTrial.gov, the scientific literature was reviewed in search of emerging drugs in Phase II or III trials, which appear to be the most promising for CKD treatment.. The great expectations for new drugs for the management of CKD over the last decade have unfortunately not been met. Encouraging results from preliminary studies with specific agents need to be tempered with caution, given the absence of consistent and adequate data. To date, several agents that showed great promise in animal studies have been less effective in humans.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrasentan; Glycosaminoglycans; Humans; Pyridines; Pyridoxamine; Pyrimidines; Pyrrolidines; Renal Insufficiency, Chronic

Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and non-diabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3-6 months of treatment. However the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade. Infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.

Topics: Animals; Clinical Trials as Topic; Diabetic Nephropathies; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Humans; Isoxazoles; Kidney Failure, Chronic; Pyridines; Pyrimidines; Renal Dialysis; Renal Insufficiency, Chronic; Thiophenes; Treatment Outcome