title: Therapeutic approaches to diabetic nephropathy--beyond the RAS.
abstract: Despite improvements in glycaemic and blood pressure control, and the efficacy of renin-angiotensin system (RAS) blockade for proteinuria reduction, diabetic nephropathy is the most frequent cause of end-stage renal disease in developed countries. This finding is consistent with the hypothesis that key pathogenetic mechanisms leading to progression of renal disease are not modified or inactivated by current therapeutic approaches. Although extensive research has elucidated molecular signalling mechanisms that are involved in progression of diabetic kidney disease, a number of high-profile clinical trials of potentially nephroprotective agents have failed, highlighting an insufficient understanding of pathogenic pathways. These include trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced-stage disease. Various strategies based on encouraging data from preclinical studies that showed renoprotective effects of receptor antagonists, neutralizing antibodies, kinase inhibitors, small compounds and peptide-based technologies are currently been tested in randomized controlled trials. Phase II clinical trials are investigating approaches targeting inflammation, fibrosis and signalling pathways. However, only one trial that aims to provide evidence for marketing approval of a potentially renoprotective drug (atrasentan) is underway-further research into the potential nephroprotective effects of novel glucose-lowering agents is required.
authors.affiliation: Division of Nephrology and Hypertension, Renal, Diabetes and Vascular Research Laboratory, IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Avenida Reyes Catolicos 2, 28040 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Fernandez-Fernandez
authors.affiliation: Fundacion Renal Iñigo Alvarez de Toledo/Instituto Reina Sofia de Investigacion Nefrologica, Universidad Autonoma de Madrid, Avenida Reyes Catolicos 2, 28040 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Division of Nephrology and Hypertension, Renal, Diabetes and Vascular Research Laboratory, IIS-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Avenida Reyes Catolicos 2, 28040 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
authors.affiliation: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders [CIBERDEM], Universidad Autonoma de Madrid, Avenida Reyes Catolicos 2, 28040 Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
mesh_terms: D002986:Clinical Trials as Topic; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D012084:Renin-Angiotensin System / Q000187:drug effects